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Monday, April 21, 2014

Final Oral Examination

Collagen Cross-Linking as a Determinant of Bone Quality: The Importance of Cross-linking to Mechanical Properties as Explored by Cross-link Inhibition and Exercise

Erin McNerny
Chair: David Kohn, Ph.D.

Monday, April 21, 2014, 9:30 AM
School of Dentistry, Room 7220 (Faculty Alumni Lounge)

Bone mineral density (BMD) and mass are primary clinical measures of fracture risk, but they do not fully describe bone quality. The organic matrix also contributes to bone mechanical properties, and this network is stabilized by enzymatically controlled collagen cross-links. Osteoporosis, aging, increased fracture incidence, and diseases including osteogenesis imperfecta are all associated with alterations in bone collagen cross-link profile. Collagen cross-links are important to bone mechanical properties, but nuances of cross-link quantity, type and maturity may affect bone quality in ways not fully understood. This dissertation work evaluated the importance of cross-link profile to bone mechanical integrity, collagen cross-link alteration in response to exercise, and the ability of exercise to rescue changes in bone mechanical properties caused by cross-link inhibition.

Inhibition of cross-linking by beta-aminopropionitrile (BAPN) treatment in growing mice dose-dependently reduced bone fracture toughness, strength, and pyridinoline cross-link content. Relative cross-link maturity significantly predicted fracture toughness, whereas mature lysylpyridinoline (LP) cross-links were the most significant predictor of tissue strength. Bone quality, in addition to quantity, is altered in response to exercise; it was hypothesized that modulation of cross-linking may be a part of this adaptation. Three weeks of treadmill running caused a shift from pyrrole to pyridinoline cross-links and increased BMD but alone did not alter tissue-level mechanical properties. However, concurrent exercise rescued the effects of BAPN treatment, increasing mature cross-link content and returning BAPN-reduced modulus and BAPN-increased yield strain to control levels. In this experiment, pyrrole, LP and HLNL cross-links were significant predictors of bone rigidity, with pyrrole content explaining 22% of the variability in modulus.

Understanding which cross-link changes are significant to bone fracture resistance is critical for developing and evaluating therapies for fracture prevention and disease management. Collectively, this work suggests greater importance of mature collagen cross-links, especially pyrrole and LP, to bone quality. Pyrrole and LP form preferentially at the collagen N-terminus, suggesting a potential importance of mature cross-linking at this particular site. Importantly, the grand total of enzymatic cross-links, the most abundant cross-link species, and BMD were not good predictors of mechanical properties among bones of the same age.

Monday, April 21, 2014

Final Oral Examination

Label-Free Optical Imaging and Quantitative Algorithms to Assess Living Biological Systems

Leng-Chun Chen
Chair: Mary-Ann Mycek, Ph.D.

Monday, April 21, 2014, 2:00 PM
2203 LBME (Lurie Biomedical Engineering)

Living biological systems need a noninvasive tool to reliably assess their functionality with spatial information. Successful realization can inform clinical practice and improve patient health. Optical imaging provides such a tool for functional assessments. In this dissertation, we developed label-free nonlinear optical molecular imaging (intensity and lifetime) without chemical staining to non-invasively and quantitatively assess living biological systems. Label-free optical molecular imaging provides functional assessments of cells lines, primary human cells, and tissue-engineered constructs manufactured with primary cells. Primary human cells freshly harvested from distinct donors have high inter-patient variability compared to immortalized cell lines. Therefore, quantitative analytic methods were developed to provide reliable functional assessments. Rigorous statistical analysis was performed to account for variability between patients.

Tissue-engineered constructs were developed for tissue/organ regeneration. Biological device manufacturing is strictly regulated by the FDA prior to product release for patient treatment to assure effectiveness and safety. We addressed this clinical need by developing quantitative methods for tissue-based, label-free nonlinear optical molecular microscopy. Label-free optical measures of local tissue structure and biochemistry characterized morphologic and functional differences between controls and stressed constructs. The technique reliably differentiated controls from stressed constructs from n = 10 patients. Further, the technique was quantitatively compared with standard viability assays including histology and WST-1 cell viability assay. The results showed significant correlations between the standard metrics and the optical metrics. Unlike the standard methods that are reliable but destructive, label-free optical assessments had the advantages of being both non-invasive and reliable. Thus, such optical measures could serve as reliable manufacturing release criteria for cell-based tissue-engineered constructs prior to human implantation.

Acquired label-free lifetime images are 3-dimensional, containing spatial and temporal information. The information-rich images of biological systems are hard to interpret. Thus, extended phasor analysis algorithms were developed, enabling visualization and interpretation of the 3-dimensional images. With the developed algorithms, tissue constituents were differentiated with one-channel lifetime imaging rather than 3-channel intensity imaging. The developed algorithms could provide users a useful tool to easily characterize the investigated biological systems.

Monday, April 14, 2014

Final Oral Examination

Histotripsy for Pediatric Cardiac Applications

Ryan Miller
Co-Chairs: Gabe Owens, M.D., Ph.D. and Zhen Xu, Ph.D.

Monday, April 14, 2014, 2:30 PM
GM Conference Room, Lurie Engineering Center (4th Floor)

Medicine continues to move towards less invasive techniques for many cardiac conditions, especially for high-risk patients that may not tolerate the alternative, more invasive approach. For instance, patients born with the congenital heart defect hypoplastic left heart syndrome often require emergent creation of a perforation through the atrial septum for survival prior to palliative surgery. However, most approaches are catheter based, still invasive, and continue to have significant challenges, limitations, and complications. A completely non-invasive technique such as histotripsy may provide the same result in a faster, safer, and more efficient manner. Using high-pressure ultrasound pulses applied outside the body and focused to the targeted tissue, histotripsy generates a cluster of micro-bubbles and the energetic growth and collapse of these micro-bubbles results in fractionation of the target tissue. Histotripsy has been demonstrated successful for non-invasive tissue fractionation in various organs. The goal of this work is to investigate the safety and efficacy of histotripsy for neonatal cardiac applications. To aid in this goal, therapy guidance and monitoring techniques are developed, and an integrated histotripsy therapy system, optimized for the human neonate with congenital heart disease, was designed and constructed.

In this dissertation, histotripsy is first demonstrated to be capable of generating targeted intra-cardiac communications when positioned outside the body in an intact neonatal animal model with minimal collateral damage or systemic side-effects. Moreover, further study showed no intermediate-term clinical, pathologic, and systemic effects of these intra-cardiac communications created by histotripsy. Second, to mitigate the possibility of unintended injury due to heart motion, real-time motion correction using ultrasound imaging is developed and integrated into a histotripsy therapy system. This motion correction is developed specifically for the high-speed motions present in a beating heart. The performance of the motion correction is quantified in vitro and a validated in a single in vivo experiment. Third, to maximize therapy efficacy, novel bubble-induced color Doppler feedback is developed to monitor the degree of tissue damage during histotripsy treatment. Strong correlations existed between the quantitative metrics derived from the bubble-induced color Doppler and the degree of tissue fractionation as examined with histology, demonstrating the feasibility of using this technique as quantitative, real-time feedback for histotripsy treatments. Finally, a histotripsy therapy transducer with appropriate physical dimensions and acoustic parameters to precisely ablate cardiac tissue non-invasively in a human neonate is developed and integrated into an ultrasound guided histotripsy therapy system. The data and the integrated system accomplished from this dissertation form the essential foundation to a pioneering clinical trial for histotripsy cardiac therapy in infants, which will position histotripsy for application on a broad range of cardiac disorders in patients of all ages.

Friday, April 11, 2014

Final Oral Examination

Mechanical and Structural Adaptations of Tendon With Aging

Lauren Wood
Chair: Dr. Susan Brooks

Friday, April 11, 2014, 11:00 AM
Classrooms A & B, Biomedical Science Research Building

The past few decades have seen an increase in the incidence of tendon dysfunction in the elderly, leading to greater functional dependence and decreased quality of life. The mechanisms underlying the increasing risk of tendon dysfunction with aging are unknown but may arise due to collagen-mediated changes in tendon mechanical properties. Although in adult animals, collagen turnover is enhanced by exercise and the drug Rapamycin, whether either intervention affects collagen turnover in a manner that improves the functional performance of tendon in old animals is unknown. The goals of this dissertation were to clarify the age-associated changes in tendon structure and mechanics that may contribute to dysfunction and establish if the changes can be delayed or reversed.

Using a novel technique of coupling regional mechanics with regional structural properties, we demonstrated that tendons from mice stiffen dramatically from adulthood to old age, with the most pronounced increases occurring in the region of the tendon nearest the muscle. The profound mechanical changes were accompanied by decreased collagen turnover and increased collagen crosslinking and tendon calcification independent of changes in collagen fibril morphology, demonstrating that age-associated stiffening arises due to changes in the properties of the tissue itself. Following ten weeks of treadmill training, tendon stiffness and calcification was reduced and collagen turnover increased in tendons from old mice. Additionally, long-term administration of Rapamycin delayed age-associated changes in the mechanical properties of mouse tendons independent of appreciable changes in cell density or collagen fibril morphology. Both interventions resulted in tendon tissue that was mechanically and structurally similar to that of adult tendon.

This work demonstrates that the mechanical properties of tendon extracellular matrix (ECM) are dramatically altered in old age. The altered mechanical properties are associated with substantial changes in the underlying structure and composition of the tissue. These studies also provide evidence that even in old age, tendon maintains the ability to respond to exercise or pharmacological intervention by remodeling the ECM through increased collagen turnover and reduced calcification. This improved understanding of the progression of age-associated tendon dysfunction will facilitate the development of methods to reduce or prevent the condition

Wednesday, April 9, 2014

BME 500 Seminar Series

“Towards integration of synthetic biology into human stem cells”

Krishanu Saha, Ph.D.
University of Wisconsin-Madison

Wednesday, April 9, 2014, 12:00 - 1:00 PM
1303 EECS

Abstract: Human stem cells provide an attractive, patient-matched source for generating many tissues found in the body, but controlling stem cells in culture remains a key challenge. To meet this challenge, our lab seeks to develop and apply synthetic biology tools in order to dissect and precisely control the complex molecular signaling processes that determine stem cell behavior in culture. Synthetic biology is an emerging biotechnology field that combines elements of engineering, mathematics, chemistry, and biology to synthesize novel systems from characterized biological components. Applying new synthetic biology tools in human stem cells to control cell behavior would enable advanced manufacturing of patient-specific tissues and cells for disease modeling and drug discovery applications.

BIOGRAPHY: Krishanu Saha is an Assistant Professor in the Department of Biomedical Engineering at the University of Wisconsin-Madison. He is also a member of the Wisconsin Institute for Discovery in the bionanocomposite tissue engineering scaffolds theme. Prior to his arrival in Madison, Dr. Saha studied Chemical Engineering at Cornell University and at the University of California in Berkeley. In his dissertation with Professors David Schaffer and Kevin Healy, he worked on experimental and computational analyses of neural stem cell development, as well as the design of new materials for adult stem cell culture. In 2007 he became a Society in Science: Branco-Weiss fellow in the laboratory of Professor Rudolf Jaenisch at the Whitehead Institute for Biomedical Research at MIT and in the Science and Technology Studies program at Harvard University with Professor Sheila Jasanoff in Cambridge, Massachusetts. Since then, he has performed research on human pluripotent stem cells, disease modeling and synthetic biology. He is the recipient of a 2012 Sage Bionetworks Young Investigator Award, a 2013 Rising Star Award from the Biomedical Engineering Society’s Cellular and Molecular Bioengineering group, and a 2014 NSF Faculty Early Career Development (CAREER) Award.

Wednesday, April 2, 2014

BME 500 Seminar Series

“Mechanical Strain Transfer to the Nucleus and its Effect on Gene Expression”

Jonathan Henderson, Ph.D. Candidate
Purdue University

Wednesday, April 2, 2014, 12:00 - 1:00 PM
1303 EECS

Abstract: The nucleus is a membrane bound organelle and regulation center for gene expression in the cell. Mechanical forces transfer to the nucleus directly and indirectly through specific cellular cytoskeletal structures and pathways. There is increasing evidence that the transferred forces to the nucleus orchestrate gene expression activity. Methods to characterize nuclear mechanics typically study isolated cells or cells embedded in 3D gel matrices, and often report only aspect ratio and volume change measures that oversimplify the inherent complexity of internal strain patterns. This presents technical challenges to simultaneously observe small scale nuclear mechanics and gene expression levels inside the nuclei of cells embedded in their native extracellular environment. Therefore a hybrid imaging technique has been developed to enabled us to explore links between biomechanical and biochemical signaling within individual cells, to understand how mechanical forces transferred to the nucleus influence gene expression.

Monday, March 31, 2014

BME Graduate Student Speaker Forum

On writing well (enough)

Barry Belmont
Monday, March 31, 2014, 12:00 - 1:00 PM
1303 EECS

Many in engineering disciplines have spent the vast bulk of their time solving difficult problems and only a minimal amount of it learning how to talk about them. This leads to the all-too-familiar frustration felt by just about everyone along the reading-writing-presenting spectrum in the sciences, where what you are trying to convey relies heavily upon how you try to convey it. In this (admittedly cursory) presentation on technical writing, I will try to show how to tell the story of one’s research as best I can, calling upon my experiences as a (rather not impressive) science writer and as a (just okay) technical editor. I’ll show what to do, what to avoid, and what really is just a matter of preference. All of this in an effort to improve our writing, to tell our stories, and to convey the importance of how we fill our days.

Monday, March 31, 2014

The Neuroscience Graduate Program Seminar

“Progress Toward High-performance Neural Prosthesis”

Dr. Andrew Schwartz,
Professor of Neurobiology
University of Pittsburgh

Monday, March 31, 2014, 4:00 PM
1230 Undergraduate Science Building

Please see Dr. Schwartz’s website for more information about his research:

Wednesday, March 26, 2014

BME 500 Seminar Series

“Instrument-free diagnostics for global health: let the physics and chemistry do the hard work”

Barry Lutz, Ph.D.
University of Washington

Wednesday, March 26, 2014, 12:00 - 1:00 PM
1303 EECS

Abstract: A key future challenge in bioengineering will be to improve access to healthcare for the world’s poorest populations. The global economic burden of disease, the increasing threat of global epidemics, and the rising cost of US healthcare is driving increased investment in low-cost health solutions. As a contribution to improving global health and reducing healthcare costs, our research focuses on simple, instrument-free disease diagnostics for this new world, be it a satellite clinic in Detroit or a makeshift health camp in sub-Saharan Africa. The extraordinary constraints of low-resource settings require creative engineering solutions and attention to non-technical factors required to reach patients. Our approach is to exploit robust physical principles and assay chemistry to provide high performance diagnostics without reliance on a trained human or expensive instrument. Here, I present development of paper-based immunoassays and nucleic acid amplification tests that demonstrate how simple principles can be manipulated to create new diagnostics, and I discuss the broader challenges and opportunities in technology for global health.

BIOGRAPHY: Dr. Lutz received his BS from the University of Texas at Austin in the Department of Chemical Engineering where he researched basic catalytic reactions on single crystal metal surfaces. He received his PhD in Chemical Engineering from the University of Washington under Professor Dan Schwartz, where he studied sound-driven flows in microfluidic devices for chemical reaction analysis and cell manipulation. As a postdoctoral researcher under a UW Genome Sciences Training Grant Fellowship, he worked in the Microscale Life Sciences Center with Professors Deirdre Meldrum and Mary Lidstrom to develop methods for analysis of single cell behavior. He was a Senior Scientist in the Intel Biomedical and Life Sciences Group working on-site at the Fred Hutchinson Cancer Research Center to develop multiplexed tissue imaging using Raman nanoparticle probes. He then returned to the University of Washington to work with Professor Paul Yager on a large project funded by the Bill & Melinda Gates Foundation to develop a point of care diagnostic system for the developing world. He is now a Research Assistant Professor of Bioengineering at UW developing rapid diagnostic devices for global health and domestic health applications. He is co-investigator on large multi-institutional projects with Professor Yager, and has independent projects in cell-phone-controlled diagnostics, HIV drug resistance testing, and multiplexed nucleic acid tests. He is also co-founder of Aqueduct Neurosciences, a UW spinout company developing devices to treat brain drainage disorders.

Tuesday, March 25, 2014

BME Career Event

FDA Corporate Information Session

Art Czabaniuk, 
Deputy District Director FDA Detroit District

Tuesday, March 25, 2014, 5:30-6:30 p.m.
2203 LBME (Lurie Biomedical Engineering)

Join the FDA for this important corporate information session Art Czabaniuk, Deputy District Director from the FDA Detroit District, will be visiting BME to present information about the FDA and discuss career opportunities, specifically Consumer Safety Officer positions and internship positions. Consumer Safety Officer (Investigator) positions may be open in the FDA Detroit District Office or Resident Post. The CSO Investigator: • The plans and conducts regulatory inspections and in-depth investigations of various establishments; such as manufacturers, warehouses, and retail shops. • Performs analyses and evaluation on data samples and documented information gathered during inspections and investigations. • Prepares final reports, position papers and other written documentation that supports investigative findings and recommendations. • Provides testimony in court regarding the conditions of the manufacturer and the circumstances surrounding the samples the incumbent has collected.

Monday, March 24, 2014

BME Graduate Student Speaker Forum

Multifunctional Microparticles for Cochlear Drug Delivery

Sahar Rahmani
Monday, March 24, 2014, 12:00 PM
1303 EECS

Hearing is an integral part of an individual’s life and any degree of hearing loss can bring about life-altering changes. In the US alone, over 17% of the population have been diagnosed with some level of hearing loss and deafness is the number one disability. [1, 2] Given the large number of people affected, it is of great importance to seek medical technologies to restore hearing for these individuals. Hearing occurs in the cochlea of the ear, where sound waves are transmitted to electrical signals by hair cells to the central nervous system.[3] In individuals where hair cells are severely damaged or destroyed, this translation cannot occur, leading to various degrees of deafness.[1] In such cases, cochlear implants are often used since they directly stimulate auditory nerves and can return some level of hearing for most individuals. However, cochlear insertion often induces trauma, which brings about the death of any remaining hair cells, thereby forcing these individuals to completely rely on the device.[4, 5] Long lasting multifunctional carriers are capable of addressing this challenge by continuously releasing therapeutics to reduce trauma and improve hearing in these patients. Here we propose microparticles composed of two distinct compartments fabricated through electrohydrodynamic co-jetting for this purpose.[6-8] After first thoroughly characterizing the microparticles, we show (i) toxicity testing in vivo to display their compatibility through hair cell counts and auditory brainstem response analysis; (ii) the in vivo survival of microparticles in the cochlea at the same concentrations after one and seven days; (iii) the prolonged release of an anti-excitotoxicity therapeutic from microparticle; and (iv) selective surface modification of microparticles to incorporate a growth factor known to improve hair cell survival. Through these data, we have demonstrated that multi-functional microparticles could be a novel solution for improving the total hearing loss experienced in patients using cochlear implants.

Monday, March 24, 2014

BME Graduate Student Speaker Forum

Characterization of Bioeffects on Endothelial Cells Under Acoustic Droplet Vaporization

Robinson Seda
Monday, March 24, 2014, 12:00 PM
1303 EECS

An ultrasound-mediated cancer treatment called gas embolotherapy has the potential for providing selective occlusion of blood vessels for therapy. Vessel occlusion is achieved by locally vaporizing micron-sized droplets through acoustic droplet vaporization (ADV), which results in bubbles that are large enough to occlude blood flow directed to tumors. Endothelial cells, lining of our blood vessels, will be directly affected by these vaporization events and as such are the subject of this study. Damage to the endothelium could lead to a number of pathological states that, if left untreated could be harmful. However, if under control, these bioeffects could provide benefits that would be synergistic with bubble occlusion like increased endothelial permeability or occlusion by thrombosis. We investigate bioeffects caused by ADV by using a static endothelial culture model.

Two insonation frequencies (3.5 MHz and 7.5 MHz) were chosen to characterize the effects of ADV and aid in the exploration of frequency dependent effects. Damage was observed through changes in peak-negative (rarefactional) pressure and pulse length, and described by the absence of cells after treatment. Damage was dependent in bubble cloud area and highly localized. Through these experiments we try to provide the reader with some of the tools necessary to make an assessment on the repercussions of performing ADV in situations that allow the droplets - and ultimately the bubbles -, to be in direct contact with the endothelium. Knowing when significant damage is expected in gas embolotherapy could help in the development of preventive measures as well as additional therapeutic aids during treatment.

Thursday, March 20, 2014

Final Oral Examination

Precise Lesion Formation in Histotripsy Therapy Using Strategic Pulsing Methods

Kuang-Wei Lin
Chair: Charles A. Cain, Ph.D.

Thursday, March 20, 2014, 2:00 PM
1180 Duderstadt Center Conference Room

Histotripsy is a noninvasive, cavitation-based ultrasound therapy that can create mechanical tissue ablation through dense energetic clouds of microbubbles generated by high-pressure and short ultrasound pulses. These microbubbles in the clouds act as “micro-scalpels” and mechanically fractionate tissue into a liquid homogenate with a well-demarcated boundary. Histotripsy therapy has been shown to be capable of 1) creating intracardiac communications for congenital heart disease treatment, 2) fractionating blood clots for treating deep vein thrombosis, 3) fractionating prostatic tissue for benign prostatic hyperplasia (BPH) treatments, and 4) fragmenting model renal calculi for treating kidney stone.

The overall objective of this dissertation is to develop ultrasound pulsing techniques that can lead to more precise and controlled bubble cloud generation in histotripsy therapy. Three strategic pulsing methods have been developed and characterized in this dissertation.

1) Bubble cloud formation using intrinsic threshold mechanism: when ultrasound pulses shorter than 3 cycles are applied, the generation of bubble clouds only depends on one or two negative half cycles exceeding an intrinsic threshold of the medium. This intrinsic threshold is highly repeatable and has a very sharp transition zone. At negative pressure amplitudes not significantly greater than this, a dense energetic lesion-forming bubble cloud is generated consistently with a spatial pattern similar to the part of the negative half cycles(s) exceeding the intrinsic threshold.

2) Dual-beam histotripsy: a low-frequency pump pulse is applied to enable a high-frequency probe pulse to exceed the intrinsic threshold. The high-frequency probe pulse provides precision in lesion formation, while the low-frequency pump pulse, which is more resistant to attenuation and aberration, raises the pressure level of the targeted treatment region.

3) Frequency compounding: a near half-cycle (monopolar) pulse is synthesized using an array transducer composed of elements at various resonant frequencies. Histotripsy using a negative-polarity half-cycle pulse can limit the influence of positive phases on bubble cloud generation, leading to a more precise and controlled lesion formation.

These three techniques were realized using custom design ultrasound array transducers and examined in red-blood-cell (RBC) tissue-mimicking phantoms, and the first two techniques were further validated in ex vivo tissues. Additionally, an application in metastatic lymph node ablation is studied in vivo using supra-intrinsic-threshold pulses.

In conclusion, this dissertation demonstrates three strategic ultrasound pulsing methods that can lead to precise lesion formation in histotripsy therapy. Future works involves examining the applicability of these pulsing methods in in vivo experiments and studying potential applications for monopolar pulses in ultrasound diagnostic imaging.

Wednesday, March 19, 2014

BME 500 Seminar Series


Max S. Wicha, M.D.
University of Michigan
Comprehensive Cancer Center

Wednesday, March 19, 2014, 12:00 - 1:00 PM
1303 EECS

Abstract: The realization that many cancers, including breast cancer, are driven by cells which display stem cell properties has significant clinical implications. Furthermore, the demonstrated role of these cells in mediating tumor metastasis and treatment resistance suggests the need to develop strategies to specifically target CSC populations. Cancer stem cell self-renewal and survival pathways represent potential therapeutic targets. These self-renewal pathways are regulated by an interacting network of cell intrinsic pathways, as well as extrinsic factors from the tumor microenvironment. These mircroenvironmental factors include cytokines such as IL-6, IL-8 and TGFβ. CSCs maintain the plasticity to transition between epithelial-like MET and mesenchymal-like EMT states, a process regulated by the tumor microenvironment through microRNA circuits. We have demonstrated that previously identified cancer stem cell markers are cancer stem cell state specific. CD44+/CD24- CSCs represent mesenchymal-like stem cells capable of tissue invasion which are largely quiescent. In contrast, Aldehyde dehydrogenase expression identifies a more epithelial-like cancer stem cell state associated with self-renewal. Reversible EMT/MET transitions play a crucial role in mediating tumor metastasis.

Preclinical breast cancer models predict that the greatest efficacy of CSC targeting therapeutics will occur when they are used in the adjuvant setting, a concept supported by preclinical models and clinical trials. Tumor regression may reflect effects on bulk cell populations explaining the lack of correlation between tumor shrinkage and patient survival. In contrast, recurrence following adjuvant therapy may be mediated by CSCs, which possesses sufficient self-renewal to form clinically significant metastasies. The important role of HER2 signaling in regulating breast cancer stem cell self-renewal may account for the remarkable clinical efficacy of targeting HER2 in the adjuvant setting. Furthermore, the clinical benefit of such therapies in classically defined HER2-negative breast cancers may be due to selective expression of HER2 in CSCs in the absence of HER2 gene amplification. These studies suggest the need for reevaluating currently used clinical endpoints and clinical trial designs. Promising new technologies including the isolation and molecular characterization of circulating cancer stem cells may provide the opportunity for real time assessment of the efficacy of CSC targeting agents. A number of agents regulating BCSCs have entered early phase clinical trials which will determine whether effective targeting of CSCs improves patient outcome.

Wednesday, March 12, 2014

BME 500 Seminar Series

“Building the Cell from Molecules to Complexes to Networks.”

Jennifer Ross, Ph.D.
University of Massachusetts Amherst

Wednesday, March 12, 2014, 12:00 - 1:00 PM
1303 EECS

The organization of the interior space of cells is essential for cell division, differentiation, and motility. Improper organizations result in disease states, such as cancer, developmental diseases, and neurological or neuromuscular diseases. In eukaryotes, intracellular organization is regulated in a spatiotemporal manner via the cytoskeleton. Cytoskeletal filaments, such as microtubules and actin not only organize space through their own intrinsic dynamics, but also as the tracks for intracellular transport via motor proteins. The motor proteins themselves can rearrange the cytoskeletal filaments and thus alter the network. The Ross Lab seeks to understand the universal laws governing network and cellular-level organization from the molecular basis using bottom-up, reductionist approaches using reconstituted, in vitro experiments. Here, we present two stories of how a minimal system of cytoskeletal proteins can create cell-like organizations and then how such cell-like organizations can direct where and when cargo-transporter motors move.

Wednesday, February 26, 2014

Final Oral Examination

Microfluidic Reduction of Osmotic Stress in Oocyte and Zygote Vitrification

David Lai
Chair: Shuichi Takayama, Ph.D.

Wednesday, February 26, 2014, 4:00 PM
GM Conference Room - 4th Floor Robert H. Lurie Engineering Center

Automated microfluidic cryoprotectant exchange enables vitrification of murine zygotes with superior developmental competence, high lipid retention, and morphology as indicated by smoother cell surface compared to conventional pipetting methods. Vitrification of bovine oocytes also benefit as evidenced by high lipid retention. Mathematical analysis followed by experimental validation indicate that advantages from microfluidic systems arise from precise fluid control that eliminates high shrinkage rates associated with abrupt and uneven cell exposure to vitrification solutions that regularly occur in current clinical pipetting protocols. This finding constitutes a new theory that shrinkage rate is the major cause of sub-lethal osmotic stress which complements and adds to findings of previous studies citing minimum cell volume as the major cause of lethal osmotic stress.

Wednesday, February 26, 2014

BME 500 Seminar Series

“Radiology and Computer Aided Detection (CAD) meet MEMS: Opportunities to change clinical practice in the prevention of surgical Retained Foreign Objects and Coronary In-Stent Restenosis.”

Theodore Cosmo Marentis, MD, MSEE
Fellow, Nuclear Medicine and Molecular Imaging
University of Michigan

Wednesday, February 26, 2014, 12:00 - 1:00 PM
1303 EECS

Abstract: Collaborative efforts, an understanding of the clinical problem, technological limitations and innovation are essential for successful translational research. The combination of MEMS devices with powerful imaging modalities, augmented by Computer Aided Detection, holds great promise. It allows for robust, streamlined MEMS devices, without a battery, an antenna or complicated electronics, that are suitable for in-vivo use and could change clinical practice.

Surgical Retained Foreign Objects (RFOs) have significant morbidity and mortality and their combined medical and legal burden to the U.S. healthcare system is $1.5 billion annually. The current approach to prevent RFOs, the surgical count, is flawed as 90% of RFO cases have a correct count. Existing barcode and RFID tagging technologies only address 2/3 of the problem as 32% of cases are surgical needles that are too small to tag. Even though surgical sponges carry x-ray visible features, these are malleable and have variable appearance and as a result the detection accuracy of radiographs is a mediocre 59%. We address the RFO problem with two complementary technologies: a Gossypiboma Micro Tag, the μTag and a Computer Aided Detection (CAD) software, that detects the μTag and can also detect other radio-opaque objects, such as surgical needles. We present validation of the CAD on 1,100 cadaveric images and preliminary data from a radiologist reader study.

Coronary Artery Disease is the leading cause of mortality in the United States. One commonly used procedures to treat it is Percutaneous Coronary Intervention (PCI), ie stenting. Stents fail through restenosis, that leads to a pressure drop across the stent. The pressure drop is quantified invasively with angiography through the Fractional Flow Reserve (FFR), the ratio of the pressure distal to the occlusion over the pressure proximal to it. The FFR has been validated through the FAME 1 and 2 trials published in the New England Journal of Medicine. We address the problem of restenosis with the X-ray Blood Pressure sensor (XBP), which changes its radiopaque (x-ray visible) size with pressure. A sensor in the proximal end and one in the distal end of a stent allow a radiologist to tell the FFR across the stent by measuring the two sensor lengths on a radiograph. We present a prototype device, microscopy, radiography and fluoroscopy testing, as well as implantation in a porcine animal model.

Wednesday, February 19, 2014

BME 500 Seminar Series

“Biomechanics and Mechanobiology in Pathology and Repair: Translational Impact from Multiscale Analyses”

Christopher Raub, Ph.D.
University of Southern California

Wednesday, February 19, 2014, 12:00 - 1:00 PM
1303 EECS

Abstract: Mechanobiology and biomechanics influence nano-, micro-, and macrostructural remodeling of connective tissues in situations of pathology and repair. In particular, the initiation and progression of diseases such as asthma and osteoarthritis, and remodeling of engineered tissues, are associated with characteristic spatiotemporal patterns of alterations to extracellular matrix and cell fate. The main goal of my research has been to determine the biomechanical origins, roles in tissue remodeling, and clinical relevance of these multiscale alterations. I have pursued this goal by developing quantitative and computational microscopy approaches and image metrics to characterize multiscale remodeling of in vitro collagen gel models of fibrosis, a rabbit model of tracheal epithelial injury and fibrosis, animal models of osteoarthritis and cartilage repair, and through analysis of tissue from human donor knees. In collagen gels subjected to cell culture, biophysical and biochemical perturbations, bulk stiffness was found to depend upon collagen network pore size, fiber diameter, crosslinks, and compaction mediated by cell contractility. Tracheal fibrosis, osteochondral repair, and cartilage degeneration were characterized by quantitative parameters from two-photon and polarized light microscopy and other methods. These analyses revealed structural and cell alterations from normal that provide evidence for deformation and remodeling of the collagen network and associated transformation, transport, proliferation, and/or loss of cells. Taken together, these results may help determine possible therapies to slow disease progression or enhance repair by targeting disregulated matrix homeostasis and restoring normal biomechanics. The developed quantitative optical techniques and scores also provide a basis for quantitative endoscopy to diagnose preclinical disease states or assess the quality of surgical and tissue-engineered repairs.

Wednesday, February 12, 2014

BME 500 Seminar Series

“Occupant Protection in Motor Vehicle Crashes: Addressing the Different Needs from a Diverse Population”

Jingwen Hu, PhD
Assistant Research Scientist
University of Michigan

Wednesday, February 12, 2014, 12:00 - 1:00 PM
1303 EECS

Abstract: Children, Small female, elderly, and obese occupants are at greater risk of death and serious injury in motor-vehicle crashes than mid-size, young, male occupants. However, due to the disproportionate emphasis on mid-size men in regulatory crash-test procedures, current injury assessment tools, including crash test dummies and finite element (FE) human models, generally do not account for body shape and composition variations among the population. The projected increases of older and obese populations in the U.S. and other countries further necessitates future efforts to develop more advanced safety systems for protecting these vulnerable populations.

The greatest opportunity to broaden crash protection to encompass all vehicle occupants lies in improved, parametric human FE models that can represent a wide range of human attributes. Recent research at the University of Michigan Transportation Research Institute (UMTRI) in human anthropometry, FE human modeling, mesh morphing, human tissue testing, and cadaver tests have laid the groundwork for this new generation of human models. In this study, a statistical human body geometry model based on medical image, body scan, and sitting posture data are linked to a baseline human FE model through an automated mesh morphing algorithm. The resulted parametric human models are validated against cadaver tests, and used in a parametric study to investigate the injury mechanism of obese occupants. Restraint design optimizations for different sizes of occupants in rear seats are also presented. This study will lead to development of tools and methods that have overarching impacts on safety designs considering the different needs from a diverse population.

Tuesday, February 11, 2014

Department of Biomedical Engineering

The Science and Sport of Curling

David Sept, PhD
Tuesday, February 11, 2014, 3:30 PM
2203 LBME (Lurie Biomedical Engineering)

The olympics are upon us once again, and to try and enhance you experience and enjoyment of the games, I'm offering to give a short seminar on the basics of curling. This is a tradition started when I was still in St. Louis. I will describe a bit of the history and physics of the game and go over the rules and basic strategy. We will watch a few ends from an actual game to illustrate some of the key points (not including post-game beer).

Wednesday, February 5, 2014

BME 500 Seminar Series

“Regenerative Peripheral Nerve Interfaces for Prosthetic Control and Sensory Feedback in Amputees”

Nick Langhals, Ph.D.
Research Assistant Professor
University of Michigan
Plastic Surgery, Biomedical Engineering

Wednesday, February 5, 2014, 12:00 - 1:00 PM
1303 EECS

Abstract: Although sophisticated upper extremity prostheses are available, optimal prosthetic interfaces which give patients high-fidelity control of these artificial limbs are limited. We have developed a novel Regenerative Peripheral Nerve Interface (RPNI), which consists of a unit of free muscle that has been neurotized by a transected peripheral nerve. In conjunction with a biocompatible electrode on the muscle surface, the RPNI facilitates signal transduction from a residual peripheral nerve to a neuroprosthetic limb. We have successfully constructed viable RPNIs out of both predominately motor peripheral nerves (peroneal and tibial) and sensory nerves (sural). Electrodes are then implanted as a signal interface. Acellular extracellular matrix is then used to secure the electrode to the muscle and isolated the RPNI from surrounding tissues. Lastly, insulating materials may be wrapped around the RPNI to isolate signals from the surrounding tissues. We have previously demonstrated viability of RPNIs up to 24 months, including sensory interface data up to 4 months. This presentation will highlight the background research leading to this original technology as well as recent advances in the development of our interface.

Wednesday, January 29, 2014

BME 500 Seminar Series

“Pharmaceutics Meet Engineering: Magnetism and Sound of Remotely-actuated and Image-monitored Drug Delivery”

Beata Chertok, Ph.D.
Assistant Professor, Pharmaceutical Sciences & Biomedical Engineering
University of Michigan

Wednesday, January 29, 2014, 12:00 - 1:00 PM
1303 EECS

Abstract: The vision of personalized, patient-tailored drug delivery and therapy encounters many exciting opportunities at the interface of multifunctional biomaterial-based drug carriers, medical imaging and magnetic/acoustic bio-actuation. This translational multi-faceted interface is uniquely positioned to enable more controllable, predictable and clinically-viable therapies with improved efficacy/toxicity profiles. This interface also promises to strengthen the ties between pharmaceutical scientists and biomedical engineers, drawing upon complementary expertise in traditional pharmaceutical sciences (e.g. drug bio-disposition, drug transport and micro-encapsulation) and engineering disciplines (e.g. medical imaging, materials, control systems).

In my talk, I will describe my research contributions within this interface toward realization of remotely-actuated and image-monitored drug delivery. I will discuss the development of “active” biomaterial-based drug platforms that combine sensitivity to external magnetic and acoustic stimuli with visibility to medical imaging modalities (MRI and ultrasound). I will also highlight the role of medical imaging in monitoring and actuation of remotely- addressable drug delivery. Specific examples will be discussed to illustrate development of multifunctional drug carriers from an idea to material preparation to the proof-of-concept targeted and image-monitored drug delivery in animal models. Lastly, I will briefly discuss future avenues toward better therapeutics building on magnetism and healing sound of next-generation drug delivery.

Tuesday, January 28, 2014

Department of Biomedical Engineering

Medtronic Career Event

Tuesday, January 28, 2014, 5:30 - 6:30 pm
1123 LBME

"Across the world, we are in a continuous quest to improve healthcare. People everywhere want better outcomes, fewer errors, quicker recoveries, and fewer side effects. We're developing medical technology solutions that not only improve healthcare, but do so while delivering better economic value." - CEO, Omar Ishrak

Friday, January 24, 2014

Final Oral Examination

Conjugated Polymer Actuators for Articulating Neural Probes and Electrode Interfaces

Eugene Dariush Daneshvar
Co-Chairs: Ronald Larson and Elisabeth Smela

Friday, January 24, 2014, 12:00 PM
Johnson Rooms B & C, Lurie Engineering Center

This thesis investigated the potential use of polypyrrole (PPy) doped with dodecylbenzenesulfonate (DBS) to controllably articulate (bend or guide) flexible neural probes and electrodes. PPy(DBS) actuation performance was characterized in the ionic mixture and temperature found in the brain. Actuation strain was monotonic under these conditions, demonstrating that conducting polymer actuators can indeed be used for neural interface and neural probe applications.

In addition, a novel MEMS device was developed to measure previously disregarded residual stress in a bilayer actuator. Residual stresses are a major concern for MEMS devices as that they can dramatically influence their yield and functionality. This device introduced a new technique to measure micro-scaled actuation forces that may be useful for characterization of other MEMS actuators.

Finally, a functional movable parylene-based neural electrode prototype was developed. Employing PPy(DBS) actuators, electrode projections were successfully controlled to either remain flat or actuate out-of-plane and into a brain phantom during insertion. Applications that do not require insertion into tissue may also benefit from the electrode projections described here.

Implantable neural interface devices are a critical component to a broad class of emerging neuroprosthetic and neurostimulation systems aimed to restore functionality, or abate symptoms related to physical impairments, loss of sensory abilities, and neurological disorders. The therapeutic outcome and performance of these systems hinge to a large degree on the proximity, size, and placement of the device or interface with respect to the targeted neurons or tissue. While advancements have been made to improve conformation with non-planar interfaces, nearly all of the current available neural-interfacing technologies are immobile, and hence cannot be actively made conformal to the irregular tissues they encounter.

Conjugated (aka electroactive or conducting) polymers are electronically conducting organic materials within a class of intelligent materials that respond to, and are a function of, their environment. By reducing and oxidizing the polymer in an aqueous environment, influx and efflux of hydrated ions cause a change in polymer volume that may be harnessed to perform mechanical work. These polymers can be readily integrated with standard microfabrication processes and their low voltage requirements (±1 V) are promising for micro-sized medical applications.

Wednesday, January 22, 2014

BME 500 Seminar Series

“Histone deacetylases in skeletal development, maintenance, and communication with other body systems”

Meghan McGee-Lawrence, Ph.D.
Senior Research Fellow
Department of Orthopedic Surgery
Mayo Clinic

Wednesday, January 22, 2014, 12:00 - 1:00 PM
1303 EECS

Abstract: The skeleton is a multifunctional and regenerative organ that is best known for its roles in facilitating locomotion and acting as a calcium reservoir for the body. However, recent studies have greatly expanded our understanding of skeletal biology, demonstrating that bone may be a key player in diverse processes including energy metabolism, glucose homeostasis, and even reproduction. Bone can quickly self-remodel in response to physical, chemical and neurological signals because changes in skeletal microenvironments instigate rapid and temporal shifts in gene expression within bone cell populations. Regulation of gene expression is controlled, in part, by histone deacetylases (Hdacs), which are intracellular enzymes that directly affect chromatin structure and transcription factor activity. Essential roles for Hdacs in osteoblast biology and signaling pathways that control bone development, calcified matrix production, and fracture resistance have been elucidated through in vitro and in vivo models. This work has revealed an intricate system by which bone cell transcription is regulated to promote osteoblast commitment, differentiation, activity, and survival. New studies point to a key role for Hdacs, and in particular, Hdac3, in regulating osteoblastic control of energy metabolism and skeletal progenitor cell differentiation. These and other studies continue to improve our understanding of the integrative, physiological role of the skeleton in the body.

Wednesday, January 15, 2014

Final Oral Examination

A Finite Element Model of the Superior Glenoid Labrum

Eunjoo Hwang
Co-Chairs: Mark Palmer, M.D., Ph.D. and John A. Faulkner, Ph.D.

Wednesday, January 15, 2014, 2:00 PM
West Conference Room, 4th Floor, Rackham Building

Despite numerous studies on the function and pathologies of the superior glenoid labrum, controversy still exists concerning the mechanism of injury for superior labral anterior to posterior (SLAP), and thus the optimal treatment. Using a finite element model, the mechanical behavior of the superior glenoid labrum in multiple conditions was studied. First, the finite element model was validated for the study of the tear mechanism in the superior labrum. The area of high strain was well correlated with the clinical findings of SLAP tears. The current work used the validated model to evaluate the effect of both superior translation of the humeral head and tension on the long head of the biceps tendon on the strain in the intact labrum. The humeral head motion was found to have relatively greater effect than the biceps tension on the initiation of the SLAP tear. Repetitive micro-trauma or tissue fatigue rather than a single loading event is most likely to cause a mid-substance failure of the labrum. This work also tested the effect of the biceps tension on the propagation of SLAP tears using the finite element model. With loading of the biceps, the model predicted high strains at the edges of the tear suggesting a high risk for progression of the tear. For larger tears, the effect of the biceps was more pronounced. Based on this work, tear size is suggested as one criterion for determining the optimal treatment of the SLAP lesion. During development of the finite element model, simplifying assumptions were necessary. With careful consideration of the effect of these assumptions and simplifications on the results, the current work suggests a plausible mechanism of injury for SLAP lesions. This work is to identify the role of humeral head translation and biceps loading in the initiation and propagation of SLAP tears by examination of the predicted strain.

Wednesday, January 15, 2014

BME 500 Seminar Series

“Photoacoustic Imaging and its Application in Biomedicine”

Xueding Wang, Ph.D.
Associate Professor
Department of Radiology

Wednesday, January 15, 2014, 12:00 - 1:00 PM
1303 EECS

Abstract: Photoacoustic imaging (PAI), also referred to as optoacoustic imaging, is an emerging biomedical imaging technology that is noninvasive, nonionizing, with high sensitivity, satisfactory imaging depth and good temporal and spatial resolution. In PAI, a short-pulsed laser source is used to illuminate a biological sample and generate photoacoustic waves due to thermoelastic expansion. Then the photoacoustic signals are measured by ultrasonic transducers to rebuild the image of the sample. Therefore, like conventional optical imaging, PAI presents the optical contrast which is highly sensitive to molecular conformation and biochemical contents of tissues and can aid in describing tissue metabolic and hemodynamic changes. Unlike conventional optical imaging, the spatial resolution of PAI is not limited by the strong light diffusion but instead determined mainly by the measurement of light-generated photoacoustic signals. As a result, the resolution of PAI is parallel to high-frequency ultrasonography. In this talk, I will present the recent advances in biomedical photoacoustic imaging in our laboratory at University of Michigan, including the development of imaging techniques and their applications in preclinical and clinical settings.

Monday, January 13, 2014

Final Oral Examination

Characterization of Multicompartmental Microparticles for Cochlear Drug Delivery

Astin Ross
Chair: Dr. Richard A. Altschuler

Monday, January 13, 2014, 10:00 AM
Great Lakes Central Room – 4th Floor of Palmer Commons

Cochlear implants (CIs) are the treatment of choice for patients with moderate to profound sensorineural hearing loss (SHL), however increasing numbers of CI recipients have remaining hearing that needs to be protected from insertion trauma. Local delivery of therapeutics could potentially protect these initially viable inner ear sensory cells. This dissertation characterizes multicompartmental microparticles and their use as vehicles for inner ear drug delivery.

The first part of this dissertation involved the determination of preferred design and infusion parameters for local drug delivery in the cochlea using multicompartmental microparticles. Parameters were classified as preferred if their modulation increased visualization of microparticles within cochlear tissues. Identified preferred parameters were associated with particle design (fluorescence intensity), particle infusion protocol (composition of delivery matrix), or tissue processing and post harvesting (non-vascular tissue fixation).

In the next part of the dissertation in vivo microparticle persistence, distribution, and impact on cochlear function and histopathology were assessed in a guinea pig animal model. Confocal laser scanning microscopy (CLSM) of cochlear cross sections demonstrated the presence of microparticles for at least 7 days post infusion. Functional analysis with auditory brainstem response and histopathological analysis via hair cell counts demonstrated that an infusion of non-drug loaded particles could be delivered with limited negative impact on hearing and cell viability. Importantly, microparticle infusion did not induce an immune response as indicated by the comparable numbers of CD45 positive (white blood) cells present in infused cochleae as compared to non-infused contralateral cochleae.

The final part of the dissertation evaluated in vitro and in vivo pharmaceutical release from the multicompartmental microparticles. Incorporation and sequestration of Piribedil, an anti-excitotoxic agent, within a particular microparticle compartment was confirmed by CLSM. In vitro assessment demonstrated sustained Piribedil release from the microparticles on the order of weeks which would be suitable for intracochlear drug delivery. Analysis of perilymph obtained 7 days after in vivo infusion of Piribedil loaded particles identified the pharmaceutical at detectable levels in all samples. For the first time, the release of therapeutic levels of a pharmaceutical from an intracochlear particle system was demonstrated. This work provides the first evaluation of multi-release particles for local drug release in the cochlea for both in vitro and in vivo environments; it defines the challenges to efficacious use of these drug carriers for modifying inner ear function; and it identifies a research pathway that may enable clinical translation of these drug carriers for treatment of inner ear pathologies.

Wednesday, January 8, 2014

BME 500 Seminar Series

"The Magnitude and Phase of Pre-clinical Imaging: Basic Science, Therapeutic Development, and Translation"

Joan Greve, Ph.D.
Assistant Professor, Biomedical Engineering
University of Michigan

Wednesday, January 8, 2014, 12:00 - 1:00 PM
1303 EECS

Abstract: Biomedical engineers are used to working at the interface of multiple disciplines and acting as interpreters in order to enable rapid and impactful collaborative science across a broad spectrum of disciplines. For many, including myself, it is this very fact which makes our pursuit of science so enjoyable. Due to the characteristics embodied by imaging: fundamentals based in the physical sciences and engineering, the capability to be applied to a plethora of (patho) physiologies, and clinical application, imaging naturally attracts biomedical engineers. Pre-clinical imaging, undoubtedly, holds the potential to help more successfully translate research from bench to bedside but is still, largely, in its nascent phase.

The focus of this talk will be on pre-clinical magnetic resonance imaging (MRI), in particular, and how it can be used to further research in basic science, therapeutic development, and translation to the clinic. Examples discussed will primarily include cardiovascular, oncology, and neuroscience applications. Complimentary expertise that is requisite for the most successful imaging endeavors will also be highlighted (e.g. in silico methods, small animal models of the human condition, and rigorous pre- and post- statistical analysis). Emphasis will be placed on how highly-optimized pre-clinical imaging or, when necessary, the novel implementation of sequences predominantly reserved for the clinic results in unique conclusions that might only be gleaned by using such technology. Lastly, due to my extensive experience in industry (Genentech, Inc.) and leading MRI labs in academia and industry, I will briefly describe what might be under-utilized opportunities for partnering with companies.

Friday, December 13, 2013

Final Oral Examination

Characterization of Bioeffects on Endothelial Cells Under Acoustic Droplet Vaporization

Robinson Seda
Chair: Dr. Joseph L. Bull

Friday, December 13, 2013, 11:00 AM
1121 LBME (Lurie Biomedical Engineering)

An ultrasound-mediated cancer treatment called gas embolotherapy has the potential for providing selective occlusion of blood vessels for therapy. Vessel occlusion is achieved by locally vaporizing micron-sized droplets through acoustic droplet vaporization (ADV), which results in bubbles that are large enough to occlude blood flow directed to tumors. Endothelial cells, lining of our blood vessels, will be directly affected by these vaporization events and as such are the subject of this study. Damage to the endothelium could lead to a number of pathological states that, if left untreated could be harmful. However, if under control, these bioeffects could provide benefits that would be synergistic with bubble occlusion like increased endothelial permeability or occlusion by thrombosis. We investigate bioeffects caused by ADV under “worst-case scenario” cases by using a static endothelial culture model.

Two insonation frequencies (3.5 MHz and 7.5 MHz) were chosen to characterize the effects of ADV and aid in the exploration of frequency dependent effects. Damage was observed through changes in peak-negative (rarefactional) pressure and pulse length and described by the absence of cells after treatment. Damage was dependent in bubble cloud area and highly localized. Additional data was obtained to elucidate the role of ADV in open or confined environments, which simulate relatively large and small vessels, respectively. Through these experiments we try to provide the reader with some of the tools necessary to make an assessment on the repercussions of performing ADV in situations that allow the droplets and ultimately the bubbles to be in direct contact with the endothelium. Knowing when significant damage is expected in gas embolotherapy could help in the development of preventive measures as well as additional therapeutic aids during treatment.

Friday, December 13, 2013

Final Oral Examination

Quantitative Optical Sensing for Non-Invasive Clinical Characterization of Biological Tissues

William Lloyd
Chair: Dr. Mary-Ann Mycek

Friday, December 13, 2013, 10:00 AM
2203 LBME (Lurie Biomedical Engineering)

It is well known that changes in tissue morphology and/or biochemistry can affect tissue function. Characterizing these changes in tissue function through non-invasive and label-free assessment can inform clinical practice and improve patient outcomes. In this thesis, we employ non-invasive, quantitative, label-free, portable, and clinically-compatible reflectance and fluorescence spectroscopic technology for use in two clinical challenges: (1) improved detection of pancreatic disease and (2) post-implantation monitoring of tissue-engineered construct wound healing in an in situ murine model.

(1) Only 6% of pancreatic cancer patients survive 5 years after diagnosis, making it the 4th leading cause of cancer death in the United States. To improve detection of pancreatic cancer, we studied the diagnostic utility of optical spectroscopy to detect pancreatic disease in 5 Stages, with Stages 1 and 2 previously reported. Stage 1 showed that ex vivo measurements of human adenocarcinoma tissue correspond well to in vivo measurements from a tumor xenograft in a murine model. Stage 2 showed that malignant tissues measured ex vivo distinguish malignant and benign tissues. In this thesis, we discuss Stages 3-5. In Stage 3, a photon-tissue interaction (PTI) model was verified with measurements from tissue-simulating phantoms and validated with measurements from a subset of ex vivo human tissues collected in Stage 2. We show that a calibrated PTI model consistently extracts biologically-relevant optical tissue scattering parameters in the presence of variable hemoglobin absorption. In Stage 4, we perform the first ever, to our knowledge, in vivo feasibility study employing optical steady-state spectroscopy to detect malignant tissues during open surgery. In Stage 5, we investigate time-resolved fluorescence spectroscopy ex and in vivo to improve pancreatic disease classification. Furthermore, we show the first ever human pancreatic tissue measurements with an endoscopically-compatible fiber-optic probe. (2) Regulatory approval for tissue-engineered combinational devices, including tissue constructs developed for human implantation, requires reliable methods to assess post-implantation wound healing in vivo, of which none currently exist. In this thesis, we investigate diffuse reflectance spectroscopy to detect hallmarks of graft wound healing, including tissue revascularization, cell proliferation, and cell density, based on construct absorption and scattering properties.

Thursday, December 5, 2013

BME 500 Seminar Series

"MRI in Radiation Therapy Planning"

Yue Cao, Ph.D.,
Professor of Departments of Radiation Oncology,
Radiology and Biomedical Engineering,
University of Michigan

Thursday, December 5, 2013, 12:00 - 1:00 PM
1005 Dow

Abstract: MRI has played a supportive role in radiation therapy for over two decades. However, current observations and guidance suggest that MRI roles in radiation therapy will be increasing over the next several years, due to superior soft tissue contrasts provided by MRI. Challenges of using MRI as a key, if not solitary, imaging methodology in the planning of radiation therapy treatments are present. Issues such as geometric distortion, electron density information, image quality, scanning time, and optimization of MRI will be discussed.

Thursday, November 21, 2013

BME 500 Seminar Series

"Rotational Electrical Waves in the Fibrillating Heart: Mechanisms and Mapping"

Omer Berenfeld, PhD
Associate Professor of Internal Medicine and Biomedical Engineering
Center for Arrhythmia Research
University of Michigan

Thursday, November 21, 2013, 12:00 - 1:00 PM
1005 Dow

Abstract: Cardiac electrical turbulences known as ventricular or atrial fibrillation are a major cause of sudden death and stroke. We take an integrative approach to study the manner in which nonlinear electrical waves, which were originally thought of being random, self-organize during fibrillation. The presentation centers on data derived from animal and computational models of fibrillation that demonstrate distinct patterns of excitation organization driving the arrhythmia. Analysis of optical mapping data reveals that excitation frequencies during fibrillation are distributed throughout the heart in clearly demarcated domains with the highest frequency domains found where a sustained reentrant activity that drives the arrhythmia is present. Using numerical and cellular electrophysiology approaches we further study the mechanism of such patterns of excitation and how to analyze them in patients.

Tuesday, November 19, 2013

Final Oral Examination

Methods for MRI RF Pulse Design and Image Reconstruction

Feng Zhao
Co-Chairs: Professor Douglas Noll and Professor Jeffrey Fessler

Tuesday, November 19, 2013, 10:00 AM
GM Conference Room - 4th Floor Robert H. Lurie Engineering Center

Magnetic resonance imaging (MRI) is a revolutionary technique that helps clinical diagnosis by non-invasively and non-radioactively imaging human tissue. This thesis describes methods to improve MRI reconstruction and the system calibration, namely, B1 field mapping which is important for multi-channel RF pulse design. Moreover, we also developed methods of RF pulse design and steady-state imaging sequence design for applications such as fat suppression.

There are five different projects: (a) We propose a framework of iterative image reconstruction with separate magnitude and phase regularization where compressed sensing is used for the magnitude and special phase regularizers that are free of phase wrapping are designed for different applications. The proposed method greatly improves the phase image reconstruction while accelerates the data acquisition with compressed sensing. (b) A modified Bloch-Siegert B1 mapping is proposed to efficiently acquire both magnitude and phase of the B1 maps of parallel excitation systems. A regularized method is then proposed to jointly estimate the B1 magnitude and phase to improve the results in low signal-to-noise ratio regions. Furthermore, we propose to optimize the coil combinations in this parallel excitation B1 mapping sequence based on Cramer-Rao Lower Bound analysis, to improve the quality of the raw data for B1 estimation. (c) We propose an efficient 4 dimensional spectral-spatial fat saturation pulse that uniformly suppresses fat without exciting water in the presence of B0 and B1 inhomogeneity with single channel or parallel excitation system. At 3T, we show that the proposed pulse can work much more robustly than the standard spectrally selective fat sat pulse with much shorter pulse length. (d) We combine the proposed fat sat pulse to steady-state incoherent sequences, namely, spoiled gradient echo and small-tip fast recovery imaging, with a modified RF spoiling scheme. We tested these proposed sequences on applications like cartilage imaging and MR angiography and demonstrated their ability to simultaneously produce fat suppression and magnetization preparation. We show that the proposed sequences have less limitation on the minimal repetition time and potentially lower the overall RF power deposition. (e) We propose to use a steady-state sequence, i.e., gradient-based small tip fast recovery imaging, combined with a post-processing method to separate water and fat and remove banding artifacts simultaneously.

Friday, November 15, 2013

The Alan J. Hunt Memorial Lecture

"Microtubule dynamics at the nanoscale"

David Odde, PhD
Professor, Biomedical Engineering
University of Minnesota

Friday, November 15, 2013, 2:00 PM
Gerald R. Ford Presidential Library

Microtubule assembly dynamics are vital to many cellular processes, including nerve growth and cell division. In the current textbook view of microtubule assembly, αβ-tubulin subunits add efficiently to growing microtubules with minimal subunit loss during growth. This view has also led to the view that the GTP cap that stabilizes is small, perhaps as little as a single layer of GTP tubulin subunits at the growing microtubule tip. In this lecture, I will review how new ultra-high resolution measurements in the laboratory of the late Prof. Alan Hunt, combined with computational modeling in my own laboratory, led to a major revision of this picture. In particular, our studies revealed that microtubule assembly is inefficient, with extensive subunit loss during overall growth, and subunit on-off dynamics are far more rapid than previously appreciated (by about a factor of 10). These findings (Schek and Gardner et al., Current Biology, 2007; Gardner et al., Cell, 2011) led us to re-examine the basic mechanisms of how microtubule-directed anticancer drugs, such as paclitaxel and vinblastine, influence microtubule assembly. In the coming years, I hope that, through ongoing collaboration with Prof. David Sept, we will come to understand how these widely prescribed drugs exert their influence on microtubules, and from this understanding eventually design next generation anticancer therapeutics.

Thursday, November 14, 2013

BME 500 Seminar Series

"Post-marketing surveillance of hip and knee replacement implants: Development of a patient registry in Michigan"

Richard Hughes, Ph.D.
Associate Professor of Orthopaedic Surgery,
Biomedical Engineering, and Industrial & Operations Engineering
University of Michigan

Thursday, November 14, 2013, 12:00 - 1:00 PM
1005 Dow

Abstract: Total joint replacement (“arthroplasty”) is a common and effective treatment for arthritis of the hip and knee. While the clinical results for most patients are very good, an unacceptable number of poor outcomes occur in these procedures. Most notably, prostheses may need to be “revised,” which means that the surgery must be repeated to replace prosthetic components. One cause of revisions is poor selection of implants. National patient registries that track medical device data are a powerful tool for identifying poorly performing implants, and they have been shown to reduce revision rates in Sweden and Norway. In the last decade the Australian Orthopaedic Association National Joint Replacement Registry identified increased revision rates for Metal-on-Metal hip replacement devices. This presentation will provide an introduction to hip and knee arthroplasty, followed by an update on the status of the Michigan Arthroplasty Registry Collaborative Quality Initiative (MARCQI). MARCQI started in early 2012 and has registered over 5000 patients. MARCQI organization, data collection, and governance will be described. The presentation will frame MARCQI within the context of both health care quality improvement and national registry efforts, including the American Joint Replacement Registry and the Food and Drug Administration’s MDEpiNet initiative.

Tuesday, November 12, 2013

Final Oral Examination

Multi-spectral Dual Axes Confocal Endomicroscope with Vertical Cross-sectional Scanning forIn-vivo Targeted Imaging of Colorectal Cancer

Zhen Qiu
Chair: Dr. Thomas D. Wang

Tuesday, November 12, 2013, 1:00 PM
1210 Robert H. Lurie Engineering Center (LEC)

Pathologists review histology cut perpendicular to the tissue surface or in the vertical cross-section (XZ-plane) in order to visualize the normal or abnormal differentiation patterns. The epithelium of hollow organs, such as the colon, is the origin of many important forms of cancer. The vertical cross-section provides a comprehensive view of the epithelium which normally differentiates in the basilar to luminal direction. Real-time imaging in this orientation has not been fully explored in endomicroscopy because most instruments collect en-face images in the horizontal cross-section (XY-plane). Imaging microstructures from the tissue surface to about half a millimeter deep can reveal early signs of disease. Furthermore, the use of molecular probes is an important, emerging direction in diagnostic imaging that improves specificity for disease detection and reveals biological function. Dysplasia is a pre-malignant condition in the colon that can progress into colorectal cancer. Peptides have demonstrated tremendous potential for in vivo use to detect colonic dysplasia. Moreover, peptides can be labeled with near-infrared (NIR) dyes for visualizing the full depth of the epithelium in small animals. This study aims to demonstrate large field-of-view (FOV) in-vivo targeted vertical optical sectioning with a multi-spectral dual axes confocal endomicroscope. The NIR multi-spectral fluorescence images demonstrate both histology-like morphology imaging and molecular imaging of specific peptide binding to dysplasia in the mouse colon. The specific aims of this study are: (1) to develop miniature vertical cross-sectional scan engine based on MEMS technology for imaging on XZ-plane; (2) to develop multi-spectral dual axes confocal endomicroscope imaging system; (3) to perform large FOV in-vivo targeted multi-spectral vertical cross-sectional imaging on CPC;Apc mouse model of colorectal cancer.

Friday, November 8, 2013

Final Oral Examination

Bubble Dynamics and Acoustic Droplet Vaporization in Gas Embolotherapy

David Li
Chair: Dr. Joseph L. Bull

Friday, November 8, 2013, 11:00 AM
2203 LBME (Lurie Biomedical Engineering)

Gas Embolotherapy is a twist on traditional catheter based embolotherapy approaches. Rather than using a solid or semi-solid embolizing agent to restrict blood flow, localized gas bubbles are used instead. These gas bubbles are formed by the controlled vaporization of intravenously injected liquid microdroplets using focused ultrasound. This vaporization process is often referred to as acoustic droplet vaporization (ADV). A greater understanding of the ADV process, bubble transport, and acoustic-bubble interactions are essential to devising a safe and effective therapy.

This dissertation delves into the dynamics throughout the ADV process from the initial conversion process up to the bubble transport in vessels. The following work has been divided into five time-scale events that may occur throughout the ADV process. First, ultra-high speed imaging investigating the initiation gas nuclei formation within liquid microdroplets is compared against a numerical model of the acoustic field within the droplet to determine the mechanism behind ADV. After the droplet is converted into a high-pressure bubble, the effect of pulse length and acoustic power are correlated with the likelihood of collapsing the newly formed bubble possibly resulting in vessel damage. Next, influences from channel resistance on the bubble expansion rates are investigated by comparing the ADV bubble evolution process in free field conditions versus in a constrained microchannel. Once a bubble is formed, transport phenomena and possible additional acoustic pulses may influence bubble dynamics and the efficacy of the treatment. The scenario of a finite-sized bubble attached to a vessel wall approaching a bifurcation point is modeled using the boundary element method in order to understand the influences of sticking conditions and bifurcation geometry on bubble lodging or dislodging. Finally, an instability resulting from short acoustic pulses impinging on a bubble attached to a solid boundary resulting in droplet atomization of the bulk liquid in the bubble is characterized. The implications from all of these dynamics are discussed in the context of gas embolotherapy as well as other bubble or ADV based therapies.

Thursday, November 7, 2013

BME 500 Seminar Series

"High-speed Intravascular Photoacoustic Catheter for Atherosclerotic Artery Imaging"

Pu Wang
PhD Candidate
Department of Biomedical Engineering
Purdue University

Thursday, November 7, 2013, 12:00 - 1:00 PM
1005 Dow

Photoacoustic imaging using the intrinsic contrast from harmonic vibration of C-H bonds allows selective mapping of lipids deposition inside the artery wall. The current developed intravascular photoacoustic endoscopes employ 10 Hz repetition excitation at 1730 nm from a Nd:YAG pumped OPO system, which is 2 orders of magnitude slower than the speed for in vivo requirement. Towards the goal of diagnosis atherosclerosis in clinical setting, we herein demonstrate a high-speed photoacoustic catheter based on a Raman laser with 1 KHz repetition rate for intravascular lipid visualization. In our study, 1730 nm excitation from a 1 KHz Raman laser was used to excite the first overtone vibration of C-H bonds. By scanning the probe with a combination of rotary and linear stages, three dimensional imaging of atherosclerotic plaques was performed. Our study enables the deployment of the photoacoustic catheter towards in vivo applications. Intravascular photoacoustic imaging is an emerging method for atherosclerotic plaque assessment due to the chemical selectivity it can provide. However, the slow imaging speed (>5s per frame) limits its implementation for in vivo application. We herein demonstrate a high-speed photoacoustic catheter by employing a Raman laser with 1 KHz repetition rate for intravascular lipid visualization. Our study enables the deployment of the photoacoustic catheter towards in vivo applications.

Friday, November 1, 2013

Final Oral Examination

Non-Invasive Quantitative Imaging Informs Early Assessment of Cancer Therapeutic Response

Benjamin A. Hoff
Chair: Dr. Craig J. Galbán

Friday, November 1, 2013, 2:00 PM
Room 4515, BSRB

Therapeutic response assessment of cancer has long been facilitated by non-invasive imaging methods such as magnetic resonance imaging (MRI) and x-ray computed tomography (CT) in the clinic. Standards of patient care are designed around the most common cases, which may not always be efficacious. However, through evidence-based medicine there has begun a shift toward more individualized care. Standard clinical practice for cancer response assessment utilizes only volumetric change, measured prior and following the completion of therapy, providing no opportunity to adjust the treatment. In addition, novel targeted therapies, which may not result in a substantial decrease in tumor volume, are becoming more prevalent in the treatment of tumors. There is a clear need for non-invasive biomarkers that provide near real-time information on the anatomical and physiological makeup of the tumor post-treatment initiation. Tools for assessing early treatment response may allow physicians to dynamically optimize treatments individually, enhancing patient prognoses and avoiding unnecessary patient morbidity. In the following studies, I have evaluated various non-invasive imaging tools for early detection of treatment response in rodent models of disease. Tissue apparent diffusion coefficients (ADC) are known to correlate well with cellular status in cancer, and have shown promise in the detection of early tumor treatment response. Several different numerical models of higher-order diffusion signal attenuation were evaluated to determine their sensitivity to treatment response compared to the standard diffusion model. Dynamic contrast-enhanced (DCE-) MRI has shown sensitivity to vascular changes in cancer and was evaluated as an imaging biomarker of treatment response using a novel vascular-targeted therapy. Quantitative indices generated from DCE-MRI data were compared to diffusion (ADC) and volumetric MRI readouts for response assessment. The utility of imaging readouts from concurrent MRI, CT, bioluminescence, and fluorescence imaging was also evaluated in a model of bone metastasis. Further, a new voxel-based analytical technique, the parametric response map (PRM), was applied to CT images of metastatic bone disease and osteoporosis to evaluate bone response to treatment and hormone deprivation, respectively. Use of these tools may help improve the clinical effectiveness of cancer patient therapy as well as drug development and testing in preclinical models.

Thursday, October 31, 2013

BME 500 Seminar Series

"Treating brittle bones to fracture less: Can we be Unbreakable?"

Ken Kozloff
Assistant Professor
Departments of Orthopaedic Surgery
and Biomedical Engineering
University of Michigan

Thursday, October 31, 2013, 12:00 - 1:00 PM
1005 Dow

Abstract: Bone is a highly regulated nanocomposite material containing mineral, collagen, and non-collagenous proteins capable of balancing both metabolic and structural needs. Failure of the skeleton to meet mechanical demands can result from a variety of genetic, environmental, or hormonal effects, and reducing one’s susceptibility to fracture can be approached through pharmaceutical, dietary, or lifestyle changes. Osteogenesis imperfecta (OI) is genetic disease of high bone brittleness in which multiple fractures during childhood are attributed to mutations in collagen or collagen-related proteins. Pharmacologic therapy for OI has focused on reducing high bone turnover and preserving bone mass through bisphosphonates. These drugs were originally developed for adults with osteoporosis, and despite showing clinical benefit at reducing vertebral fractures in OI, show much lower efficacy in preventing long bone fractures. Recent studies demonstrating the molecular mechanisms behind high bone mass diseases such as Sclerosteosis and Van Buchem’s have led to identification of the protein sclerostin as a negative regulator of bone formation. The development of antibodies for sclerostin has led to a new effort to treat low bone mass diseases through anabolic bone formation mediated by sclerostin inhibition. This seminar will present recent data contrasting the effects of increasing bone mass through inhibited turnover or increased bone formation. Bisphosphonates and sclerostin antibody each affect bone mass and strength across multiple hierarchical size scales and their usage may provide contrasting long-term therapy implications for patients with OI.

Thursday, October 24, 2013

BME 500 Seminar Series

"Got Quality of Life? The Myths & Truths of Disability"

Claire Kalpakjian, Ph.D.
Assistant Professor of Physical Medicine and Rehabilitation
University of Michigan, Medical School

Thursday, October 24, 2013, 12:00 - 1:00 PM
1005 Dow

Abstract: This presentation will address key assumptions about the quality of life of persons with disabilities. The “disability paradox”, response shift and set-point theories provide a framework for discussing commonly held assumptions, such as the more severe the disability, the worse the quality of life. Ethical implications of discordant proxy ratings of quality of life and key predictors of high quality of life in the context of disability are reviewed. Finally, the application of key principles to biomedical engineering in clinical populations is addressed.

Thursday, October 10, 2013

BME 500 Seminar Series

"Medical Device Infections as Transport Phenomena: Improving Therapy by Thinking Quantitatively About the Bacterial Experience in the Bloodstream"

John Younger, MD
Professor of Emergency Medicine,
University of Michigan – Medical School

Thursday, October 10, 2013, 12:00 - 1:00 PM
1005 Dow

Abstract: From the perspective of infection, the bloodstream is one of the most sacred, and therefore most heavily guarded, compartments in the body. The ascendancy of long-term implanted medical devices, including catheters, pacemakers and defibrillators, grafts, and stents, have significantly changed the clinical nature of blood stream infection, with opportunistic skin-dwelling bacteria suddenly provided with the ‘keys to the castle.’ Bacterial contamination of a device located within the bloodstream focuses the abstract concept of ‘infection’ to a biomechanical process localized in space in which bacteria, engineered surfaces, flowing blood, and immunity converge. By treating this problem as essentially one of mass, momentum, and possibly even heat transport, it’s possible better define the design requirements for new therapies, materials, and devices that minimize the chances of harm while maximizing device life span.

Wednesday, October 9, 2013

Rehabilitation Robotics Seminar Series

“Techniques for Active User Engagement in Robotic Rehabilitation”

Marcia O’Malley, Ph.D.
Associate Professor
Mechanical Engineering & Material Science,
Rice University

Wednesday, October 9, 2013, 12:00 PM
1006 Dow

Abstract: The Mechatronics and Haptic Interfaces Lab at Rice University has been developing robotic devices, objective assessments, and control architectures for upper extremity rehabilitation robots employed after stroke and incomplete spinal cord injury. In this talk, a range of techniques for ensuring active engagement of the participant in therapeutic interventions with robotic devices will be discussed. Objective measures of motor impairment can provide frequent feedback to the participant regarding their performance during therapy. Control architectures can require initiation or sustained input from the user in order to generate desired movements. Further, controllers can be designed to adapt to the user’s changing capabilities, which may be dependent on position or direction of movement. Results from a variety of ongoing clinical evaluations will be discussed in relation to these topics. These research efforts embody the collaborative, interdisciplinary nature of my group’s research in biorobotics, haptics, neural engineering, and robotic rehabilitation.

Marcia O’Malley is an Associate Professor in the Mechanical Engineering and Materials Science Department at Rice University, serves as the Director of Rehabilitation Engineering at TIRR-­‐ Memorial Hermann, and is a co-­‐founder of Houston Medical Robotics, Inc. She holds a joint appointment in Computer Science at Rice, and is an Adjunct Associate Professor in the Departments of Physical Medicine and Rehabilitation at both Baylor College of Medicine and the University of Texas Medical School at Houston. At Rice, her research interests focus on the issues that arise when humans physically interact with robotic systems. One thrust of her lab is the design of haptic feedback and shared control between robotic devices and their human users for training and rehabilitation in virtual environments. Psychophysical studies provide insight into the effect of haptic cues on human motor adaptation, skill acquisition, and the restoration of motor coordination. She has also explored the use of haptic devices for teaching the fundamentals of dynamic systems and control in the mechanical engineering curriculum. In 2008, she received the George R. Brown Award for Superior Teaching at Rice University. O’Malley is a 2004 Office of Naval Research Young Investigator and the recipient of the NSF CAREER Award in 2005. Additionally, she served as chair of the IEEE Technical Committee on Haptics. She is a former Associate Editor for both the IEEE Transactions on Haptics and the ASME/IEEE Transactions on Mechatronics.

Friday, October 4, 2013

BME Alumni Award Seminar

“Some Personal Epiphanies from a Career in Biomedical Engineering.”

Timothy Kriewall, Ph.D. (BSE EE 1967)
Friday, October 4, 2013, 10:00 - 11:15 AM
2203 LBME (Lurie Biomedical Engineering)

Bio: Tim is a Michigan grad in electrical engineering (’67). He received his masters in ECE from Stanford (’68). Tim returned to The University of Michigan on a NIH Special Fellowship where he earned a Ph. D. in biomedical engineering in 1974. After graduating, he remained on the faculty in the department of obstetrics and gynecology, conducting research in perinatal and teaching ultrasound to engineering and medical students.

In 1981, Tim joined 3M Company in St. Paul, MN where he held positions of increasing responsibility in research and development focusing on medical device development.

In 1997, Tim joined Medtronic where he held positions of increasing responsibility. He left Medtronic in 2003 as a Vice President of R&D at their Jacksonville facility.

Tim departed Medtronic to become president of Wisconsin Lutheran College in Milwaukee, WI, a comprehensive liberal arts college with no engineering curriculum. After five years, Tim attempted to retire and was granted the title of president emeritus.

However, his retirement was short lived inasmuch as he was immediately recruited by the Kern Family Foundation of Waukesha, WI to become Program Director of the Kern Engineering Entrepreneurship Network (KEEN). Tim had the privilege of using Foundation resources to financially support a network of over 25 private U.S. colleges that worked together to change engineering education by instilling the entrepreneurial mindset in their graduates.

Tim is a senior life member of the Institute of Electrical and Electronic Engineers (IEEE) and a Fellow in the American Institute of Medical and Biological Engineers (AIMBE). He is the author of numerous professional articles and has organized international meetings for IEEE on computer-based medical systems and for the International Conference on Mechanics in Medicine and Biology.

Thursday, October 3, 2013

BME 500 Seminar Series

"MRI in Radiation Therapy Planning"

Yue Cao, Ph.D.,
Professor of Departments of Radiation Oncology,
Radiology and Biomedical Engineering,
University of Michigan

Thursday, October 3, 2013, 12:00 - 1:00 PM
1005 Dow

Abstract: MRI has played a supportive role in radiation therapy for over two decades. However, current observations and guidance suggest that MRI roles in radiation therapy will be increasing over the next several years, due to superior soft tissue contrasts provided by MRI. Challenges of using MRI as a key, if not solitary, imaging methodology in the planning of radiation therapy treatments are present. Issues such as geometric distortion, electron density information, image quality, scanning time, and optimization of MRI will be discussed.

Tuesday, October 1, 2013

Final Oral Examination


Jacob Ceccarelli
Chair: Andrew J. Putnam, PhD

Tuesday, October 1, 2013, 5:00 PM
GM Conference Room - 4th Floor Robert H. Lurie Engineering Center

The ultimate goal of tissue engineering is to develop thick, implantable tissues capable of recapitulating, in whole or in part, the function of healthy organs. However, creating such tissues has proven difficult because cells implanted into the body soon die due to lack of oxygen and the inability to remove waste. This challenge can be overcome by including a blood vessel network in engineered tissues and connecting it with the host vasculature to nourish the constituent cells. One method to achieve this goal is to incorporate endothelial cells into an engineered tissue and allow them to self-assemble into such a network, a method now used routinely in assays for studying blood vessel formation (angiogenesis). Our laboratory uses one such method that is capable of generating bona fide capillaries with patent lumens in 3D hydrogels composed of fibrin, the primary component of blood clots and a major constituent of the provisional matrix during wound healing and angiogenesis. Although the creation of such capillary networks is becoming widespread, the cues that control how they are organized are not well understood. We have developed a system capable of applying static and cyclic strain to this assay to study how mechanical cues affect directional capillary growth. Co-cultures of endothelial and smooth muscle cells in fibrin gels undergoing cyclic strain were observed to form capillaries parallel to the applied strain, in contrast to their randomly-oriented growth under static conditions. Upon examination of the fibrin matrix under comparable strain, the existence of a contact guidance cue from the matrix was ruled out, prompting an investigation of intracellular mechanotransduction as a mediator of the directional sprouting. Myosin heavy chain contains the molecular motor primarily responsible for traction force generation in mammalian cells, and its activation is partly under the control of a signaling pathway containing the proteins RhoA, Rho-kinase, myosin light chain kinase, and myosin light chain. However, the use of genetic modulation and pharmacological inhibition of each of these proteins revealed that they are unnecessary for capillary alignment in this system. This finding opens the door to alternative hypotheses to explain endothelial cell mechanosensing.

Tuesday, October 1, 2013

U-M Biomedical Engineering Society

Surface-enhanced Raman Scattering in Biosciences and Medicine

Mustafa Culha, Ph.D
Tuesday, October 1, 2013, 5:00 - 6:00 PM
LBME (Lurie Biomedical Engineering) Atrium

Abstract The use of surface-enhanced Raman scattering (SERS) has been investigated for the solution of a wide range problems in medicine and biomedical sciences. The capacity to provide fingerprint information from molecular structures in short time with a high sensitivity can be given the major advantage of the technique. However, the technique suffers from the irreproducibility issues related to the substrate used in the experiment. In this talk, I will summarize our effort to utilize the SERS as characterization technique to gather information for detection and discrimination from bio-macromolecules and biological systems such as proteins, microorganism, living cells and tissue by addressing the pros and cons of the technique.

Biography Professor Mustafa Culha obtained his Ph.D degree in chemistry under the supervision of Prof. Michael Sepaniak at the University of Tennessee-Knoxville in 2002. Then, he joined in Prof Vo-Dinh’s research group (Advanced Biomedical Research Group) as a post-doctoral researcher at Oak Ridge National Laboratory (2002-2003) before joining to Schering-Plough Corporation, NJ as an investigator. In 2004, he accepted a faculty position in Genetics and Bioengineering Department of Yeditepe University, Istanbul, Turkey. He is currently involved active teaching and research there. His current research interest includes elements from chemistry, medicine, biology, material science, photonics, nanoscience and nanotechnology. The utility of spectroscopic techniques such as surface-enhanced Raman scattering (SERS) to shed light onto living-nonliving interactions, development of novel detection and diagnostic tools for medical and biomedical applications, understanding nanomaterial-living interactions to develop novel approaches for delivery and therapeutic applications are ongoing research projects in his laboratories. He and his colleagues have authored of more than 65 papers in refereed international journals, several book chapters and patents in the area of analytical and bioanalytical chemistry, and nanotechnology. He is also the editor of a special issue for Surface-enhanced Raman Scattering of Journal of Nanotechnology, and he is on the editorial board of Applied Spectroscopy.

Thursday, September 26, 2013

BME 500 Seminar Series

“Cerebral Blood Flow MRI as an Indicator of Brain Function”

Research Associate Professor, Biomedical Engineering & Functional MRI Laboratory

Thursday, September 26, 2013, 12:00 - 1:00 PM
1005 Dow

Abstract: In this talk, I will give an overview of the existing technology for functional MRI and focus on the development of the "arterial spin Labeling" (ASL) technique. ASL allows us to image cerebral blood flow quantitatively and dynamically. ASL images can be collected relatively rapidly and do not require injection of tracers into the subject. New developments in ASL technology are pushing the technique into the forefront of functional MRI imaging, but many challenges still lie ahead.

Tuesday, September 24, 2013

BME Career Event

St. Jude Medical Corporate Information Session

St. Jude Medical
Tuesday, September 24, 2013, 6:00-8:00 p.m.
1123 LBME (Lurie Biomedical Engineering Building)

At St. Jude Medical, each employee can make a difference and has the power, either individually or as a team, to influence the success of the company. We are team-oriented, fast-paced and progressive. We value people with great ideas who partner with others both internally and externally to take action and accomplish goals. We strive for and are committed to maximizing everyone’s potential. We place a premium on conducting business following the highest ethical standards. Your role will be as challenging as you make it. We look for people who are bright, focused and who want to be successful. St. Jude Medical is looking for potential candidates for our co-op and intern programs.

Thursday, September 19, 2013

BME 500 Seminar Series

“Biomechanical Modeling of Human Anatomy for Radiation Therapy”

Kristy Brock-Leatherman, Ph.D.
Associate Professor, Radiation Oncology
Associate Professor, Biomedical Engineering

Thursday, September 19, 2013, 12:00 PM - 1:00 PM
1005 Dow

Abstract: Radiation therapy is a high precision treatment that requires accurate delineation of the tumor, often using multi-modality imaging for definition, knowledge of the motion and uncertainty of the patient over the course of treatment, and an estimation of the delivered dose to the tumor and normal tissue over the course of treatment to improve our understanding of the therapeutic response of both the tumor and normal tissue to radiation. Biomechanical models have been developed using finite element models to describe the both the physiological motion of the patient, including breathing, rectal/bladder filling, and peristalsis, and recently the therapeutic response of the patient to treatment. Dr. Brock will describe the clinical requirements in radiation oncology, the biomechanical models that she has developed in her lab, and the applications of these models to improve the understanding of the delivered dose in radiation therapy.

Wednesday, September 18, 2013

Rehabilitation Robotics Seminar Series

"Rehabilitation robotics - paradigm shift or going through the motions?"

Carolynn Patten, P.T., Ph.D.
Wednesday, September 18, 2013, 12:00 PM - 1:00 PM
SPH II, 1122

Associate Professor, Department of Physical Therapy, University of Florida

Friday, September 13, 2013

Final Oral Examination

Parametric Modeling of the Brain Vascular System and its Application in Dynamic Contrast-Enhanced Imaging Studies

Siamak. P. Nejad Davarani
Chair: Dr. Douglas C. Noll

Friday, September 13, 2013, 2:00 PM
GM Conference Room - 4th Floor Robert H. Lurie Engineering Center

Dynamic Contrast-Enhanced Imaging (DCE) is one of the main tools for in vivo measurement of vascular properties of pathologies such as brain tumors. In DCE imaging, one of the key components for estimation of vascular perfusion and permeability parameters using Pharmacokinetic models is the Arterial Input Function (AIF). To measure these parameters more accurately, there have been many approaches for estimating the AIF profile at the capillary level; however, a practical and realistic estimate is still missing.

As a solution to this problem, we have developed a model of the brain vascular system, based on laws of fluid dynamics and vascular morphology, to address dispersion and delay of the contrast agent (CA) concentration profile at different levels of the brain vascular tree. Using this model, we introduced a transfer function that can describe changes of the AIF profile along a vascular pathway, from a major artery to the capillary bed. Our simulations and also testing this model on DCE Computed Tomography (DCE-CT) and Magnetic Resonance (DCE-MR) Imaging data of the human brain, all showed that our model can give a realistic estimation of the CA concentration profile, at all levels of the vascular tree in the brain.

In the next step, to apply this model to pathologies such as brain tumors, in which leakage of the contrast agent to the extravascular-extracellular space (EES) can happen, we extended our model to address vascular leakage as well. Using this extended vascular (EV) model, we are able to decompose the tissue response signal in DCE images to its intravascular and EES components. This feature has provided us with an excellent tool that can lead to relatively unbiased measurements of perfusion and permeability parameters, especially in areas with vascular leakage. We tested this on DCE-CT and DCE-MR images and compared the performance of our model to conventional methods. Also, using a simulation study, we measured the levels of overestimation and underestimation of the permeability parameters using conventional processing methods and demonstrated the superior performance of the EV model for more accurate estimation of these parameters.

Overall, the results show that the EV model proposed in this study can provide a platform for better understanding of the role of the AIF in DCE studies as well as identification and estimation of AIF for more accurate measurement of perfusion and permeability parameters. This model can have a significant impact on the application DCE Imaging in clinical studies.

Thursday, September 12, 2013

Final Oral Examination

On the Phenotype of White-Tailed Deer Antlerogenic Progenitor Cells

Ethan Daley
Chair: Steven A. Goldstein, Ph.D.

Thursday, September 12, 2013, 3:00 PM
Great Lakes North Room – 4th Floor of the Palmer Commons

Repair of large bone defects is one of the key unmet clinical needs in musculoskeletal medicine. A rare exception to the limits of mammalian regeneration is the deer antler, the only example of complete, repeated organ regrowth in an adult mammal. The antlerogenic progenitor cells (APC) at the heart of antler regeneration could provide insights into potential strategies for directing adult somatic progenitor cells to achieve large scale tissue repair. As basic questions about the APC phenotype remain unanswered, we embarked on a wide ranging investigation of progenitor cells from the antlers and marrow of white-tailed deer (Odocoileus virginianus), both in vitro and in an in vivo murine ossicle model.

Our findings suggest that antler tip APC are likely more lineage-committed osteo-/chondroprogenitors compared to animal-matched marrow MSC with different, often opposing, responses to glucocorticoid steroids. Moreover, we found that apoptosis, rather than being antagonistic to antler regeneration, may actually contribute to short duration APC homeostasis. We were not able to make definitive statements regarding APC and MSC mechanoresponsiveness. However, our investigation of the effects of oscillatory fluid shear stress uncovered more evidence of the differing effects of substrate on APC growth. In addition, the robust basal production of prostaglandin E2 by APC could contribute to antler-specific behavior.

The observed pattern of time, factor, and milieu dependence of APC expansion and differentiation may reflect a system of regulation required to confine antler growth to a specific anatomical and temporal range. Overall, we have demonstrated that APC are mesenchymal stromal cells with a distinct phenotype compared to animal-matched bone marrow-derived MSC.

Thursday, September 12, 2013

BME 500 Seminar Series

"Developing a brain-controlled robotic lower limb exoskeleton"

Daniel Ferris, Ph.D.
Thursday, September 12, 2013, 12:00 PM - 1:00 PM
1005 Dow

Abstract: Robotic technology has greatly advanced in recent years, leading companies and university research laboratories to develop powered mechanical exoskeletons for assisting human movement. Unfortunately, human performance with the devices has generally been very poor. Even slight antagonism between human and machine during movement can cause motor performance to greatly degrade. I will present results from my laboratory revealing principles of human motor adaptation to robotic lower limb exoskeletons. I will also show results from mobile brain imaging studies suggesting that brain-controlled robotic lower limb exoskeletons are feasible in the near future, and should allow exoskeleton devices to work together with humans in a more beneficial manner.

Thursday, September 5, 2013

BME 500 Seminar Series

“Controlling body fluids: BME experiences in industry and academia”

Tim Bruns, PhD
Assistant Professor, Biomedical Engineering

Thursday, September 5, 2013, 12:00 – 1:00 PM
1005 Dow

Abstract: In this seminar to kick off the semester, Dr. Bruns will discuss his experiences as an R&D biomedical engineer in industry and academia, working on diverse medical device approaches to control different body fluids. As a systems engineer in industry, Dr. Bruns was part of a product development team for an automated blood collection medical device. These apheresis instruments are designed to optimize the blood donation process by increasing yield while returning fluids to the donor to maintain an isovolemic state. Dr. Bruns helped develop an optical subsystem that controlled product quality and also designed and tested algorithms for different blood component collection protocols. Biomedical engineers on this product team played a critical central development role, interfacing with other engineering groups such as electrical, mechanical and computer science as well as clinical release and marketing personnel. As an academic researcher in the BME sub-discipline of neural engineering, Dr. Bruns focuses on the use of electrodes placed in or near peripheral nerves to control function and probe physiology. A primary research objective is the development of a neural prosthesis to restore bladder function, which is an important need for a wide range of patient groups. Specific sensory nerves in the pelvis can be electrically stimulated to evoke reflex bladder responses; however this approach has yet to be clinically implemented. A novel neural interface with dorsal root ganglia, where sensory nerves enter the spinal cord, may improve upon earlier peripheral nerve approaches while also allowing for feedback on the bladder state for closed-loop control. As this talk will illustrate, biomedical engineers can have divergent career paths but still play critical roles in the research and development of medical devices designed to improve the human condition.

Saturday, August 31, 2013

Final Oral Examination

“Practical Design Guidelines for Synthetic Multivalent Nanoparticles as Targeted Biomedical Nanodevices”

Ming-Hsin Li
Chair: James R. Baker, Jr., MD

Saturday, August 31, 2013, 9:30 AM - 12:00 PM
1515 Biomedical Science Research Building (BSRB)

This dissertation explores the heterogeneity of synthetic nanoparticles and systematically investigates factors that regulate the multivalent binding avidity of these particles. We aim to establish parameters for designing multivalent nanoparticles, and define the role the heterogeneity of nanoparticles plays in this process from both structural and kinetic perspectives. In these studies, the kinetic and thermodynamic binding parameters of heterogeneous nanoparticle populations are identified and evaluated. We assess the effect of varied design parameters on the function of multivalent nanoparticles to provide these design guidelines. In the end, we prove the binding avidity of nanoparticles can be optimized using this approach.

We first developed a novel method for evaluating the avidity distribution of nanoparticles. This involved the design and synthesis of a model multivalent nanoparticle system and a unique kinetic analysis to quantify the avidity distribution. We used mono-dispersed PAMAM dendrimers functionalized with ssDNA oligonucleotides as a platform, and used complementary oligonucleotides as targeted receptors to create this well-controlled model nanoparticle system and an SPR biosensor to evaluate their binding. We found the binding curves were characterized by heterogeneity, including fast- and slow-dissociation subpopulations. By using a parallel initial rate analysis and dual-Langmuir analysis, the avidity distribution of nanoparticles were determined and compared to chemical diversity of ligand distribution.

Second, we probed the avidity distributions, resulting from a variety of parameters, including the number and the affinity of functionalized ligands. Based on both experimental and simulation results, we showed that multivalent interactions were dependent on these design parameters and developed strategies to enhance the binding avidity of ligand-functionalized nanoparticles and the frequency of high-avidity subpopulations in the heterogeneous nanoparticle populations.

Finally, we tested the principles defined in our prior studies by synthesizing ligand-functionalized nanoparticles that demonstrated homogeneous high-avidity interactions with SPR surfaces. This was accomplished by using copper-free click chemistry, which allowed us to synthesize uniform and densely ligand-functionalized nanoparticles. As hypothesized, these nanoparticles demonstrated uniform binding to the targeted surface with pM-level avidity. This avidity is comparable to the avidity of antigen-antibody interaction, suggesting that these guidelines can be used in the design of nanoparticles in targeting drugs in vivo.

Tuesday, August 27, 2013

Final Oral Examination

The Effects of Deep Brain Stimulation in the Ventral Pallidum and the Central Nucleus of the Amygdala on Food Consumption, Motivation, and Palatability

Shani Ross
Co-Chairs: J. Wayne Aldridge, Ph.D. and Susan Shore, Ph.D.

Tuesday, August 27, 2013, 1:00 PM
Earl Lewis Room (3rd floor), Rackham

Deep brain stimulation (DBS) has been shown to be an effective treatment for Parkinson’s disease and other movement disorders including essential tremor and dystonia. Given its success, DBS is also being investigated as potential treatment for psychiatric disorders including depression, obsessive compulsive disorder, eating disorders, and addiction. Although the specific therapeutic mechanisms of DBS are not known, studies suggest that this type of electrical stimulation may be causing an entrainment or regularization of firing patterns in neurons, interfering with the information being processed in the underlying neural circuit.

My overall goal is to evaluate the potentially neural interference effects of DBS-like stimulation on motivation and reward consumption. I targeted the ventral pallidum (VP), which is thought to be an area of convergence for processing reward and reward-related information, and the central nucleus of the amygdala (CeA), which is thought to be especially involved in focusing motivation for particular cues and rewards. The effects on DBS in the VP and CeA on reward-seeking behaviors, food consumption, and hedonic value of tastes were assessed. I found that DBS in the VP produced complex patterns of neuronal firing; however, it did not disrupt neural coding of reward and had only minimal effects on food consumption and motivation. DBS in the CeA also resulted in similar complex firing patterns, and additionally (in contrast to what happen in the VP) disrupted neural coding of reward. This disruption was reflected in altered behavior. DBS in the CeA invoked an immediate and profound decrease in the consumption of and motivation to work for sucrose pellets. We also showed that DBS decreased palatability of tastes.

Overall results suggest the DBS is modulating neural activity in the underlying target structure, but target location is very important and this DBS-induced change in neuronal firing may or may not disrupt coding for reward. Data suggests that CeA may be an effective target for blocking food consumption and motivation.

Thursday, July 18, 2013

Final Oral Examination

Focused Ultrasound Thermal Therapy Monitoring using Ultrasound, Infrared Thermal, and Photoacoustic Imaging Techniques

Yi-Sing Tina Hsiao
Co-Chairs: Dr. Cheri X. Deng and Dr. Albert Shih

Thursday, July 18, 2013, 9:30 AM
1303 EECS

Focused ultrasound (FUS) is a promising thermal treatment modality which deposits heat noninvasively in a confined tissue volume to treat localized diseased tissue or malignancy through hyperthermia or high temperature ablation. FUS compatible guiding and monitoring systems to provide real-time information on tissue temperature and/or status (e.g. native or necrotized) are important to ensure safe and effective treatment outcome; however, current development of such systems are restricted to ultrasound and magnetic resonance imaging (MRI). The work described in this dissertation represents efforts to explore new tools to improve current thermometry techniques as well as to develop new imaging modalities. In the first study, infrared (IR) thermography was applied as a new tool to evaluate ultrasound thermometry in phantoms during FUS heating, providing a fast calibration and validation tool with spatiotemporal temperature information unavailable with traditional thermocouple measurements. In the second study, IR thermography and bright-field imaging were applied to high temperature FUS ablation monitoring in which the spatiotemporal temperature characteristics in correspondence to lesion formation and bubble activities were identified. Tissue-specific thermal damage threshold, which is critical for accurate estimation of tissue status based on temperature time history, was also obtained using the same system. In the final study, we developed a novel dual-wavelength photoacoustic (PA) sensing technique for monitoring tissue status during thermal treatments, which is capable of separating the two effects from temperature rise and changes in optical properties due to tissue alteration. Experimental validations of the theoretical derivation were carried out on ex-vivo cardiac tissue using water-bath heating on lesions generated by FUS. Future directions of research include in-vivo technique demonstration where effects such as blood perfusion on FUS heating need to be considered. When FUS operates in the non-ablative regime without causing irreversible changes in tissue, treatment monitoring techniques investigated in this study also have the potential to be translated into diagnostic tools.

Wednesday, July 17, 2013

Final Oral Examination

Characterization and Monitoring of Cardiac Electrophysiological Changes During High Intensity Focused Ultrasound Ablation

Ziqi Wu
Chair: Dr. Cheri X. Deng

Wednesday, July 17, 2013, 1:30 PM
GM Conference Room - 4th Floor Robert H. Lurie Engineering Center

Atrial fibrillation (AF), the most common cardiac arrhythmia, is characterized by disorganized electrical activities that cause atrial quivering and uncoordinated contraction. AF significantly affects the quality of life for patients and increases the risk of stroke. Ultrasound ablation surgery has been proposed a decade ago as a treatment for AF. By focusing ultrasound energy at a narrow spot, rapid temperature rises along with tissue necrosis are generated in seconds within confined volume. In this thesis, we investigated high-intensity focused ultrasound (HIFU), an ablation technology has been used to modify atrial substrates and eliminate arrhythmogenic foci for treatment of AF. During HIFU cardiac ablation, little is known regarding the detailed characteristics of cellular electrophysiological (EP) changes. The first part of the thesis aims to characterize EP changes during HIFU corresponding with temperature increases. Langendorff-perfused intact rabbit heart model stained with di-4-ANEPPS, a fluorescent dye sensitive to the voltage changes of cellular membrane was used. Simultaneous optical mapping and infrared imaging were employed to measure epicardial EP and temperature during HIFU application. The results revealed the temperature-dependent spatiotemporal characteristics of HIFU-induced EP changes including changes of action potential (AP) amplitude, duration, and electrical activation. Temperature dosage criterions for generating irreversible tissue physical and AP changes were obtained. Intra-procedural imaging is important for guiding cardiac ablation for AF. However, it is difficult to obtain intra-procedural correlation of thermal lesion with AP changes in tissue transmural plane. The second part of the thesis developed parametric ultrasound imaging techniques for transmural lesion and AP detection in HIFU ablation. Coronary perfused canine ventricular wedge model was used. Simultaneous optical mapping and high frequency (30 MHz) ultrasound imaging of the same tissue trasnsmural plane were performed during HIFU. Tissue transmural EP changes were characterized and the AP changes were spatiotemporally correlated between optical and ultrasound images. The results show parametric ultrasound imaging using cumulative extrema of statistical parameters (log-normal and Rayleigh) can detect HIFU lesions and surrounding AP amplitude changes. Overall, the information obtained from this thesis enhances our understanding of the EP mechanisms of HIFU ablation and can help promote the development of effective HIFU ablation strategies. Ultrasound parametric imaging provides a promising technique to identify lesion transmurality which is critically important in clinical cardiac ablation. Future works shall focus on developing safe HIFU ablation metrics and real-time implementation of ultrasound imaging techniques to reduce HIFU ablation related complications.

Friday, July 12, 2013

Final Oral Examination

Aqueous Two-Phase Systems for Next-Generation Biotechnological Assays

Joshua White
Chair: Professor Shuichi Takayama

Friday, July 12, 2013, 2:00 PM
1180 Duderstadt Center

Next-generation biotechnological assays, described here as those that increase throughput, improve upon physiological relevance, accomplish previously impossible biological and/or engineering tasks, or some combination thereof, will play increasingly crucial roles in the healthcare, biotechnology, and pharmaceutical industries in the next several decades. Unfortunately, although many of the recent technological innovations that have been achieved accomplish these goals, they are also commonly burdensome, technologically challenging, and perform highly niche tasks, thereby making them difficult and sometimes impossible to adopt into the healthcare, biotechnology, and pharmaceutical industries that would benefit most from them. This dissertation has four chapters, each of which describes the application of an aqueous two-phase system (ATPS) for next-generation biotechnological assays. The importance and relevance of these assays is discussed in the context of drug development in the pharmaceutical industry, where there has been decreasing return-on-investment despite the influx of billions of dollars in research and development. First, the use of an ATPS for localizing antibodies to perform arrayed and/or multiplexed immunocytochemistry was investigated. The second method discussed is a technique for patterning monocultures of cells that can be used for high-throughput screening analysis of cell migration, as well as patterning of co-cultures of cells to achieve more physiologically relevant cell behavior that can be used as a toxicological and/or functional screening assay. Next, an assay is described that utilizes ATPS to localize trypsin to achieve in vitro wounding that can be applied to more physiologically relevant substrates such as transwells and soft gels. Finally, an ATPS-based method is presented that localizes detection antibodies in enzyme-linked immunosorbent assays (ELISAs), thereby completely eliminating antibody cross-reactivity and enabling higher levels of sensitivity in a multiplexed format. Such next-generation technologies will provide a launching point for the development of user-friendly, easily adoptable, and scalable assays that can be utilized by both basic science researchers and for-profit biotechnology industries.

Monday, June 24, 2013

Final Oral Examination

Spectral Ultrasound Characterization of Tissues and Tissue Engineered Constructs

Madhu Sudhan Reddy Gudur
Chair: Dr. Cheri X. Deng

Monday, June 24, 2013, 10:30 AM
General Motors Conference Hall, 4th Floor Lurie Engineering Center (LEC)

Even though ultrasound imaging is widely used in clinical diagnosis and image-guided interventions, the field is far behind other areas of clinical image analysis, such as MRI, CT and X-ray mammography. In this thesis, non-destructive and non-invasive ultrasound characterization techniques were developed to study the tissue micro-structural details using high frequency spectral ultrasound imaging (SUSI). The techniques were explored in in-vitro conditions of acellular and cellular tissue engineered constructs and then on ex-vivo tissues for their characterization. SUSI was used to assess the amount of hydroxyl-apatite (HA) mineral, differentiate HA mineral types and study their distribution in acellular tissue engineered constructs. The process of mineral deposition from surrounding mineralizing media onto simple collagen constructs was also studied and characterized with SUSI. 3D morphological changes of the constructs with MC3t3 cells was monitored and characterized for the developmental changes such as net cell proliferation/apoptosis and cell differentiation process through mineral production by the early osteoblastic MC3t3-cell constructs in-situ. A novel method was introduced using SUSI to estimate the amount of mineral secreted by the differentiated osteoblast cells in a non-destructive method. Then, SUSI was investigated in ex-vivo cardiac tissues to monitor and characterize the cellular changes during high-intensity focused ultrasound ablation with high-frame-rate and high-resolution ultrasound imaging. The mechanistic hypotheses behind the improvement in lesion detection were investigated and best identification methods to assess lesion formation and transient gas body activities were proposed to provide a method for visualizing spatiotemporal evolution of lesion and gas–body activity and for predicting macroscopic cavity formation upon its implementation as a real-time monitoring technique with feedback control system for HIFU treatment of atrial fibrillation to improve the ablation process. Even though the results from the developed techniques show great promise in in-vitro and ex-vivo settings, additional work needs to be carried out to demonstrate the applicability of the techniques in in-vivo.

Friday, June 21, 2013

Final Oral Examination

Polycationic Polymers in Nucleic Acid Delivery: Cytosolic Nucleases, the Cellular Response

Rahul Rattan
Chair: Dr. Mark M. Banaszak Holl

Friday, June 21, 2013, 12:00 PM
Earl Lewis Room (3rd floor), Rackham

Genetic Engineering is the manipulation of a cell’s genome to heal or provide new functions to the cell. One important therapeutic application of Genetic Engineering is Gene Therapy, in which nucleic acid residues (NAR) are used as a pharmaceutical agent to treat diseases. Because cells are inherently resistant to foreign NAR, vector systems must be used in order to selectively and efficiently transfer functional forms of NAR into the cell. Currently, the most efficient vector systems are viruses. However, safety concerns over their use in humans make virus-based strategies non-viable in the long term. Polymer-based vector systems, however, circumvent the safety issue and tend to be more practical in terms of customization and mass production. Despite these safety and manufacturing advantages, polymer-based vector systems are inefficient when compared to virus-based vector systems. Efforts to improve the polymer-based vector systems have assumed that cells play a passive role and don’t actively respond to polymer vector systems. However, I will show this assumption is incorrect. In my talk, I will show that cells respond to polymer systems by activating cytosolic nucleases and how this nuclease activity can be measured with the help of Molecular Beacon (MB). We see that nuclease activation as measured by MB has direct impact on gene expression facilitated by the polymer system used. In doing this, I show that it is possible to screen multiple polymer-based vector systems, thereby increasing the probability of identifying and designing a safe and efficient polymer vector system. The second half of my talk will concentrate on degradation characteristics of cytosolic nucleases. High-throughput sequencing was used to identify and quantify degradation pattern of these cytosolic nucleases on a plasmid. We will also see that S1 nuclease (a known nuclease) has a similar degradation pattern as cytosolic nucleases, supporting the hypothesis that nucleases like S1 nuclease are part of this cytosolic nuclease milieu. Designing polymer vector systems that protect these labile sites on DNA can improve gene expression.

Wednesday, June 5, 2013

Final Oral Examination


Rameshwar Rao
Chair: Dr. Jan P. Stegemann

Wednesday, June 5, 2013, 3:00 PM
GM Conference Room - 4th Floor Robert H. Lurie Engineering Center

Large bone defects are a significant clinical problem in the United States and worldwide. “Non-unions” are fractures that fail to heal due to a lack of blood supply to the defect site. In our approach to bone regeneration, we create modular engineered tissues (“microbeads”) designed to form bone, and combine them with a surrounding vascularizing tissue to generate a dual-phase injectable matrix for enhanced bone formation. In the first Aim, human bone marrow mesenchymal stem cells (bmMSC) or human adipose stem cells (AdSC) were embedded in collagen/fibrin (COL/FIB) or collagen/fibrin/hydroxyapatite (COL/FIB/HA) microbeads. Both cell types mineralized microbeads, indicating differentiation towards the osteogenic lineage. The second Aim used a co-culture model of bmMSC and human umbilical vein endothelial cells in COL/FIB composite hydrogels to create a vasculogenic matrix. Cell ratio and matrix composition were varied in a systematic manner. Vascular network formation increased in vitro with increasing fibrin content in composite materials, although the 40/60 COL/FIB and pure fibrin materials exhibited similar responses. Hydroxyapatite (HA) was found to recover endothelial network formation in unconstrained hydrogels. Over 7 days of dorsal subcutaneous implantation in nude mice, these matrices exhibited increasing neovascularization, though there was no significant effect of HA. The final Aim combined osteogenic microbeads with a surrounding vasculogenic matrix to evaluate the effect of this dual-phase tissue in vivo. Both vasculogenesis and osteogenesis were examined in a subcutaneous bone formation model in the mouse at 4 and 8 weeks. Blood flow measured by Doppler imaging was not significantly different between any conditions at any time point, except at 8 weeks where the vasculogenic matrix alone was lower than all other groups. Micro-computed tomography of ectopic bone demonstrated significantly higher bone volume in the osteogenic microbead condition at 4 weeks and both the blank and osteogenic microbead conditions at 8 weeks, compared to the dual osteogenic/vasculogenic condition. These data suggest an inhibitory effect of the vasculogenic component on bone formation in the non-ischemic model. Dual-phase implants may be more effective in ischemic orthotopic bone regeneration models, and these results demonstrate that such constructs can be designed, fabricated, and delivered for therapeutic use.

Friday, May 31, 2013

University of Michigan

“Biomechanical regulation of blood vessel formation: Insights using microscale technology”

Jon Song
U-M alumnus and Harvard Research Fellow

Friday, May 31, 2013, 10:30 AM
1180 Duderstadt Center

Blood vessels support tissue growth in development, physiology, and disease. Our understanding of how new blood vessels form is incomplete due in large part to the lack of appropriate systems for studying vessel guidance cues under well-controlled yet physiologically relevant conditions. Microscale technology has emerged as a means of delivering mechanical and biochemical stimuli to cellular microenvironments at unprecedented levels of precision. Here I will present my work in leveraging this technology to investigate the role of fluid mechanical forces, such as intravascular shear stress and transvascular flow, in guiding new vessel formation. More specifically, I will discuss new insights on how endothelial cells in blood vessels sense fluid forces during sprouting, morphogenesis, and lumenized network formation in vitro. Furthermore, this presentation will highlight the versatility of microscale technology as it pertains to vascular physiology to enable further exploration of the key physical, cellular, and molecular determinants that coordinate vessel growth.

Wednesday, May 15, 2013

BME Guest Speaker

“The Magnitude and Phase of Pre-clinical Imaging: Basic Science, Therapeutic Development, and Translation”

Joan Greve, Ph.D.
Pre-clinical Imaging Expert

Wednesday, May 15, 2013, 10:00 – 11:00 a.m.
2203 LBME (Lurie Biomedical Engineering)

ABSTRACT: Biomedical engineers are used to working at the interface of multiple disciplines and acting as interpreters in order to enable rapid and impactful collaborative science across a broad spectrum of disciplines. For many, including myself, it is this very fact which makes our pursuit of science so enjoyable. Due to the characteristics embodied by imaging: fundamentals based in the physical sciences and engineering, the capability to be applied to a plethora of (patho)physiologies, and clinical application, imaging naturally attracts biomedical engineers. Pre-clinical imaging, undoubtedly, holds the potential to help more successfully translate research from bench to bedside but is still, largely, in its nascent phase.

The focus of this talk will be on pre-clinical magnetic resonance imaging (MRI), in particular, and how it can be used to further research in basic science, therapeutic development, and translation to the clinic. Examples discussed will primarily include cardiovascular, oncology, and neuroscience applications. Complimentary expertise that is requisite for the most successful imaging endeavors will also be highlighted (e.g. in silico methods, small animal models of the human condition, and rigorous pre- and post- statistical analysis). Emphasis will be placed on how highly-optimized pre-clinical imaging or, when necessary, the novel implementation of sequences predominantly reserved for the clinic results in unique conclusions that might only be gleaned by using such technology. Lastly, due to my extensive experience in industry (Genentech, Inc.) and leading MRI labs in academia and industry, I will briefly describe what might be under-utilized opportunities for partnering with companies.

About the speaker: Joan is trained in bioengineering from U. of Washington and Stanford University, at the latter of which she led the pre-clinical MRI lab for three years; she has over 10 years experience in therapeutic development at Genentech, Inc., including leading the MRI pre-clinical research group for five years and four years of project team experience successfully translating an antibody to treat Alzheimer’s disease from the bench into Phase I and II clinical trials; more recently, Joan partnered with a subject matter expert in neural coding at the Allen Institute for Brain Science to help formulate the scientific and operational strategy for a new 10-year initiative. She is driven by the enjoyment that comes from addressing important scientific questions that hold the potential for treating unmet medical needs and which are best answered using complex imaging systems and a team of highly-motivated cross-functional researchers.

Thursday, May 9, 2013

Final Oral Examination

Customizable Intraoperative Neural Stimulator and Recording System for Deep Brain Stimulation Research and Surgery

Sunjay Dodani
Chair: Dr. Parag Patil

Thursday, May 9, 2013, 9:30 AM
3755 Med Sci II

Intraoperative targeting systems provide neurosurgeons with raw electrophysiological data through microelectrodes used for determining location in the brain. Typical analysis of these signals is subjective and heavily dependent on experience and training. There are significant deficits to the available targeting systems, limiting the use in both clinical and research applications.

The work presented in this dissertation is of the development and validation of an intraoperative neural stimulator and recording system for use in deep brain stimulation (DBS) surgeries. The novel system described in this work enables neurosurgeons, electrophysiologists, and researchers to significantly improve clinical efficacy of DBS and the understanding of physiological effects of neurodegenerative diseases. This intraoperative data acquisition system (IODA) was validated in three applications to ensure efficacy and improvements in research and clinical studies.

The first application investigated was a clinical study illustrating the improvement IODA had on the targeting accuracy of DBS leads in the subthalamic nucleus (STN) over current targeting methods. It was demonstrated that the novel navigation algorithm developed for use with IODA targeted microelectrode probe locations significantly closer to final DBS lead positions compared to preoperatively planned trajectory positions.

The second study investigated a clinical science application. There are considerable differences in recently published studies for the optimal chronic stimulation site in the STN region. It was shown, using beta oscillations of local field potentials (LFP) recorded by IODA, that optimal stimulation sites were significantly correlated with locations of peak beta activity when DBS leads were medial to the STN midpoint. While DBS lead trajectories lateral of the STN midpoint were significantly correlated with the dorsal border of the STN.

The third study explored a basic science application involving the role of the STN in movement inhibition. Through wideband recordings made with IODA, it was shown that the STN is significantly activated during movement and movement inhibition cues as seen in the theta, alpha, and beta bands and single unit activity.

Overall the results indicate the utility and adaptability of this system for use within DBS surgeries. There is significant potential use of IODA outside of DBS in other surgical procedures requiring precise neural targeting. Additionally there are many applications of IODA for use in research for other neurodegenerative disease including Essential Tremor and Depression. The use of this system has enables neurosurgeons to reduce surgical time, risk, and error for DBS procedures and made entry for those less experienced in this procedure easier.

Saturday, May 4, 2013

University of Michigan

2013 Spring Commencement

Saturday, May 4, 2013, 10:00 a.m.
Michigan Stadium

Spring Commencement is a University-wide event, and the main commencement ceremony for the College of Literature, Science, and the Arts. The ceremony will last approximately one and a half hours. All graduates (bachelor's, master's and doctoral) of this term, from each of the schools/colleges are welcome to attend. All graduates are recognized, and the University's honorary degrees are conferred. Twitter CEO and U-M alumnus Richard (Dick) Costolo will deliver the Spring Commencement address. William K. Brehm, Suzanne Farrell, Rosabeth Moss Kanter, Dale E. Kildee, David McCullough, and Jeffrey D. Sachs have also been announced as honorary degree recipients.

Graduate Schedule for Saturday, May 4:

Friday, May 3, 2013

University of Michigan

University Graduate Exercises

Friday, May 3, 2013, 11:00 a.m.
Hill Auditorium

Graduates receiving master's or doctoral degrees through the Horace H. Rackham School of Graduate Studies are invited to attend University Graduate Exercises. This formal ceremony celebrates and individually recognizes the achievements of the Graduate School's master's and doctoral recipients.

Friday, May 3, 2013

Department of Biomedical Engineering

BME Commencement Reception

BME Faculty and Staff
Friday, May 3, 2013, 3:00 PM - 5:00 PM
Lurie Biomedical Engineering Building Atrium

The University of Michigan's Biomedical Engineering Departement proudly recognizes the graduating Classes of 2012/2013 with a reception in their honor.

Please join us for this special celebration and opportunity to socialize with your fellow graduates, families, and BME professors. All graduates from the August 2012, December 2012, May 2013 and August 2013 classes and their families are invited.

Monday, April 29, 2013

Final Oral Examination

Acoustic Aberration in Non-Invasive Histotripsy Therapy

Yohan Kim
Chair: Dr. Zhen Xu

Monday, April 29, 2013, 9:30 AM
1180 Duderstadt Center (Conference Room)

Acoustic aberration effects have been extensively studied over the years for high intensity focused ultrasound (HIFU) due to the significant therapeutic disruption they can cause in thermal ablation procedures, often rendering treatments ineffective without the implementation of specific aberration correction mechanisms.

Histotripsy therapy is a relatively novel ablation technique that uses highly energetic cavitation bubble clouds to mechanically fractionate tissue. The cavitation cloud initiation is dependent on a pressure threshold mechanism, which allows the process to be controlled primarily by the instantaneous pressure amplitude available at the therapy focus, rather the total average power intensity applied. Treatments are typically performed at low sonication duty cycles (< 1%) and can be easily monitored in real-time using conventional ultrasound imagers. These unique characteristics represent a major paradigm shift from traditional thermal ablation methods, introducing features that are particularly well-suited for non-invasive surgical procedures.

This dissertation explores the therapeutic effects of acoustic aberration specifically in the context of histotripsy therapy and investigates the feasibility of performing non-invasive histotripsy ablation without using correction mechanisms in three distinct therapeutic scenarios likely to introduce high degrees of acoustic aberration.

The first context investigated is transcostal therapy. It is demonstrated that histotripsy therapy is able to generate precise lesions in vitro through rib obstacles without aberration correction despite the presence of large secondary lobes in the focal profile. In vivo experiments are presented in which comparable porcine liver lesions were created through windows with and without full ribcage obstruction, inducing minimal thermal effects on overlying tissues.

The second context is transabdominal therapy. It is shown that histotripsy therapy can achieve precise fetal tissue ablation in sheep models in vivo through the intact maternal abdomen without aberration correction. A long-term study on the impact of the therapy in the course of pregnancy demonstrates the potential safety of this technique for non-invasive fetal intervention procedures.

The third context involves transcranial therapy. A novel sonication mechanism using extremely short ultrasound pulses with large negative pressures is introduced. The design of a large aperture transcranial transducer array is described, and it is shown that precise, sub-wavelength histotripsy lesions can be created transcranially as long as sufficient rarefactional pressures are generated at the treatment focus.

Overall results indicate that the pressure threshold mechanism governing the initiation of histotripsy bubble clouds lends the therapy a considerable degree of immunity against acoustic aberration effects. In combination with the low thermal impact of the therapy and the ready availability of treatment monitoring options, this feature could bring significant advantages for a variety of non-invasive tissue ablation applications.

Monday, April 29, 2013

BME Guest Speaker

“Systems Tissue Engineering”

Lonnie Shea, Ph.D.
Professor of Chemical and Biological Engineering
Northwestern University

Monday, April 29, 2013, 9:00 AM - 10:30 AM
1017 Dow

Abstract: A central component for many tissue engineering approaches is a biomaterial scaffold, which provides a tool to modulate the local environment with the objective of promoting development or regeneration into a function tissue. Tissues are complex, and systems to promote tissue formation must present multiple signals that can target a range of cellular processes. These environmental signals are derived from parameters such as adhesive proteins, mechanical properties, growth factors, hormones, and cytokines. We have developed biomaterial scaffolds as a platform to target multiple barriers to regeneration. This potential of targeting multiple barriers is exemplified in our work with islet transplantation for diabetes therapy, in which we must promote the engraftment of transplanted cells while also limiting attack by the immune system. These platform technologies capable of targeting multiple processes represent a systems approach to engineering functional tissue replacements. Furthermore, the ability to present multiple factors raises the challenge of identifying the combination that will maximally promote tissue formation. Toward this goal, we have developed an array for the large scale profiling of transcription factor activity throughout tissue formation, which we propose can identify the factors necessary to drive cells towards the desired phenotype. This array represents a novel systems biology tool for molecularly dissecting tissue formation.

Biosketch: Lonnie D. Shea is a professor in the Department of Chemical and Biological Engineering at Northwestern University. He received his BS and MS degrees at Case Western Reserve University in Chemical Engineering. He received his PhD in Chemical Engineering and Scientific Computing while working with Jennifer Linderman at the University of Michigan and was a postdoctoral fellow with David Mooney in the Department of Biologic and Materials Science in the Dental School at the University of Michigan.

He joined the faculty at Northwestern in 1999 and established a research group working at the interface of tissue engineering, gene therapy, and drug delivery. He received an NSF CAREER Award in 2000, which helped start the work on developing new technologies based on combining biomaterials and gene/drug delivery. The overall objective is to create controllable microenvironments for directing or molecularly dissecting tissue growth. These systems are being applied to clinical problems such as ovarian follicle maturation for treating infertility, islet transplantation for diabetes therapies, nerve regeneration for treating paralysis, and most recently, cancer diagnostics. His lab consists of approximately 20 graduate students/postdoctoral fellows who work closely with basic science and clinical collaborators throughout the medical school. Dr. Shea has received funding from NIH, NSF, and multiple foundations, and has published in excess of 130 manuscripts on his research. In addition to his teaching and research commitments, he is director of the NIH Biotechnology Training Grant at Northwestern University. Dr. Shea is a fellow of the American Institute of Medical and Biological Engineering, and is a member of the editorial boards for Molecular Therapy, Biotechnology and Bioengineering, and Drug Delivery and Translational Research.

Wednesday, April 24, 2013

BME Guest Speaker

“Regulation of Tumor Dormancy by the Perivascular Niche”

Cyrus M. Ghajar, PhD
Lawrence Berkeley National Laboratory
Life Sciences Division

Wednesday, April 24, 2013, 10:00 – 11:00 a.m.
2203 LBME (Lurie Biomedical Engineering)

ABSTRACT: In a significant fraction of breast cancer patients, distant metastases emerge after years or even decades of latency. How disseminated tumor cells (DTCs) are kept dormant in the interim, and what ‘wakes them up’, are fundamental questions of tumor biology. To address these questions, we adopted a multi-disciplinary approach incorporating murine models of human breast cancer dissemination and engineered tumor microenvironments. Metastasis assays in mice revealed that dormant DTCs reside upon the microvasculature of lung, bone marrow (BoMa), and brain. To determine whether this association reflected functional interactions, we engineered organotypic models of lung and BoMa microvascular niches in which breast cancer cells (BCCs) could be tracked long-term. Whereas lung and BoMa stroma each promoted rampant outgrowth of sparsely seeded BCCs, lung and BoMa microvascular niches restrained BCC outgrowth and induced sustained quiescence of up to 90% of resultant tumor cell clusters. To identify endothelial-derived (angiocrine) factors mediating this effect, we performed comparative tandem mass spectrometry on extracellular matrix from decellularized stroma and decellularized microvascular niches. This approach revealed a number of potential angiocrine regulators of DTC dormancy, and a combination of gain- and loss-of-function studies identified one such mediator. Our experiments suggested also that suppressive angiocrine cues are downregulated in endothelial tip cells, and time-lapse analysis showed that sprouting neovasculature does not just permit, but accelerates BCC growth. We confirmed this surprising result in culture and in zebrafish, and utilized comparative mass spectrometry in combination with gain-of-function studies to identify endothelial tip cell-derived factors that promote tumor growth. In sum, this work provides the first cellular and molecular definition of the ‘dormant niche,’ and identifies also a mechanism by which this suppressive microenvironment is overcome. My long-term objectives are to develop a more complete understanding of the biochemical and physical factors comprising the dormant niche, and to use this information to formulate therapeutic regimens that either eradicate dormant DTCs, or render them dormant indefinitely.

Wednesday, April 17, 2013

BME 500 Seminar Series

“The Make and Break of Electrical Waves in the Turbulent Heart”

Omer Berenfeld, PhD
Associate Professor of Internal Medicine and Biomedical Engineering
Center for Arrhythmia Research
University of Michigan

Wednesday, April 17, 2013, 12:00 - 1:00 PM
1303 EECS

ABSTRACT: Cardiac electrical turbulence known as ventricular fibrillation (VF) is the major cause of sudden and unexpected death. We take an integrative approach to study the manner in which nonlinear electrical waves that were originally thought of being random organize to result in VF. The presentation centers on data derived from animal and computational models of stable VF that demonstrate distinct patterns of excitation organization driving the fibrillation. Analysis of optical mapping data reveals that VF excitation frequencies are distributed throughout the ventricles in clearly demarcated domains with the highest frequency domains found where a sustained reentrant activity that drives the arrhythmia is present. Using numerical and cellular electrophysiology approaches we further study how certain transmembrane potassium currents determine the rotor stability and frequency as well as their intermittent blockades.

Wednesday, April 10, 2013

Final Oral Examination

Bead Assembly Magnetorotation as a Signal Transduction Mechanism for Measuring Protein Concentration

Ariel Hecht
Chair: Dr. Raoul Kopelman

Wednesday, April 10, 2013, 3:00 PM - 5:00 PM
East Conference Room, Rackham (4th floor)

The concentration of protein biomarkers in the bloodstream can be an effective indicator of disease processes taking place inside the body. Rapid, simple, portable and inexpensive diagnostic devices have the potential to improve healthcare by increasing access to protein-based diagnostic technologies, shifting them from centralized laboratories to decentralized point-of-care locations. There are three primary components within a protein diagnostic system: the target protein, the affinity molecules that bind to the protein, and a mechanism for transducing a binding event into a measurable and quantifiable signal. This dissertation describes the development of Bead Assembly Magnetorotation (BAM) as a magnetic bead-based signal transduction mechanism for protein diagnostic applications.

BAM uses the concentration of the target protein to mediate the formation of a magnetic bead assembly. The protein concentration is measured through the rotational period of the assembly in a magnetic field. BAM is performed by taking 1 μm magnetic beads, functionalizing them with affinity molecules against the target protein, mixing them with a solution containing the target protein, and then plating small 1 μL inverted droplets of the solution on a Teflon-coated slide. As the beads fall through the solution to the bottom of the droplet, the protein will mediate the formation of the beads into an assembly. In the case of high protein concentration, the protein will serve as a linker to bind the beads together, forming a loosely-packed assembly. In the case of low protein concentration, there will be nothing to bind the beads together, and they will fall to the bottom of the droplet and form a tightly-packed assembly. In a rotating magnetic field, the rotational period will depend on the packing density of the assembly.

This thesis discusses the development of BAM through several iterations and into its final form, where it yields one of the lowest limits of detection ever reported for the protein thrombin. Additionally, it discusses the development of fractal analysis as an alternative signal transduction method, the development of a portable laser-and-photodiode diagnostic platform prototype, attempts to translate BAM into serum, and a separate project showing aptamers as affinity molecules in a gel electrophoresis platform.

Wednesday, April 10, 2013

BME 500 Seminar Series

“Seeing Drugs in Action Imaging Therapeutics in vivo at Subcellular Resolution”

Greg M. Thurber, PhD
Assistant Professor, Chemical Engineering
Assistant Professor, Biomedical Engineering
University of Michigan

Wednesday, April 10, 2013, 12:00 - 1:00 PM
1303 EECS

ABSTRACT: Drug development is a multi-billion dollar industry spanning disciplines from chemistry, biology, engineering, and medicine. Despite the large investment in these therapeutics, the clinical efficacy of new drugs is highly unpredictable, and development relies heavily on animal models and clinical trials. We are developing in vivo imaging techniques that allow us to visualize drugs at the whole animal, organ, tissue, and subcellular level to study and better predict how these drugs reach their targets and affect cells at the site of action. A series of novel fluorescent drug conjugates that inhibit their target but can be tracked at subcellular spatial resolution and seconds temporal resolution are used to study the salient properties of delivery. By pairing these drugs with readouts of efficacy, we are opening the black box of typical animal experiments to see exactly how these therapeutics work, or fail, in vivo.

Wednesday, April 3, 2013

BME 500 Seminar Series

“Analytical micro-technologies for single-cell analysis of immune-cell responses: Applications for the study of T cells and the immunological synapse”

Alexis J. Torres, PhD
Postdoctoral Research Associate
Massachusetts Institute of Technology

Wednesday, April 3, 2013, 12:00 - 1:00 PM
1303 EECS

ABSTRACT: Autoimmune disorders arise as a consequence of self-antigen recognition in tissue and organs by the immune system. The molecular and physiological basis of such processes mediated by T cell autoreactivity is still not well understood, particularly due to the lack of analytical tools and technologies available to interrogate the state of immune system dysregulation. We have developed a novel set of single-cell assays based on microengraving for on-chip activation of T cells, which allow us to characterize low-abundance cells for surface expression levels of regulatory molecules as well as cytokine secretion patterns. In particular, we have used subnanoliter wells (nanowells) modified with immobilized lipid bilayers and tethered ligands as artificial antigen-presenting cell (APC) mimics that induce the formation of the immunological synapse. This novel technique has allowed detailed investigations on how biophysical and structural aspects of the immunological synapse influence the activation of individual T cells and their subsequent functional responses in autoreactive T cells. Using this approach we have investigated the functional consequences of impaired synapse formation that seems to characterize autoractive T cells cloned from patients with Multiple Sclerosis.

Wednesday, March 27, 2013

Final Oral Examination

Biomimetic Electrospun Fibers for Peripheral Nerve Regeneration

Michelle Leach
Chair: Dr. Joseph Corey

Wednesday, March 27, 2013, 1:00 PM
GRECC Conference Room, Rm. F206, Bldg. 28, Veterans Affairs Hospital

Endogenous neural regeneration is a slow and error-prone process. As a result, injury to the peripheral nervous system is a significant cause of morbidity and permanent disability. Even under optimal repair conditions, severely injured nerves rarely reach complete functional recovery. One promising approach to improving these outcomes is the use of artificial nerve conduits. The primary goal of this dissertation was to develop an artificial nerve conduit that outperformed the current gold standard – the autograft. The design approach was to mimic the internal microenvironment of native nerve physically and chemically. In order to evaluate candidate materials for the artificial nerve conduit, it was necessary to develop a system with which to investigate peripheral nerve regeneration in vitro. Electrospun fibers were chosen as the platform on which to develop the conduit and experimental system. The system was verified and used to select candidate materials for further study in vivo. The results to date of this in vivo work are presented, along with recommendations for further research.

Wednesday, March 27, 2013

BME 500 Seminar Series

“Computational Analysis in Biomedical Applications”

Khalil Khanafer, Ph.D.
Frankel Vascular Mechanics Lab
Biomedical Engineering & Vascular Surgery
University of Michigan

Wednesday, March 27, 2013, 12:00 - 1:00 PM
1303 EECS

ABSTRACT: Computational hemodynamics has become a powerful and attractive tool in investigating various vascular diseases such as cerebral aneurysm, aortic aneurysm and dissection, and peripheral artery disease. Measuring the hemodynamic factors such as wall shear stress and pressure is still beyond the capabilities of in vivo measurements or experiments. With high resolution 3D medical imaging, it is now possible to simulate pulsatile blood flow in physiologically realistic geometries derived from in vivo imaging in relation to their pathogenesis and treatment.

Advanced modeling techniques have enabled multiphysics computations to investigate hemodynamic and other factors contributing to vascular disease progression. Since blood flow interacts with the vascular wall motion, Fluid-Structure Interaction (FSI) approach is utilized in computational analysis and its importance is a growing interest in mechanical, aerospace, and biomedical engineering applications.

In this talk, we present an overview of a number of vascular diseases studied using FSI such as artificial lung, aortic dissection and aneurysms.

Bio: Dr. Khalil Khanafer holds a Ph.D. in Mechanical Engineering from Ohio State University and is currently an Associate Research Scientist in the Department of Biomedical Engineering at University of Michigan, Ann Arbor. Dr. Khanafer has over 15 years of experience in modeling a wide variety of problems in fluid dynamics, thermal management, and vascular diseases. He has authored more than 60 peer-reviewed journal articles and nine invited book chapters. He is an associate editor of Special Topics and Reviews in Porous Media Journal and is a member on the editorial board of Annals of Vascular Surgery.

Monday, March 25, 2013

Final Oral Examination

"Computation Framework for Lesion Detection and Response Assessment Based Upon Physiological Imaging for Supporting Radiation Therapy of Brain Metastases"

Reza Farjam
Co-Chairs: Dr. Yue Cao and Dr. Douglas C. Noll

Monday, March 25, 2013, 10:30 AM - 12:30 PM
GM Conference Room - 4th Floor Robert H. Lurie Engineering Center

Brain metastases are the most prevalent form of cancer in the central nervous system and up to 45% of cancer patients eventually develop brain metastases during their illness. Selection of whole brain radiotherapy (WBRT) versus stereotactic radiosurgery, two routine treatments for brain metastases, highly depends on the number and size of metastatic lesions in a patient. Our clinical investigations reveal that up to 40% of brain metastases with a diameter <5mm could be missed in a routine clinical diagnosis using contrast-enhanced MRI. Hence, this dissertation describes initially the development of a template-matching based computer-aided detection (CAD) system for automatic detection of small lesions in post-Gd T1-weighted MRI to assist radiological diagnosis. Our results showed a significant improvement in detecting small lesions using the proposed methodology.

When a cancer patient is given a treatment, it is very important to early assess the tumor response to therapy. This is traditionally performed by measuring a change in the gross tumor volume. However, changes in tumor physiology, which happen earlier than the volumetric changes, have the potential to provide a better means in prediction of tumor response to therapy and also could be used for therapy guidance. But, there are several challenges in assessment of tumor response to therapy, especially due to the heterogeneous distribution pattern of the physiological parameters in a tumor, image mis-registration issues caused by tumor shrinkage/increase across the time of followups, lack of methodologies combining information from different physiological viewpoints, and etc. Hence, this dissertation mainly focused on development of techniques overcoming the current challenges in early assessment of tumor response to therapy using information from two important aspects of tumor physiology: tumor vascular and cellularity properties derived from dynamic contrast-enhance and diffusion-weighted MRI. Our proposed techniques were evaluated with lesions treated by either WBRT alone or combined with Bortezomib as a radiation sensitizer. We found that changes in both tumor vascular and cellularity properties play an important but different role for determining tumor response to therapy, depending on the tumor types and underlying treatment. Also, we found that combing the two parameters provides a better tool for response assessment.

Wednesday, March 20, 2013

BME 500 Seminar Series

“The role of PTH and Mechanical Loading in Periprosthetic Bone Formation and Implant Osseointegration.”

Hayden Courtland, Ph.D.
Assistant Scientist
Hospital for Special Surgery

Wednesday, March 20, 2013, 12:00 - 1:00 PM
1303 EECS

ABSTRACT: Osteoarthritis (degenerative joint disease), rheumatoid arthritis, and other musculoskeletal diseases including post-traumatic joint degeneration affect over 40 million people aged 45 years and older in the United States. This number is expected to increase dramatically over the next 20 years. While orthopaedic implant fixation methods have advanced over the last several decades, failure rates of cemented total joint arthroplasties (replacements or repairs) remain similar to those of cementless total joint arthroplasties. Therefore, enhancing bone integration of cementless implants has great clinical significance. Therapies to stimulate bone formation or prevent bone resorption, such as intermittent administration of parathyroid hormone (PTH), may benefit osseointegration (bone ingrowth) by improving implant fixation and long-term surgical outcomes. In addition, since patients resume normal activities of daily living post-operatively, mechanical loading, a proven anabolic treatment, must be considered in conjunction with pharmacologic interventions. However, before these treatments can be implemented clinically, the influence that mechanical loading and PTH have on osseointegration must be investigated both at the tissue and cellular levels. The work in our lab is aimed at better understanding the role that systemically delivered anabolic agents and mechanical loads play in the osseointegration of metallic implants. To accomplish this we have employed an in vivo mechanically loaded rabbit model. Our hypothesis is that mechanical loading combined with an anabolic agent (PTH) will additively or synergistically enhance peri-implant cancellous bone volume and osseointegration of a porous metallic implant through molecular mechanisms that regulate the differentiation and activity of osteoblasts, osteoclasts, and adipocytes.

Wednesday, March 13, 2013

BME 500 Seminar Series

Modular Scaffold Engineering for Tissue Reconstruction: from Concept to Clinic

Scott Hollister, Ph.D.
Professor, Biomedical Engineering
University of Michigan

Wednesday, March 13, 2013, 12:00 - 1:00 PM
1303 EECS

ABSTRACT: Despite over 25 years of research, tissue engineering has made minimal clinical inroads. This is in part due to the inherent paradox of tissue engineering therapies. Relying on integrated materials and biologics for tissue reconstruction, there is an ingrained desire to replicate developmental biology as a paradigm for tissue engineering therapies. However, this push to replicate developmental biology creates greater multi-modality (i.e. more growth factor and cell types) and multi-scale complexity that collides head-on with a regulatory and commercial environment which favors simpler therapeutics. To address these issues, our research effort has focused on engineering modular systems as a platform for therapies with a sliding scale of complexity. This modularity is incorporated in both the therapeutic systems themselves and the engineering design and fabrication processes which create these systems. However, the creation of these multi-modal systems is only half the battle. We must further test these systems to determine the best combination of parameters (scaffold pore design, scaffold material, scaffold functionalization, and biologics) that bests regenerates tissue for a given application. This testing requires that we produce systems with rigorously controlled parameters and evaluate these systems in appropriate pre-clinical models. In this talk, I will first describe the technical, regulatory, and commercial environment that constrains the engineering of regenerative medicine systems. I will then describe the design, fabrication and functionalization processes we have put together to create modular tissue engineering systems. Finally, I will present results from testing these systems in pre-clinical models to determine how modular scaffold parameters affect tissue regeneration, with an example of how we have utilized this approach for clinical applications, now and in the future.

Wednesday, February 27, 2013

BME 500 Seminar Series

“History and Future of Prosthetics: Moving toward Intelligent Technology”

Deanna Gates, Ph.D.
Assistant Professor of Kinesiology
School of Kinesiology and Biomedical Engineering
University of Michigan

Wednesday, February 27, 2013, 12:00 - 1:00 PM
1303 EECS

ABSTRACT: Prosthetic technology has advanced rapidly in the last 50 years to include increased function, range of motion and control. The first part of this talk will focus on the advances in ankle prostheses including the incorporation of external power, muscle control, and new materials to enhance durability and energy storage and return. We will focus on the models used to develop these devices and patient performance with this technology in real-world environments. The second part of this talk will explore advances in upper extremity prosthetic technology, focusing on control systems used (muscle, brain, position), degrees of freedom, and patient outcome measures. We will focus on the major limitations of these devices from patient surveys and a study of upper extremity function during activities of daily living.

Tuesday, February 26, 2013

Final Oral Examination

Auditory-Somatosensory Integration in Dorsal Cochlear Nucleus Mediates Normal and Phantom Sound Perception

Seth D. Koehler
Chair: Dr. Susan Shore

Tuesday, February 26, 2013, 9:00 AM
Forum Auditorium, Palmer Commons Building (4th Floor)

The dorsal cochlear nucleus (DCN) is the first auditory brainstem nucleus that processes and relays sensory information from multiple sensory modalities to higher auditory brain structures. Converging somatosensory and auditory inputs are integrated by bimodal DCN fusiform neurons, which use somatosensory context for improved auditory coding. Furthermore, phantom sound perception, or tinnitus, can be modulated or induced by somatosensory stimuli including facial pressure and has been linked to somatosensory-auditory processing in DCN. I present three in vivo neurophysiology studies in guinea pigs investigating the role of multisensory mechanisms in normal and tinnitus models.

1) DCN fusiform cells respond to sound with characteristic spike-timing patterns that are controlled by rapidly inactivating potassium conductances. I demonstrated here that somatosensory stimulation alters sound-evoked firing rates and temporal representations of sound for tens of milliseconds through synaptic modulation of intrinsic excitability or synaptic inhibition.

2) Bimodal plasticity consists of alterations of sound-evoked responses for up to two hours after paired somatosensory-auditory stimulation. By varying the interval and order between sound and somatosensory stimuli, I demonstrated stimulus-timing dependent bimodal plasticity that implicates spike-timing dependent synaptic plasticity (STDP) as the underlying mechanism. The timing rules and time course of stimulus-timing dependent plasticity closely mimic those of STDP at synapses conveying somatosensory information to the DCN. These results suggest the DCN performs STDP-dependent adaptive processing such as suppression of body-generated sounds.

3) Finally, I assessed stimulus-timing dependence of bimodal plasticity in a tinnitus model. Guinea pigs were exposed to a narrowband noise that produced temporary shifts in auditory brainstem response thresholds and is known to produce tinnitus. Sixty percent of guinea pigs developed tinnitus according to behavioral testing by gap-induced prepulse inhibition of the acoustic startle response. Bimodal plasticity timing rules in animals with verified tinnitus were broader and more likely to be anti-Hebbian than those in sham animals or noise-exposed animals that did not develop tinnitus. Furthermore, exposed animals with tinnitus had weaker suppressive responses than either sham animals or exposed animals without tinnitus. These results suggest tinnitus development is linked to STDP, presenting a potential target for pharmacological or neuromodulatory tinnitus therapies.

Thursday, February 21, 2013

BME Guest Speaker

"Sensory neural interfaces for bladder control"

Tim Bruns, Ph.D.
Rehab Neural Engineering Lab
Department of Physical Medicine & Rehabilitation
University of Pittsburgh

Thursday, February 21, 2013, 10:00 – 11:00 a.m.
2203 LBME (Lurie Biomedical Engineering)

ABSTRACT: Recovery of bladder control is a top priority for individuals with neurological disorders such as spinal cord injury. Typical bladder dysfunctions include an overactive bladder, undesirable leakage and urinary retention, each of which negatively impact quality of life. A failure to adequately manage bladder care can lead to infections and renal failure. The ultimate goal of this research is a medical device that provides closed-loop control of the bladder by stimulating and recording from nerves. Electrical stimulation of pudendal nerve sensory pathways for reflex control of retaining and expelling urine from the bladder has shown promise, but has not been adopted clinically. Current limitations of this approach for emptying the bladder include insufficient bladder recruitment, concurrent stimulation of nerves that close the bladder outlet path and difficulty monitoring bladder status. A novel neural interface location is with dorsal root ganglia (DRG), where sensory nerve cell bodies are located next to the spinal cord. Selective stimulation with microelectrodes inserted in sacral DRG can evoke reflex bladder activity without closing the ladder outlet path. The use of physiologically-based stimulation patterns improves bladder contractions and may yield clinically relevant bladder emptying. Also, neural recordings from the sacral DRG microelectrodes can be used to estimate the bladder pressure. These results demonstrate the potential efficacy of a DRG-based closed-loop bladder neuroprosthesis. This envisioned device will give inhibitory stimuli when high bladder pressure is detected and will switch to excitatory stimuli to empty the bladder when instructed by a user. Moreover, this approach using multichannel neural recording and stimulation provides new opportunities for gaining insight into the neurophysiology of the lower urinary tract.

Wednesday, February 20, 2013

BME 500 Seminar Series

“When light meets sound: biomedical photoacoustic imaging”

Xueding Wang, Ph.D.
Associate Professor
Radiology & Biomedical Engineering
University of Michigan

Wednesday, February 20, 2013, 12:00 - 1:00 PM
1303 EECS

ABSTRACT: Photoacoustic imaging (PAI), also referred to as optoacoustic imaging, is an emerging biomedical imaging technology that is noninvasive, nonionizing, with high sensitivity, satisfactory imaging depth and good temporal and spatial resolution. In PAI, a short-pulsed laser source is used to illuminate a biological sample and generate photoacoustic waves due to thermoelastic expansion. Then the photoacoustic signals are measured by ultrasonic transducers to rebuild the image of the sample. Therefore, like conventional optical imaging, PAI presents the optical contrast which is highly sensitive to molecular conformation and biochemical contents of tissues and can aid in describing tissue metabolic and hemodynamic changes. Unlike conventional optical imaging, the spatial resolution of PAI is not limited by the strong light diffusion but instead determined mainly by the measurement of light-generated photoacoustic signals. As a result, the resolution of PAI is parallel to high-frequency ultrasonography. In this talk, I will present the recent advances in biomedical photoacoustic imaging in our laboratory at University of Michigan, including the development of imaging techniques and their applications in preclinical and clinical settings.

Monday, February 18, 2013

Final Oral Examination

Near Infrared Microsensor for Continuous In-vivo Intraocular and Intracranial Pressure Monitoring

Mostafa Ghannad-Rezaie
Chair: Dr. Nikos Chronis

Monday, February 18, 2013, 3:00 PM
1180 Duderstadt Center

Pressure as a major form of environmental cue, play central role in pathological and accidental neural damages and has been recognized as an important diagnostic tool for neurological disorders such as traumatic brain injury and glaucoma. Continuous, long-term in-vivo pressure monitoring, therefore is a necessity for planning interventional treatment for patients in the risk of elevated pressure in the central nervous system. We present a new family of implantable, wireless and power-free optical microsensors that can potentially be used to accurately monitor in-vivo pressure over long periods of time. These microsensors vertically integrate a glass mini-lens with a two-wavelength quantum dot micropillar that is photolithographically patterned on a pressure-exposed silicon nitride membrane. The operation principle is based on a novel opto-mechanical transduction scheme that converts in-vivo pressure changes into changes in the intensity ratio of the two-wavelength, near infrared fluorescent light emitted from the quantum dots. These microsensors are microfabricated using silicon bulk micromachining and they operate at an in-vivo pressure clinically relevant pressure dynamic range (0-100mmHg). They have a maximum error of less than 15 % throughout their dynamic range and they are extremely photostable. We adapt the sensor to measure intracranial pressure (ICP) and intraocular pressure (IOP). We believe that the proposed microsensors will open up a new direction not only in ICP and IOP monitoring but in other pressure-related biomedical applications.

Wednesday, February 13, 2013

BME 500 Seminar Series

“Biomechanical Models of the Human Body: Applications in Radiation Oncology”

Kristy Brock-Leatherman, Ph.D.
Associate Professor of Radiation Oncology,
University of Michigan, Medical School

Wednesday, February 13, 2013, 12:00 - 1:00 PM
1303 EECS

Abstract: Imaging is rapidly becoming a central factor in the detection, characterization, and treatment of cancer. The rich information content of advanced imaging methods, combined with the growing capacity to collect multiple images from various sources and time points during therapy opens an exciting prospect for image-based guidance and assessment of interventions. However, a major obstacle to full exploitation of this paradigm is the natural deformations in anatomy between imaging events of between imaging and intervention events. The development of biomechanically based models of human anatomy can regularize these variations and allow maximum information extraction from these data sources. During this seminar, I will describe the development of finite element models of human anatomy and their applications in the detection and treatment of cancer.

Monday, February 11, 2013

BME Guest Speaker

“Engineering Biomaterials and Tissues to Control Synthetic Gene Networks”

Tara Deans, Ph.D.
John Hopkins University

Monday, February 11, 2013, 10:00 – 11:00 a.m.
2203 LBME (Lurie Biomedical Engineering)

ABSTRACT: The rapidly emerging field of synthetic biology originated in simple model organisms such as yeast and bacteria. However, as synthetic biology has expanded into mammalian systems, it is increasingly more important to consider the complex environments in which these cells are grown. Biomaterials will play an important role in advancing synthetic biology to mammalian systems because they provide a three-dimensional (3D) environment where cells can behave as they do in vivo, in addition to organizing and delivering therapeutic cells to locations of interest in vivo. In this talk I will present a multidisciplinary approach interfacing synthetic biology and biomaterials to activate and control genetic circuits in 3D scaffolds. Using this approach, it is possible to locally and systemically induce synthetic circuits for the spatial and temporal control of gene expression by engineering new materials for the passive and controlled release of genetic inducers. Furthermore, I will demonstrate how interfacing synthetic biology and biomaterials can be used to engineer synthetic tissues, which are tissues programmed with alternative functions. Together, this approach offers a unique platform for mimicking cellular microenvironments, in addition to providing mechanisms for translating synthetic biology for clinical applications.

Friday, February 8, 2013

Final Oral Examination

Development and Modeling of a Perfusion Construct for Perfusion Imaging and Tissue Engineering

Auresa Thomas
Co-Chairs: Dr. James M. Balter and Dr. Scott J. Hollister

Friday, February 8, 2013, 2:00 PM
GM Conference Room - 4th Floor Robert H. Lurie Engineering Center

This thesis develops and computationally models an in vitro perfusion construct that captures the differential flow characteristics of healthy and diseased tissue imaged by Computed Tomography (CT), and the flow-induced shear stress range optimal for the promotion of angiogenesis. The perfusion construct consisted of a branched vascular tree adjoined to modular scaffolds with controllable perfusion. Aim 1 investigated the design and spatial resolution realizable to generate bifurcating vascular trees using rapid prototyping. The design was evaluated with computational fluid dynamics (CFD) to validate and predict the differential flow metrics measured in Aim 2, and to estimate the flow rates of spherical and orthogonal pore scaffold architectures adopted in Aim 3. Aim 2 investigated the application of the perfusion construct as a dynamic contrast enhanced (DCE) - CT imaging phantom for quality assurance of differential flow-based quantitative imaging metrics. Three scaffold methods were explored to determine the best method and design characteristics to fabricate “tissue compartments” with different levels of perfusion. Aim 3 examined the enhancement of endothelial cell-scaffold biocompatibility and the effect of shear stress within a vascular-like angiogenesis perfusion bioreactor. The cell viability and cell spatial distribution of human umbilical vein endothelial cells cultured under static conditions on surface-modified (peptide conjugation, growth factor conjugation and hydrolysis) polycaprolactone (PCL) matrices was assessed.

The results demonstrated that a bifurcating vascular tree with an inner diameter ranging from 2.2 mm to 620 microns could be reliably fabricated using selective laser sintering (SLS). SLS scaffolds provided a differential flow range between -22% to -90%, representative of hypo- to normal perfusion. The construct served as a viable imaging phantom capable of simulating perfusion typically imaged with DCE-CT.

Simulations of the perfusion construct as a bioreactor showed that the spherical architecture imposed an average physiologically-relevant shear stress between 1 - 10 dynes/cm2 (8.6 ± 1.5 dynes/cm2) over a larger surface area than the orthogonal scaffold. All biological and chemical surface modifications to PCL exhibited similar cell viability and cell function. However, the Arg-Gly-Asp (RGD)-surface modified scaffolds exhibited optimal distribution for cells for future bioreactor investigations.

This work demonstrates a method for modeling and physically simulating microcirculation for application to quantitative cancer biomarker imaging and tissue engineering. It also provides the basis for engineering in vitro tumors.

Wednesday, February 6, 2013

BME 500 Seminar Series

“A New Perspective of Bone Morphogenetic Protein-2 on Suppressing Tumorigenesis of Bone Cancer Stem Cells”

Chia-Ying Lin, PhD
Assistant Professor of Neurosurgery,
Biomedical Engineering, and Orthorpaedic Surgery
Director, Spine Research Laboratory

Wednesday, February 6, 2013, 12:00 - 1:00 PM
1303 EECS

Abstract: Recombinant human bone morphogenetic proteins (BMP) have been recently approved to augment spinal fusion and recalcitrant long-bone non-unions for their equivalent or superior efficacy to autogenous bone graft in enhancing bony fusion. Nonetheless, the use of BMP-2 is contraindicated in surgery for bone tumors due to concerns that this anabolic growth factor may cause tumor proliferation. Recent evidence suggests that there is a small fraction of tumor-initiating cells present in a variety of cancers, including bone tumors. These cells express properties resembling stem cells (so-called cancer stem cells) that might be responsible for tumor growth, recurrence, and resistance to treatment. Our current investigations suggest that exposure of heterogeneous populations of cancer cells containing stem-like cells to BMPs can induce osteogenic differentiation of the stem-like cells and thereby reduce tumor growth and improve responsiveness to treatment. We hypothesize that BMP-2 induction reduces tumorigenic capacity of osteosarcoma while promoting osseous reunion of the intervened skeleton to facilitate surgical reconstruction after tumor resection. In particular, BMP-2 restricts the tumorigenecity of osteosarcoma by inducing “differentiation” of the osteosarco-stem cells, making them more susceptible to the affiliated therapies, restricting their expansion and plasticity. The primary goal of this translational research is to collect necessary information that will lead to the development of a new clinical strategy for possibly attenuating bone sarcoma expansion and enhancing bone union, particularly in skeletal reconstruction after tumor resection.

Personal Statement: Dr. Lin is a tissue engineer trained by the BME program at the University of Michigan. After the completion of his doctorate education, he was recruited by the Department of Neurosurgery at Medical School to start the new research venture of spine research laboratory. The main research focuses in the spine lab is primarily on translation of inductive therapies that are applied to treat degenerative disc disorders and spinal tumors. The lab has also collaboratively developed image-based design and analysis techniques with Dr. Hollister, which have been currently applied in clinical biomechanics and development of new implants.

Friday, February 1, 2013

BME Guest Speaker

“Patient-Specific Cardiovascular Blood Flow Modeling: Theory and Applications”

Alberto Figueroa, Ph.D.
Associate Professor (Senior Lecturer)
Kings College London

Friday, February 1, 2013, 10:00 – 11:00 a.m.
2203 Lurie Biomedical Engineering Building

ABSTRACT: Advances in numerical methods and three-dimensional imaging techniques have enabled the quantification of cardiovascular mechanics in subject specific anatomic and physiologic models. Patient- specific models are being used to guide cell culture and animal experiments and test hypotheses related to the role of biomechanical factors in vascular diseases. Furthermore, biomechanical models based on noninvasive medical imaging could provide invaluable data on the in vivo service environment where cardiovascular devices are employed and on the effect of the devices on physiologic function. Finally, the patient-specific modeling has enabled an entirely new application of cardiovascular mechanics, namely predicting outcomes of alternate therapeutic interventions for individual patients.

In the first part of this talk, we present an overview of a number of methods used to create anatomic and physiologic models, obtain properties, assign boundary conditions, and solve the equations governing blood flow and vessel wall dynamics. In the second part of the talk, we demonstrate a few applications of patient-specific cardiovascular modeling in the areas of medical device design and evaluation and arterial wall growth & remodeling.


Friday, February 1, 2013

BME Guest Speaker

"Biomechanical Forces: Role in Articular Cartilage Engineering"

Bernd Rolauffs, M.D., Ph.D.
Laboratory for Molecular Biomechanics
Center for Regenerative Biology and Medicine
University of Tuebingen, Germany

Friday, February 1, 2013, 2:00 - 3:00 PM
2203 Lurie Biomedical Engineering Building

Come see Dr. Rolauffs from our sister university in Germany give this guest lecture. If you would like to meet separately with Dr. Rolauffs on Friday, please contact Professor Jan Stegemann.

Wednesday, January 30, 2013

BME 500 Seminar Series

“Caveat Emptor: Unreliable EEG recordings from microelectrodes”

William Stacey MD PhD
Assistant Professor
Department of Neurology
Department of Biomedical Engineering
University of Michigan

Wednesday, January 30, 2013, 12:00 - 1:00 PM
1303 EECS

Abstract: Recent advances in epilepsy and BCI research have led to increased demand for high resolution intracranial electrodes. These electrodes were developed alongside specialized systems designed for such work. However, after receiving FDA approval for use in patients, some of these electrodes were marketed directly to physicians, ready to be attached to clinical EEG systems that were not suited for such work. We measured the impedances of several of these electrodes and determined a transfer function to simulate how they record EEG signals. When connected directly to clinical EEG systems, signals become distorted and disrupt clinical interpretation. Additionally, current manufacturing processes leave several irregularities on the electrode surfaces. This situation is an example of how engineers must be very careful when designing a device for clinical use.

Wednesday, January 23, 2013

BME 500 Seminar Series

“Molecular endoscopy for detection of neoplasia in the digestive tract”

Thomas D. Wang, MD, PhD
Associate Professor of Medicine and Biomedical Engineering
University of Michigan

Wednesday, January 23, 2013, 12:00 - 1:00 PM
1303 EECS

Abstract: Molecular imaging aims to visualize and quantify cellular and molecular processes in living tissues. Molecular changes specific for neoplasia in the digestive tract can be visualized using in vivo “immunohistochemistry” and can serve as an adjunct to conventional endoscopy. Peptides can be developed that have high binding affinity, are easy to label, and can be produced in large quantity. Their small size (~1 kDa) allows for deep tissue penetration through leaky cell junctions for rapid binding to surface targets over-expressed by pre-malignant and malignant mucosa. Peptides can establish a clear biological mechanism for cancer progression to achieve image contrast with sufficient target-to-background ratio for endoscopic detection. After preclinical testing, rigorous validation strategies are needed for novel imaging agents and methods to enable translation into the clinic. Here, we describe the pre-clinical and clinical application of fluorescent-labeled peptides that are specific for dysplasia in the digestive tract. Validation of the purity, efficacy, safety, and non-toxicity of a novel agents, methods, and instruments is performed to provide data required for the long and complex regulatory path to ultimately achieve FDA approval. We demonstrate that peptides can be detected in vivo in real time on endoscopy, and may be promising for early detection of cancer in the digestive tract.

Friday, January 18, 2013

Final Oral Examination

Exploring the Interactions between Mesenchymal Stem Cells and Endothelial Cells in Engineered Perivascular Niches

Bita Carrion
Chair: Dr. Andrew Putnam

Friday, January 18, 2013, 1:00 PM
Baer Conference Room (2906 Cooley)

The long term survival of engineered tissue constructs is strongly dependent on oxygen delivery and nutrient exchange provided by the neovasculature. Therapeutic approaches to induce neovascularization comprise cell-based therapies using endothelial cells (ECs) co-cultured with stromal cells to form long lasting functional blood vessels. This dissertation investigates the role of cross-talk between ECs and stromal cells in governing the processes of neovascularization in fibrin matrices that are representative of wound healing environment in vivo. Special attention was paid to a specific molecular interaction between the α6β1 integrin adhesion receptor on bone marrow derived stromal cells (BMSCs) and EC-deposited laminin.

Crosstalk between ECs and stromal cells supported the formation of robust blood vessel networks; to validate this phenomenon in vitro, we utilized an established three dimensional (3D) microfluidic device as a model system. ECs suspended within 2.5 mg/mL fibrin gels patterned in the device adjacent to stromal cells (either fibroblasts or BMSCs) executed a morphogenetic process akin to vasculogenesis, forming a primitive vascular plexus and maturing into a robust capillary network with hollow well-defined lumens. Both BMSCs and fibroblasts formed pericytic associations with the ECs but promoted capillary morphogenesis with distinct kinetics. Furthermore, biochemical assays revealed that the perivascular association of BMSCs required interaction between their α6β1 integrin receptor and EC-deposited laminin.

To further investigate the α6β1 integrin-laminin interactions, we used a 3D in vitro model of angiogenesis in which ECs coated on microcarrier beads were co-cultured with BMSCs within a fibrin matrix. Using RNA interference, we were able to demonstrate that α6 integrin inhibition in BMSCs reduces capillary sprouting, and causes their failure to associate with nascent blood vessels. Furthermore, we demonstrated that the BMSCs with attenuated α6 integrin have significantly lower proliferation rate relative to either control cells expressing non-targeting shRNA or wild type BMSCs, and despite the addition of cells to compensate for the deficit in proliferation, deficient sprouting persists.

These data collectively underline the importance of understanding the integrin-mediated interactions established between ECs and supporting stromal cells that are involved in different processes of vessel formation. The results presented in this dissertation could have significant implications for studying physiological and pathological neovascularization.

Thursday, January 17, 2013

BME Research Seminar

“Biomechanical Signaling in Pulmonary Fibrosis”

Daniel Tschumperlin, Ph.D.
Associate Professor Molecular and Integrative Physiological Sciences
Harvard School of Public Health

Thursday, January 17, 2013, 10:00 – 11:00 a.m.
1006 Dow

Abstract: Fibrosis is defined as aberrant and excessive deposition of extracellular matrix. It is a pathological process that contributes prominently to diseases of soft tissues, including skin, liver, kidney, and the cardiovascular system. In the lungs, fibrosis stiffens and distorts the normal matrix, alters mechanics and disrupts gas exchange, and ultimately compromises respiratory function. There are currently no approved therapies for fibrosis, though it is an area of active investigation and clinical development. It is now widely appreciated that alterations in matrix architecture, composition, and mechanical properties can be sensed by cells, and profoundly influences their function. We have found that increases in matrix stiffness, spanning the range observed in pulmonary fibrosis, by itself promotes fibroblast activation to a proliferative, contractile and matrix synthetic state. We are currently exploring the mechanisms by which matrix stiffness signals to lung fibroblasts, how mechanical signals converge with pro- and anti-fibrotic biochemical signals, and whether novel strategies can be designed to interrupt mechanical signaling in fibroblasts. These studies merge bioengineering tools, animal and cell culture models, and discovery-based approaches to enhance our understanding of fibroblast function and the underlying pathobiology of fibrosis, with the ultimate goal of improving outcomes for patients with pulmonary fibrosis and other fibrotic pathologies.

Wednesday, January 16, 2013

Final Oral Examination

Development of "Smart" Particles for Silencing Anti-apoptotic Bcl-2 Protein Expression in Epithelial Cancer Cells

Yen-Ling Lin
Chair: Dr. Mohamed El-Sayed

Wednesday, January 16, 2013, 9:00 AM
Baer Conference Room (2906 Cooley)

B-cell lymphoma 2 (Bcl-2) is an anti-apoptotic protein that is over-expressed in head and neck squamous cell carcinomas and has been implicated in increased radio- and chemo-resistance. Short interfering RNA (siRNA) inhibits anti-apoptotic Bcl-2 protein expression resulting in enhanced cancer cell death and reduction of tumor growth. Transforming anti-Bcl-2 siRNA into a viable therapy with a defined dosage regimen requires the development of a biocompatible carrier that can shuttle a large dose of siRNA into the cytoplasm of head and neck cancer cells. This dissertation describes the development of degradable, pH-sensitive, membrane-destabilizing, comb- and star-shaped polymers that proved effective in condensing anti-Bcl-2 siRNA into “smart” nanoparticles, which bypassed the endosomal membrane and delivered the cargo into the cytoplasm of multiple epithelial cancer cells resulting in efficient knockdown of Bcl-2 expression at the mRNA and protein levels. Specifically, comb-like polymers were synthesized by grafting random copolymers of cationic trimethyl aminoethyl methacrylate (TMAEMA) and hydrophobic hexyl methacrylate (HMA) monomers from a diblock linear backbone via acid-labile hydrazone linkages. Similarly, β-cyclodextrin (β-CD) was used as a core to synthesize star-shaped polymers where pH-sensitive dimethyl aminoethyl methacrylate (DMAEMA) and hydrophobic HMA monomers were grafted from the secondary face of the β-CD via acid-labile hydrazone linkages to form β-CD-P(HMA-co-DMAEMA) polymers. Both comb- and star-shaped polymers condensed siRNA molecules into “smart” particles that were stable at physiologic pH but rapidly degraded into membrane-active fragments in acidic pH similar to those present in the endosome. We systematically evaluated the effect of hydrophobic/hydrophilic balance (HMA/DMAEMA ratio), percentage of DMAEMA monomers quaternized into cationic TMAEMA, and molecular weight of grafts on the ability of star polymers to destabilize the endosomal membrane and deliver the siRNA cargo into the cytoplasm of multiple epithelial cancer cells. Results show that star-shaped polymers incorporating P(HMA-co-DMAEMA-co-TMAEMA) grafts with an average molecular weight of 25 kDa, 50/50 HMA/DMAEMA monomers, and 50% of DMAEMA monomers transformed to cationic TMAEMA exhibit the highest transfection efficiency. Star-shaped β-CD-P(HMA-co-DMAEMA-co-TMAEMA) polymers delivered anti-Bcl-2 siRNA into the cytoplasm of UM-SCC-17B cells causing 50-60% and 65-75% reduction in Bcl-2 mRNA and protein levels, respectively. Further, combining “smart” particles loaded with anti-Bcl-2 siRNA with AT-101(a Bcl-2 small molecule inhibitor) synergistically inhibited the proliferation of cancer cells by 63% while increasing cancer cell apoptosis by 12-14%. These results collectively confirm the successful development of a new family of degradable, pH-sensitive, membrane-destabilizing star-shaped polymers that enhance the cytoplasmic delivery of anti-Bcl-2 siRNA into the cytoplasm of head and neck cancer cells.

Wednesday, January 16, 2013

BME 500 Seminar Series

“A Product Development-Driven Approach to Medical Innovation”

Lindsay E. Klee
Commercialization Director
Medical Innovation Center
University of Michigan

Wednesday, January 16, 2013, 12:00 - 1:00 PM
1303 EECS

Abstract/Summary: Innovation in academic medical centers and medical innovation in universities has been approached using a variety of research and translational research-driven methods. Efforts have been undertaken at the University of Michigan via the Concept to Commercialization (C2C) Program at the Medical Innovation Center to implement product development-driven methods. Results have been positive and medical product advancement has occurred along product lifecycle stages, such as those advocated for by the Center for Devices and Radiological Health (CDRH) at the Food and Drug Administration (FDA). Successes include those relevant to adult indications as well as to the FDA-sponsored pediatric device consortium. The structure and role of MIC programs/features will be briefly highlighted. Challenges/strategies for both achieving medical product commercialization and meeting regulatory requirements will be covered.

Friday, January 11, 2013

Final Oral Examination

Design, Construction, and Application of Synthetic Microbial Consortia

Alissa Kerner
Chair: Dr. Xiaoxia Nina Lin

Friday, January 11, 2013, 12:00 PM
GM Conference Room - 4th Floor Robert H. Lurie Engineering Center

Mixtures of interacting microbes, or microbial consortia, may be a key part of the solution to overcoming current environmental and technological challenges, such as a dearth of renewable fuel sources. Microbial consortia have various advantages over single species, or “superbugs”, such as efficiency, robustness, and modularity. The goal of this dissertation is to develop tools for making use of microbial consortia and to demonstrate their utility through practical applications. Specifically, our efforts in technology development and application include: a tunable, programmable cross-feeding circuit; production of isobutanol (a next-generation biofuel); and sensing/screening of metabolite secretion.

First, we designed and constructed a programmable genetic circuit based on engineered symbiosis between two E. coli auxotrophs. By regulating and tuning the export or production of the cross-fed metabolites we were able to tune the exchanges and achieve a wide range of growth rates and strain ratios. In addition, we created two-dimensional design space plots by inverting the relationship of growth/ratio vs. inducer concentrations. Using the plots, we could “program” the co-culture for pre-specified outcomes. This proof-of-concept circuit can be applied to more complex systems where precise tuning of the consortium would facilitate the optimization of specific objectives.

Next, we engineered a consortium of E. coli specialist strains fermenting either hexose or pentose sugars into isobutanol, and demonstrated that this co-culture exhibits improved isobutanol production over a diauxic monoculture under several growth conditions. Notably, the co-culture outperformed the monoculture on an enzymatically-hydrolyzed lignocellulosic biomass, producing up to almost 3 g/L isobutanol without detoxification or supplementation.

Lastly, we demonstrated the utility of a microbial consortium for detecting highly-secreting L-valine (and subsequently isobutanol) production strains. We designed a secretor/sensor pair that can be used to detect increased L-valine secretion by the “secretor” via the changes in growth of the “sensor”, a fluorescently-tagged L-valine auxotroph. This will be part of a larger effort to develop a new method for high-throughout screening of microbial over-production strains.

This dissertation presents the design, construction, and/or application of three synthetic microbial consortia. Through tool development and biofuel applications, our work demonstrates the potential, utility, and benefits of microbial consortia in synthetic biology.

Wednesday, January 9, 2013

BME 500 Seminar Series

“Towards Clinical Translation of Ultrasound-Guided Photoacoustic Imaging”

Stanislav Emelianov, Ph.D.
Cockrell Professor of Biomedical Engineering
Director of Center for Emerging Imaging Technologies
University of Texas at Austin

Wednesday, January 9, 2013, 12:00 - 1:00 PM
1303 EECS

Abstract: A quantitative morphological, functional and molecular imaging technique capable of visualizing biochemical, pharmacological and other processes in vivo and repetitively during stages of various pathologies (e.g., cancer or cardiovascular diseases) is desired for many fundamental, preclinical and clinical applications. Recently, we introduced high-resolution, high-sensitivity, depth-resolved ultrasound-guided photoacoustic imaging where ultrasound (US) is used to visualize the anatomical structures and photoacoustics (PA) is used to provide both functional and molecular/cellular information about the tissue. Furthermore, targeted contrast agents were developed to enable the cellular and molecular sensitivity of the developed imaging techniques. Our long-term goal is to translate ultrasound-guided photoacoustic (USPA) imaging, augmented with targeted nano-sized contrast agents, to preclinical research and, ultimately, to clinical practice. Indeed, an USPA imaging system, capable of simultaneous anatomical, functional, cellular and molecular visualization of tissue, will have a significant impact on disease detection, diagnosis, therapy, and monitoring of treatment outcome.

In this presentation, following a brief historical introduction, several USPA imaging systems will be introduced. Specifically, an USPA imaging system for detection of sentinel lymph node and micrometastatic lesions, and an intravascular USPA (IVUS/IVPA) imaging system for characterization of vulnerable atherosclerotic plaques will be described. Design and synthesis of clinically relevant contrast nanoagents with properties desired for cellular/molecular USPA imaging will also be discussed. Finally, the presentation will conclude with the discussion of advanced development of USPA imaging for diagnostic and therapeutic applications.

Tuesday, January 8, 2013

Final Oral Examination

Development of Biomechanical Models for Describing Hand and Finger Placements in Handling Work Objects

Wei Zhou
Chair: Prof. Thomas Armstrong

Tuesday, January 8, 2013, 3:00 PM
Johnson Room C, Lurie Engineering Center (LEC)

This work presents new data and models that describe how hand and finger placement is influenced by the design and placement of work objects.

First, a conceptual model was proposed to describe the overall relationship among hand postures, motions, forces, factors, memory, and feedback.

Second, logistic regression models were developed based on a study of 10 male and 10 female subjects that showed relative hand load greater than 34% of maximal strength motivated subjects to reach and grasp cylindrical work objects using underhand posture (rather than overhand), and relative hand load as low as 24% motivated subjects to hold the objects (for about 8s) using palm grip at shoulder height (vs. hook grip at mid-thigh height). The relative hand load threshold increased to 53% for selecting underhand over overhand posture for placing the objects.

Third, a study of relative finger loads for 6 male and 6 female subjects lifting cylinders showed that selection of hand posture appears to be related to the preference of reducing thumb and finger tip forces and joint loads. Subjects demonstrated strong preferences of underhand over overhand grasp, and hook grip over pinch to lift cylinders, while thumb tip and sum of fingertip forces can be reduced up to 60% by selecting the preferred postures. Biomechanical models were developed to predict overhand grasp finger forces for zero and non-zero friction cases, where the zero friction model predicted about 2 times the measured normal forces, while the prediction of the non-zero friction model agreed with data.

Fourth, finger force distribution and placement were determined for 6 males and 6 females holding unbalanced plate objects. Regression models showed that thumb and finger center-of-force (CoF) locations were generally aligned with the load moment arm. The distance between thumb and finger CoF locations increased by 39% as load moment increased from 0.98 Nm to 2.35 Nm, and reduced by 17% as hand length increased from 16.2 cm to 21.1 cm when the plate was held horizontally.

Preferred posture can be predicted using the proposed models integrated in the conceptual model. Posture prediction can be used to help best design and place objects that must be grasped and held, and provide workers with sufficient control and help reduce injury risk factor exposure.

Thursday, December 20, 2012

Final Oral Examination

An Experimental Investigation of Human/Bicycle Dynamics and Rider Skill

Stephen M. Cain
Chair: Dr. Noel C. Perkins

Thursday, December 20, 2012, 10:00 AM
2211 GG Brown

Humans have ridden bicycles for centuries, yet human/bicycle dynamics are far from well understood. The overall goals of this dissertation are to advance our understanding of how human riders control bicycles, to identify the major control strategies that humans utilize to balance and steer bicycles, and to reveal performance metrics that distinguish rider skill. To achieve these goals, we introduced: a) a novel instrumented bicycle to measure major rider control inputs and bicycle response outputs, b) an experimental design for tracking and quantifying rider learning, and c) an experimental design to measure the dynamics of human/bicycle balance and quantify rider balance performance. We employ variations of the instrumented bicycle in three major studies that focus on: 1) rider control and bicycle kinematics during steady-state turning, 2) the initial learning of steering and balance control as non-riders transition to riders, and 3) the balance skill of expert and novice riders.

The findings from these studies advance our understanding of the types of control used by human riders, and simultaneously, quantify rider learning and skill. During steady-state turning, rider lean strongly influences steering torque, suggesting that rider lean plays an important role in bicycle control. Non-riders learn to ride after successfully learning how to steer in the direction of bicycle roll, which is quantified by increasing correlation between steer and bicycle roll angular velocities. Compared to novice riders, skilled riders achieve superior balance performance, as indicated by highly correlated lateral positions of the center of pressure and center of mass. In achieving superior balance performance, skilled riders employ more rider lean control, less steer control, and use less control effort than novice riders. Overall, we conclude that rider lean (i.e., any lateral movements of the rider) plays a dominant role in both steering and balancing a bicycle, and that achieving balance requires correlating both steer and rider lean (the two rider control inputs) with bicycle roll (the bicycle response).

Tuesday, December 11, 2012

Final Oral Examination

Brain Tissue Response in Neurochemical Sampling Methods: Microdialysis and Low-Flow Push-Pull Perfusion

David Cepeda
Chair: Dr. Robert T. Kennedy

Tuesday, December 11, 2012, 1:00 PM
1180 Duderstadt Center

Neurochemical sensing via sampling probes is essential for deciphering neuronal communication and enabling technologies to alleviate brain disorders e.g. mental illness, addiction. The tissue response associated with neural probes is one of the major barriers to sustained, accurate measurements of neurotransmitters in vivo. Ultrastructural tissue response studies following Microdialysis (MD), the most established method of neurochemical sampling, have shown intercellular disruption up to 1.4 mm from the probe. However, information on whole-cell populations has been limited. Push-Pull Perfusion (PPP) is a less popular method that offers up to a 500-fold increase in spatial resolution. Yet, macroscopic tissue lesions in its initial high-flow stages have deterred its widespread use. The current low-flow PPP method has reduced the potential tissue damage significantly, but has not been investigated thoroughly.

To quantitatively characterize the brain tissue response in low-flow PPP versus MD, cell viability (CV) measurements and immunohistochemical (IHC) labeling of specific neural cell types were conducted in rat specimens, as well as computational modeling of fluid flow. To calculate CV in terms of dead/total cell ratio, Sytox Orange and Hoechst 33342 nuclear stains were infused in situ to label damaged and all cells, respectively, within reach of the dye cocktail. By labeling cell nuclei, neurons, microglia, and vasculature with IHC stains, changes in cytoarchitecture could be examined. Finally, the mechanical effect of fluid flow in PPP and MD was evaluated with COMSOL models of velocity, pressure, and shear stress.

Results from all studies indicated that low-flow PPP caused no more, mostly less, damage than MD. Since MD has been a valuable tool for neurochemical monitoring, data supports the use of low-flow PPP for elucidating brain function, disease, and treatments through in vivo sampling. Furthermore, CV, IHC, and computational modeling methods have the potential to evaluate the tissue response in improved probe designs and sampling conditions, facilitating the advancement of neurochemical sensing technology.

Tuesday, December 11, 2012

Final Oral Examination

Influence of Calcium Phosphate Composition and Design on Bone Regeneration, Degradation and Mechanical Function

Alisha B. Diggs
Chair: Dr. Scott J. Hollister

Tuesday, December 11, 2012, 11:00 AM
2203 Lurie Biomedical Engineering Building

The prevalence of bone or bone-related injuries has been the impetus for the discovery of surgical procedures resulting in the tissue’s repair and eventual return to function. Solutions for such injuries and defects have often been based on the implantation of materials with desired mechanical and structural function, yet limitations of treatment options include donor site morbidity, mechanical failure, and inadequate tissue infiltration and implant fixation. Ideal scaffolding solutions should be osteoconductive, encourage bonding with nascent tissue, provide requisite mechanical support, and in the end, have degradation by-products that are efficiently removed from the body. For these reasons, an understanding of the dynamic of mutable properties of degrading scaffolds and their impact on bone regeneration would have clear value; perhaps allowing for the development of methods to control property loss over the lifetime of the implant. This dissertation targets the identification of critical scaffold properties that drive performance in terms of bone regeneration within the calcium phosphate ceramic (CaP) construct.

Composition and sintering temperature were demonstrated to influence powder sinterability and microporosity; properties which in turn influence initial scaffold properties, strength retention through degradation, and ultimately regeneration. “High” and “low” levels of various design variables (macroporosity, permeability, and surface area) were combined with materials processing parameters (composition and thermal treatment) to produce CaP scaffolds with regular architectures. Bone growth and structural quality were evaluated in an ectopic mouse model. Macroporosity was most influential in the amount of newly generated bone. Low macroporosity scaffolds promoted better bone ingrowth and supported better tissue penetration into the scaffold center than its high macroporosity counterpart. These scaffold designs were also low in permeability and high in surface area. The structural quality of the neotissue was dependent on both composition and thermal treatment, where b-TCP scaffolds and high sintering temperatures produced tissue that was higher in trabecular thickness and spacing, mineral content, and mineral density.

This thesis demonstrated that designed architectural features were more critical in facilitating bone regeneration from CaP scaffolding materials, but inherent materials attributes were more instrumental in the quality of tissue growth.

Thursday, December 6, 2012

BME 500 Seminar Series

“Microscale electrode implantation during nerve repair: effects on nerve morphology, electromyography, and recovery of muscle contractile function.”

Paul S. Cederna, MD, FACS
Chief, Section of Plastic Surgery
Professor of Biomedical Engineering
University of Michigan

Thursday, December 6, 2012, 12:00 - 1:00 PM
1005 Dow

Abstract: Over 1.7 million people in the United States are currently living with limb loss. This number is increasing by at least 185,000 each year. Limb loss is a life-altering event with potentially devastating repercussions impacting a patient’s physical, psychosocial, and economic well-being.Despite modern technological advances, the most widely available prostheses provide little functional recovery beyond basic grasping. Current prosthetic technology can only marginally replicate the numerous degrees of freedom and tactile dexterity unique to the human arm and hand. A modest range of prostheses exists, from passive cosmetic limbs to functional body-powered or myoelectric devices. Studies have shown that abandonment of upper limb devices occurs in up to 30% of patients for reasons that include poor comfort and lack of functionality. In the field of neuroprosthetics, researchers are not only working to develop more sophisticated hardware, but they are also investigating neural control methods that can harness the patient’s own volition for downstream command of a robotic limb. One example is targeted muscle reinnervation, which relies on skin-surface electromyogram (EMG) for signal acquisition. However, this interface exhibits signal instability and requires daily computer calibration for pattern recognition. To improve signal fidelity, recent work has focused on the development of peripheral nerve interfaces that physically connect human severed nerves to engineered devices. From extraneural cuff electrodes to intrafascicular electrodes, such interfaces are limited by microshearing forces and foreign body reactions that lead to scarring and signal degradation. They are also inhibited by the formation of neuromas, which not only cause pain but also signal interference.

To minimize biological fouling, our group has developed a living in vivo regenerative peripheral nerve interface (RPNI) in the rat model consisting of a free muscle graft that is neurotized by a severed nerve. Specifically, the extensor digitorum longus (EDL) muscle is grafted into the experimental hind limb, where the proximal end of the transected common peroneal nerve is implanted into the muscle belly. A recording electrode is fixated to the muscle graft surface, and the construct is wrapped in a bioelectrical insulator. We have found that the muscle tissue dampens micromotion and improves signal-to-noise ratio. It also serves as a target for the regenerating nerve, thereby preventing neuroma formation and permitting neuromuscular amplification of signal. Having demonstrated the stability and durability of this interface, ongoing studies are focused on high-fidelity signal acquisition with the ultimate goal of facilitating the volitional control of a neuroprosthetic device. This treatment option has the potential to revolutionize the field of prosthetics and the clinical management of patients living with amputations.

Thursday, November 29, 2012

BME 500 Seminar Series

“Interpreting the vascular microenvironment through quantitative biosensors & computational modeling”

P. I. Imoukhuede, PhD
Assistant Professor, Department of Bioengineering
University of Illinois -- Urbana Champaign

Thursday, November 29, 2012, 12:00 - 1:00 PM
1005 Dow

Abstract: Vascular endothelial growth factor (VEGF) is a potent regulator of angiogenesis, and its role in cancer biology has been widely studied. Many cancer therapies target angiogenesis, with a focus being on VEGF-mediated signaling, such as antibodies to VEGF. However, it is difficult to predict the effects of VEGF-neutralizing agents. We have developed a whole-body model of VEGF kinetics and transport under pathological conditions (in the presence of breast tumor). The model includes two major VEGF isoforms VEGF121 and VEGF165, receptors VEGFR1, VEGFR2 and co-receptors Neuropilin-1 and Neuropilin-2. We have also profiled the levels of these receptors on endothelial cells, and parenchymal cells (muscle fibers and tumor cells), and incorporated these experimental data into our models. Through this integrative approach, we investigate the action of VEGF-neutralizing agents (called “anti-VEGF”) in the treatment of cancer.

Thursday, November 15, 2012

BME 500 Seminar Series

“Analyzing Discharge Policies at a Generic Acute Care Hospital”

Nan Kong
Assistant Professor
Weldon School of Biomedical Engineering,
Purdue University

Thursday, November 15, 2012, 12:00 - 1:00 PM
1005 Dow

Abstract: Despite the United States defining the cutting edge of biomedical research and development in many fields, much accomplishment has yet been translated into good practice in care delivery. While care spending in the U.S. is experiencing tremendous growth, it is critical to make care providers accountable with respect to the spending. The contention between care spending and service quality is reflected in many aspects of care delivery, including patient transitions along the care continuum.

In this talk, we will focus on the acute care discharge timing issue. It is evident that medically unnecessary readmissions waste $17 billion per year in U.S. hospitals on Medicare patients alone. Therefore, hospitals are increasingly pressured to lower readmission rates. On the other hand, incentives on finance and resource utilization have pushed hospitals to discharge patients earlier. The objective of our study is to analyze the effect of acute patient discharge timing on a variety of performance measures relevant to acute care hospitals. We develop a discrete-event simulation model for acute care patient flow. We compare several static and dynamic discharge policies. Our results show that the dynamic policies outperform the static policy with respect to many performance measures.

Throughout the talk, we intend to showcase the application of healthcare delivery operations management and engineering. We will make the argument that it is important for the development of clinical engineering as a scientific subject to embrace healthcare systems research.

Bio: Dr. Nan Kong is an Assistant Professor in the Weldon School of Biomedical Engineering at Purdue University. His research interest lies in the intersection between clinical engineering and computational sciences, with focus on the emerging area of health operations research. He has published papers in Operations Research, Medical Decision Making, Mathematical Programming, and European Journal of Operational Research. His research has been funded by the National Science Foundation and the Air Force Office of Scientific Research.

Tuesday, November 6, 2012

Final Oral Examination


Jing Liu
Chair: Dr. Xudong Fan

Tuesday, November 6, 2012, 8:30 AM
GM Conference Room, Lurie Engineering Center (4th Floor)

Micro-gas chromatography, which is capable to conduct fast on-site gas analysis, has broad applications in various fields, such as environmental monitoring, homeland security, anti-terrorism, and disease screening. This dissertation presents the development and applications of a smart adaptive two-dimensional (2-D) micro-gas chromatography (micro-GC), which not only greatly improves the separation capability but also resolves many disadvantages associated with traditional 2-D GCs.

The proposed micro-GC consists of a preconcentrator to sample gas analytes, microfabricated separation columns to conduct rapid analyte mixture separation, on-column optical detectors to detect separated analytes, and Knudsen pumps to provide carrier gas flow. The working principle, fabrication method, and calibration of each component are introduced in detail. One-dimensional micro-GC sub-system is also tested to have improved separation capability and shortened analysis time.

Finally, a smart adaptive 2-D micro-GC system is demonstrated. In this system, a on-column gas detector and a flow routing system are installed between the first dimensional separation column and multiple second dimensional separation columns. The eluent from the first dimensional column is monitored in real-time and decision is then made to route the eluent to one of the second dimensional columns for further separation. As compared to conventional 2-D GC systems, the greatest benefit of the smart adaptive 2-D micro-GC architecture is the enhanced separation capability of the second dimensional column and hence the overall 2-D GC performance. All the second dimensional columns are independent of each other, whose coating, length, flow rate and temperature can be customized for best separation result. In particular, there is no limit on the second dimensional column length and separation time in our architecture. Such flexibility is critical when long second dimensional separation is needed for optimal gas analysis. In addition, the smart micro-GC is advantageous in terms of elimination of the power intensive thermal modulator, higher peak amplitude enhancement, simplified 2-D chromatogram re-construction and potential scalability to higher dimensional separation.

Two important applications are explored based on this system. First, a mixture of plant emitted volatile organic compounds (VOCs) that can provide highly specific information for use in agriculture and defense is analyzed. We then employed it in analysis of 31 workplace hazardous VOCs, and rapid detection and identification of target gas analytes from interference background.

Thursday, November 1, 2012

BME 500 Seminar Series

“Cartilage Tissue Engineering: Cells, Extracellular Matrix, and Growth Factors”

Rhima Coleman, Ph.D.
Assistant Professor,
Department of Biomedical Engineering,
University of Michigan

Thursday, November 1, 2012, 12:00 - 1:00 PM
1005 Dow

Abstract: Tissue homeostasis involves the complex interaction of autocrine/paracrine signaling and extracellular matrix constituents in the regulation of local cell behavior. Replicating this microenvironment for cartilage tissue engineering applications is an area of intensive research for modulation of stem cell and primary cell phenotype. Interaction of growth factors, scaffold type, and mechanical stimulation at multiple hierarchical length scales determine the final properties of any engineered tissue. Techniques allowing characterization of matrix properties at multiple length scales are constantly emerging allowing researchers to correlate final construct properties with modifications at each level. This talk will address some of these factors in the chondrogenic differentiation of mesenchymal stem cells, cartilage calcification, and fracture healing.

Tuesday, October 30, 2012

Department of Biomedical Engineering

Meet Our Newest Faculty Members

Cindy Chestek, Ph.D.
Rhima Coleman, Ph.D.
Ariella Shikanov, Ph.D.

Tuesday, October 30, 2012, 3:00 - 5:00 pm
Lurie Biomedical Engineering Building Atrium

BME would like to invite you to meet our newest faculty members.

*Refreshments and hors d'oeuvres will be served*

Thursday, October 25, 2012

BME 500 Seminar Series

"Engineering approaches for fertility preservation"

Ariella Shikanov, Ph.D.
Assistant Professor,
Department of Biomedical Engineering,
University of Michigan

Thursday, October 25, 2012, 12:00 - 1:00 PM
1005 Dow

Abstract: The increasing number of young survivors of cancer with favorable outcomes is defining the need for a more comprehensive approach that will improve the quality of life after cancer, including the preservation of fertility. Options such as oocyte preservation and ovarian tissue banking followed by tissue transplantation have produced a limited number of live births in humans, but are not applicable to every patient. Successful hydrogel system for in vitro follicle culture and ovarian tissue transplantation may therefore be beneficial to many young girls and women. Natural and synthetic hydrogels with controllable physico-chemical properties, such as mechanical stiffness and degradation rate can regulate cellular processes such as cell proliferation and differentiation, as well as tissue growth and development. In the ovary, immature follicles reside in the cortex of the ovary, which is a less permissive environment, but as they grow they expand to a more permissive, perimedullar interior region of the ovary. We developed a fibrin-alginate inter penetrating network (FA-IPN) that has the potential to mimic the in vivo conditions by having the same transition from high to low modulus. Follicle encapsulation and development in FA-IPN system resulted in improved egg health and developmental potential. To further explore the effects of mechanical properties and biodegradation on follicle development we designed a poly(ethylene-glycol) (PEG) based synthetic follicle culture system. The mechanical properties and the biological activity of the matrix can be adjusted to meet the requirements for cell function, differentiation and growth. In the engineered system the encapsulated follicles locally degraded the surrounding matrix, but maintained their global integrity, in agreement with the cyclic spatial and temporal tissue dynamics present in the ovarian tissue. This system is the first synthetic biomaterial created for in vitro follicle culture, and is currently being investigated as a platform for engineering an artificial ovary. Both approaches, in vitro follicle culture and artificial ovary transplantation, can be used as a fertility preservation technology for women facing premature infertility from cancer therapies or other disorders.

Tuesday, October 23, 2012

Final Oral Examination

Nanopors with Fluid Walls for Characterizing Proteins and Peptides

Erik Yusko
Chair: Dr. Michael Mayer

Tuesday, October 23, 2012, 2:15 PM
2203 LBME (Lurie Biomedical Engineering)

Nanopore-based, resistive-pulse sensing is one of the simplest single-molecule techniques, is label free and employs basic electronic recording equipment. This technique shows promise for rapid, multi-parameter characterization of single proteins; however, it is limited by transit times of the proteins through a nanopore that are too fast to be resolved, non-specific interactions of proteins with the nanopore walls, and poor specificity of individual nanopores for a particular protein.

This dissertation introduces the concept of nanopores with fluid walls and their applications in single-molecule sensing and characterization of proteins, disease-relevant aggregates of amyloid-b peptides, and membrane-active enzymes. Inspired by lipid-coated nanostructures found in the olfactory sensilla of insect antennae, this work demonstrates that coating nanopores with a fluid lipid bilayer confers unprecedented capabilities to a nanopore such as precise control and dynamic actuation of nanopore diameters with sub-nanometer precision, well-defined control of protein transit times through the nanopore, simultaneous multi-parameter characterization of proteins, and an ability to monitor membrane-active enzymes such as phospholipase D.

Using these bilayer-coated nanopores with lipids presenting a ligand, proteins binding to the ligand were captured, concentrated on the surface, and selectively transported to the nanopore, thereby, conferring specificity to a nanopore. These assays enabled the first combined determination of a protein’s volume, shape, charge, and affinity for the ligand using a single molecule technique. For non-spherical proteins, the dipole moment and rotational diffusion coefficient could be determined from a single protein.

Additionally, the fluid, biomemtic surface of a bilayer-coated nanopore was non-fouling and enabled direct characterization of Alzheimer’s disease-related amyloid-b aggregates. The presented method and analysis fulfills a previously unmet need in the amyloid research field: a method capable of determining the true size distributions and concentrations of amyloid-b aggregates in aqueous solution.

The experiments presented here demonstrate that the concept of a nanopore with fluid walls enables new nanopore-based assays that were previously inaccessible. In particular, it demonstrates the benefits of this concept for simultaneous, multi-parameter characterization of proteins with a single-molecule method; this technique may, therefore, be well-suited for identification of proteins directly in complex biological fluids. Based on these findings, the addition of fluid walls to nanopores holds great promise as a tool for simple, portable single molecule assays and protein characterization.

Friday, October 19, 2012

Rackham Centennial Lecture in Biomedical Engineering

“Engineering the health care of the 21st century”

William Heetderks, MD, PhD.
Associate Director, National Institute of Biomedical Imaging
and Bioengineering
National Institutes of Health

Friday, October 19, 2012, 3:00 pm
Johnson Rooms in the Lurie Engineering Center (LEC)

Abstract: The National Institute of Biomedical Imaging and Bioengineering has a mission to improve health by leading the development and accelerating the application of biomedical technologies. This has lead to the nick name ‘the institute of cool stuff’ and in this talk I will briefly highlight some of the exciting developments going on among researchers supported by the Institute. The talk will then focus on one goal in our new strategic plan – patient centered health care. One can look at a variety of economic and demographic projections and come to the inescapable conclusion that in fifty years health care in the US will be fundamentally different from what it is today. Innovation in engineering will be essential if we are to move to a world where improved quality of care and the inclusion of care for all is realized. I will offer one vision of decentralized, patient-centered health care. While not anticipating the demise of physicians and hospitals, the potential for change associated with care delivered by a variety of health care providers in a variety of settings will be considered. The emerging tools of mobile health, point-of-care technologies, new therapeutic devices, advanced imaging, electronic health records, and advanced medical decision support will be briefly reviewed in the context of their potential for innovation in patient–centered care.

Thursday, October 18, 2012

BME 500 Seminar Series

"Extracellular Matrix (ECM) Scaffold Technologies for Rotator Cuff Repair"

Kathleen Derwin, PhD
Department of Biomedical Engineering and
Orthopaedic Research Center, Cleveland Clinic

Thursday, October 18, 2012, 12:00 - 1:00 PM
1005 Dow

Abstract: Rotator cuff tears affect 40% or more of patients over the age of 60 and are a common cause of debilitating pain, reduced shoulder function and weakness. Despite improvements in our understanding of this disease process and advances in surgical treatment, healing following rotator cuff repair remains a significant clinical challenge. Repair failure rates of 20-70% continue to be reported, depending on factors such as patient’s age, tear size and chronicity, muscle atrophy and degeneration, tendon quality, repair technique and the post-operative rehabilitation. Hence, there is a need for repair strategies that can augment the repair by mechanically reinforcing it, while at the same time biologically enhancing the intrinsic healing potential of the tendon. We investigate the use of extracellular matrix (ECM) scaffold technology as a strategy for reducing re-tear rate and enhancing healing following rotator cuff repair. ECM scaffolds are believed to provide mechanical augmentation and a chemically and structurally instructive environment for host cells. Our work involves the development of ECM scaffold technologies, testing them in relevant model systems, and translating the technologies to human patients. We are also developing imaging techniques to monitor the integrity and quality of healing tendon repairs during the post-operative period.

Bio: Dr. Kathleen Derwin is an Associate Staff (Associate Professor) in Biomedical Engineering, Lerner Research Institute, Cleveland Clinic. She holds joint appointments in Orthopaedic Surgery and the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University. She is a graduate of the University of Massachusetts (B.S.E.) and the University of Michigan (M.S., PhD).

Dr. Derwin leads the tendon research program at the Cleveland Clinic, specializing in issues of rotator cuff injury/repair, abdominal wall and other musculoskeletal soft tissue repair, extracellular matrix scaffolds, and new approaches to tissue engineering for healing such injuries. She has extensive expertise with mechanical and biologic testing of tendon and other extracellular matrix materials in a variety of animal models. Her contribution to the field of orthopaedics was recently recognized by her induction into the American Shoulder and Elbow Society. She also serves on the advocacy committee of the Orthopaedic Research Society and has previously served as the Chair of Tendon and Ligament Committee for the Orthopaedic Research Society Annual Meeting. She is on the Board of Consulting Editors for Research for the Journal of Bone and Joint Surgery and an Ad hoc reviewer for the Musculoskeletal Tissue Engineering (MTE) and Special Emphasis Study Sections at NIH.

Friday, October 12, 2012

BME Alumni Merit Award Seminar: Michigan Engineering Homecoming Weekend

"How I Accidentally Started a Company Focused on Metabolic and Phenotypic Analysis and Identification of Microbial and Mammalian Cells"

Barry Bochner, Ph.D.
CEO, & CSO, Biolog, Inc.
Hayward, CA

Friday, October 12, 2012, 10:30 – 11:30 a.m.
2203 LBME (Lurie Biomedical Engineering)

Abstract: In 1975, as a Bioengineering student at University of Michigan, I made a fortuitous discovery in the lab. There were practical applications and products that could be made from this discovery and many years later I used the technology as a springboard to start a company called Biolog, Inc. The heart of the technology involves using redox dyes to colorimetrically measure energy (NADH) produced by cells. Different bacteria metabolize different chemical substrates for food, so initially Biolog made test kits for identifying bacteria based on what chemicals they would "eat". Over time we have evolved the technology to provide detailed and high throughput metabolic and phenotypic analysis of diverse cell types, from bacteria to human cells. Although bacteria identification is still a major part of Biolog's business, we are now involved in applying the technology to very diverse applications of basic research and applied biotechnology. Applications range from determination of gene function to bioprocess development to cancer research. Specific examples and discoveries will be presented to illustrate the many uses of this live cell assay technology. I am very grateful to my mentors at the University for instilling in me a scientific education and curiosity that I used to find a unique path combining biological sciences with engineering approaches.

Biographical Sketch - Barry Bochner

Barry Bochner, President, CEO and CSO at Biolog, Inc. in Hayward, California, has a broad background and diverse interests in cell physiology and metabolic analysis. Dr. Bochner's educational background includes S.B. and S.M. degrees from MIT and a Ph.D. in Bioengineering from University of Michigan. This was followed by postdoctoral work in Biochemistry at the University of California at Berkeley. Prior to cofounding Biolog, he was a Senior Scientist at Genentech, Inc. heading a group in microbial physiology and fermentation development. Dr. Bochner maintains memberships in a large number of biochemistry and microbiology professional organizations. In 2007 he was elected as a fellow of the American Academy of Microbiology.

Thursday, October 11, 2012

BME 500 Seminar Series

"Role of Micro- and Nanotechnologies in Cancer Detection and Management"

Sunitha Nagrath, Ph.D.
Assistant Professor of Chemical Engineering
University of Michigan

Thursday, October 11, 2012, 12:00 - 1:00 PM
1005 Dow

Abstract: More than two decades ago, microfluidics began to show its impact in biological research. Since then, the field of microfluidics has evolved rapidly. Cancer is one of the leading causes of death worldwide. Microfluidics holds great promise in cancer diagnosis and also can serves as an emerging tool for understanding cancer biology. Microfluidics can be valuable for cancer investigation due to its high sensitivity and throughput, less material-consumption, low cost, and enhanced spatio-temporal control. The physical laws on microscale offer an advantage enabling the control of physics, biology, chemistry and physiology at cellular level. Developing and applying the state of the art microfluidic technologies to address the unmet challenges in cancer can expand the horizons of not only fundamental biology but also the management of disease and patient care. We present here an integrated micro- nanotechnology for the isolation of circulating tumor cells (CTCs) shred from primary tumor, which presumably give rise to blood borne metastases. Gaining insights into biological composition and functional properties of CTCs is the key to assess their application in early diagnosis, monitoring and therapeutics. However, the precise origin and composition of these circulating epithelial cells is still unknown, and estimates of their quantity and frequency among cancer patients have been based on available detection strategies with limited sensitivity, and often found to be inadequate for reliable molecular analyses. To address this, we have applied engineering principles and developed a highly sensitive and high throughput microfabricated chip for the isolation of circulating tumor cells from whole blood. Using this novel technology, we were able to successfully isolate CTCs from patients with lung, prostate, colon, breast, and pancreatic cancers at very low frequencies with very high purity at ultrahigh-throughput. Following capture of CTCs, a number of tumor-specific molecular markers were tested, either by directly staining for cell surface protein expression (immunohistochemistry) on the chip, or by lysis of cells on the chip and extraction of RNA and DNA.

Thursday, October 4, 2012

Final Oral Examination

Biomolecular Interactions with Synthetic Surfaces

Aftin Ross
Chair: Joerg Lahann

Thursday, October 4, 2012, 10:00 AM
General Motors Room, Lurie Engineering Center (4th floor, LEC)

Augmenting the surface properties of synthetic materials can modulate biomolecular functions. In this dissertation research, the chemical vapor deposition (CVD) platform is used to generate reactive polymeric surfaces for various applications including sensing, “click” chemistry, and tissue engineering. For the first time, thin CVD films are used as novel sensors for imaging surface plasmon resonance enhanced ellipsometry (SPREE), a tool used in biosensing/diagnostics. CVD coatings are advantageous because they have better long-term stability and do not require special storage conditions. CVD-coated sensors are capable of detecting many biomolecules which may be tuned by altering film reactivity.

Another area of this dissertation research is the use of a reactive CVD coating as a binding partner in thiol-based “click” chemistry reactions and a Diels Alder “click” reaction, types of immobilization strategies used to modify surfaces. Successful surface modification with thiols and maleimides is demonstrated and further exploited to create multifunctional surfaces, which may serve as building blocks for complex surface architectures. CVD coatings are beneficial as they extend the utility of thiol-based “click” chemistry reactions by increasing the number of binding substrates.

In the final portion of the dissertation research, a polymeric brush was generated that undergoes a change in wettability (how water interacts with a surface) as a function of brush thickness. At low thicknesses, this brush is known to maintain human stem cells in a form that allows them to become any cell type. The use of a synthetic substrate to maintain this state is advantageous because material parameters can be tightly controlled. By altering wettability and other material characteristics, properties important for maintaining these cells are evaluated and may be utilized for future biomaterials designs. This dissertation research has made numerous contributions to the field of biomaterials science through the generation of a range of surface modification platforms that could ultimately aid in elucidating cellular and biomolecular behaviors, which have applications in diagnostics, molecular self-assembly, and tissue engineering/regenerative medicine.

Thursday, September 27, 2012

BME 500 Seminar Series

"Cortical Brain Machine Interfaces for the Treatment of Paralysis"

Cindy Chestek, Ph.D.
Assistant Professor, Biomedical Engineering

Thursday, September 27, 2012, 12:00 - 1:00 PM
1005 Dow

Abstract: Brain machine interfaces or neural prosthetics have the potential to restore movement to people with paralysis by bridging gaps in the nervous system with an artificial device. Cortical implants can record from hundreds of individual neurons in motor cortex. Machine learning techniques can be used to generate useful control signals from this neural activity. In recent years, there has been substantial progress improving these systems in several areas. Performance can now surpass typically used EMG control signals for artificial limbs, and animals can control computer cursors with brain activity 80-105% as well as they can with their native hand. There have also been substantial improvements in electrode longevity, due to signal processing techniques, which can enable devices to function across multiple years. Also, several integrated circuits have been developed to process many channels of neural activity with a very small device. However, significant challenges still remain to package these systems such that the active electronics can remain in the brain for many years, or to develop fully implantable neural interfaces that require no external wearable components. Finally, there is a large portion of the paralyzed community whose primary need is for finger and grasp control, which has not previously been attempted in a real time experiment. Currently, two human safety trials are being completed using multi-channel neural implants in motor cortex. If these challenges can be met, it is possible for this brain machine interfaces to become widely available for the treatment of paralysis.

Thursday, September 20, 2012

BME 500 Seminar Series

"Nonlinear Optical Probes of Ovarian Cancer"

Paul Campagnola
Associate Professor
University of Wisconsin, Madison
Dept. of Biomedical Engineering

Thursday, September 20, 2012, 12:00 - 1:00 PM
1005 Dow

ABSTRACT: Remodeling of the extracellular matrix (ECM) has been implicated in ovarian cancer, and we hypothesize that these alterations may provide a highly sensitive optical marker of early disease. For this investigation we use Second Harmonic Generation (SHG) imaging microcopy to study changes in the structure of the ovarian ECM in human normal and malignant ex vivo biopsies. The normal and malignant tissues have highly different collagen fiber assemblies, where collectively, our findings show that the malignant ovaries are characterized by lower cell density, denser collagen, as well as higher regularity at both the fibril and fiber levels. This further suggests that the assembly in cancer may be comprised of newly synthesized collagen as opposed to modification of existing collagen. This suggestion is further corroborated by the spectral dependence of the reduced scattering coefficients. Because invasion and metastasis of human ovarian cancer are thought to be synchronous, it is also crucial to understand the cancer cell adhesion, migration, and detachment dynamics. We use multiphoton excited (MPE) photochemistry to fabricate crosslinked laminin nanofibers to investigate these processes as a function of metastatic potential. The migration rates increase with increasing metastatic potential, and the more invasive cells are less rigid and more weakly adhered to the nanofibers. We further use MPE photochemistry to fabricate laminin gradients with dynamic ranges of 10 and 40 in concentration to study haptotaxis (i.e. migration in response to an insoluble gradient) of ovarian cancer cells. Using these constructs, we find that all the cells display enhanced directed migration on crosslinked laminin gradients. Moreover, the migration speed and directionality depends not only on the local concentration and slope of the gradient but also on the cell polarity. Collectively, the results suggest that contact mediated migration, haptotaxis, as well as decreased adhesion may be operative in metastasis of ovarian cancer in vivo.

Tuesday, September 18, 2012

U-M Biomedical Engineering Society

''Biomedical Engineering: State of the field 2012''

Jan Stegemann, Ph.D.
Tuesday, September 18, 2012, 6:00pm - 7:00pm
Lurie Biomedical Engineering Building Atrium

The medical products industry is highly diversified and is shaped by scientific, consumer, political, and regulatory influences. This interactive session will give an overview of our field in the current global environment. Topics to be covered include: major companies in the field, medical market segments, distinguishing features of the field, recent trends, new products, potential career paths, and other topics of interest to the audience. The intent of the session is to provide undergraduate students with a sense of context about their field, and an appreciation of the challenges and opportunities of a career in biomedical engineering. Our overview will be based on the “Healthcare: Products & Supplies (Aug 2012)” industry survey compiled by Standard & Poor’s and available through the UM library on the NetAdvantage database (link below). Students may wish to read parts of this document in preparation for the session. Healthcare: Products & Supplies: Link

Thursday, September 13, 2012

BME 500 Seminar Series

“The changing role of academia in drug and device research and development: overview and case study in pancreatic cancer research”

Villas Distinguished Professor of Pharmacy, Surgery, and Biomedical Engineering
Director of UW Center for Nanomedicine
Assistant Executive Director and Core Director of UW Institute for
Clinical and Translational Research (NIH CTSA)
Associate Dean of the Division of International

Thursday, September 13, 2012, 12:00 - 1:00 PM
1005 Dow

Abstract: The landscape of translational research for medical devices and therapeutics is undergoing a major transformation. Academia has the potential opportunity to redefine its traditional role. In this talk, a background in the critical pathway of therapeutic development from discovery to commercialization is presented. The specific challenges facing academia in the development of therapeutics are described in the context of this development path. Specific gap filling solutions in the development of cancer therapeutics are presented as a case study.

BIO: Kao is a Vilas Distinguished Achievement Professor of School of Pharmacy, Departments of Surgery and Biomedical Engineering. He serves as the founding co-director in UW Center for Nanomedicine, UW Translational Research Center in Advanced Wound Therapies, and as a researcher in the UW Carbone Cancer Center. He has effectively integrated this unique faculty appointment in the multidisciplinary training of students and the execution of research projects that have broad impacts ranging from basic science and engineering to clinical medicine. His extensive involvement with industry, regulatory, and public policy-making agencies has enabled him to successfully translate enabling technologies to pre-clinical and clinical applications, as well as for him to fully understand the complexity that is involved in this process. He has been credited to pioneer the use of biomimetic biomaterials to probe the specific biological mechanisms at protein, cellular, tissue, and organism levels that impact material biocompatibility. In addition, Kao serves as an associate dean in the UW Division of International Studies, where he helps coordinate UW strategic international programs in the areas of health, sciences, and technology. He oversees the operation of the newly launched UW Shanghai Innovation Office, the first of its kind.

Thursday, September 13, 2012

U-M Biomedical Engineering Society

BMES @ Michigan Mass Meeting

Thursday, September 13, 2012, 6:00pm - 7:00pm
1500 EECS

Come, learn & get involved!

Wednesday, September 12, 2012

Michigan Health Engineered for All Lives (M-HEAL)

M-HEAL Project Expo & Mass Meeting
Wednesday, September 12, 2012, 6:30pm - 7:30pm
Michigan League, Koessler Room

INTERESTED IN GLOBAL HEALTH, DESIGN, MEDICAL TECHNOLOGIES, OR SOCIAL ENTREPRENEURSHIP? Come learn more at our Fall 2012 PROJECT EXPO & MASS MEETING This is your opportunity to learn more about the project teams, volunteer opportunities, and new leadership positions available in our organization. Click to learn more about M-HEAL Project Teams Or email us at:

Thursday, September 6, 2012

BME 500 Seminar Series

“Engineering approaches to regulate immunity”

James Moon
Assistant Professor
Department of Pharmaceutical Sciences
Department of Biomedical Engineering

Thursday, September 6, 2012, 12:00 - 1:00 PM
1017 Dow

Abstract: The immune system is a complex network of cells and organs that can detect and eliminate foreign pathogens by eliciting local and systemic immune responses. If we can engineer strategies to harness the potential of our own immune system, these new therapeutic approaches will transform the field of biomedicine, ranging from vaccines against infectious diseases to immunotherapies for cancer and autoimmunity. In this talk, I will discuss how fundamental principles of engineering in drug delivery and materials science can be utilized to control and manipulate the immune system. Specifically, I will describe our research efforts directed towards 1) the development of biologically-inspired nanoparticles that can mimic the key features of microbes to activate T-cells and B-cells, and 2) application of these nanoparticle vaccines in vivo to generate potent cellular and humoral immune responses against pathogens, including malaria sporozoites and HIV. These new synthetic materials coupled with a powerful set of engineering tools offer unique opportunities to advance our understanding of the immune system and translate discoveries from basic immunology towards new diagnostics and immunotherapies.

Tuesday, September 4, 2012

University of Michigan

Classes Begin (Fall Term 2012)

University of Michigan
Tuesday, September 4, 2012, 8:00 AM
Lurie Biomedical Engineering Building

Classes begin for the Fall 2012 term. Welcome back and good luck this semester!

Tuesday, August 14, 2012

University of Michigan

Classes End (Spring/Summer)

University of Michigan
Tuesday, August 14, 2012, 5:00pm
Lurie Biomedical Engineering Building

Full Term + Summer Half Term end. Study Day, Aug 15. Examinations held August 16 - 17.

Friday, August 10, 2012

Department of Biomedical Engineering Master's Thesis Defense

Tofu as a phantom material of compressed soft biological tissue for real-time electrical impedance spectroscopy measurements

Barry Belmont
Chair: Dr. Albert Shih

Friday, August 10, 2012, 2:00 PM - 3:00 PM
1100D Dow Conference Room, H.H. Dow Building

Bioimpedance is an indirect measure of meaningful physiological happenings. From the analysis of single cells and cultures to tissues and organs to whole bodies and across populations, bioelectrical impedance has proven its value quantifying physiology time and again. While the spatial scale of the samples ranges from cells membranes to human populations, the temporal range is not nearly as robust. Though the longest studies can span years, typical bioimpedance frequency sweeps can often last several seconds. Hidden behind the veil of these seconds are many important and interesting physiological events, not the least of which are changes in tissues under physical deformation. One of the most significant ways tissues become mechanically deformed is through compression, which may occur physiologically, pathologically, clinically, and in basic research. Given this ever-present reality of tissue compression, an investigation into describing the mechanical deformation through a noninvasive, passive electrical approach was warranted. However, the measurement times associated with traditional systems are incapable of dealing with many rapid biological processes including most realistic instances of soft tissue compression, though many researchers agree that extracellular fluid loss accounts for the rise in impedance seen in compressed tissue. To solve this issue, a multisine (Schroeder-phased) electrical impedance spectroscopy system was developed, capable of evaluating the complex impedance of a sample in real time, and thus providing an indirect means of monitoring fluid flow out of a sample. To validate the system, an inexpensive, readily available, porous, biological phantom, tofu, was used. The stress relaxation of the tofu was fit to a standard Maxwell model and correlations were made to the normalized admittance of the tofu samples for a series of strain levels from 0-40%. Though the experiments described within are simple – tracking the impedance of tofu as it is compressed – the underlying phenomena are complex. As such this thesis is best thought of as an initial exploration of a broader field investigating the correlative effects of tissue deformation and electrical impedance in need of rigorous and multidisciplinary consideration.

Monday, July 30, 2012

Final Oral Examination

Functional MRI Using Pseudo-Continuous Arterial Spin Labeling

Hesamoddin Jahanian
Co-Chairs: Dr. Douglas C. Noll and Dr. Luis Hernandez-Garcia

Monday, July 30, 2012, 10:00 AM
General Motors Conference Hall, 4th Floor Lurie Engineering Center (LEC)

Functional Magnetic Resonance Imaging (fMRI) goes beyond the anatomy to explore the brain function. Arterial spin labeling (ASL) is a non-invasive MRI technique that employs magnetically labeled arterial water as an endogenous tracer for measuring cerebral blood flow that can be used for fMRI. Functional ASL offers a number of advantages over the conventional blood oxygenation level dependent (BOLD) fMRI technique. The widespread use of ASL for functional neuroimaging, however, has been hampered by its low signal to noise ratio (SNR) and poor temporal resolution.

In this dissertation, we propose a novel method to optimize the SNR of pseudo-continuous arterial spin labeling (pCASL) technique. pCASL has been the most popular ASL method, however, in this study it is demonstrated through experiment and computer simulation that the SNR of this technique can be degraded due to off-resonance effects. The proposed method can effectively recover the lost SNR of pCASL using the B0 field map information. In our preliminary study the proposed method improved the inversion efficiency of the original pCASL by up to 56%. This method allows the use of pCASL in a wider range of conditions and applications, including real-time fMRI and ultra-high field MRI, where it may have otherwise been impractical.

ASL is traditionally used for measurement of cerebral blood flow (CBF). In this dissertation we also develop a new framework for dynamic imaging of arterial blood volume (aCBV) utilized for functional brain imaging. This method employs the developed optimized pCASL technique, takes advantage of the kinetics of ASL signal and provides a signal, which is primarily determined by arterial blood volume with little or no contributions from the parenchyma. The proposed aCBV ASL approach has several important advantages over existing CBF ASL techniques for functional imaging. The temporal resolution of the developed aCBV ASL technique is approximately half of the temporal resolution of the conventional perfusion ASL. We also found that the activation detection sensitivity of the aCBV ASL was by average 30% higher than that of the CBF ASL. Consequently, aCBV produced wider activated areas compared to CBF. The active areas in the aCBV map were also more focal compared to BOLD.

Thursday, June 28, 2012

Final Oral Examination

Bone Tissue Engineering Using High Permeability Poly-e-caprolactone Scaffolds Chemically Conjugated with Bone Morphogenetic Protein-2

Anna G. Mitsak
Chair: Scott J. Hollister

Thursday, June 28, 2012, 1:00 PM
GM Conference Room, Lurie Engineering Center (4th Floor)

Bone is the second most commonly transplanted tissue in the United States. Limitations of current bone defect treatment options include morbidity at the autograft harvest site, mechanical failure, and poorly controlled growth factor delivery. Combining synthetic scaffolds with biologics may address these issues and reduce dependency on autografts. The ideal scaffolding system should promote tissue in-growth and nutrient diffusion, control delivery of biologics and maintain mechanical integrity during bone formation. This dissertation evaluates how scaffold permeability, conjugated bone morphogenetic protein-2 (BMP-2) and differentiation medium affect osteogenesis in vitro and bone growth in vivo.

“High” and “low” permeability polycaprolactone (PCL) scaffolds with regular architectures were manufactured using solid free form fabrication. Bone growth in vivo was evaluated in an ectopic mouse model. High permeability scaffolds promoted better 8 week bone growth, supported tissue penetration into the scaffold core, and demonstrated increased mechanical properties due to newly formed bone. Next, the effects of differentiation medium and conjugated BMP-2 on osteogenesis were compared. Conjugation may improve BMP-2 loading efficiency, help localize bone growth and control release. High permeability scaffolds were conjugated with BMP-2 using the crosslinker, sulfo-SMCC. When adipose-derived and bone marrow stromal cells were seeded onto constructs (with or without BMP-2), BMSC expressed more differentiation markers, and differentiation medium affected differentiation more than BMP-2. In vivo, scaffolds with ADSC pre-differentiated in osteogenic medium (with and without BMP-2) and scaffolds with only BMP-2 grew the most bone. Bone volume did not differ among these groups, but constructs with ADSC had evenly distributed, scaffold-guided bone growth.

Analysis of two additional BMP-2 attachment methods (heparin and adsorption) showed highest conjugation efficiency for the sulfo-SMCC method. BMP-2 release from all constructs was minimal, proving that BMP-2 was tightly bound to constructs regardless of the attachment method. However, C2C12 myoblasts did not produce alkaline phosphatase when seeded onto heparin- and sulfo-SMCC-conjugated scaffolds suggesting hindrance of BMP-2 bioactivity.

This thesis demonstrated that high permeability PCL scaffolds promote bone growth better than low permeability scaffolds and that in vitro pre-differentiation of cells affects osteogenesis more than conjugated BMP-2. Future work will optimize BMP-2 conjugation to ensure maintenance of bioactivity.

Friday, June 8, 2012

Final Oral Examination

Unlocking Possibilities While Preserving Performance: Putting the "Interface" Back in Brain-Computer Interface

David E. Thompson
Co-Chairs: Jane E. Huggins, Ph.D., and Daniel P. Ferris, Ph.D.

Friday, June 8, 2012, 9:30 AM
2203 Lurie Biomedical Engineering Building

Brain-computer interfaces (BCIs) allow communication without requiring physical movement; for individuals with the most severe movement impairments, BCIs may be the only available form of communication. Unfortunately, BCIs are slow and inaccurate, prompting research into ways to increase throughput. However, the problem of slow and inaccurate communication is not limited to BCIs. For many years, the field of assistive technology (AT) has provided means of communication to individuals with movement impairments.

This dissertation focuses on the design and testing of a plug-and-play BCI that can interface with existing AT solutions. The dissertation also addresses issues of BCI performance measurement, which were uncovered during early experiments.
Results include the following:

Thursday, May 17, 2012

Final Oral Examination

Development of Targeted, Enzyme-Activated, Dendrimer-Drug Nano-Conjugates for Hepatic Cancer Therapy

Scott H. Medina
Chair: Mohamed E. H. El-Sayed, Ph.D.

Thursday, May 17, 2012, 8:00 AM
GM Conference Room - 4th Floor Robert H. Lurie Engineering Center

Primary liver cancer is the 4th most common malignancy worldwide, accounting for >600,000 deaths/year globally. Loco-regional chemotherapy fails to deliver anticancer drugs specifically to hepatic cancer cells resulting in low anticancer activity and severe toxicities. This dissertation describes development of targeted nanoparticles that can deliver and release chemotherapeutic agents selectively to the cytoplasm of hepatic cancer cells.

Specifically, we conjugate doxorubicin (DOX) chemotherapeutic molecules to generation 5 (G5) poly(amidoamine) dendrimers via aromatic azo-linkers to prepare G5-DOX conjugates. We engineered these azo-linkers to be cleaved by liver-specific azoreductase enzymes, with tunable DOX release achieved by modulating the linker’s enzyme affinity via increased azo-bond electronegativity, indicated by decreasing Hammett values (σ). We synthesized four G5-L(x)-DOX conjugates incorporating azo-linkers L1-L4 with decreasing σ values and evaluated their cleavage by human liver microsomal (HLM) enzymes, HepG2 hepatic cancer cell and rat cardiomyocyte S9 enzyme fractions, or control proteins. This resulted in selective cleavage of G5-L(x)-DOX by azoreductase enzymes with increased DOX release rates observed as azo-linker σ value decreased, achieving 100% DOX release from G5-L4-DOX conjugates by HLM enzymes. We evaluated the anticancer activity of G5-L(x)-DOX towards hepatic cancer cells using a clonogenic cell survival assay. Results showed increased cytotoxicity of G5-L(x)-DOX which matched their DOX release rank order, reaching a similar IC50 for G5-L4-DOX and free DOX in HepG2 cells at equivalent drug concentrations.

Hepatic cancer cell-specific delivery of G5 dendrimers was achieved by surface functionalization with N-acetylgalactosamine (NAcGal) sugars, resulting in binding and receptor-mediated endocytosis of G5-NAcGal by the liver-specific asialoglycoprotein receptor. Biodistribution of G5-NAcGal in liver-tumor bearing mice showed a 2-fold increase in tumor-specific carrier accumulation versus non-targeted dendrimers, while attachment of poly(ethylene glycol) (PEG) to the G5 surface limited carrier distribution to healthy liver tissue. This prompted synthesis of G5-PEG carriers displaying the targeting ligand at the PEG terminus, leading to selective carrier internalization into HepG2 cells while avoiding opsonization and subsequent uptake into liver macrophages and rat hepatocytes.

By combining this targeting approach with tunable G5-DOX conjugates we expect to achieve specific delivery of free DOX to hepatic cancer cells for effective liver cancer therapy with minimal side effects.

Thursday, May 17, 2012

Final Oral Examination


Carl S. McGill
Co-Chairs: Joseph L. Bull, Ph.D. and Albert J. Shih, Ph.D.

Thursday, May 17, 2012, 2:00 PM
3725 Bob and Betty Beyster Building (CSE)

This research investigates needle insertion through soft tissue, enabling the development and validation of force models and insertion techniques for accurate needle tip placement. During needle insertion into the prostate, the needle deflects en route to the target which leads to seed misplacement and suboptimal dose to cancerous cells. While much work has been achieved on slow needle insertion speed and axial - needle insertion direction - force distribution, little work has been performed on stiffer needle material properties, tissue deformation with needle deflection, and normal - perpendicular to needle insertion direction - force distribution. This lack of knowledge have led to tissue deformation, needle deflection, and misplaced target when performing needle insertion procedures.

This research aims to quantify the impact of an optimized needle grid, insertion techniques, and needle-tissue force interaction on needle deflection and phantom deformation. First, an improved grid used to guide the needle was investigated and inserted via different hand insertion techniques to acquire needle deflection. To measure needle deflection, a measurement apparatus with acceptable gauge repeatability and reproducibility (GR&R) and documented accuracy was introduced. Next, stiffer needle properties were explored and inserted at much faster speed via a pneumatic device, when compared to hand insertion or current robotic devices. Finally, finite element analysis (FEA) models were developed to predict relative needle-phantom motion using measured force data, while simultaneously obtaining needle deflection and phantom deformation experimental data. The needle and phantom FEA models and the normal force distribution on the needle shaft were validated with experimental results. Findings from this dissertation include a 40% decrease in average needle deflection with the improved grid (and the same fast hand insertion technique), in addition to a 60% decrease in average needle deflection with the stiffer needle at higher pneumatic speed (compared to the less stiff needle and slow speed). Also, the needle and phantom FEA models are reasonably accurate to experimental data, 7% and 18%, respectively at the worst data point. These findings can be used to improve needle insertion techniques, while understanding force distribution effect on needle bending and compensate during the insertion path.

Tuesday, May 15, 2012

Final Oral Examination

Effect of Age and Peripheral Neuropathy on Responses to an Unexpected Underfoot Perturbation During Gait

Hogene Kim
Co-Chairs: James A. Ashton-Miller, Ph.D. and James K. Richardson, M.D.

Tuesday, May 15, 2012, 10:00 AM
2233 G.G. Brown

Advancing age and diabetic peripheral neuropathy (DPN) are both associated with an increased risk of falls and fall-related injuries, especially when walking on uneven surfaces. In fact little is known about the effect of a single unexpected underfoot perturbation on gait kinematics. This is because the stimulus can be difficult to quantify, and the stimulus-response relationship can be confounded by carryover effects from earlier perturbations. So a custom perturbing shoe was invented to present a single unexpected medial or lateral underfoot perturbation during level gait. We then used the shoe to test the primary hypotheses that both age and increasing severity of DPN would affect the kinematic response to these perturbations, chiefly by affecting the myoelectric latencies, ankle proprioceptive thresholds, and ankle and hip muscle strength capacities.

We recruited 42 older subjects with and without DPN, and 26 healthy young subjects. We measured manual reaction times, unipedal balance times, lower extremity strength capacities, gait kinematics, lower extremity electromyographic latencies and ground reaction forces during gait trials with underfoot perturbations randomly presented on 16 out of 60 trials. The results showed that hip strength was a significant predictor of unipedal stance time (R2 = 0.73). Hip abduction/adduction and ankle inversion strengths explained almost 70% of the variation in gait speed over an uneven surface. The perturbing shoe proved a reliable method for affecting step kinematics following an unexpected underfoot perturbation. In healthy young adults, the single perturbation affected the kinematics of up to four of the recovery steps, but did not affect pelvic displacements. In healthy old, despite EMG responses on the first step, step kinematic responses were unaltered, but lateral pelvic displacement was affected. In the moderate DPN, no EMG response or step kinematic responses were observed on the first recovery step, but on the second step their lateral pelvic displacement was significantly larger than healthy old. Lastly, a vocal choice reaction time task that divided attention during perturbed gait resulted in significantly prolonged vocal reaction times in healthy young adults.

These results suggest that future interventions for patients with moderate DPN should aim to increase maximum hip strength and rate of strength development.

Monday, May 14, 2012

Final Oral Examination

The Effect of Gender-Related Differences in Knee Morphology on Peak Anterior Cruciate Ligament Strain During Repeated Simulated Pivot Landings: An In Vitro Investigation

David B. Lipps
Chair: James A. Ashton-Miller, Ph.D.

Monday, May 14, 2012, 3:00 PM
GM Conference Room - 4th Floor Robert H. Lurie Engineering Center

Anterior cruciate ligament (ACL) injuries are associated with considerable morbidity, including the development of knee osteoarthritis. A smaller ACL cross-sectional volume and a steeper lateral tibial slope have been associated with increased ACL injury risk. A knowledge gap exists as to why adolescent females have a 2- to 8-fold greater ACL injury rate than males, and whether the human ACL is susceptible to a fatigue failure. This dissertation tests the research hypotheses that (1) the female ACL exhibits greater peak strain than the male ACL during a two-times body weight (2*BW) simulated pivot landing because of a smaller ACL cross-sectional area and stepper lateral tibial slope, and (2) the ACL is susceptible to fatigue failure under repeated 3 - 4*BW simulated pivot landings.

Ten male and 10 female knees from age- and size-matched donors were subjected to 3T MR imaging to measure ACL cross-sectional area and lateral tibial slope. Each knee was loaded into a custom testing apparatus which delivered a standardized 2*BW compound impulsive load (compression force, knee flexion moment, internal tibial torque and muscle forces). The quadriceps’ resistance to rapid stretch was modeled using a novel non-linear spring. The 3-D tibiofemoral kinematics and kinetics, muscle forces, and anteromedial ACL relative strain were recorded for 100 ms. Females ACLs exhibited 95% greater peak strain than the male ACLs knees during the pivot landing, and ACL cross-sectional area and lateral tibial slope explained 59% of the variance in peak ACL strain. These results suggest an individual’s knee morphology can predispose them to an ACL injury.

Using similar methods and 10 pairs of knees, the human ACL exhibited fatigue failure under repetitive 3*BW and 4*BW pivot landings. The larger the applied cyclic loading, and the smaller the ACL cross-sectional area, the fewer cycles it took for the ACL to fail. Finally, in 12 female knees increasing quadriceps tensile stiffness by 33% reduced peak ACL strain by 16%, thereby reducing the risk for injury.

These results suggest that future interventions should target that the magnitude and frequency of pivot landing loading cycles, as well as knee morphology, to reduce ACL injury risk.

Saturday, April 28, 2012

University of Michigan

Spring Commencement

Saturday, April 28, 2012, 10:00 a.m.
Michigan Stadium

Spring Commencement is a University-wide event focusing on undergraduates, and all graduates of this term are welcome to attend. Held on Saturday, April 28, it is the ceremony at which the University's honorary degrees and all undergraduate degrees are conferred.

School and College commencement ceremonies will be held April 26-29, 2012.

Dr. Sanjay Gupta, CNN chief medical correspondant and U-M alumnus will deliver the spring commencement address. Five others also will receive honorary degrees.

Friday, April 27, 2012

Department of Biomedical Engineering

BME Undergraduate Graduation Celebration

BME Faculty and Staff
Friday, April 27, 2012, 4 - 6 p.m.
Lurie Biomedical Engineering Building Atrium

The University of Michigan's Biomedical Engineering Department proudly recognizes the graduating Baccalaureate Classes of 2011/2012 with a reception in their honor. Please join us for this special celebration and opportunity to socialize with BME graduates, families, BME professors and staff.

All graduates from August 2011, December 2011 and May 2012 classes and their families are invited. Refreshments and hors d'oeuvres served. Remarks by Douglas Noll, BME Department Chair at 5:00 p.m.

Friday, April 27, 2012

University of Michigan

University Graduate Exercises

Friday, April 27, 2012, 10:00 AM
Hill Auditorium

Graduates receiving master's or doctoral degrees through the Horace H. Rackham School of Graduate Studies are invited to attend University Graduate Exercises. This formal ceremony celebrates and individually recognizes the achievements of the Graduate School's master's and doctoral recipients.

Thursday, April 26, 2012

Final Oral Examination

Mouse Embryonic Stem Cells Differentiated into Neuron-like Cells or Schwann Cell-like Cells for the Development of Strategies to Ameliorate Deafness

Poornapriya Ramamurthy
Chair: Kate F. Barald, Ph.D

Thursday, April 26, 2012, 10:00 AM
2203 LBME (Lurie Biomedical Engineering)

Cochlear prostheses (CI) can restore hearing to patients with extensive sensorineural hearing loss (SNHL) by replacing lost or damaged cochlear mechanosensory hair cells (HC) with an electrode array. For the CI to send meaningful acoustic information to the brain, as large a population of remaining inner ear spiral ganglion neurons (SGN) as possible must become functionally coupled to the CI. SGN-CI coupling would be enhanced by a means of inducing directed neurite extension from the remaining SGN to the CI. Macrophage migration inhibitory factor (MIF) is a neurotrophic cytokine, which is expressed in early embryogenesis in the central and peripheral nervous systems, the eye and inner ear, where it is expressed in the supporting cells that underlie the HC and in all Schwann Cells. MIF is capable of inducing directional neurite outgrowth and supporting the survival of both early stage statoacoustic ganglion neurons (SAG) and their adult counterparts in the SGN. This laboratory produced the first embryonic stem cell (ESC) derived model of the Schwann Cell. These Schwann cells produce MIF, as do all Schwann Cells. We have coated CIs with mESC-MIF-producing “Schwann Cells” and observed directional outgrowth and contact formation between the “Schwann Cell”-coated CI and primary mouse embryonic SAG or adult SGN. We have also produced a mESC-derived neuron-like population of cells from mESC exposed to recombinant MIF that in many respects resemble SGN. Maturation of these MIF mESC-derived neuron-like cells was enhanced by Docosahexaenoic acid, a fatty acid that helps promote neuronal maturation. Such cells could be used eventually to replace lost of damaged SGN. Thus two different stem cell-based approaches have been used to address two different problems in deafness: improved integration of CI with native SGN and replacement of SGN themselves with a stem cell population molecularly engineered to resemble SGN.

Tuesday, April 17, 2012

U-M Academic Calendar

Last day of Winter 2012 Classes

Tuesday, April 17, 2012,

Classes end. Good luck on exams!

Friday, April 13, 2012

BME Career Event

Abbott Labs Corporate Info Session

Abbott Laboratories
Friday, April 13, 2012, 12:30 - 1:30 PM
1123 LBME (Lurie Biomedical Engineering Building)

Abbott Laboratories is a global diversified healthcare company. With over 90,000 employees world wide, Abbott provides access to its products in more than 130 countries. Abbott is heavily invested in innovation with 4 billion dollars spent in 2011 for research and development alone to discover, enhance, and pioneer new products to improve the quality of life for Abbott's new and existing customers. Employees of Abbott are proud to follow in a tradition that has brought a great deal of success. This emanates from Abbott's workplace excellence where we strive to exhibit initiative, innovation, integrity, teamwork, and adaptability. Abbott's mission is clear. We turn science into caring.

Tuesday, April 10, 2012

BME 500 Seminar Series

Thoracic Artificial Lung Design

Rebecca E. Schewe-Mott
Chair: Keith E. Cook, Ph.D.

Tuesday, April 10, 2012, 1:00 PM
GM Conference Room, Lurie Engineering Center (4th Floor)

Currently there is no sufficient bridge to lung transplant for patients with end-stage lung disease. Thoracic artificial lungs (TAL) are being developed for this purpose. TALs are attached to the pulmonary circulation, and thus their blood flow is provided by the right ventricle (RV). Current TALs possess blood flow impedances greater than the natural lungs, resulting in low cardiac output (CO) when implanted in series with the natural lung or in parallel under exercise conditions. In series attachment is desired so that the natural lung will still filter blood and perform its non-respiratory functions. However, in parallel attachment may allow for high flow applications. The goal of this research was to design a device with minimal impedance which does not cause a significant decrease in CO when attached in series, or in parallel with cases of high device flows, such as exercise. This was done both through the examination of geometry changes to the TAL housing and through the use of a compliant housing material.

A new compliant TAL (cTAL) was designed, prototyped and tested both in vitro and in vivo. First, computational fluid dynamics (CFD) and fluid-structure interaction (FSI) modeling were used to investigate inlet and outlet expansion and contraction angles, θ, of 15°, 45°, and 90° in both hard-shell TALs and cTALs. The 45° model was chosen for the cTAL prototype and tested in vitro and in vivo in the acute setting, attached both in parallel and in series with the native lungs.

The combination of a gradual entrance and exit to the device, as well as a compliant housing resulted in a device impedance of 0.5 mmHg/(L/min), much lower than the native lungs and all other existing TAL designs. The fiber bundle of the cTAL provided excellent gas transfer, with a rated flow well above 7 L/min. The cTAL developed with this research is capable of lower flow PA-PA attachment, with up to 50% of CO to the cTAL. PA-LA attachment of the cTAL will allow for excellent exercise tolerance and unloading of the RV in patients with pulmonary hypertension.

Wednesday, April 4, 2012

BME 500 Seminar Series

“Modular Scaffold Engineering for Regenerative Medicine”

Scott Hollister, Ph.D.
Professor of Biomedical Engineering and Mechanical Engineering,
Associate Professor of Surgery
University of Michigan

Wednesday, April 4, 2012, 12:00 - 1:00 PM
1303 EECS

Abstract: Despite a great deal of hype during the past 25 years, regenerative medicines, and especially, regenerative medicine for skeletal reconstruction, have failed to achieve significant clinical impact. This failure is multifaceted, resulting from technical challenges and business regulatory challenges. The technical challenges and business/regulatory challenges tend to push potential regenerative medicine therapies in polar extremes in terms of complexity and simplicity. The question is how to address these challenges simultaneously. In this talk, I will outline these challenges along with a modular engineering approach for regenerative medicine scaffolds, which are a key component of many regenerative medicine therapies. Modularity is an approach to building increasingly complex systems form simpler subsystems. It is seen in both natural and engineered systems. Specifically, in this talk I will propose modular approaches for the design and manufacture of regenerative medicine scaffolds, demonstrating that both the scaffolds themselves as well as the processes to create the scaffolds can fit a modular paradigm.

Wednesday, March 28, 2012

BME Career Event

nanoRETE Company Visit

Wednesday, March 28, 2012, 5:30-6:30 p.m
2203 LBME

Join nanoRETE for this important corporate information session! nanoRETE, Inc. is a Michigan-based company that provides real-time detection of pathogens using customized nanoparticle biosensors. The company has developed a platform that has the ability to test for numerous pathogens (anthrax, E. Coli, salmonella, tuberculosis, etc.) using a simple-to-use handheld device which generates screening results in about one hour.

Wednesday, March 28, 2012

BME 500 Seminar Series

“Evolving imaging applications in Radiation Oncology”

James Balter, Ph.D.
Professor of Radiation Oncology
Biomedical Engineering

Wednesday, March 28, 2012, 12:00 - 1:00 PM
1303 EECS

Abstract: Radiation Oncology has been highly dependent on imaging systems and analyses for improvements in precision. While technical advances have improved the precision with which we model anatomy to design treatments, guide daily patient position so as to limit erroneous consequences of geometric variations, and occasionally respond to large observed anatomic changes as treatment progresses, these efforts may be reaching their theoretical limit of benefit. A new era of imaging as a quantitative biomarker, for prognosis as well as response assessment, is emerging. Methods to use physiological, molecular and anatomic imaging more quantitatively may significantly extend the potential for tailoring radiation therapy to individual patients. This talk will explore the current and emerging state of quantitative imaging systems and tools in radiation Oncology.

Wednesday, March 21, 2012

Department of Biomedical Engineering

FDA Information Session

Art Czabaniuk, FDA
Wednesday, March 21, 2012, 5:30-6:30 p.m
1121 LBME (Lurie Biomedical Engineering)

Art Czabaniuk, Supervisory Investigator from the FDA Detroit District, will be visiting BME to present information about the FDA discuss career opportunities, specifically Consumer Safety Officer positions. Join HHS and help to make our world healthier, safer and better for all Americans. These positions represent an operating investigator in an FDA District Office or Resident Post. The consumer safety officer exercises sound judgment and professional competence to plan and carry out inspections and investigations, analyzing significant facts, developing logical conclusions and documenting evidence for regulatory action. Assignments encompass the full range of commodities and manufacturing processes in their districts related to human and animal foods and drugs, biological products, medical devices, or other products to ensure their safety and efficacy (as appropriate) for use by the public and for marketing in the U.S. and abroad.

Be sure and join us and learn how to apply for great job opportunities. Bring your resumes.

Food and beverages provided!

Wednesday, March 21, 2012

BME 500 Seminar Series

“Dysregulation of Receptor Tyrosine Kinase Signaling in Tumor Cell Migration and Invasion”

Shannon K. Hughes-Alford, Ph.D.
MIT Biological Engineering

Wednesday, March 21, 2012, 12:00 - 1:00 PM
1303 EECS

Abstract: Approximately 90% of human breast cancer deaths are due to metastasis of the primary tumor. An important aspect of carcinoma invasion is the presence of multiple stimuli from within the tumor microenvironment, including a wide variety of biochemical factors, biophysical effects of the extracellular matrix, and interstitial flow. Understanding how cells transiently adapt their intracellular signaling machinery to respond to these cues is essential to design interventions that block this process. In this presentation I will discuss how the aberrant expression of a member of the Ena/VASP family of actin binding proteins, MenaINV, acts as a catalyst for increased growth factor sensitivity and invasion through the dysregulation of tyrosine phosphatase activity. Using a combination of cell biological, advanced live- and fixed-cell imaging, quantitative biochemistry and cellular engineering techniques, this work illustrates one mechanism by which breast carcinoma cells can subvert clinically-relevant receptor tyrosine kinase inhibitors and demonstrates a novel role for Ena/VASP proteins in growth factor signaling. Finally, I will discuss how these studies can be combined with relational modeling techniques to elucidate more effective therapeutic targeting of the invasive cell population.

Monday, March 19, 2012

Department of Biomedical Engineering

BME Undergraduate Program Town Hall Meeting

Doug Noll, Ph.D.
Chair, Biomedical Engineering
Jan Stegemann, Ph.D.
Associate Undergraduate Chair, Biomedical Engineering

Monday, March 19, 2012, 6:00-7:30 pm
1121 LBME (Lurie Biomedical Engineering)

Undergraduates: This meeting will be a chance for you to hear about the department, share your views, and provide feedback on the BME program. This input is very important to the department and helps us make changes that will improve the undergraduate experience in BME. Please attend if you can! A pizza and salad dinner will be served.

Thursday, March 15, 2012

U-M Biomedical Engineering Society

Light-based methods for minimally-invasive disease detection in human tissues

Robert H. Wilson, Ph.D.
Biomedical Optical Diagnostics Laboratory, University of Michigan
P.I.: Professor Mary-Ann Mycek, Ph.D.

Thursday, March 15, 2012, 6 - 7 pm
1121 LBME (Lurie Biomedical Engineering)

This event is free, open to anyone, and food will be provided!

Abstract from Dr. Wilson: For disease diagnostics, there is an increasing prevalence of techniques (including some commercially-available devices) that shine light on human tissues to provide biomedically-significant information about the tissue components. For example, when white light is incident on tissue, each wavelength is scattered differently by cell nuclei, other organelles, and collagen fibers, and each wavelength will be absorbed in different amounts by blood. This information can then be employed to detect diseases like cancer, because the structure and composition of diseased tissue is different than that of healthy tissue so it will interact differently with the incident light. These optical methods are of great potential use to the medical field because they are minimally-invasive, clinically-compatible, and provide quantitative biophysical information about the tissue in real time. This talk will discuss the mechanisms by which light interacts with human tissue, the clinical optical measurements performed to acquire information about these processes, and the mathematical models employed to obtain diagnostically-significant tissue parameters, focusing on the application of pancreatic cancer detection.

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Wednesday, March 14, 2012

BME 500 Seminar Series

“Development of polymeric prodrugs as dually functioning nucleic acid delivery vectors”

David Oupicky, Ph.D.
Department of Pharmaceutical Sciences
Wayne State University

Wednesday, March 14, 2012, 12:00 – 1:00 PM
1303 EECS

Abstract: Nonviral gene delivery vectors based on complexes of nucleic acids with synthetic polycations (polyplexes) show promise for cancer gene therapy but they often cause adverse toxic effects and show poor therapeutic response due to low transfection activity. To help address the toxicity and low transfection activity, we have investigated new approaches to the design of polycations for gene delivery. The traditional design paradigm aims to synthesize biodegradable polycations that are degraded into safe low-molecular-weight byproducts to overcome the adverse toxicity. Our alternative approach to this traditional paradigm has been to synthesize biodegradable polycations that either degrade into active pharmacologic agents or function as pharmacologic agents themselves prior to biodegradation. This approach not only reduces toxicity of the polycations but it also enhances activity of the polyplexes when combined with properly selected therapeutic genes. Such combination approaches have the potential to greatly enhance the efficacy of non-viral gene therapy by the possibility to overcome low transfection by targeting multiple disease pathways. I will describe progress made towards development of non-viral gene delivery vectors based on (1) polycationic prodrugs targeting dysregulated polyamine metabolism in cancer and (2) polycationic cyclam-based antagonists of CXCR4, a chemokine receptor involved in cancer metastasis.

Monday, March 12, 2012

Department of Biomedical Engineering

“Precision Bioengineering – Interdisciplinary Development of Precision Bioinstruments”

Keisuke Goda, Ph.D.
University of California, Los Angeles

Monday, March 12, 2012, 10:00 – 11:00 a.m.
2203 LBME (Lurie Biomedical Engineering)

Abstract: Precision engineering – the interdisciplinary study and practice of high-precision engineering, metrology, and manufacturing – is the basis of modern technologies. In the last century, it has enabled measurement, fabrication, and control with unprecedented precision in virtually all branches of physical sciences. In this talk, I will discuss how the principles and methods of precision engineering can be applied to life sciences and medicine for exploitation of new tools and instruments. Starting with precision measurement in gravitational physics, I will talk about my recent development of an entirely new type of camera that holds the world record in shutter speed, frame rate, and sensitivity for continuous running cameras and also discuss the ultrafast camera’s utility to high-throughput single-cell imaging flow cytometry for high-precision detection of rare cells in blood and other biomedical applications.

Biography: Dr. Keisuke Goda is currently a Program Manager in the Photonics Laboratory (PI: Bahram Jalali), Microfluidic Biotechnology Laboratory (PI: Dino Di Carlo), and California NanoSystems Institute at UCLA. He obtained a B.S. degree summa cum laude from UC Berkeley in 2001 and a Ph.D. degree from MIT in 2007, both in physics. Building on interdisciplinary approaches that integrate the strengths of various physical sciences, his research focuses on the development of novel platform technologies for a diverse range of biomedical applications that require high precision. His previous and current research interests lie in precision measurement, biomedical imaging, fiber-optic communication, biophysics, microfluidic biotechnology, gravitational physics, quantum optics, and particle physics. He has published more than 80 journal and conference publications and holds 3 pending patents. He is the recipient of the Gravitational Wave International Committee Thesis Award (2008), UCLA Chancellor’s Award for Postdoctoral Research (2010), and Burroughs Wellcome Fund Career Award at the Scientific Interface (2011). He served as Co-Chair of the IEEE Photonics Society Los Angeles Chapter (2007 – 2011).

Wednesday, March 7, 2012

BME 500 Seminar Series

“Hierarchical Models of Cancer Cell Motility and Locomotion”

Krishna Garikipati, Ph.D.
Associate Professor, Mechanical Engineering

Wednesday, March 7, 2012, 12:00 - 1:00 PM
1303 EECS

Abstract: In this talk I will discuss the models with which we are currently studying the motility and locomotion of breast cancer cells. These include finite element-based structural mechanics models for the protrusion and retraction of the actin cytoskeleton, a non-equilibrium thermodynamics model of focal adhesion dynamics, and a continuum model of cytoskeletal remodeling. These models address aspects of motility and locomotion at a hierarchy of scales from the macro-molecular scale through the sub-cellular scale to the scale of the cell-extra cellular matrix interactions.

Tuesday, February 21, 2012

BME 500 Seminar Series

“Biomechanical interactions between endothelial cells and smooth muscle cells or mesenchymal stem cells”

Li Cao, Ph.D.
Duke University

Tuesday, February 21, 2012, 12:30 - 1:30 PM
G906 Cooley

Abstract: In native blood vessels, the biomechanical environment of endothelial cells (ECs) and smooth muscle cells (SMCs) influences their biological responses and likely regulates key functions of engineered blood vessels. The flowing blood exerts shear forces that are transmitted to the cytoskeleton of ECs and which regulate EC’s mechanical property that directly impacts its cellular function. The continuous interactions between ECs and underlying SMCs also influence SMC phenotype and function and are crucial in blood vessel homeostasis. The work described in this presentation focuses on the effect of flow and coculture environment on the mechanical property of ECs and the biological responses of SMCs or mesenchymal stem cells (MSCs) when culturing a confluent layer of ECs on top of SMCs or MSCs. Our findings show that coculture and flow have significant effects on the biomechanical behavior of ECs. The ECs cultured on SMC substrates became significantly stiffer than those on rigid substrates, yet the value of elastic modulus declined after exposure to flow. Changes to biomechanical properties of ECs in coculture and/or flow are correlated with changes in the cortical stress fiber density. Coculture and flow also have large impact upon the differentiation of MSCs to SMC lineage in a coculture model of tissue engineered blood vessels. MSCs cocultured with ECs under static condition expressed significantly higher levels of SMC specific markers as compared to monoculture and the expression of these markers was further elevated after exposure to flow. The findings of these studies highlight the important role of cell-cell and cell-matrix interactions in maintaining normal vascular function and possible implications in the pathogenesis of cardiovascular disease.

Thursday, February 16, 2012

BME Research Seminar

“Cartilage Tissue Engineering: Cells, Extracellular Matrix, and Growth Factors”

Rhima Coleman, Ph.D.
Postdoctoral Fellow
Hospital for Special Surgery New York, NY

Thursday, February 16, 2012, 3:00 - 4:00 p.m.
1123 LBME (Lurie Biomedical Engineering Building)

Abstract: Tissue homeostasis involves the complex interaction of autocrine/paracrine signaling and extracellular matrix constituents in the regulation of local cell behavior. Replicating this microenvironment for cartilage tissue engineering applications is an area of intensive research for modulation of stem cell and primary cell phenotype. Interaction of growth factors, scaffold type, and mechanical stimulation at multiple hierarchical length scales determine the final properties of any engineered tissue. Techniques allowing characterization of matrix properties at multiple length scales are constantly emerging allowing researchers to correlate final construct properties with modifications at each level. This talk will address some of these factors in the chondrogenic differentiation of mesenchymal stem cells, cartilage calcification, and fracture healing.

Thursday, February 16, 2012

U-M Biomedical Engineering Society

Understanding the mechanisms of knee impact injury: A multi-scale approach

Katie Ewing Ph.D.
Whitaker Fellow

Thursday, February 16, 2012, 6 - 7 pm
1121 LBME (Lurie Biomedical Engineering)

In addition to discussing her biomechanical work, Katie will talk about her Whitaker Fellowship to the University of Melbourne. If you are interested in learning more about this fellowship program and how to apply/win the award, be sure to attend this event!

This event is free, open to everyone, and food will be provided!

Abstract from Katie Ewing:

Knee injuries are prevalent in many sporting activities, which often involve high demand manoeuvres such as landing. The anterior cruciate ligament (ACL), despite being a strong stabilising ligament in the knee joint, is one of the most common injuries among young and fit athletes, with greater risk found in female athletes. The overall aim of our research is to better understand the underlying mechanism of ACL injuries during landing by obtaining quantitative information on lower extremity muscle activity. Furthermore, in addition to gross injuries such as ACL rupture, micro-fractures and damages to the knee joint are risk factors leading to post-traumatic osteoarthritis. Therefore, aiming to study joint injury in a multi-scale approach, we also investigated impact-induced injury to osteochondral explants by simulating the contact pressure in the joint during drop landing. Together, the results of these studies provide further insight into the possible mechanisms of knee impact injury and could lead to the development of better strategies for treatment and prevention of ACL injuries.

Katie Ewing is a first-year PhD student in the Department of Mechanical Engineering at the University of Melbourne. After obtaining her Bachelor’s and Master’s degrees in biomedical engineering from the University of Michigan, Katie received a one-year Whitaker Fellowship to conduct biomechanics research at the University of Melbourne. The Whitaker Program is open to graduating seniors, graduate students, and post-docs who are interested in pursuing a BME-related activity overseas. For more information, see

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Wednesday, February 15, 2012

Department of Biomedical Engineering

Exponent - Engineering and Scientific Consulting BME Grad Student Seminar

Robert Giachetti, Ph.D., P.E.
Sr. Engineer, Mechanical Engineering

Wednesday, February 15, 2012, 5:30 - 6:30 p.m. (Presentation and Q&A)
1121 LBME (Lurie Biomedical Engineering)

Exponent is a leading engineering and scientific consulting firm. Our multidisciplinary team of scientists, engineers, physicians, and regulatory consultants brings together more than 90 different disciplines to solve complicated problems facing corporations, insurers, government entities, associations and individuals. Our more than 850 staff members work in over 25 offices across the United States and abroad. Exponent has approximately 600 consultants, including more than 350 that have earned a doctorate in their chosen field of specialization. We currently have 40+ Michigan alumni on our staff!

Dinner Will Be Provided By Zingerman’s

Abstract: The presentation will provide a general description of the biomechanics and biomedical engineering practices and working at Exponent. Several exemplar projects that demonstrate the breadth and diversity of problems that an Exponent engineer faces will be reviewed. Specifically, analysis designed and executed for an alleged whole body vibration injury will be reviewed. Additionally, several other case examples will be overviewed to give a more robust account of what tasks an engineer performs at Exponent.

Wednesday, February 15, 2012

BME 500 Seminar Series

“Optofluidic lasers: principles and applications”

Dr. Xudong (Sherman) Fan
Associate Professor
Department of Biomedical Engineering

Wednesday, February 15, 2012, 12:00 - 1:30 PM
1303 EECS

Abstract: I will review various optofluidic lasers and compare their performance. Direct and indirect excitation schemes will be discussed followed by possible biosensing applications and future research directions.

Dr. Fan obtained B.S. and M.S. from Peking University in 1991 and 1994, respectively, and Ph.D. in physics and optics from Oregon Center for Optics at the University of Oregon in 2001. Between 2000 and 2004, he was a project leader at 3M Company on fiber optics and photonic sensing devices for biomedical applications. In August of 2004, he joined the Department of Biological Engineering at the University of Missouri as an assistant professor. In January of 2010, he joined the Biomedical Engineering Department at the University of Michigan as an associate professor.

Dr. Fan’s research includes photonic bio/chemical sensors, micro/nano-fluidics, and nano-photonics for disease diagnostics and bio/chemical molecule analysis. He has nearly 70 peer-reviewed publications and over 12 issued/pending patents. Presently, Dr. Fan serves as Associate Editor for Optics Express, responsible for optical biological and chemical sensors and optofluidics, and as a chair and organizer of numerous conferences for OSA, SPIE, and MRS. He is a recipient of 3M Non-Tenured Faculty Award (2004, 2005, and 2006), American Chemical Society Young Faculty Award, the Wallace H. Coulter Early Career Award (Phase I and Phase II), and the National Science Foundation CAREER Award. His research is supported by the National Science Foundation, National Institute of Health, private foundations, and industrial companies.

Tuesday, February 14, 2012

Final Oral Examination

"Engineering Functional Capillary Networks"

Stephanie Grainger
Chair: Andrew J. Putnam, Ph.D.

Tuesday, February 14, 2012, 1:00 PM
GM Conference Room - 4th Floor Robert H. Lurie Engineering Center

A major translational challenge in the fields of therapeutic angiogenesis and tissue engineering is the ability to form functional networks of blood vessels. Cell-based strategies to promote neovascularization have led to the consensus that co-delivery of endothelial cells (ECs) with a supporting stromal cell type is the most effective approach. However, the choice of stromal cells has varied across studies, and their impact on the functional qualities of the capillaries produced has not been examined.

Our lab has developed methods to form interconnected networks of pericyte-invested capillaries both in vitro in a 3D cell culture model and in vivo. However, if the engineered vessels contain ECs that are misaligned or contain wide junctional gaps, they may function improperly and behave more like the pathologic vessels that nourish tumors. The purpose of this thesis was to determine if stromal cells of different origins yield capillaries with different functional properties, in complementary in vitro and in vivo models.

In vitro, a fluorescent dextran tracer was used to visualize and quantify transport across the endothelium. In EC-fibroblast co-cultures, the dextran tracer penetrated through the vessel wall and permeability was high through the first 5 days of culture, indicative of vessel immaturity. Beyond day 5, tracer accumulated at the vessel periphery, with very little transported across the endothelium. When ECs were co-cultured with bone marrow-derived mesenchymal stem cells (MSCs) or adipose-derived stem cells (AdSCs), tighter control of permeability was achieved.

In vivo, all conditions yielded new vessels that inosculated with mouse dorsal vasculature and perfused the implant, but there were significant functional differences, depending on the identity of the co-delivered stromal cells. EC alone and EC-fibroblast implants yielded immature capillary beds characterized by high levels of erythrocyte pooling in the surrounding matrix, while EC-MSC and EC-AdSC implants produced more mature capillaries characterized by less extravascular leakage and expression of mature pericyte markers. Injection of dextran tracer into the circulation also showed that EC-MSC and EC-AdSC implants formed vasculature with more tightly regulated permeability. These results suggest that the identity of the stromal cells is key to controlling the functional properties of engineered capillary networks.

Wednesday, February 8, 2012

BME 500 Seminar Series


Michael Mayer
Department of Biomedical Engineering & Chemical Engineering
University of Michigan

Wednesday, February 8, 2012, 12:00 - 1:00 PM
1303 EECS

Abstract: Synthetic and biological nanopores can be used for fundamental and applied studies of individual biomolecules in high throughput. By measuring resistive current pulses during the translocation of single molecules through an electrolyte-filled nanopore, this technique can characterize the size, conformation, assembly, and activity of hundreds of unlabeled molecules per second. Inspired by the olfactory sensilla of insect antennae, we demonstrate that coating nanopores with a fluid lipid bilayer considerably extends the capabilities of nanopore-based assays. For instance, coating nanopores with different lipids allows fine control of the surface chemistry and diameter of nanopores. Incorporation of mobile ligands in the lipid bilayer imparts specificity to the nanopore for targeting proteins and introduces precise control of translocation times for targeted proteins based on their net electric charge. Most recently, we explored the potential of this technique for determining the affinity constant of a protein-ligand interaction, monitoring the kinetics of binding of this interaction, and characterizing the aggregation of Alzheimer’s disease-related amyloid peptides.

Wednesday, February 1, 2012

BME 500 Seminar Series

“Multiscale approaches to measure cellular mechanotransduction in 3D settings”

Wesley Legant, PhD.
University of Pennsylvania

Wednesday, February 1, 2012, 12:00 - 1:00 PM
1303 EECS

Abstract: The forces exerted by cells against the extracellular matrix can feedback through focal adhesions (mechano-sensitive protein complexes) to affect processes including migration, proliferation, and differentiation. However, despite the emerging importance of cell and tissue mechanics in biology, relatively few techniques exist to measure cell-generated forces. Those methods that do exist typically require that cells be cultured on 2D planar surfaces even though many cellular processes are altered or lost completely when cells are removed from a 3D extracellular matrix. I will discuss recent techniques to measure the 3D forces exerted by cells and tissues across multiple length scales. In the first approach, we used MEMS technology to generate arrays of microtissues consisting of cells encapsulated within 3D collagen matrices. Microcantilevers were used to simultaneously constrain the remodeling of a collagen gel and to report forces generated during this process. By modulating the cantilever stiffness or the collagen density, we could manipulate cellular forces, tissue stress, and the composition of cell-derived matrix within the tissues. However, this approach was still limited to measuring the integrated force derived from hundreds of cells within a tissue. In a second approach, we generated high resolution mappings of the 3D forces exerted by individual cells by utilizing linearly elastic polyethylene glycol hydrogels. By coupling observations of cell induced matrix displacement to finite element models, we spatially mapped the forces that cells exert on both 2D planar and fully 3D matrices with sub-cellular resolution. We found that on 2D planar surfaces, cells exert rotational moments about focal adhesions, but that such moments were not apparent when cells were fully encapsulated within 3D matrices. In contrast, cells in 3D matrices reach out thin protrusions and pull back inward toward the center of mass with strong forces at the tips of the extensions. Dynamic measurements of 3D tractions within growing protrusions revealed a reduced contractility, with strong inward forces exerted approximately 10 microns behind the invading tip. Together, these studies highlight novel approaches to understand the nature of cell-ECM interactions in multiple settings. Such mechanical insights will help us to understand how physical forces drive cell migration and behavior within physiologically relevant environments.

Wednesday, January 25, 2012

BME 500 Seminar Series

“Architectural and mechanical signals in the tumor microenvironment as driving forces in cancer progression”

Paolo Provenzano, PhD.
Fred Hutchinson Cancer Research Center
University of Wisconsin

Wednesday, January 25, 2012, 12:00 - 1:00 PM
1303 EECS

Abstract: Epithelial cancers, or carcinomas, behave like a complex “organ” and are comprised of multiple cell populations, including primary carcinoma cells, stromal fibroblasts, immune cells, endothelial cells, and structural and signaling components such as the stromal extracellular matrix (ECM). In this complex microenvironment, cells encounter a multitude of coordinated, simultaneously active, stimuli that are biochemical, structural, and mechanical in nature. The presence of these elements is neither random nor uniform across the tumor. Rather, these elements and the dynamic interactions among them evolve coordinately during tumor progression, conspiring to promote and sustain the carcinoma while also contributing to its ability to resist chemical therapies. As such, the first portion of the presentation will discuss recent work elucidating the influence of mechanical signals and ECM micro-architecture on tumor progression. The second portion will discuss novel therapeutic interventions to ablate physical barriers in the tumor stroma that impede delivery of chemotherapy.

Thursday, January 19, 2012

Final Oral Examination


Dae Woo Park
Co-Chairs: Professor William F. Weitzel and Professor Albert J. Shih

Thursday, January 19, 2012, 11:00 AM
2269 GG Brown

This study evaluates novel measurement methods of determining vascular wall strain and wall shear rate, which are interrelated physiologic parameters fundamentally important in vascular disease. Wall strain during vascular wall dilation was performed using ultrasound 2D speckle tracking and vascular wall edges and vascular wall shear rate were performed using decorrelation based velocity measurement method for in-vitro and in-vivo flow measurement. These experiments and measurements were performed to investigate both the novel measurement methods as well as the relationship between the vascular wall shear rate and vascular wall dilation. First, this study measures the strains of the arterial wall using the ultrasound radio-frequency (RF) signals. The RF signals were acquired from B-mode images of a human brachial artery for healthy adult subjects under normal physiologic pressure and the use of external pressure (pressure equalization) to increase strain. Strains in the arterial wall during arterial dilation (from diastole to systole) were determined using a 2D speckle tracking algorithm. These ultrasound results were compared with measurements of arterial strain as determined by finite-element analysis (FEA) models with and without the effects from surrounding tissue, which was represented by homogenous material with fixed elastic modulus. Second, this research aims to measure wall edges and wall shear rate for in-vitro flow experiment using decorrelation ultrasound based velocity measurement. By moving transducer with a given speed on a tissue-mimicking phantom, the speckle movements vs. correlation curves were obtained for each depth using 2D tracking. The flow velocity was obtained by multiplying the speckle movement in two consecutive frames by the acoustic frame rate. The wall edge was determined using B-mode images and 2nd order gradient of flow velocity profiles. The wall shear rate was measured at the wall edge and evaluated by comparing with velocity gradients from parabolic flow velocity profile based on Poiseuille theory. Third, this research measures the vascular wall shear rate in the brachial artery for nine healthy, six chronic kidney disease and two end-stage renal disease subjects using the decorrelation based ultrasound velocity measurement. The vascular wall shear rate and vascular diameter pre-, during- and post-vascular occlusion with pressure cuff were compared for five healthy and three renal disease (two chronic kidney disease and one end-stage renal disease) subjects at top and bottom wall edges. The vascular wall shear rate and vascular wall dilation were different between pre- and post-vascular occlusion for healthy vs. renal disease subjects. These research findings validate the underlying novel measurement methods and determine the relationship between the vascular wall shear rate and vascular wall dilation. This relationship can be corroborated by considering vascular wall elasticity during vascular dilation and these results indicate that these measurements can be improved by incorporating the effects of surrounding tissue in vascular modulus estimation.

Wednesday, January 18, 2012

BME 500 Seminar Series

“Natural and synthetic hydrogels for ovarian follicle culture in vitro

Ariella Ahikanov, Ph.D.
Northwestern University

Wednesday, January 18, 2012, 12:00 - 1:00 PM
1303 EECS

Abstract: The increasing number of young survivors of cancer with favorable outcomes is defining the need for a more comprehensive approach that will improve the quality of life after cancer, including the preservation of fertility. Options such as oocyte preservation and ovarian tissue banking followed by tissue transplantation have produced a limited number of live births in humans. Successful hydrogel system for in vitro follicle culture and ovarian tissue transplantation may therefore be beneficial to many young girls and women. Natural (fibrin and alginate) and synthetic (poly ethylene glycol (PEG)) hydrogels with controllable physico-chemical properties, such as mechanical stiffness and degradation rate can regulate cellular processes such as cell proliferation and differentiation, as well as tissue growth and development. In the ovary, immature follicles reside in the cortex of the ovary, which is a less permissive environment, but as they grow they expand to a more permissive, perimedullar interior region of the ovary. We hypothesized that fibrin-alginate inter penetrating network (FA-IPN) has the potential to mimic the in vivo conditions by having the same transition from high to low modulus. In the beginning of the culture, when FA-IPN is formed it has a modulus of 300Pa that is contributed by both components of the system, and follicles encapsulated in the matrix experience greater compressive force. During the culture the fibrin component of the system is degraded by proteases and the hydrogel becomes softer (40Pa). Importantly, fibrin incorporation in the system allowed reducing alginate solid content from 0.25% to 0.125% w/v and resulted in greater follicle expansion and improved maturation and fertilization rates compared to the alginate alone system. However, the narrow range of control of the mechanical properties of alginate and fibrin became a limiting factor for culture of primate and human follicles that require longer culture period. The mechanical properties and the biological activity of synthetic materials, such as PEG can be adjusted to meet the requirements for cell function, differentiation and growth. Inspired by the fact that fibrin can be degraded by plasmin activated by the encapsulated follicle, we synthesized plasmin-sensitive peptides with varying proteolytic sensitivity and prepared PEG hydrogels cross-linked via Michael-type addition. Mouse ovarian follicles were encapsulated and cultured in vitro for 8 days and the extent of follicle expansion was dependent of the sensitivity of the cross-linking peptide to the proteolytic activity of plasmin. Differentiation of immature granulosa cells and the development of a fluid-filled antral cavity were observed within the follicle and the oocytes from cultured ovarian follicles matured to metaphase-II (MII) arrested eggs. Interestingly, hydrogels degraded locally around the expanding follicle in response to protease secretion, but maintained their global integrity, in agreement with the cyclic spatial and temporal tissue dynamics present in ovarian tissue. This is the first synthetic biomaterial system created for in vitro follicle culture, and is currently being investigated as fertility preservation technology for women facing premature infertility from cancer therapies or other disorders.

Tuesday, January 17, 2012

U-M Biomedical Engineering Society

BMES Seminar Series and Mass Meeting

Tuesday, January 17, 2012, 5:00 - 7:00 PM
Lurie Biomedical Engineering Building Atrium

This coming Tuesday, 1/17, the Biomedical Engineering Society will be holding its monthly seminar series for the month of January! The seminar will be from 5-6pm in the LBME atrium, and presenting this month will be Dr. Tim Hall, and the topic will be Histotripsy Therapy in Urology. An abstract for Professor Hall's talk can be found below. Immediately following the Seminar Series presentation, BMES will be holding its Winter Mass Meeting for all BMES members, anyone who is still interested in joining BMES, and anyone who just wants to find out more about our organization! The mass meeting will be held from 6-7pm in the LBME atrium, and we will be giving a presentation on BMES, discussing what we do, upcoming events, and how to get involved. Food will be provided for both events! Abstract for Dr. Hall's presentation: Title: Histotripsy Therapy in Urology Histotripsy ultrasound therapy is a method of soft tissue ablation where extremely intense acoustic bursts cause microscopic bubbles to form and collapse energetically (cavitation) disrupting cell membranes and fragmenting nearby tissues. In this talk, we look at urologic applications for histotripsy including non-invasive ablation of renal masses and rapid erosion of kidney stones.

Tuesday, January 17, 2012

Department of Biomedical Engineering

LBME Planet Blue Open House (free lunch!)

Planet Blue Operations Teams
Tuesday, January 17, 2012, 11:30 am – 12:30 pm
Lurie Biomedical Engineering Building Atrium

We are pleased to invite you to participate in the "Planet Blue" open house for the Lurie Biomedical Engineering Building on Tuesday, Jan. 17, from 11:30 am – 12:30 pm in the Atrium. Come learn about energy use and conservation efforts in your building and receive a free water bottle, Planet Blue t-shirt, and catered lunch! This your chance to share your observations, questions, and suggestions about energy use in the building, talk with the engineers who understand how your building works, and learn how you can reduce your environmental footprint at work and at home. A wide array of information related to energy use and campus sustainability efforts will be available at the Open House, including utility consumption trends, energy conservation best practices, recycling, green purchasing, green computing, transportation alternatives, and more. Planet Blue is a campus-wide outreach campaign designed to promote awareness of opportunities for energy conservation and recycling in our facilities. You can show your support for sustainability efforts at UM and Planet Blue by signing up ahead of time to become a Planet Blue Citizen at Your participation and involvement are key to making a sustainable difference. Thanks, and I hope to see you next Tuesday — come hungry and curious!

Wednesday, January 11, 2012

Final Oral Examination

Biomechanical Analyses of Leaning and Downward Reaching Tasks: Importance of Rapid, Targeted Center of Pressure Submovements in Young Versus Older Women With and Without Stooping, Crouching, or Kneeli

Manuel Hernandez
Co-Chairs: Neil Alexander and James Ashton-Miller

Wednesday, January 11, 2012, 1:00 PM
Johnson Rooms in the Lurie Engineering Center (LEC)

Stooping crouching or kneeling (SCK) difficulty is prevalent among older adults yet few studies have explored the mechanisms underlying downward reaching and pick-up difficulty. During targeted movements tradeoffs are expected between the speed and accuracy of center of pressure (COP) movements as balance is maintained. Thus, this research focused on how age-related changes in COP control strategies affect the performance of tasks with a large range of truncal motion and momenta. It was hypothesized that while performing leaning and downward reaching movements, older women, compared to younger women, would exhibit slower but more frequent COP submovements in order to accomplish the task and regain the upright posture.

First, we investigated the limiting factors in downward reach and pick-up movements. Using an age-adjusted proportional odds model, increased SCK difficulty was found to be independently associated with balance confidence, leg joint limitations, and knee extension strength.

Secondly, we explored the age-related changes in COP control in healthy women. Despite being 27% slower, older women rely on nearly twice as many submovements to maintain a similar level of endpoint accuracy in volitional COP movements, particularly when moving posteriorly. Furthermore, older women used slower primary submovements that more often undershot their target, in comparison to young women, particularly as movement amplitude increased.

Lastly, healthy older women were found to lose their balance more often than young women in downward reaching tasks, but rely on similar COP control strategies when successful. Modeling results suggest that a simple forward dynamic model that accounts for changes in musculoskeletal factors may distinguish between healthy young and healthy older women with and without SCK difficulty.

We conclude that biomechanical factors can distinguish between older women with and without SCK difficulty. Given the significance of the rate of torque development in arresting downward reaching movements, changes in COP control may be effective tools in evaluating early signs of physical impairment. Undershooting primary submovements and increased secondary submovements are indicative of an increasingly conservative strategy used by older adults near the limits of the base of support that may explain their slower speeds during whole body movements to maintain balance.

Wednesday, January 11, 2012

BME 500 Seminar Series

“Light, Sound, nanoAction: nanoparticle-augmented ultrasound-guided photoacoustic imaging for cancer detection, differentiation and therapy guidance”

Stanislav Emelianov
Ultrasound Imaging and Therapeutics Research Laboratory
Department of Biomedical Engineering
University of Texas at Austin

Wednesday, January 11, 2012, 12:00 - 1:00 PM
1303 EECS

A quantitative morphological, functional and molecular imaging technique capable of visualizing biochemical, pharmacological and other processes in vivo and repetitively during various stages of tumor progression and cancer treatment is desired for many fundamental, preclinical and clinical applications. Recently, we introduced several imaging techniques capable of visualizing anatomical structures and functional information about the tissue. Furthermore, targeted contrast agents were developed to enable the cellular and molecular sensitivity of the developed imaging techniques.

In this presentation, combined ultrasound and photoacoustic (USPA) imaging augmented with imaging contrast nanoagent will be introduced. Specifically, USPA imaging to simultaneously obtain the anatomical and molecular map of tumor in-vivo will be presented. An example using gold nanospheres (AuNPs) functionalized to target cancer biomarker (e.g., EGFR) will be given. Furthermore, we will demonstrate the role of USPA imaging in therapy planning, guidance and monitoring. For example, image-guided photothermal therapy of cancer using targeted metal nanoparticles will be discussed. Finally, design and synthesis of contrast nanoagents with properties desired for cellular/molecular USPA imaging will be presented and discussed.

The presentation with conclude with the discussion of advanced developments in morphological, functional and molecular USPA imaging. Applications of the nanoparticle-augmented USPA imaging ranging from macroscopic to microscopic visualization will be presented, and future directions will be described.

Friday, January 6, 2012

Final Oral Examination

Optimized Beamforming and Limited Angle Tomography of the Compressed Breast

Fong Ming Hooi
Chair: Paul L. Carson

Friday, January 6, 2012, 2:00 PM
Taubman Medical Library, 2903

Breast cancer is one of the most predominant forms of cancer, comprising of 22.9% of all cancers in women, causing approximately 450,000 deaths in 2008. The conventional imaging standard procedure for screening studies encompasses mammography followed by handheld ultrasound. However, there is a decrease in specificity and sensitivity when imaging younger women with dense breast tissue.

This dissertation will investigate ultrasound grayscale, speed of sound, and attenuation imaging of the compressed breast to improve current screening procedure. Enabling improved efficiency in 3D volume B-mode imaging would remove operator dependency on acquiring ultrasound data and improve diagnosis because handheld ultrasound sometimes is focused on a different lesion compared to the suspicious one found on the mammogram. Beamforming algorithms for use in reconfigurable arrays were investigated. A transmit beam with an extended depth of focus was developed by minimizing a cost function that reduced the side lobe energy while maximizing the depth of focus generated by the beam. Optimized channel selection of subelements in reconfigurable arrays was illustrated in order to remove excess side lobe energy caused by overall phase delay across the aperture.

Speed of sound and attenuation imaging represent different imaging modes and have been shown to increase sensitivity and specificity in breast imaging studies. In the compressed breast, these transmission modes have limited views similar to those in X-ray tomosynthesis, resulting in a major streaking artifact in the axial direction. Using a regularized cost function, a priori information was used to aid the speed of sound and attenuation inversion to produce images with minimal streaking artifacts. The speed of sound images were employed in a forward model to produce attenuation coefficient images with only speed of sound artifacts, allowing creation of attenuation images representative of the bulk properties of the different tissues in the breast, i.e., including attenuation from local absorption and isotropic scattering of the ultrasonic energy.

Wednesday, January 4, 2012

BME 500 Seminar Series

BME Seminar Series

Doug Noll, Ph.D.
Chair, Biomedical Engineering

Wednesday, January 4, 2012, 12:00 - 1:00 PM
1303 EECS

Topic TBD

Friday, December 9, 2011

Final Oral Examination

Asynchronous Magnetic Bead Rotation (AMBR) Microfluidic Biosensor Platform for Rapid Microbial Growth and Susceptibility Studies

Irene Sinn
Co-Chairs: Raoul Kopelman and Mark A. Burns

Friday, December 9, 2011, 2:00 PM
2210 Lurie Engineering Center (LEC)

The emergence and spread of antimicrobial resistance is considered to be ‘one of the world’s most pressing health problems.’ An effective way to address this global concern is to develop more rapid and accurate diagnostic systems to identify and determine the antibiotic susceptibility of infectious organisms, so as to enable patients to be promptly prescribed the most appropriate therapies. In this dissertation, we present an innovative platform that rapidly measures bacterial growth/no-growth. This platform integrates a sensitive asynchronous magnetic bead rotation (AMBR) biosensor with microfluidics. The AMBR biosensor is a recently developed technology in which the rotation of a magnetic bead that is placed within a rotating magnetic field provides information regarding the physical properties of the bead complex and the bead’s environmental conditions. By compartmentalizing individual AMBR sensors in microfluidic droplets, we enhance the sensitivity, parallelization capabilities, and portability of the AMBR system. We have successfully demonstrated the suitability of the AMBR microfluidic biosensor platform for rapid bacterial growth studies and its applicability to antimicrobial susceptibility testing (AST). We envision that this platform will have the sensitivity to reduce significantly the turnaround time for AST, specifically in determining the minimum inhibitory concentration (MIC) of an antibiotic, or other drug, that inhibits bacterial growth, and provide test results much more rapidly than available commercial systems. This would not only help the specific patient, but also prevent the current use of wide-spectrum antibiotics, which leads to the proliferation of drug resistant microbes.

Thursday, December 8, 2011

BME 500 Seminar Series

“Intramolecular Strain and Worm-like Chains: Control of Processivity in Kinesin Molecular Motors”

William Hancock, PhD
Associate Professor
Penn State University

Thursday, December 8, 2011, 12:00 - 1:00 PM
1017 Dow

Abstract: Kinesin motor proteins both exert and respond to mechanical forces, and as such they serve as a model system to study mechanobiology at the molecular level. The mechanism of kinesin transport involves mechanical and biochemical coordination between the two motor domains, which alternately step along microtubules. We are studying the neck linker domain, a sequence that connects each kinesin motor domain to their shared coiled-coil dimerization domain. Because tension between the two motor domains must be transmitted through the neck linkers, the mechanical properties of this domain are very important. However, they are not well understood. We are using single-molecule microscopy experiments, computational modeling, molecular dynamics simulations, and biochemical assays to understand similarities and differences between kinesins that are involved in axonal transport, ciliagenesis, and cell division. These diverse motors contain neck linkers of different lengths and we find that the length of the neck linker determines motor properties considerably more than do differences in the biochemical properties of the motor domains. This paradigm helps to unify mechanisms of diverse kinesins and has implications for understanding myosin, dynein, and other molecular machines.

Friday, December 2, 2011

Final Oral Examination

Noninvasive Thrombolysis Using Histotripsy Pulsed Ultrasound Cavitation Therapy

Adam Maxwell

Friday, December 2, 2011, 10:00 AM
2901 Taubman Medical Library

Several cardiovascular conditions are a result of an obstructive blood clot in the vasculature (thrombosis). In this thesis, histotripsy is proposed as a method of thrombolysis. Histotripsy is a noninvasive therapy that utilizes short, high-amplitude, focused ultrasound pulses to mechanically reduce targeted tissue structures to liquid debris by acoustic cavitation. This work investigated the mechanisms by which histotripsy generates cavitation and clot disruption, and evaluated the efficacy and safety of such a therapy for thrombolysis.

The cavitation activity responsible for tissue breakdown during histotripsy was studied by high-speed photography and numerical simulation. It was found that cavitation clouds form at the transducer focus due to scattering of shock waves in each ultrasound pulse from individual cavitation bubbles. This scattering activity generates a large tensile wave which expands a cluster of microbubbles when the tensile pressure is greater than a measured threshold of approximately 30 MPa in blood or thrombus. The interaction of the cavitation with tissue and cell structures was studied in a phantom containing agarose and red blood cells that allowed visualization of cavitation-based mechanical damage. The results suggested that cell lysis may be achieved by tensile strain causing rupture of the cell membrane that occurs with expansion of the cavitation bubbles.

Based on these studies, focused histotripsy therapy transducers were designed to controllably generate cavitation clouds in the vasculature for performing thrombolysis. Transducers were integrated with an ultrasound imaging system to provide feedback for targeting and monitoring the progress of the treatment. Rapid thrombolysis was observed when histotripsy was applied to clots during in-vitro experiments. The resulting debris generated by the procedure was found to be mainly subcellular in size and thus unlikely to cause significant embolism. It was also noted that histotripsy can attract, trap, and destroy free clot fragments flowing through a vessel. Based on this observation, a noninvasive embolus trap (NET) was developed, acting as a filter for particles to prevent embolism during the thrombolysis procedure. Finally, a porcine model of deep-vein thrombosis was used to evaluate histotripsy thrombolysis in-vivo. These experiments confirmed the feasibility of the treatment and suggest histotripsy can noninvasively achieve clot breakdown in a controlled manner.

Thursday, December 1, 2011

BME 500 Seminar Series

“Compensatory Networks and Skeletal Function”

Karl J. Jepsen, PhD
Professor, Department of Orthopaedic Surgery

Thursday, December 1, 2011, 12:00 - 1:30 PM
1017 Dow

Abstract: Susceptibility to common diseases is generally thought to originate at the molecular-level. However, adaptive processes at higher levels of biological organization also define the performance of complex systems. The extent to which these adaptive processes compensate for genetic and environmental factors and whether limited compensation increases disease susceptibility are unclear. We identified a network of compensatory trait interactions in the mouse and human skeletal systems that explained the vast majority of the variation in bone function among young adults. However, intrinsic cellular constraints limited the degree of compensation, leading to disparity in bone function among individuals and increased fracture susceptibility. Thus, insufficient compensation of a common trait variant contributed to disease susceptibility. Whether constraints at this biological level can be circumvented to better equilibrate function among individuals remains to be determined.

Thursday, November 17, 2011

BME 500 Seminar Series

“Manipulation of the Cellular Microenvironment to Study Tissue Development and Disease”

Kristyn S. Masters, Ph.D.
University of Wisconsin-Madison

Thursday, November 17, 2011, 12:00 - 1:30 PM
1017 Dow

Abstract: Multiple features of the cellular microenvironment can influence cell function, including soluble factors, mechanics, and the extracellular matrix (ECM). Understanding the roles of these stimuli in tissue development and disease can enable the construction of appropriate engineered environments for applications such as guiding stem cell fate for tissue regeneration or elucidating disease etiology to identify potential treatment targets. For example, our work in manipulating the cellular microenvironment in the context of calcific aortic valve disease has revealed information about the roles of extracellular matrix components, growth factors, peptide-receptor interactions, and intracellular signaling pathways in valve calcification, advancing us toward the creation of physiologically-relevant in vitro platforms for testing disease treatments. Using similar approaches, we also investigate how dermal wound healing is affected by the manner in which growth factors are presented, as well as the relationship between ECM remodeling and human embryonic stem differentiation. This presentation will concentrate on ways to tailor both 2-D and 3-D in vitro environments to regulate cell phenotype or fate and create defined systems that mimic elements of native pathologies.

Personal Bio: Kristyn S. Masters is an Associate Professor in the Department of Biomedical Engineering and the Materials Science Program at the University of Wisconsin-Madison. Dr. Masters has a bachelor’s degree in Chemical Engineering from the University of Michigan and a Ph.D. in Chemical Engineering from Rice University, and she performed her post-doctoral work in Chemical and Biological Engineering at the University of Colorado-Boulder. Her research program focuses upon applying tissue engineering techniques to elucidate disease etiologies and studying how microenvironmental cues regulate cell function, and her work is funded by the NSF, NIH, American Heart Association, and W.H. Coulter Foundation for Translational Research. Dr. Masters has also won numerous national, regional, and local teaching awards, and she co-directs a program that aims to advance effective educational and mentoring practices for both current and future faculty.

Thursday, November 10, 2011

BME 500 Seminar Series

“Single Cell Membrane Poration by Directional Tandem Bubbles”

Pei Zhong, Ph.D.
Duke University

Thursday, November 10, 2011, 12:00 - 1:30 PM
1017 Dow

Abstract: In the past decade, the feasibility of ultrasound-mediated drug, gene and siRNA delivery has been well demonstrated and cavitation has been shown to play a central role in this process. There is a growing interest in applying this promising technology to various clinical applications, propelled by the advances in MRgFUS technology, nano/micro-scale drug and gene carriers, and multi-functional ultrasound contrast agents. Despite great potential and enthusiastic scientific interest, the fundamental mechanism by which ultrasound produces membrane poration, especially at the cellular level, is still poorly understood. We have recently developed a new method that utilizes tandem microbubble for producing directional and targeted membrane poration at single cell level with unprecedented precision and flexibility [1]. This method allows us to observe in real-time bubble-bubble interaction with microjet and vortex formation, cell deformation, and pinpoint membrane rupture (with pore size ranging from 200 ~ 2,000 nm) and progressive diffusion of marker molecules into the target cell. Furthermore, we have implemented tandem bubble generation using micron-sized gold dots patterned on a glass substrate in a microfluidic channel made of polydimethylsiloxane (PDMS) [2]. Combined with cell patterning, this approach provides a versatile platform to investigate the mechanisms of cavitation-induced membrane poration with high consistency and spatial/temporal resolution.

[1] Sankin, G.N., F. Yuan, and P. Zhong, Pulsating tandem microbubble for localized and directional single-cell membrane poration. Physical Review Letters, 2010. 105(7): p. 078101.
[2] Yuan, F., G.N. Sankin, and P. Zhong, Dynamics of tandem bubble interaction in a microfluidic channel Journal of the Acoustical Society of America, 2011 (in press).

Thursday, November 3, 2011

BME 500 Seminar Series

“Finite Element Modeling in Biomechanics: Bones, Eyes and Collagen Gels”

Richard T. Hart, Ph.D.
Edgar C. Hendrickson Designated Professor and Department Chair
Department of Biomedical Engineering
The Ohio State University

Thursday, November 3, 2011, 12:00 - 1:30 PM
1017 Dow


A key challenge in tissue mechanics is the characterization of the mechanical behavior of biological tissues due to mechanical forces. This talk will give a survey of mechanical structure-function behavior with three different systems: bones, eyes, and cell-induced stress transmission in collagen gels. For bone, an overview of the adaptation of living tissue to mechanical usage will be presented, along with techniques to understand and model bone and it’s adaptive responses at the organ (continuum) level.

For the eye, the discussion will center on the optic nerve head. The optic nerve head is the small portion in the back of the eye through which the major nutrient vessels pierce the sclera and through which the neural tissues exit to connect to the brain. Abnormally high fluid pressure in the eye can deform the nerve head, and progressive loss of vision can result (glaucoma). Progress in understanding the structure-function behavior of the optic nerve head will be described based on 3-D geometries of continuum and discrete finite element models.

For cells, we are studying a possible mechanism of cell-cell communication via stresses transmitted by collagen fiber networks in the Extra Cellular Matrix (ECM). Fibroblasts seeded on bovine collagen cells compact and reorganize collagen fibers over 24 hours. Our initial 2D finite element models of these cell-fiber networks predict that stresses generated by the centripetal shrinking of a cell can transmit significant stresses to neighboring cells, perhaps over a distance of 10 cell diameters or more. This mechanical signaling may provide cues for cell motion and organization over longer distances that would be possible via chemical signaling.


Rich Hart grew up in Wilmington, Delaware and earned B.E.S. (Bachelor of Engineering Science, 1975) and M.S. (Engineering Mechanics, 1977) degrees from the Georgia Institute of Technology in Atlanta, Georgia. Georgia Tech subsequently awarded him a yearlong World Student Fund scholarship to study Biomechanics at the Technische Universität in Berlin (West) Germany from 1977-78. Upon his return, he enrolled in the Department of Mechanical and Aerospace Engineering at Case Western Reserve University in Cleveland, Ohio (Ph.D. awarded January 1983).

He joined the faculty in Tulane’s Department of Biomedical Engineering as an Assistant Professor in December 1982. He served as Department Chair at Tulane’s Department of Biomedical Engineering from 1997-2006, and in 2001 was appointed as the Alden J. “Doc” Laborde Professor of Engineering.

He joined the faculty of Biomedical Engineering at the Ohio State University as the Edgar C. Hendrickson Designated Professor and Department Chair on July 1, 2006.

His research interests are in finite element analysis of biological tissues and structures, with a primary focus on work that seeks to describe, simulate, and predict the response of bone tissue to mechanical stimuli. In addition, he has collaborated on research projects in brain physics, spine mechanics, ophthalmology, and cell-initiated stress transmission in collagen gels.

In 1999, he was elected a Fellow of the Institute for Medical and Biological Engineering and in 2001 he was given the American Society for Engineering Education’s Theo C. Pilkington Outstanding Educator Award. In 2004 he and co-authors shared the Association of International Glaucoma Societies Award. He has completed two terms as an Associate Editor for the Journal of Biomechanical Engineering and is currently on the Editorial Board for the journal Computer Methods in Biomechanics and Biomedical Engineering, and in 2006 was elected to the board of directors for the Biomedical Engineering Society, was elected a fellow in 2010, and currently serves as the Secretary for the Society.

Friday, October 28, 2011

BME Guest Speaker and 2011 Alumni Award Recipient

“From Bones to Genomes and Corporate Loans”

Monique Mansoura, Ph.D.
Sloan School of Management
Massachusetts Institute of Technology
MIT Sloan Fellows Program in Innovation and Global Leadership, Class of 2012

Friday, October 28, 2011, 11:00 - 12:00 PM
2203 LBME (Lurie Biomedical Engineering)

Bio: Monique Mansoura has led an impressive 15-year career shaping U.S. science policy in genomics and biodefense. Her career direction was fixed as a U-M BME doctoral student studying cystic fibrosis under BME professor Dave Dawson and leading geneticist Francis Collins. When Collins moved to the National Institutes of Health to lead the Human Genome Project, Mansoura joined his staff to address concerns raised by the sequencing of the human genome.

Deeply offended by the misuse of science in the 2001 anthrax attacks, Mansoura changed direction. She took advantage of a training detail to help launch an office in Health and Human Services responsible for developing and acquiring medical countermeasures for chemical, biological, radiological, and nuclear threats. In nine years, she has contributed to anthrax and smallpox vaccine readiness as well as a major strategic roadmap for allocating billions in Project BioShield funds to acquire drugs, vaccines, and diagnostics.

Thursday, October 27, 2011

BME 500 Seminar Series

“Photon plus Ultrasound: a new tool for medical imaging”

Xueding Wang, Ph.D.
Department of Radiology
University of Michigan

Thursday, October 27, 2011, 12:00 - 1:30 PM
1017 Dow

Abstract: Photoacoustic imaging (PAI), also referred to as optoacoustic imaging, is an emerging biomedical technique that is noninvasive and nonionizing, with high sensitivity, satisfactory imaging depth and good temporal and spatial resolution. PAI uses a short-pulsed laser source to illuminate a biological sample and generates photoacoustic waves due to thermoelastic expansion. Then the photoacoustic signals are measured by wide-band ultrasonic transducers to rebuild the image of the sample. Therefore, like conventional optical imaging, PAI presents optical contrast which is highly sensitive to molecular conformation and biochemical contents of biological tissues and can aid in describing tissue metabolic and hemodynamic changes. Unlike conventional optical imaging, the spatial resolution of PAI is determined mainly by the measurement of light-generated photoacoustic signals and is not limited by the strong light diffusion. As a result, the resolution of PAI is parallel to high-frequency ultrasonography. In this talk, the basic idea, current status and potential future applications of this novel technique will be introduced.

Wednesday, October 19, 2011

BME 500 Seminar Series

“Hierarchical Models of Cancer Cell Motility and Locomotion”

Krishna Garikipati, PhD
Associate Professor
Mechanical Engineering

Wednesday, October 19, 2011, 12:00 - 1:30 PM
1017 Dow

Abstract: In this talk I will discuss the models with which we are currently studying the motility and locomotion of breast cancer cells. These include finite element-based structural mechanics models for the protrusion and retraction of the actin cytoskeleton, a non-equilibrium thermodynamics model of focal adhesion dynamics, and a continuum model of cytoskeletal remodelling. These models address aspects of motility and locomotion at a hierarchy of scales from the macro-molecular scale through the sub-cellular scale to the scale of the cell-extra cellular matrix interactions.

Thursday, October 13, 2011

Final Oral Examination

Nitric oxide therapies for local inhibition of platelets on blood-contacting surfaces

Kagya A. Amoako

Thursday, October 13, 2011, 11:30 AM
GM Conference Room, Lurie Engineering Center (4th Floor)

About two hundred million blood-contacting devices are used clinically worldwide every year. These devices are made up of mostly artificial materials that lack the physiological mechanisms used by a healthy endothelium to modulate hemostasis. Consequently, upon blood contact, they activate the contact system of blood coagulation leading to clot formation. Current approaches used to inhibit blood clotting are associated with many problems. Systemic heparinization can lead to bleeding complications. Surface coatings on clinical devices have not shown significant benefits and testing outcomes from experimental surface modification approaches, although promising, indicate the need for a substantial amount of research before clinical trials.

This research investigates nitric oxide (NO) therapies for local inhibition of platelets on blood-contacting medical devices including adult artificial lungs and intravascular catheters. NO is accepted as an effective inhibitor of platelet activation and has been investigated by several research groups. Incorporation of catalytic agents in biomaterials for local NO generation from the decomposition of NO donors is one of the proven methods for functionalizing biomaterials. This method has shown promising non-thrombogenic outcomes in extracorporeal circulation (ECC) large bore circuits and small surface area chemical sensors. However, no knowledge exists on the applicability of this technique to large surface-area, low-flow devices like the artificial lung. Therefore silicone membranes were first synthesized to incorporate catalytic Cu(II) nanoparticles and characterized for their surface properties in relation to NO flux and anticoagulation in vitro. That knowledge was carried over to develop optimized NO-generating hollow silicone fibers. These fibers were then used to manufacture the first NO-generating artificial lung prototype, which was incorporated into PVC ECC circuits coated with Cu-doped silicone for in vivo thromobogencity testing.

Immobilization of NO molecules inside polymer matrices is another method used for functionalizing surfaces to produce NO. This method was applied to intravascular catheters, as those used in clinical practice still activate platelets, leading to thrombus formation and stagnation of blood flow. Despite best practices, these catheters are often compromised because of thrombosis complications leading to an increase in morbidity, extended hospital stay, and, in some cases, mortality. In this work, silicone rubber catheters were extruded with chemistry incorporated within that enables post-extrusion charging with NO to create NO-releasing diazeniumdiolate structures within the walls of the extruded catheter. Catheters were characterized in vitro for their NO flux and release duration by chemiluminescence. They were then tested for their patency using a thrombogenicity model in adult rabbits.

Both methods of NO functionalization show promising results but also involves complicated and expensive chemical formulations and or manufacturing. A relatively simpler approach for achieving the same goal is adding NO to the sweep gas of artificial lungs (ALs). A wide range of sweep gas NO concentrations have been tested over a decade in search of an ideal concentration that significantly reduces clotting. However, no knowledge exists on what NO concentrations will yield endothelial NO flux levels in the AL. This concentration was determined for the MC3 Biolung and the Terumo capiox rx25 oxygenators in vitro.

All these ideas have shown positive results in short-term studies, and each may play a necessary role in inhibiting clot formation in future ALs. The sufficiency however, of each idea or of a combination for clot inhibition in long-term ALs remains to be determined.

Thursday, October 13, 2011

BME 500 Seminar Series

“Optical Tweezers, Helicases and beyond”

Wei Cheng, PhD
Ara G. Paul Assistant Professor
Basil O'Connor Starter Scholar
Department of Pharmaceutical Sciences

Thursday, October 13, 2011, 12:00 - 1:30 PM
1017 Dow

Abstract: The advent of single-molecule and single-cell techniques in recent years has brought many interesting discoveries and excitement in broad scientific fields of chemistry, physics, and life sciences. One unique advantage of single-molecule technique is the ability to measure chemical reactions and biophysical processes in a heterogeneous environment without the need of synchronizing these molecules, making it possible to unveil the transient intermediates that are hidden in ensemble experiments, and to use live cells as test tubes to probe mechanisms of cellular pathways. As a major technique in my lab, we have been focusing on the development and use of optical tweezers. Recently we have constructed an optical tweezers instrument using a new generation diode laser, which has eliminated a number of problems associated with current optical tweezers and offers a truly biological friendly instrument for single-molecule manipulation. I will show that this instrument allows us to monitor the enzymatic unzipping of double-stranded RNA by NS3 helicase at single base pair resolution, and resolve the coupling ratio between base pair opening and ATP consumption. The laser wavelength at 830 nm also allows us to develop optical tweezers into a single-molecule imaging tool. We can use optical tweezers to excite green fluorescent proteins through two-photon process and use it to visualize single fluorescent proteins inside mammalian cells. Combining these technical elements, we are developing new strategies to study mechanisms of viral infection of host cells, with the ultimate goal to provide targets for therapeutic intervention.

Friday, October 7, 2011

BME 500 Seminar Series

Designed Biodegradable and Osteoconductive Porous Scaffolds for Human Trabecular Bone

Eiji Saito
Chair: Scott J. Hollister, Ph.D.

Friday, October 7, 2011, 2:30 PM
G550 School of Dentistry

Current bone graft substitutes, such as calcium phosphate and metals, do not have proper mechanical properties to match native bone tissues and/or permanently stay in the body, which leads to stress shielding and chronic inflammation. As an alternative approach, synthetic biodegradable polymer scaffolds, including Poly (lactic-co-glycolic acid) (PLGA), poly (L-lactic acid) (PLLA) and poly (?-caprolactone) (PCL), have been developed using conventional fabrication techniques, such as porogen leaching and phase separation techniques. However, these scaffolds still have some limitations, including poor mechanical properties, poorly interconnected porous architectures, and lack of osteoconductivity. We developed osteoconductive porous biodegradable scaffolds using indirect solid freeform fabrication (SFF) and a biomineral coating techniques to match bone properties and enhance bone formation.

First, two designs of 50:50PLGA scaffolds were fabricated that achieved mechanical properties within those of human trabecular bone. Micro-computed tomography (µ-CT) data confirmed that the fabricated scaffold architectures matched the designs. The µ-CT data was further utilized to computationally simulate scaffold mechanical properties using a voxel-based finite element method. Secondly, the effect of scaffold architectures and materials on bone formation was examined. Three types of scaffolds were designed and fabricated using 50:50PLGA and PLLA, and bone formation in the scaffolds were tested in vivo. 50:50PLGA scaffolds did not support bone formation/ingrowth into scaffolds due to their rapid degradation, while PLLA scaffolds maintained their architectures and supported bone ingrowth. However, there was no effect of scaffold pore architecture on bone formation. Thirdly, we examined the effect of PLLA scaffolds architectures on long term in vivo degradation. We found that the scaffolds? degradation rates were determined by their initially designed architectures. Lastly, to achieve better bone formation on and into scaffolds, PLLA and PCL scaffolds were coated with calcium phosphate biomineral layers using a modified simulated body fluid technique. In vivo data showed that the biomineral coated scaffolds had improved bone ingrowth compared with the uncoated scaffolds. Furthermore, advanced bone ingrowth supported mechanical properties of the coated PLLA scaffolds.

Overall, this study provides beneficial information to develop bone scaffolds with enhanced bone formation as well as controlled scaffold degradation for craniofacial, orthopaedic and spinal applications.

Thursday, October 6, 2011

BME 500 Seminar Series

“Novel Designs for Performing Real-Time 3D Optical Sectioning with Confocal and Multi-Photon Endomicroscopy”

Presented by: Thomas D. Wang, M.D.,Ph.D.
Associate Professor of Biomedical Engineering and Medicine
University of Michigan
109 Zina Pitcher Pl. BSRB 1522
Ann Arbor, MI 48109-2200

Thursday, October 6, 2011, 12:00 - 1:00 PM
1017 Dow

Abstract: We present novel designs for performing real-time 3-dimensional (3D) optical sectioning with confocal and multi-photon endomicroscopy to achieve in vivo imaging with sub-cellular resolution. The dual axes confocal architecture uses low numerical aperture (NA) objectives to overlap the illumination and collection beams, creating a long working distance with high dynamic range. A MEMS scanner placed in post-objective position allows for scalability of the package dimensions. Consequently, optical sections can be collected in both the vertical and horizontal cross-sections. This allows for visualizing the relationship among tissue micro-structures as they vary with depth, achieving the preferred view of pathologist. A multi-photon endomicroscope can be achieved using a single mode optical fiber to deliver ultra-short laser pulses that are directed by a MEMS scanner for focusing with a miniature aspheric relay lenses system and a high NA GRIN lens. The relay lens system expands the beam diameter and images the MEMS mirror to the back aperture of the objective lens so the light will overfill the objective lens during scanning to provide high NA at the tissue surface to achieve a lateral and axial resolution is <1 µm and <5 µm, respectively. Lateral scanning is performed using a compact 2D MEMS mirror that has a gimbal geometry. Actuation for this micro-mirror is driven by parametric resonance to achieve high speed scanning with large tilting angles, resulting in large fields-of-view. Axial scanning is performed using a thin-film piezoelectric (PZT) out-of-plane actuator. These instruments are designed for endoscope-compatibility for use in the clinic and in small animal models of disease.

Thursday, September 29, 2011

BME 500 Seminar Series

“Neural Engineering and Epilepsy: searching for an electrical biomarker”

William Stacey, Ph.D.
Assistant Professor of Neurology
Assistant Professor of Biomedical Engineering

Thursday, September 29, 2011, 12:00 - 1:00 PM
1017 Dow

Abstract: Millions of people worldwide continue to suffer from uncontrolled epilepsy despite numerous new medications. One promising new avenue for anti-epilepsy research is the use of implanted devices that can detect and abort seizures. The abnormal electrical signatures of epileptic seizures have been known for over 60 years, yet only recently have technological advances begun to explore these signals for potential treatments. Several neural engineering strategies are currently under development to produce this next generation of seizure control devices.

Monday, September 26, 2011

Final Oral Examination

In Vitro Study of Sonoporation at the Single Cell Level

Zhenzhen Fan
Chair: Cheri X. Deng, Ph.D.

Monday, September 26, 2011, 9:00 AM
GM Conference Room, Lurie Engineering Center (4th Floor)

Successful delivery of drug molecules and therapeutic genetic materials across the plasma membrane into the target cells in sufficient dosage is important for satisfactory treatment effects. Ultrasound excitation of microbubbles generates disruption of the cell membrane (sonoporation) and opens new opportunities for non-viral intracellular drug and gene delivery. When excited by ultrasound, microbubbles undergo rapid volume expansion and contraction as well as collapse (cavitation) and can temporally disrupt the cell membrane, creating a direct physical route for the transport of extracellular agents into viable cells. However, despite increasing interest and progresses made recently, challenges and difficulties remain to be overcome, including relatively low delivery efficiency and large variation in delivery outcomes. These difficulties are mainly due to the insufficient understanding of the underlying mechanisms and process of sonoporation. This study aims to obtain a comprehensive understanding of sonoporation mechanisms and process at the single cell level. We employed various strategies to precisely control microbubbles location and cavitation, using fast-frame bright field video-microscopy combined with real-time fluorescence microscopy to reveal ultrasound excited microbubble dynamics. These results were spatiotemporally correlated with cellular responses, such as membrane rupture, calcium transient and waves, and gene transfection. The specific aims of this study are: 1) to investigate the intracellular transport and calcium transient generated by sonoporation; 2) to exploit dynamics activities of microbubbles driven by ultrasound and correlate with delivery outcomes; 3) to achieve controlled and enhanced delivery outcomes facilitated by targeted microbubbles.

Wednesday, September 21, 2011

Final Oral Examination

Optofluidic Ring Resonator: a Versatile Microfluidic Platform for Chemical Vapor Detection and Intra-cavity Biomolecular Analysis

Yuze Sun
Chair: Xudong (Sherman) Fan, Ph.D.

Wednesday, September 21, 2011, 1:00 PM
GM Conference Room, Lurie Engineering Center (4th Floor)

Starting from initial idealization in 1995 and subsequent ground-breaking work in early 2000s, the optical ring resonator has quickly emerged in the past few years as a new sensing technology that has a wide range of applications in healthcare, biomedical research, homeland security, and environmental monitoring to detect target analytes in either liquid or vapor phase rapidly and sensitively. Although a number of optical ring resonator configurations have been explored, there is still a great need for a synergistic configuration that integrates optical and fluidic components. To meet this challenge, the optofluidic ring resonator (OFRR) is developed in this thesis. The OFRR is a thin-walled glass capillary whose circular cross section forms the ring resonator with an ultra-high Q-factor (>107). It naturally integrates the highly sensitive ring resonator sensing technology and the superior fluidic handling capability of the capillary. The whispering gallery mode (WGM) circulating along the OFRR wall interacts with the analyte near the inner surface of the capillary, thus providing quantitative and temporal information of the analyte flowing through the capillary. Based on this versatile optofluidic platform, chemical vapor detection and microfluidic laser intra-cavity biodetection are extensively investigated in this thesis.

In the chemical vapor detection, the OFRR gas sensing platform is built by coating a vapor sensitive polymer layer on the OFRR capillary inner surface. The polymer-vapor interaction results in a change in the polymer thickness and refractive index, which in turn causes a spectral shift in the WGM that has the electric field present in the polymer layer. To improve the gas sensing specificity, the OFRR sensing technique is further integrated with micro-gas chromatography (mGC) separation technology, and the OFRR-based mGC system is thus developed. The dual use of the OFRR capillary as a separation column and an optical detector renders the OFRR-based mGC system unique multi-point on-column detection capability. In this research, the OFRR vapor sensing feasibility is first demonstrated with detection of representative gas analytes, followed by the theoretical analysis using a four-layer Mie model, which provides guidelines to the sensor design. Then, experimental studies are carried out on the OFRR-mGC system, where rapid and sensitive detection of dinitrotoluene vapor out of interfering background at room temperature is demonstrated. Finally, a tandem-column setting of the OFRR-mGC system is investigated to enhance the chromatographic resolution. A vapor mixture of twelve analytes of different volatilities and polarities are separated and detected within four minutes.

In the microfluidic laser intra-cavity biodetection, the OFRR platform is studied for active biosensing. In this research, a bio-compatible optofluidic laser is developed based on the OFRR. DNA scaffolds are incorporated into the laser gain medium and control the lasing emission properties through efficient fluorescence resonant energy transfer. This platform is further used to explore highly selective intra-cavity DNA detection. Two orders of magnitude improvement in detection selectivity is achieved over the conventional fluorescence detection method in differentiating the target and the single-base mismatched DNA sequences.

Thursday, September 15, 2011

BME 500 Seminar Series

“The Trouble with Bubbles: Diagnostic and therapeutic applications of microbubbles in medical ultrasound”

J. Brian Fowlkes, PhD
Professor Department of Radiology
Department of Biomedical Engineering

Thursday, September 15, 2011, 12:00 - 1:00 PM
1017 Dow

Abstract: Ever wondered why bubbles repeatedly form on the side of a drinking glass and how this would ever relate to medical imaging? Why does Mentos make such a great explosion when drop in diet Coke? How do you make the “Best Chips Ever”? The phenomenon of cavitation and some other popular bubble facts will be revealed in this presentation. Several groups in the engineering and medical schools are interested in the use of microbubbles for diagnosis and therapy. The interaction of bubbles with an ultrasonic field can be referred to as acoustic cavitation and small gas bubbles, either occurring naturally in the body or introduced as contrast agents, can potentiate this process. Ultrasound contrast agents based on stabilized microbubbles (<10 micron diameter) produce nonlinear signals enhance blood flow detection, responding to specialized pulse sequences that suppress undesired tissue signal. These fragile microbubbles can also be eliminated from the imaging plane with modest acoustic fields to provide a method for measuring contrast replenishment and thus perfusion. However, at sufficiently high ultrasound intensity, microbubbles undergo inertial cavitation where the inertia of the fluid is so large that the bubble has difficulty resisting the collapse. The physical effects to tissue surround the bubble can range from very small hemorrhage sites to complete cellular disruption depending on the pulse parameters used. An additional method for microbubble introduction is to inject superheated perfluorocarbon droplets that when activated by ultrasound, vaporize to form gas bubbles in a process termed Acoustic Droplet Vaporization. The droplets (<6 micron diameter) produce relatively large bubbles by ADV within tissue for vascular occlusion. The bubbles can also act as barriers and reflectors of ultrasound to shield or enhance acoustic fields. We will discuss the many uses of microbubbles in medical ultrasound, how such innovations are advancing both diagnosis and therapy, and how to keep your “favorite carbonated beverage” from going flat.

Friday, September 9, 2011

Final Oral Examination


Peter A. Galie
Chair: Jan P. Stegemann

Friday, September 9, 2011, 3:00 PM
1123 LBME (Lurie Biomedical Engineering)

Abstract: Cardiac fibrosis occurs after myocardial infarction, and contributes to both systolic and diastolic heart failure. Activation of cardiac fibroblasts to a myofibroblast phenotype is essential for fibrotic scar development. The present dissertation focuses on this phenotypic transition, specifically on the effects of mechanical stress and interactions with mesenchymal stem cells (MSC). The experimental platform used was a flexible 3D culture well that allowed simultaneous application of fluid flow and cyclic strain to collagen type I hydrogels seeded with primary rat neonatal cardiac fibroblasts.

The results indicated that fibroblasts transitioned to myofibroblasts in static culture in the absence of exogenous biochemical or mechanical stimulation. Interstitial fluid flow significantly stimulated the myofibroblast transition, while cyclic strain had an opposing effect. Using chemical antagonists and lentivirally-delivered shRNA, it was found that the acute response to flow was mediated by angiotensin II receptor type I (AT1R) and transforming growth factor ? (TGF-?). Cyclic strain also influenced the TGF-? pathway by attenuating the phosphorylation of smad2, a downstream effector of this signaling pathway.

The experimental results were augmented with a poroelastic model of flow and gel displacement within the collagen hydrogels, which indicated that cyclic strain produced substantial interstitial fluid flow in the absence of applied cross flow. The results of the analytical model, combined with the experimental findings, suggested that cyclic strain decreased fibroblast activation even in the presence of interstitial flow.

Finally, GFP-labeled MSC were injected into the cell-seeded collagen hydrogels to examine their effect on the cardiac fibroblast response. The presence of MSC significantly attenuated cardiac fibroblast activation under both static conditions and during biochemical and mechanical stimulation. Hypoxia, not mechanical stress, induced the highest levels of MSC migration, as well as the highest release of the paracrine factor, VEGF.

The data suggest that AT1R can be targeted to prevent the myofibroblast transition, due to its role in fluid shear-induced fibroblast activation. Additionally, the observed beneficial effects of cyclic strain may have implications for therapies that unload the myocardium, including the use of ventricular assist devices (VADs). Finally, the effects of MSC on fibroblast activation may illuminate the mechanisms of MSC-based therapies.

Thursday, September 8, 2011

BME 500 Seminar Series

“Microfluidic Engineering of Cell Microenvironments”

Professor Shuichi “Shu” Takayama
Thursday, September 8, 2011, 12:00 - 1:00 PM
1017 Dow

Abstract: Many biological studies and drug assays require culture and manipulation of living cells outside of their natural environment in the body. The gap between the cellular microenvironment in vivo and in vitro, however, poses challenges for obtaining physiologically relevant responses from cellular drug screens and for drawing out the maximum functional potential from cells used therapeutically. One of the reasons for this gap is because the fluidic environment of mammalian cells in vivo is microscale and dynamic whereas typical in vitro cultures are macroscopic and static. This presentation will give an overview of efforts in our laboratory to develop microfluidic systems that enable spatio-temporal control of both the chemical and fluid mechanical environment of cells. The technologies and methods close the physiology gap to provide biological information otherwise unobtainable and to enhance cellular performance in therapeutic applications. Specific biomedical topics that will be discussed include, in vitro fertilization on a chip, lung-on-a-chip, engineering tumor environments for drug screening, aqueous two phase system micropatterning, and self-switching microfluidic circuits.

Tuesday, September 6, 2011

U-M Academic Calendar

Fall Semester 2011

Tuesday, September 6, 2011,
Lurie Biomedical Engineering Building

Classes begin.

Thursday, September 1, 2011

College of Engineering

New Graduate Student Welcome

Registration & Additional Information
Thursday, September 1, 2011, 10:00 am - 3:00 pm
Stamps Auditorium Walgreens Drama Center

The College of Engineering New Graduate Student Welcome serves as the kick-off for the fall term. The event provides an introduction to graduate studies and life in the College of Engineering, and is complemented by the other orientation events. The New Graduate Student Welcome is sponsored by the College of Engineering Office of Graduate Education.

Thursday, September 1, 2011

Final Oral Examination

Imaging Feedback for Pulsed Cavitational Ultrasound Therapy: Histotripsy

Tzu-Yin Wang
Co-Chairs: Charles A. Cain and Cheri X. Deng

Thursday, September 1, 2011, 9:00 AM
GM Conference Room, Lurie Engineering Center (4th Floor)

Histotripsy is a cavitational ultrasound therapy which mechanically and progressively fractionates soft tissue into subcellular debris using high intensity short ultrasound pulses. Histotripsy can be an effective tool for many clinical applications where non-invasive tissue removal is desired, including tumor therapy. For non-invasive tissue ablation therapy like histotripsy, image based feedback information allowing for accurate targeting, optimization of the on-going process, and prediction of the treatment efficacy in real time is the key to successful treatments.

The overall goal of this research is to develop image based feedback methods that can accurately predict the clinical outcomes during and after histotripsy treatments. To achieve this goal, the research was conducted in two stages.

In the first stage, new treatment strategies were investigated to produce homogeneous tissue fractionation. This ensures that feedback metrics obtained with any tissue characterization method are representative of the whole lesion instead of a misleading average of fully homogenized and non-homogenized zones. Specifically, two treatment strategies were developed. A focal zone sharpening technique, which limited the spatial extent of cavitation by preconditioning the cavitation nuclei in the surrounding area, was developed to create highly confined lesions with minimum scattered damage in the lesion boundaries. A cavitation memory removal strategy, which allowed for random distribution of cavitation in response to each therapy pulse, was developed to produce homogeneously fractionated lesions with a dramatically reduced therapy dose.

In the second stage, three ultrasound image based methods were investigated to provide quantitative feedback information regarding the degree of tissue damage. These methods included ultrasound backscatter intensity analysis, ultrasound shear wave elasticity imaging, and characterization of shear wave propagation patterns. Strong correlations existed between the quantitative metrics derived from these methods and the degree of tissue fractionation as examined with histology, demonstrating the feasibility of using these metrics as quantitative feedback for histotripsy treatments.

In conclusion, this research demonstrates that histotripsy can be a highly controllable tissue ablation therapy via precise control of cavitation. Significant potential exists for histotripsy to be developed into an image-guided modality for noninvasive ultrasound tissue ablation therapy.

Wednesday, August 10, 2011

Final Oral Examination

Mechanics of mitotic spindle poles and polymerization dynamics of microtubules

Blake D. Charlebois
Chair: Alan J. Hunt

Wednesday, August 10, 2011, 1:00 PM
1123 Lurie Biomedical Engineering Building

During cell division, chromosomes must faithfully segregate to maintain genome integrity, and this dynamic mechanical process is driven by the macromolecular machinery of the mitotic spindle. However, little is known about spindle mechanics. For example, spindle microtubules are organized by numerous cross-linking proteins yet the mechanical properties of those cross-links remain unexplored. To examine the mechanical properties of microtubule cross-links we applied optical trapping to mitotic asters that form in mammalian mitotic extracts. These asters are foci of microtubules, motors, and microtubule-associated proteins that reflect many of the functional properties of spindle poles and represent centrosome-independent spindle pole analogs. We observed bidirectional motor-driven microtubule movements, showing that microtubule linkages within asters are remarkably compliant (mean stiffness 0.025 pN/nm) and mediated by only a handful of cross-links. Depleting the motor Eg5 reduced this stiffness, indicating that Eg5 contributes to the mechanical properties of microtubule asters in a manner consistent with its localization to spindle poles in cells. We propose that compliant linkages among microtubules provide a mechanical architecture capable of accommodating microtubule movements and distributing force among microtubules without loss of pole integrity -- a mechanical paradigm that may be important throughout the spindle.

Microtubule assembly and disassembly are vital for many fundamental cellular processes. Our current understanding of microtubule assembly kinetics is based on a one-dimensional assembly model, which assumes identical energetics for subunits exchanging at the tip. In this model, the subunit disassociation rate from a microtubule tip is independent of free subunit concentration. Using total-internal-reflection fluorescence (TIRF) microscopy and an optical tweezers assay to measure in vitro microtubule assembly with nanometer resolution, we find that the subunit dissociation rate from a microtubule tip increases at higher free subunit concentrations. This is because, as predicted by Hill, there is a shift in microtubule tip structure from relatively blunt at low free subunit concentrations to relatively tapered at high concentrations, which we confirmed experimentally by TIRF microscopy. Because both the association and the dissociation rates increase with free subunit concentrations, we find that the kinetics of microtubule assembly are an order of magnitude faster than currently estimated in the literature.

Tuesday, August 9, 2011

Final Oral Examination

Investigation of Cytotoxicity and Ion Flux Induced by Various Aggregation States of Amyloid-beta Peptides

Panchika Prangkio
Chair: Michael Mayer

Tuesday, August 9, 2011, 3:00 PM
1180 Duderstadt Center Conference Room

The pathological feature of Alzheimer's disease (AD) involves accumulation of amyloid-beta (Ab) peptides into plaques in brain tissues. Two species of Ab peptides, Ab(1-40) and Ab(1-42), have been identified as the major components of the amyloid plaques. Most studies have reported that the intermediate oligomeric forms of Ab are responsible for neurodegeneration; the exact mechanisms of neurotoxicity, however, are still unclear. An increasing number of evidence indicates that Ab peptides can form pores in neuronal membranes and cause uncontrolled ion flux through cellular membranes, leading to a disruption of the ion homeostasis.

With regard to a controversy on the mechanism of Ab-induced ion flux: ion channel formation versus thinning membrane hypotheses, we provided an evidence that Ab can form pores which permit ion flux through the artificial lipid and neuronal membranes, while the proposed membrane thinning effect was due to the residual amounts of the solvent hexafluoroisopropanol, which was used in the preparation procedure.

In this thesis, we used planar lipid bilayer recordings to study the formation of ion channel, and cytotoxicity assays to determine the toxicity of Ab from various preparation methods of Ab. We characterized the aggregation states of Ab using biochemical and biophysical techniques to correlate the relative abundance of aggregated Ab species with pore formation and cytotoxicity. Our statistical analyses revealed that in the case of Ab(1-40), pore formation was correlated most strongly with tetramers to 13mers, while cytotoxicity correlated with pentamers to 18mers. In case of Ab(1-42), pore formation was correlated with the relative abundance of tetramers to hexamers, while cytotoxicity was correlated with hexamers. The partial overlap of Ab oligomers that induced the highest probability of pore formation with those that were most toxic suggests that pore formation is likely a contributing mechanism to the toxicity of Ab.

In the second part of this research, we characterized two synthetic molecules containing oligo(ethylene glycol), which self-assemble to form ion channels across lipid membranes. We found that these molecules also exhibited antibacterial activity against gram-positive bacteria, which might be appealing as a starting material for the development of antibiotics.

Friday, August 5, 2011

Final Oral Examination

The Microenvironment Effects on the Osteogenesis of Human Embryonic Stem Cells

Shelley E. Brown
Co-Chairs: Paul H. Krebsbach and Scott J. Hollister

Friday, August 5, 2011, 10:00 AM
Dental School G390

Human embryonic stem cells (hESCs) present a potentially unlimited supply of cells that may be directed to differentiate into all cell types within the body and used in regenerative medicine for tissue and cell replacement therapies. An area of particular interest is stem cell transplantation for bone tissue regeneration. Current techniques used for bone tissue repair employ the use of auto- and allografting methods, however, these methods have inherent limitations that restrict their universal application. The limitations of these reparative strategies suggest that an alternative approach is required, and hESCs may provide a repository of cells for such an approach. One of the major gaps in the knowledge regarding hESCs is the lack of understanding the biological cues from the microenvironment that control and direct differentiation. Previous work has demonstrated that hESCs can be differentiated into osteoblasts, however, how to achieve directed differentiation still remains a pivotal question that remains unanswered. Therefore, we tested the hypothesis that controlling the local in vitro and in vivo microenvironments can direct osteoblastic differentiation of hESCs.

Overall, we demonstrated the importance of cell culture conditions in the in vitro microenvironment, and the importance of implantation site and scaffold design in the in vivo microenvironment. First, we developed a transwell co-culture system consisting of hESCs with human bone marrow stromal cells (hBMSCs), which demonstrated that pro-osteogenic soluble signaling factors secreted by hBMSCs into the in vitro cellular microenvironment directed differentiation of hESCs into osteoblasts. Secondly, we reproducibly derived mesenchymal progenitors from hESCs (hES-MSCs) that possess the characteristic hBMSC surface marker expression profile and are capable of undergoing differentiation along the mesenchymal lineage. Subsequently, via FACS analysis, we isolated multiple subpopulations of osteoprogenitors from within the hES-MSC population in order to identify candidate cells for biomaterial studies. Distinct osteoprogenitor cells were identified and when implanted in vivo in an orthotopic calvarial defect microenvironment, participated in the bone regeneration process. Lastly, we delivered osteoprogenitor hES-MSCs subcutaneously within designed hydroxyapatite/tri-calcium phosphate (HA/TCP) scaffolds to investigate the effects that porosity has on cell differentiation and overall bone tissue formation. We demonstrated that osteoprogenitors derived from hESCs survive and play a role in in vivo bone tissue formation within designed HA/TCP scaffolds with high porosity.

The long-term goal of this research is to further understand the biology of human embryonic stem cell development and more specifically, provide information about the effects the microenvironment has on the osteogenesis of hESCs. Utilizing the knowledge we have acquired on effects of the in vitro and in vivo microenvironments, we hope to have provided a platform for future studies aimed at developing hESC-based bone tissue engineering strategies.

Friday, August 5, 2011

Final Oral Examination

Neural Biosensor Probes for Simultaneous Electrophysiological and Neurochemical Measurements with High Spatial and Temporal Resolution

Matt Gibson
Chair: Daryl Kipke

Friday, August 5, 2011, 1:00 PM
GM Conference Room, Lurie Engineering Center (4th Floor)

Neural systems communicate through coordinated synaptic neurotransmitter release and electrophysiological signals, yet few tools exist for simultaneously recording these multimodal neural signals with high spatial and temporal resolution. Bridging the electrophysiological and neurochemical domains with sufficient fidelity, resolution, sensitivity, and selectivity can provide novel insights into neurophysiology that lead to improved therapeutic approaches for treating neurological disorders. This work presents the development and validation of multimodal neural biosensor arrays for recording and modulating multimodal neural dynamics through simultaneous electrophysiology recordings, neurochemical recordings, and localized drug delivery. We utilize multiple electrochemical methods for site-selective functionlization coatings of enzymes (choline oxidase and glutamate oxidase) and polymers (p-3,4-ethylenedioxythiophene or PEDOT, and poly-m-phenylenediamine) to individual, high-density microelectrode sites to enable simultaneous recordings of choline, glutamate, and electrophysiology. The devices also allow for localized nanoliter injections through an integrated drug delivery channel, which is used for the validation of sensing modalities. We additionally investigate the influence of calibration media on performance characteristics of amperometric biosensors to improve our ability to interpret in vivo neurochemical recordings. This technology has been developed to interface with the complex environment of the brain for more advanced experimental investigations at the intersections of neurophysiology, neuropathology, and neuropharmacology.

Tuesday, July 12, 2011

Final Oral Examination

Alveolar Microfluidic Systems for Study of Barrier Function, Cell Damage, and Migration at the Air-Blood Barrier

Nicholas J. Douville
Chair: Shuichi Takayama

Tuesday, July 12, 2011, 3:00 PM
Johnson Rooms in the Lurie Engineering Center (LEC)

The exchange of oxygen and carbon dioxide occurs across the air-blood barrier (or alveolar-capillary barrier). This barrier must be sufficiently thin to allow the passive diffusion, yet sufficiently strong to maintain a dry alveolar environment. When solid and fluid mechanical stresses damage the air-blood barrier's integrity, edema fills this normally air-filled alveolar environment and pathology results. The specific mechanisms by which these stresses impact the cells of the air-blood barrier remain poorly understood. The role of solid mechanical stress (cyclic stretch) has been explored through traditional, culture techniques, but only recently have microfluidic systems allowed systematic exploration on combined solid and fluid stresses. Although such systems can be tailored to the biological phenomena being studied, key design parameters include: (i) two-layered channel design (to mimic "alveolar" and "endothelial" compartments), (ii) ability to convey combined solid and fluid stresses, (iii) co-culture, and (iv) the integration of biological sensors to detect real-time changes.

A microfluidic "Alveoli-on-a-Chip" system was designed and fabricated. By varying the degree of fluid-filling within the "alveolar" channel, differential strain conditions were applied to alveolar epithelial cells. Experiments using this system, demonstrated significant increases in cell death and detachment in alveolar cell populations exposed to fluid and solid mechanical stresses compared to populations exposed solely to solid mechanical stresses. Because nearly all pathological processes of alveoli alter barrier permeability, detection of changes to the integrity of this barrier is an essential feature in alveolar models. A technique for embedding Ag/AgCl recording electrodes within a two-layered PDMS microsystem, allowing impedance to be measured across a porous cell culture membrane was also developed. This fabrication technique eliminated the need for direct deposition of recording electrodes onto the elastomer, avoiding the frequent and deep cracking pattern resulting from the modulus mismatch between conductive metals and PDMS polymer. The impact of mechanical stresses on the alveolar immune response was also studied by patterning alveolar macrophages onto confluent monolayers of alveolar epithelial cells using aqueous two-phase (ATPS) printing. Using this technique, increased migration rates in co-cultures experiencing physiologic stretch levels were demonstrated compared to migration in static cultures.

Thursday, April 28, 2011

Final Oral Examination

3D Spheroid Culture Systems for Metastatic Prostate Cancer Dormancy Studies and Anti-Cancer Therapeutics Development

Amy Yu-Ching Hsiao
Chair: Shuichi Takayama

Thursday, April 28, 2011, 1:00 PM
1121 LBME (Lurie Biomedical Engineering)

Prostate cancer is the most common non-skin cancer in United States men. Despite recent advances, mortality still remains high due to the emergence of therapy-resistant cancer cells that metastasize. Recently it has been postulated that only cancer stem cells (CSCs) are able to establish metastases, and therefore are the essential targets to destroy. Unfortunately, current use of CSCs is limited by the small number of CSCs that can be isolated, and the difficulty of culturing the CSCs in vitro. Furthermore, current in vitro-based metastatic prostate cancer models do not faithfully recreate the complex multi-cellular, three-dimensional (3D) tumor microenvironment seen in vivo. It is therefore crucial to develop effective in vitro prostate cancer culture and testing systems that mimic the actual in vivo tumor niche microenvironment. Here we utilized novel microscale technologies to develop an accurate 3D metastatic tumor model for detailed study of metastatic prostate cancer dormancy as well as accurate anti-cancer therapeutics screening and testing in vitro. Guided by the observation that prostate cancer cells parasitize and stay quiescent in the hematopoietic stem cell niche that is rich in osteoblasts and endothelial cells in vivo, a microfluidic device was established to create 3D spheroid culture of prostate cancer cells supported by osteoblasts and endothelial cells. This 3D metastatic prostate cancer model recapitulates the physiologic, dormant growth behavior of prostate cancer cells in the hematopoietic stem cell niche. Furthermore, we developed a hanging drop-based high-throughput platform for general formation, stable long-term culture, and robust drug testing and screening of 3D spheroids. Using this platform, we found significant differences in drug sensitivities against cells cultured under conventional 2D conditions versus physiological 3D models. A variety of techniques and methods were also established to specifically pattern the spatial localization of different co-culture cell types within a spheroid in this platform for accurate engineering of the 3D metastatic prostate cancer niche microenvironment. Collectively, these biological findings and technological innovations have led to advances in the understanding of prostate cancer biology and progress towards development of novel tools and therapeutics to fight against tumorigenic cancer cells.

Thursday, April 28, 2011

Final Oral Examination

Electrical Stimulation of Rat Primary Motor Cortex for Neurorehabilitation and Neuroprosthetic Applications

Azadeh Yazdan-Shahmorad
Chair: Daryl R. Kipke

Thursday, April 28, 2011, 9:00 AM
GM Conference Room - 4th Floor Robert H. Lurie Engineering Center

Cortical electrical stimulation (CES) has been used extensively in experimental neuroscience to modulate neuronal or behavioral activity, which has led this technique to be considered in neurorehabilitation. Because the cortex and the surrounding anatomy have irregular geometries as well as inhomogeneous and anisotropic electrical properties, the mechanisms by which CES has therapeutic effects are poorly understood. Therapeutic effects of CES can be improved by optimizing the stimulation parameters for targeted brain regions.

In this dissertation, the effects of CES pulse polarity on neural signals such as unit activity (spikes), local field potentials (LFP), and electrocorticograms (ECoG) recorded from rat primary motor cortex were investigated. The results showed that units located in lower cortical layers are preferentially excited by anodic stimulation, while cathodic stimulation excites those located in upper cortical layers. These opposing effects were also frequency- and amplitude-dependent. Time-frequency analysis of LFPs showed high correlation of gamma (30-120Hz) power with unit activity in corresponding layers. On the other hand, high gamma (60-120Hz) power of ECoG signals only showed high correlation with the unit activity in lower layers. Time-frequency correlations, which were found between LFPs, ECoGs and unit activity were also frequency- and amplitude-dependent. In addition the intracortical microstimulation study showed that lower motor thresholds can be obtained by anodal stimulation in upper layers of motor cortex compared to cathodal and vice versa in lower layers (V/VI). The data demonstrates that the poststimulus effects in neural activity after manipulation of CES parameters changes according to the location (depth) of the recorded neural activity in motor cortex. The signature of the neural activity observed in LFP and ECoG signals provides a better understanding of the effects of stimulation on the affected network and has a promising potential to be used in closed-loop control stimulation systems. These results demonstrate that the neurorehabilitation and neuroprosthetic applications of CES can be further improved by optimizing CES parameters.

Wednesday, April 27, 2011

Department of Biomedical Engineering

Biomedical Engineering Commencement Reception

BME Graduating Seniors and BME Faculty
Wednesday, April 27, 2011, 4:00 - 6:00 PM
Lurie Biomedical Engineering Building Atrium

The University of Michigan Department of Biomedical Engineering faculty would like to invite the graduating Biomedical Engineering seniors to a commencement reception to be held in your honor. Biomedical Engineering Chair, Douglas Noll will provide remarks while hors d'oeuvres will be served to guests who RSVP.

Graduates: Please see your email or message Susan Bitzer for details.

Wednesday, April 20, 2011

Final Oral Examination

Phase-Field Simulations of Multicomponent Lipid Membranes Coupling Composition with Deformation

Chloe M. Funkhouser
Co-Chairs: Katsuyo Thornton and Michael Mayer

Wednesday, April 20, 2011, 10:00 AM
1690 CSE

Lipid rafts are structures that can form in the plasma membrane of mammalian cells, defined as regions of the membrane enriched in cholesterol and sphingolipids. These rafts have been found to interact with numerous membrane proteins, in some cases modulating their functions. Since the nanometer-sized, highly-dynamic lipid rafts are difficult to study, phase behavior is often studied in simple membrane systems such as planar lipid bilayers, vesicles, and tubules. These simpler systems additionally have potential for use in biotechnology and drug delivery applications. In this work, we have developed a model and simulation method to study simple membrane systems, and apply it to our global aim of developing an understanding of the thermodynamics and kinetics involved in phase-separating lipid membrane systems. A continuum-level phase-field method is applied to model the phase separation, and a Helfrich free energy is used to couple the composition with the mechanical properties of the two separated phases, accounting for their bending rigidities and spontaneous curvatures. Four versions of this model are presented here: a planar background model for nearly planar portions of membranes, a spherical background model for vesicles, a cylindrical background model for tubules, and an extension of the planar background model that additionally accounts for interactions between the two leaflets of the bilayer. The planar model is used to investigate what types of initial compositional and geometric configurations would lead to a stripe phase morphology, finding that perturbations or rigid supports are able to induce such a morphology. With the vesicle model, the effects of initial vesicle shapes, phase fractions, spontaneous curvatures, and bending rigidities on vesicle dynamics and equilibrium are investigated. The tubule model is applied to investigate how bending energy can stabilize or destabilize against the so-called pearling instability observed experimentally. Lastly, we use the planar bilayer model to investigate the effects of the interleaflet coupling strength on equilibrium morphologies, producing morphological phase diagrams in composition space for a few values of the coupling strength. Overall, it is found that composition and shape are closely related, such that compositional morphologies can alter the shape of the membrane, and vice versa.

Monday, April 11, 2011

Final Oral Examination

Preliminary Study of an Intra-operative PET Imaging Probe System

Sam Seoung Huh
Co-Chairs: W. Leslie Rogers and Neal H. Clinthorne

Monday, April 11, 2011, 1:00 PM
GGBL 1371

PET imaging has gained widespread acceptance in cancer imaging because Positron Emission Tomography (PET) can identify physiological changes due to cancer. Nevertheless conventional PET imaging has difficulty detecting small tumors less than 1cm in clinical use due mainly to undesired uptake of radio-tracers in surrounding tissue, statistical noise, resolution loss due to lack of depth resolution in detectors, and annihilation photon acolinearity.

Conventionally if detected tumors are surgically removable, surgeons locate and remove the tumors during surgery based on the preoperatively acquired diagnostic images. One of the drawbacks of relying solely on preoperative imaging is that tumor locations could be displaced during surgery due to patient’s movement. It is also possible occult tumors could be removed if detected at surgery.

In this dissertation, a preliminary study of an intra-operative PET imaging probe system is presented. The proposed PET imaging probe system consists of a low resolution partial ring detector and a high resolution imaging probe that is equipped with a position tracker. The PET imaging probe operates in coincidence with the partial ring detector. The high resolution imaging probe and its proximity to target lesions contribute to the localization of small tumors. The ultimate goal is to provide incremental 3-dimensional reconstructed images that are re-projected in real time onto a plane whose orientation is driven by the tracking device.

A prototype of the PET imaging probe system was built to test the feasibility of the intra-operative PET imaging probe system. Coincidence detection efficiency of about 0.00012% was observed. A variant of 3-dimensional one-pass list-mode maximum likelihood algorithm (OP-LML) was developed to reconstruct images from the measured data. A row-action maximum likelihood algorithm was integrated to the OP-LML. In order to speed up image reconstruction up to 30-40 times faster, the proposed algorithm was parallelized and was run on a graphics processing unit.

Both simulation studies and measured-data studies showed that the effects of limited angle tomography were not severe in the longitudinal direction. The transverse spatial resolution of the prototype of the PET imaging probe system was mainly dominated by the imaging probe crystal size as predicted in theory.

Wednesday, April 6, 2011

BME 500 Seminar Series

Nanometer-scale fluctuations in growth rate require reassessment of models for microtubule self-assembly

Alan J. Hunt
Professor, Biomedical Engineering
University of Michigan

Wednesday, April 6, 2011, 12:00 - 1:00 PM
1303 EECS

ABSTRACT: Microtubule assembly and disassembly is vital for many fundamental cellular processes, such as mitosis and cell polarization. Our current understanding of microtubule assembly kinetics is based on the classic one-dimensional(1D) assembly model of Oosawa, which assumes that the multiprotofilament microtubule behaves as if it were a single protofilament. In this classic 1D model the subunit off rate is independent of free subunit concentration, an assumption that has yet to be confirmed experimentally. Using Total Internal Reflection (TIRF) microscopy and a laser tweezers assay to measure in vitro microtubule assembly with nanoscale accuracy, we find that the off rate is not constant, but rather increases with increasing free subunit concentration. Consistent with this observation, we find that a simple two-dimensional (2D) model predicts the increasing off rate with subunit concentration due to a shift in tip structure from relatively blunt at low concentrations to relatively tapered at high concentrations, which we confirmed experimentally by TIRF microscopy. Because both the on rate and the off rate increase with free tubulin concentration, the 2D model requires an association rate constant that is an order-of-magnitude larger than the 1D model. We tested this prediction by measuring the variability in assembly rate, and found that the on and off rates are consistent with the 2D model predictions and are an order-of-magnitude higher than currently thought. In summary, we find that the kinetic rates of microtubule assembly have been severely underestimated in the literature. Because net microtubule growth results from a small difference between large on rates and large off rates, the growth rate can thus be significantly altered by subtle effects of microtubule associated proteins and therapeutic drugs.

Monday, March 28, 2011

U of M College of Engineering Systems Science Seminar

Problems in Biological Imaging: Opportunities for Signal Processing

Professor Jelena Kovacevic
Department of Biomedical Engineering
Department of Electrical and Computer Engineering
Director, Center for Bioimage Informatics
Carnegie Mellon University

Monday, March 28, 2011, 3:00 - 4:00 PM
1303 EECS

Abstract: In recent years, the focus in biological sciences has shifted from understanding single parts of larger systems, sort of vertical approach, to understanding complex systems at the cellular and molecular levels, horizontal approach. Thus the revolution of "omics" projects, genomics and now proteomics. Understanding complexity of biological systems is a task that requires acquisition, analysis and sharing of huge databases, and in particular, high-dimensional databases. Processing such huge amount of bioimages visually by biologists is inefficient, time-consuming and error-prone. Therefore, we would like to move towards automated, efficient and robust processing of such bioimage data sets. Moreover, some information hidden in the images may not be readily visually available. Thus, we do not only help humans by using sophisticated algorithms for faster and more efficient processing but also because new knowledge is generated through use of such algorithms.

The ultimate dream is to have distributed yet integrated large bioimage databases which would allow researchers to upload their data, have it processed, share the data, download data as well as platform-optimized code, etc, and all this in a common format. To achieve this goal, we must draw upon a whole host of sophisticated tools from signal processing, machine learning and scientific computing. I will address some of these issues in this presentation, especially those where signal processing expertise can play a significant role.

Biosketch: JELENA KOVACEVIC received a Ph.D. degree from Columbia University. She then joined Bell Labs, followed by Carnegie Mellon University in 2003, where she is currently a Professor in the Departments of BME and ECE. She received the Belgrade October Prize and the E.I. Jury Award at Columbia University. She is a co-author on an SP Society award-winning paper and is a coauthor of the book "Wavelets and Subband Coding”. Dr. Kovacevic is the Fellow of the IEEE and was the Editor-in-Chief of the IEEE Transactions on Image Processing. Her research interests include multiresolution techniques and applications.

Open to the public.

Wednesday, March 23, 2011

BME 500 Seminar Series

Engineered Microenvironments for Understanding Complex Tissue Physiology

Geeta Mehta
University of Michigan

Wednesday, March 23, 2011, 12:00 - 1:00 PM
1303 EECS

ABSTRACT: Cells obtain spatially- and temporally-specific cues from their microenvironments, which include mechanical stimuli, cellular signals, and chemical cues. In order to study cell biology and pathology under well-controlled and versatile, yet physiologically relevant conditions, synthetic microenvironments that replicate physical tissue, and correct biomolecular cues, found in vivo must be created in vitro. In such in vitro systems, cells can be manipulated to gain insight into native homeostatis and disease progression, leading to clinical applications that elicit maximum therapeutic potential. In this seminar, I will share examples of how engineering principles and biological phenomena can be utilized to create appropriate microenvironments for primary adult hepatocytes and bone marrow hematopoietic stem cells (HSC) to create functional tissues. Overall, these examples demonstrate the applicability of engineering tools towards gaining biological insights in complex tissues. These models can be readily utilized for creating artificial tissues, effective testing of pharmacological agents and developing new treatment modalities.

Monday, March 21, 2011

Department of Biomedical Engineering

Regenerative Medicine: Deconstructing Recipes

Thomas Keenan, Ph.D.
University of Washington

Monday, March 21, 2011, 11:00 - 12:00 PM
2203 LBME (Lurie Biomedical Engineering)

Abstract: A major challenge for human regenerative medicine is deciphering the extracellular cues that steer stem cell differentiation towards cell types that can have therapeutic effects in damaged or diseased tissues. Although differentiation within a developing animal is determined by combinations of extracellular cues that are exquisitely regulated both temporally and spatially, the most common way in which differentiation decisions in human stem cells are currently studied relies upon methods incapable of mimicking the chemically-intricate and highly-dynamic nature of in vivo microenvironments. Dr. Keenan will present how microfluidic technology in combination with engineered biomaterials can be used to recapitulate much of the chemical complexity observed in the developing animal, and how these engineered in vitro tools could be used to decipher the combinatorial codes needed to generate specific cell types and organize them into functional tissues.

Wednesday, March 16, 2011

BME 500 Seminar Series

Long-term stable neural prosthetics systems

Cindy Chestek, Ph.D.
Stanford University

Wednesday, March 16, 2011, 12:00 - 1:00 PM
1303 EECS

Abstract: Recent advances in intracortical brain machine interface (BMI) in non-human primates have demonstrated near-native limb level control of computer cursors, control of functional electrical stimulation of muscles, and control of a robotic arm for self-feeding. However, a number of engineering challenges remain before translating this work into a practical system for paralyzed humans. This talk will present a body of work addressing three of these challenges. First, several studies have shown a substantial decline in the amplitude of recorded neural waveforms across the first year after implantation. However, we have demonstrated that BMI performance remains high despite these declines over up to three years. Second, current BMI systems require daily recalibration to maintain high performance. We will show that this this does not result from a changing relationship between individual neurons and motor behavior, but rather a changing population of neurons recorded on each day. Third, a wireless system to record neural data from freely moving primates will be presented, which could be used to substantially reduce the size of the equipment currently required for clinical BMI systems. These advances could enable future work moving towards native-limb level control of anthropomorphic robotic arms as well as functional electrical stimulation systems.

Bio: Cynthia Chestek is a Research Associate in the Neural Prosthetics Translational Laboratory. She received her B.S. and M.S. degrees from Case Western Reserve University in 2003 and 2005, Summa Cum Laude. and her PhD in Electrical Engineering from Stanford University in 2010. She was awarded the NSF Graduate Research Fellowship, as well as the William Hewlett Stanford Graduate Fellowship. Her PhD research focused on the stability of cortical neural recordings from chronically implanted electrode arrays, as well as wireless technology for neural prosthetic implants. Her current research interests are translating recent advances in neural interface technology into a real world, clinical system.

Monday, March 14, 2011

Department of Biomedical Engineering

Mechanics of cells and tissues and mechanosensing to control the fate of progenitor cells

Nuria Gavara, Ph.D.

Monday, March 14, 2011, 1:00 PM - 2:00 PM
2203 LBME (Lurie Biomedical Engineering)

ABSTRACT: The mechanical properties of cells and its surrounding extracellular matrix (ECM) play a key role on cellular functions such as proliferation, differentiation, migration or mechanosensation. Mechanical properties are largely determined in cells by the cytoskeleton; and in ECM by its proteins. In my talk, I will present two studies I have carried out on this subject. The first study illustrates how application of external force changes the mechanical properties of cells. The second study shows how the directional organization of proteins determines the mechanical properties of ECMs. Furthermore, I will introduce the novel methodologies I have developed for those studies. Finally, I will outline how mechanosensing can be used to control the fate of progenitor cells. In particular, the topology of non-adherent spherical cell aggregates offers unique conditions to alter the mechanical properties of cells by mechanical means and thus induce progenitor cells to proliferate or differentiate.

Thursday, March 10, 2011

Department of Biomedical Engineering

Stem cell-Inspired Therapy

Biju Parekkadan, Ph.D.
Harvard Medical School

Thursday, March 10, 2011, 11:00 - 12:00 PM
2203 LBME (Lurie Biomedical Engineering)

ABSTRACT: The bone marrow contains multipotent stromal cells, commonly referred to as mesenchymal stem cells (MSCs). There is recent interest in the clinical use of MSCs for cell-based therapy, however rational/targeted therapy has not been realized because no mechanism of action has been defined. I will describe the development of new engineered drug delivery systems that use that leverage the endogenous functions of MSCs for therapeutic use. These studies have materialized in new molecular drugs, cellular devices, and cell grafts that are currently being developed for translational studies.

Wednesday, March 9, 2011

BME 500 Seminar Series

Leveraging the microscale with microfluidics

David Eddington, Ph.D.
Assistant Professor, Department of Bioengineering,
University of Illinois at Chicago

Wednesday, March 9, 2011, 12:00 - 1:00 PM
1303 EECS

Abstract: Microfabrication enables many exciting experimental possibilities for medicine and biology that are not attainable through traditional methods. However, in order for microfabricated devices to have an impact they must not only provide a robust solution to a current unmet need, but also be simple enough to seamlessly integrate into standard protocols. Despite their clear advantages, broad dissemination of microdevices has been stymied by the common aim of replacing established and well accepted protocols with equally or more complex devices, methods, or materials. The marriage of a complex, difficult to fabricate device with a highly variable biological system is rarely successful. Instead, the design philosophy of my lab aims to leverage a beneficial microscale phenomena (e.g. fast diffusion at the microscale) within a microfabricated device and adapt to established methods (e.g. multiwell plate cell culture) and demonstrate a new paradigm for the field (adapt instead of replace). Towards this aim, I will outline ongoing projects from my lab including dynamic oxygenation control via microfluidic gas channels, add-ons for standard electrophysiology perfusion chambers, and our attempts at making a predictive assay for islet transplantation.

Friday, February 25, 2011

Rehab Robotics Faculty Candidate

Human-Machine Interactions for Sensorimotor Rehabilitation

Cara Stepp, Ph.D.
University of Washington

Friday, February 25, 2011, 11:00 - 12:00 PM
2203 LBME (Lurie Biomedical Engineering)

Abstract: Loss of sensorimotor function due to neurological impairment or injury can impede mobility, communication, and the ability to perform the activities necessary for independent living. Engineering offers unique tools that can be applied to improve the quality of life of individuals with sensorimotor injury. This presentation will introduce the use of multimodal sensory feedback and virtual reality to improve sensorimotor rehabilitation outcomes and chronic assistive device experience for individuals with neurological impairment or amputation, and will highlight some current projects: sensory substitution for users of prosthetic hands, modulation of neural coherence during fine motor control of the hand and vocal mechanism, and future work utilizing videogaming for swallowing rehabilitation.

Wednesday, February 23, 2011

BME 500 Seminar Series

Multiscale Biothermostability Engineering for Cell-Based Medicine and Cancer Treatment

Xiaoming He, Ph.D.
Assistant Professor
University of South Carolina

Wednesday, February 23, 2011, 12:00 - 1:00 PM
1303 EECS

Abstract: The capability of engineering the stability of living systems at various temperatures is important to many biomedical applications. In the last three years, my lab has taken a multiscale approach to engineer the thermostability of desired (e.g., pluripotent) and unwanted (e.g., cancerous) cells for the emerging cell-based medicine and cancer treatment, respectively. For the former, we are capable of encapsulating living cells in small (~ 100 µm), biocompatible microcapsules with high viability to achieve immunoisolation and enhanced diffusion of nutrients to and metabolites away from the encapsulated cells. As a result, the cells can survive well in the long run after transplantation. Moreover, we have identified that confining living cells in the small microcapsules significantly improves their stability for ice-free cryopreservation. We have also been striving to learn from nature to engineer mammalian cells for banking at not only cryogenic but ambient temperature (just like what we are doing with pharmaceutical drugs today). This is of great importance to the wide distribution of cell-based products for the eventual success of cell-based medicine. For cancer treatment, we have synthesized thermally responsive nanocapsules with great biocompatibility to encapsulate anticancer drugs for temperature controlled release to specifically destroy tumor cells. The goal is to develop novel strategies for cancer treatment with much improved safety and efficacy.

Biosketch: Dr. He is an assistant professor of mechanical and biomedical engineering at the University of South Carolina. Research in Dr. He’s lab has been focused on applying the modern micro and nano technology to engineer the thermostability of living systems for cancer treatment and the emerging cell-based medicine. His research has been supported by the Wendy Will Case Cancer Fund, National Science Foundation (NSF), and National Institutes of Health (NIH). Dr. He has been active in professional activities. He has (co-)chaired sessions at various conferences including the ASME Summer Bioengineering Conference, Society for Cryobiology Annual Meeting, and International Conference on Biomedical Engineering/World Congress on Biomechanics. Dr. He received his Ph.D. in 2004 from the University of Minnesota-Twin Cities and completed his postdoctoral training in 2007 at Harvard Medical School.

Friday, February 18, 2011

Final Oral Examination


Takashi Daniel Yoshida Kozai
Chair: Daryl R. Kipke

Friday, February 18, 2011, 11:00 AM
2203 Lurie Biomedical Engineering Building

Penetrating electrodes allow investigators and clinicians direct access to the underlying neural pathway via stimulation and recording. While demonstrating acute reliability, chronic implants exhibit variability and limited reliability in recording performances and inflammatory tissue responses. Although flexible probe technology has been developed for many years, penetrating microscale microelectrodes made from flexible polymers tend to bend or deflect and may fail to reach their target location. In the first study, we investigate the use of an electronegative self-assembled monolayer (SAM) as a coating on a stiff insertion shuttle to carry a polymer probe into the cerebral cortex without deflection, and then the detach the shuttle from the probe by altering the shuttle's hydrophobicity is investigated.

While advances in technology are pointing to incremental improvements for solving this longstanding problem, understanding the role of vascular disruption on implants have been limited by challenges in vivo. During insertion, the highly-regulated blood brain barrier is compromised leading to plasma release into the surrounding parenchyma and adsorbtion onto the electrode surface. In the second study, we investigate localized bleeding resulting from inserting microscale neural probes into the cortex using in vivo 3D multi-photon vascular mapping to explore an approach to minimize blood vessel disruption.

These findings combined with the growing literature emphasize electrode designs that have a significantly reduced footprint compared to conventional microelectrode arrays. Recent progress in biomaterials enables an innovative carbon based sub-cellular ultramicroelectrode design by applying advanced materials that are flexible, yet strong, and that have advanced bioactive surfaces for controlling intrinsic biological processes. The third study shows preliminary results using these new electrodes that suggest chronic recording stability and reduction in tissue response. This 'Microthread' electrode could lead to paradigm shifts in both neuroscience research and clinical neurotechnologies by allowing researchers to explore the micro-architecture of the brain in novel ways.

Wednesday, February 16, 2011

BME 500 Seminar Series

Modular Microenvironments for Stem Cell Differentiation and Delivery

Jan P. Stegemann
Dept. of Biomedical Engineering
University of Michigan, Ann Arbor

Wednesday, February 16, 2011, 12:00 - 1:00 PM
1303 EECS

Our laboratory studies how cells interact with the 3D protein environment that surrounds them in tissues, and how cell function can be controlled by defined extracellular environments. By recreating specific tissue environments in vitro, cell function can be tailored for the purpose of promoting desired cell behaviors. Biologically-derived proteins and polysaccharides are of particular interest in such applications due to their structural and functional roles in tissues, and the range of effects they can have on cells. We are developing composite materials that combine the structural and biochemical features of these polymers, in order to direct the phenotype of adult stem cells toward desired lineages. These materials are designed to mimic key features of the cellular environment in specific tissues, and can also be used to deliver cells in a minimally invasive manner. This talk will give an overview of our research and will highlight recent work in using such engineered microenvironments to direct the differentiation of adult mesenchymal stem cells for bone repair.

Wednesday, February 9, 2011

BME 500 Seminar Series

Multiplexed Electrodes for High Resolution Brain Machine Interface using Flexible Silicon Electronics

Jonathan Viventi, Ph.D.
Postdoctoral Fellow
Translational Neuroengineering Lab
University of Pennsylvania

Wednesday, February 9, 2011, 12:00 - 1:00 PM
1303 EECS

ABSTRACT: In all current brain-machine interface devices for both clinical and research applications, each electrode is individually wired to a separate electronic system. Establishing a high resolution interface over broad regions of the brain is infeasible under this constraint, as an electrode array with thousands of passive electrodes would require thousands of wires to be individually connected. To overcome this limitation, I have developed new implantable electrode array technology that incorporates active, flexible electronics. This technology has enabled extremely flexible arrays of 720 and, soon, thousands of multiplexed and amplified sensors spaced as closely as 250 µm apart, which are connected using just a few wires. These devices yield an unprecedented level of spatial and temporal micro-electrocorticographic (µECoG) resolution for recording and stimulating distributed neural networks. µECoG is one of the many possible applications of this technology, which also include cardiac, peripheral nerve and retinal prosthetic devices. I will present the development of this technology and examples of retinotopic and tonotopic maps produced from in vivo recordings. I will also present examples of finely detailed spatial and temporal patterns from epileptic feline neocortex that may give rise to seizures and may suggest new stimulation paradigms to terminate seizures and treat epilepsy.

Friday, February 4, 2011

Final Oral Examination

Spatially Controlled Organic/Inorganic Hybrids Designed to Enhance Cellular Response

Linh N. Luong
Chair: David H. Kohn

Friday, February 4, 2011, 10:00 AM
G390 Dental School

Bone is a complex organ that serves many functions including providing motility and support for the body while maintaining a supply of essential minerals. In the cases of trauma, congenital malformations, and skeletal disorders, the regulatory system may not function properly leading to delayed or impaired healing. Bone tissue engineering is a growing alternative to conventional therapies such as bone grafting, which can lead to donor site morbidity and pathogen transfer. The work presented in this dissertation involves the development a bone engineering approach where coprecipitation, a bimimetic strategy to precipitate apatite, is used to incorporate DNA or growth factors in a spatially controlled manner. Employing coprecipitation imparts osteoconductivity, derived from apatite, and osteoinductivity, derived from DNA and growth factors, into the design of the biomaterial.

The global hypothesis is that the coprecipitation of biomolecules with apatite can enhance cellular response, transfection efficiency for DNA delivery and osteogenic differentiation for growth factor delivery, by controlling spatial localization. Coprecipitation demonstrated an ability to spatially localize a protein within the apatite while simultaneously allowing for higher protein retention compared to adsorption. Applying these advantages towards gene delivery, the coprecipitation of DNA-Lipoplexes transfected cells with a higher efficiency compared to other methods of delivery. Next, to provide the design criteria for the development of a delivery system for multiple growth factors, the concentrations and sequence of BMP-2 and FGF-2 were defined based upon the osteogenic differentiation of BMSCs cultured on TCPS. The release kinetics of BMP-2 and FGF-2 were significantly affected by the growth factor concentration used during coprecipitation. In the first iteration of the hybrid delivery system, the localization of BMP-2 and FGF-2 were manipulated utilizing coprecipitation to mimic the sequential exposure required by BMSCs.

These organic/inorganic delivery systems have the potential of delivering multiple biomolecules to better mimic spatiotemporal gradients that cells are exposed to in vivo. Utilizing coprecipitation controls biomolecule localization and release from within apatite, thereby enhancing bone regeneration. Utilizing this novel approach to better simulate the cellular environment by manipulating interfaces involving apatite can facilitate the development of multiple tissue systems such as bone and cartilage.

Wednesday, February 2, 2011

BME 500 Seminar Series

Systems Analysis of Clathrin-Coated Pit Dynamics

Allen Liu,
Cellular Biomechanics Faculty Candidate
The Scripps Research Institute,
La Jolla, CA

Wednesday, February 2, 2011, 12:00 - 1:00 PM
1303 EECS

ABSTRACT: Clathrin-mediated endoctyosis (CME) maintains cellular and organismal homeostasis by mediating the uptake of essential nutrients, controlling the surface expression of membrane transporters and modulating activity of signaling receptors. A cell not only responds to a myriad of chemical inputs with temporal and spatial precision, but also constantly senses and reacts to its mechanical microenvironment. The fundamental unit of CME is a clathrin-coated pit (CCP) and the dynamic behaviors of individual CCPs have been observed to be highly heterogeneous. To capture and quantify this heterogeneity and use it as a source of mechanistic information, we have combined live cell total internal reflection fluorescence microscopy (TIR-FM) with computational analysis. I will present two aspects of CCP regulation, first on how cortical actin mechanics alters CCP behaviors, and second on how clustering of receptors promotes CCP formation. Understanding these complex interactions leading to CCP formation will be required in order to fully appreciate the role of CME in health and disease.

Wednesday, January 26, 2011

BME 500 Seminar Series

Lipid Rafts Reach a Critical Point

Sarah Veatch,
Assistant Professor of Biophysics,
University of Michigan

Wednesday, January 26, 2011, 12:00 pm - 1:00 pm
1303 EECS

ABSTRACT: Multicomponent lipid bilayer membranes can contain two coexisting liquid phases, named liquid-ordered and liquid-disordered. Large (micron-scale) and dynamic critical fluctuations are found in simple ternary bilayer membranes prepared with critical compositions. Remarkably, robust critical behavior is also found in compositionally complex vesicles isolated directly from living cell plasma membranes. This finding suggests that cells tightly regulate plasma membrane protein and lipid content to reside near a critical point and we postulate that critical fluctuations provide a physical basis of functional membrane heterogeneity in living cells at physiological temperatures. We are currently probing for critical fluctuations in intact cells using high resolution imaging techniques (including the super-resolution fluorescence localization methods called PALM and STORM). In addition, we are investigating possible structural and functional consequences of plasma membrane criticality using computational approaches, and are testing these predictions experimentally in the context of immune signaling in mast and B cells.

Wednesday, January 19, 2011

BME 500 Seminar Series

Subcellular Drug Transport: A Trip along the Roads Less Traveled

Dr. Gus Rosania, Ph.D.,
Associate Professor of Pharmaceutical Sciences,
University of Michigan

Wednesday, January 19, 2011, 12:00 - 1:00 PM
1200 EECS

ABSTRACT: The ability to predict the transport and distribution properties of drug molecules in the body from the chemical structure of a drug is dependent on the physicochemical properties of these molecules and their interaction with cellular membranes. However, once drug molecules penetrate cellular membranes, they can also accumulate within cells and change cells, by interacting with resident cellular macromolecules and partitioning into subcellular membranes and membrane-bound organelles. In this talk, I will present three conceptual advances that help us study and understand the subcellular transport properties of passively diffusing small molecules in the cells of the body: (1) Chemical Address Tags, or the measurable, additive contribution of specific chemical moieties to the subcellular transport and biodistribution properties of small molecules; (2) Xenosomes, or drug induced changes in membranes, and downstream changes in organelle structure and function, that can account for the often strange (but not uncommon) behaviors of small molecules inside cells; and (3) Virtual Cells, or mathematical models that help us simulate, visualize and plan experiments to probe the distribution of small molecules from subcellular organelles, through single cells to whole organs. With a little help from my students and collaborators, I will relate how we are embarking on a few unexplored subcellular drug transport pathways, in search for new therapeutic modalities.

Tuesday, January 18, 2011

Final Oral Examination

Temporal Regularization Use in Dynamic Contrast-Enhanced MRI

Kimberly A. Khalsa
Chair: Jeffrey Fessler

Tuesday, January 18, 2011, 10:00 AM
1005 EECS

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) studies demand both high spatial and high temporal resolution. We need high spatial resolution to accurately visualize tissue morphology, and we need high temporal resolution to accurately follow the contrast kinetics of the tissue, which provide clinically important physiological information. We can only acquire so many measurements per unit time, however, and this limited data implies an inherent tradeoff between spatial and temporal resolution in the reconstructed image sequence. Most existing methods undersample the data and then employ some sort of data sharing technique in the k-space domain to recover the missing data points. These data sharing schemes are based on an implicit assumption that the dynamic object varies smoothly in time.

We present an image reconstruction scheme based on an object domain model that does not attempt any k-space data recovery, but rather explicitly uses the assumption of temporal smoothness in the image domain to estimate the image sequence that best fits the available data. Our proposed method is called Temporal Regularization Use in Image Reconstruction (TRUIR), and is a penalized likelihood formulation that includes spatial and temporal regularization terms in addition to the data fidelity term. This work presents our TRUIR formulation for both single coil and parallel imaging, and explores various aspects of TRUIR reconstructed image sequences. We evaluate the effect of the spatial and temporal regularization parameters on the resolution properties of TRUIR reconstructed image sequences, and present our work toward establishing selection criteria for these parameters.

In evaluating our proposed TRUIR method, we focus on the application of DCE-MRI in the characterization and assessment of breast cancer. Our simulation studies model contrast uptake in a dynamic digital breast phantom. Results show that TRUIR reconstructions offer improved temporal resolution when compared to more traditional frame-by-frame reconstructions, as well as more accurate estimates of kinetic parameters, particularly when TRUIR is used in conjunction with two new proposed k-space sampling trajectories, which are also presented in this work. These new trajectories are also shown to be more robust to regularization parameter choice. Future work will focus on improving TRUIR.s spatial resolution

Friday, January 14, 2011

Final Oral Examination

Bioimpedance of Soft Tissue Under Compression and Applications to Electrosurgery

Robert E. Dodde
Co-Chairs: Albert Shih and Joseph Bull

Friday, January 14, 2011, 9:30 AM
2203 Lurie Biomedical Engineering Building

This research studies the impact that compression has on the electrical impedance of soft tissue and looks at how these changes effect electrosurgery. Soft tissue compression occurs in many ways, either physiologically (vessel compression) or imposed on by the outside world (electrosurgery, blunt trauma). While much work has been done in characterizing the electrical properties of soft tissues, little work has been done in correlating the compression of tissue to subsequent changes in the electrical properties. This lack of knowledge has lead to the use of less than ideal instrumentation within electrosurgery resulting in unneeded quality of life issues in patients post-operatively.

This thesis aims to quantify the impact of high compression on the electrical properties of tissue. First, a baseline for understanding thermal spread is developed by documenting the thermal profiles developed in tissue during energized surgical procedures. Then, a finite element model of the bipolar electrosurgical procedure is developed and analyzed suggesting various mechanisms that can be at play during this procedure that affect the resulting thermal profile. Next, a surgical thermal management system is developed and validated for the minimization of thermal spread. To perform more detailed research on electrical impedance changes in compressed tissue, a bioimpedance measurement system is then developed and tested. Finally, basic tissue compression tests are performed where mechanical and electrical properties of the tissue are monitored during the tissue compression. These findings are correlated at the end to suggest a mechanism for fluid movement during the process of tissue compression and how this impacts electrosurgery.

Wednesday, January 12, 2011

Final Oral Examination

Quantitative Assessment Of Volume Change In Tumors Using Image Registration

Saradwata Sarkar
Chair: Charles R Meyer

Wednesday, January 12, 2011, 2:30 PM
2203 Lurie Biomedical Engineering Building

The temporal evolution of tumor mass in a patient is a complicated process in three spatial dimensions. Standard clinical techniques for tumor response evaluation, like the unidimensional RECIST 1.1 or bidimensional WHO measurement methods make many assumptions and may be hopelessly challenged in accurately assessing small, early changes. Volume change measurement is likely a more reliable marker for response assessment and there is evidence to believe that accurate early quantification of tumor volume change could lead to shorter phase III clinical trials as well as the possibility of interactively adapting an individual patientâ??s therapy such as drug or dose modification to achieve optimal response. Standard approaches estimate tumor volume change indirectly by individually segmenting the interval exams in 3D and then subtracting the volumes between time points to obtain a change estimate. Such indirect methods tend to ignore the crucial mutual information present in the tumors and ensuring the consistency of the segmentations across intervals can hence become a significant challenge.

This thesis develops a low noise, low bias direct algorithm to measure volume change using 3D image registration. In the proposed algorithm, the tumor of interest is spatially registered between two interval scans and the volumetric deviation of the tumor is calculated by summing local changes in volume obtained from integrating the resulting spatially varying Jacobian map of the deformation. Such an approach not only provides a summary statistic of volume change but can also potentially show regions of differential growth and contraction across the lesions that are difficult to obtain via binary segmentation approaches. The algorithm is evaluated using synthetic and in-vivo interval scans where true tumor volume change is unequivocally known. Statistical models are developed to show that using the proposed algorithm the error in measuring volume change increases with increase in the volume of the tumor and decreases with the increase in its normalized mutual information content even when that is not the similarity measure being optimized. The developed registration-based change measurement algorithm is also compared with other approaches to demonstrate that it has the potential to outperform indirect segmentation-based volume change measurement methods. The potential of an accurate registration-based volume change measurement algorithm in tracking progression of chronic obstructive pulmonary lung disease is also suggested through an initial study on a normal and a diseased patient.

Wednesday, January 12, 2011

BME 500 Seminar Series

Intracellular Mechanics in Physiology and Disease

Jan Lammerding, Ph.D.
Assistant Professor/Associate Biophysicist
Department of Medicine; Harvard Medical School/Brigham and Women’s Hospital

Wednesday, January 12, 2011, 12:00 - 1:00 PM
1303 EECS

The nucleus is the distinguishing feature of eukaryotic cells. Recent discoveries provide compelling evidence that the physical properties of the nucleus and its structural organization are critical for a multitude of cellular functions. For example, embryonic stem cells modify their nuclear envelope composition and chromatin structure during differentiation, resulting in stiffer nuclei with decreased transcriptional plasticity; neutrophils have evolved characteristic lobulated nuclei that increase their physical plasticity, enabling passage through narrow tissue spaces in their response to inflammation. Not surprisingly then, disturbed nuclear structure and mechanics, often caused by inherited mutations in nuclear envelope proteins such as lamins or nesprins, are responsible for at least 10 different human diseases, including Emery-Dreifuss muscular dystrophy, dilated cardiomyopathy, familial partial lipodystrophy, and Hutchinson-Gilford progeria syndrome. In the Lammerding laboratory, we have developed novel experimental techniques to study the structure of the nucleus and its physical properties in mutant and wild-type cells, to investigate the physical coupling between the nucleus and the cytoskeleton, and to examine how changes in these properties can modulate cellular functions. Using these techniques, we have demonstrated that lamin mutations associated with muscular dystrophies can cause severe defects in nuclear stability, thereby rendering cells more susceptible to damage in mechanically active tissues such as muscle and providing a potential explanation for the tissue specific phenotype. Interestingly, muscular dystrophies can also result from mutations in nesprins, proteins involved in connecting the nuclear envelope to the cytoskeleton. Using dominant negative nesprin mutants, we found that nesprins are critical for intracellular force transmission, cellular polarization, and migration. In this seminar, I will present these and other recent findings from our laboratory and discuss the close relationship between nuclear mechanics and cellular organization and its role in pathological and physiological processes.

Thursday, January 6, 2011

Final Oral Examination

Strategies for Optimizing Information Extraction from Cortical Recordings

Nicholas Brandon Langhals
Chair: Daryl R. Kipke

Thursday, January 6, 2011, 3:00 PM
GM Conference Room - 4th Floor Robert H. Lurie Engineering Center

Penetrating neural probe technologies provide researchers with the capability to stimulate and record chemical and electrical signals in the brain. While present technology has yielded significant insight into the function of the brain, this technology is limited in a number of ways. Although recent breakthroughs have enabled the fabrication of three dimensional probes with hundreds of recording sites, information processing strategies to utilize this new technology are currently unrealized. Moreover, increasing channel numbers creates larger devices and concurrently highlights data processing and classification problems. Analyzing more channels not only takes more time, but also precludes many of the user-directed sorting and analysis schemes that are commonly used. We have addressed these issues by developing and testing novel information processing strategies to take full advantage of the three dimensional probe as well as evaluating site modifications to revitalize recording sites.

In the first study, we developed an efficient, automated spike sporting package using MATLAB software incorporating various techniques to more efficiently analyze large volumes of data from high channel neural probes. Overall algorithm performance has been evaluated with respect to current commercially available alternatives and performance has been comparable and objective. The algorithm will be provided online for free distribution.

In the second study, we developed a method to determine neural morphology by utilizing multichannel simultaneous electrophysiological recordings. Our technique identifies dendritic contributions to the potential recorded on distant electrode sites using event-triggered averaging from known firing times of isolated unit potentials to provide additional information about the morphology of recorded neurons in the space around the array.

In the third study, we have investigated the use of PEDOT to lower the impedance of small, gold recording electrodes with initial impedances outside the effective recording range. Smaller electrode sites enable more densely packed arrays and promote smaller overall probe designs.

In the final study, we have validated a 3D probe technology consisting of 16 silicon shanks in a 4x4 grid arrangement with four electrode sites per shank. Using this new technology, we have generated one of the first simultaneous, 3D intra-cortical, electrophysiological maps of primary auditory cortex responses.

Tuesday, January 4, 2011

Final Oral Examination

An Experimental Model Of Human Aortic Dissection

Martin Schlicht Jr.
Co-Chairs: Ramon Berguer and Joseph L. Bull

Tuesday, January 4, 2011, 9:00 AM
2203 Lurie Biomedical Engineering Building

Vascular diseases such as aortic dissections, aneurysms and stenosis are becoming frequent disorders in the industrialized world, and aortic diseases constitute an emerging share of these. An acute aortic dissection of the ascending aorta has an increasing mortality rate of 1% to 2% per hour after symptom onset. Determining whether an aortic dissection is at risk for rupture is not straightforward, and a better understanding of the role of thrombus, vessel geometry and wall components, entry tears, and other features of the diseased aorta is needed.

The focus of this dissertation is to build an experimental bench top model of an aortic dissection which provides a fundamental knowledge of the flow characteristics and flap behavior under various physiological conditions. This model may help to emulate the forces and appearance of a dissection and explain the flow/pressure events that affect the stability or progression of a dissection. The operation of such a model will permit ranking the variables that determine the evolution of a dissection towards aneurysm or rupture. The mechanical properties of the polydimethylsiloxane (PDMS) material used to create experimental models of aortic dissections were investigated in the range of physiological parameters. This research may also be used as a benchmark to validate numerical models of aortic dissection. It also paves the road for researchers in the area of imaging to determine the elastic modulus of a living in-vivo arterial wall based on dynamic DICOM files in a non-invasive manner using high resolution CT scans.

Monday, December 20, 2010

Final Oral Examination

Investigation of Mineral and Collagen Organization in Bone Using Raman Spectroscopy

Mekhala Raghavan
Co-Chairs: Michael D. Morris and David H. Kohn

Monday, December 20, 2010, 1:30 PM
West Conference Room, 4th Floor, Rackham Building

The extraordinary toughness and stiffness of bone are associated with its three main constituents - apatite mineral, type I collagen and water. Variations in composition and organization of these constituents are known to exist as a function of disease and aging. These variations greatly influence bone quality and need to be understood in greater detail. This thesis advances the understanding of molecular organization in bone along three directions: quantification of molecular orientation, analysis of mineral deformation in response to hydration changes and loading and investigation of age-dependent bone quality.

First, polarized Raman spectroscopy was adapted for bone tissue applications to quantify molecular organization in non-deproteinated, turbid tissue. This enabled the simultaneous quantitative measurements of altered mineral and collagen orientations in Osteogenesis Imperfecta, a bone disease associated with collagen mutations. Second, the effect of distorting the water environment in bone was investigated by replacing matrix water with deuterium oxide. Changes in hydrogen bonding affected collagen secondary structure, resulting in compression of the mineral lattice as evidenced by changes in peak positions and widths of mineral Raman bands. Further, polarized Raman spectroscopy was used to probe nano-scale deformations due to tensile loading and orientation-dependent strains within the mineral lattice were observed. These results demonstrate the potential of Raman spectroscopy to provide insights on molecular orientation and interaction at the nano-scale.

Third, exploratory data mining tools were employed to identify tissue-level compositional (Raman) and mechanical (nanoindentation) metrics that predict bone quality, instead of the traditionally used linear regressions. The results showed that compositional properties offer only a partial understanding of mechanical properties at the tissue-level and vice versa. Hence, a specific combination of compositional and mechanical metrics was required to reliably classify femoral specimens according to age. These findings suggest that combined metrics will better predict transformations in bone quality than individual metrics and call for novel techniques to explore the complex multi-scale interactions in bone. The multiple lines of evidence presented in this thesis provide an insight into the complex roles that mineral, collagen and water play in governing tissue quality and mechanical properties of bone.

Friday, December 10, 2010

Final Oral Examination

Use of Scanning Acoustic Microscopy to Examine and Evaluate Physical Characteristics of Mucosal Tissues

Frank Winterroth
Co-Chairs: Scott J. Hollister and J. Brian Fowlkes

Friday, December 10, 2010, 10:00 AM
2203 LBME (Lurie Biomedical Engineering)

Elastic properties of mucosal tissues (namely within the oral cavity and the uterine lining) are poorly understood. Deformation, flow, and remodeling are fundamental to a variety of higher cell functions including cell contraction, adhesion, spreading, wound healing, and division, and have been implicated as well in mechanotransduction, regulation of protein and DNA synthesis, and programmed cell death. Our understanding of the physical elastic measurements are unclear, both for natural and synthetically engineered soft tissues. The characteristics of tissue engineered oral mucosal tissues have resulted in successful transplantation. These oral mucosal tissues have also been incorporated into vaginoplasty. The versatility of the oral mucosal tissues shows the potential to incorporate as a surrogate for other soft tissues to repair/replace damaged or missing tissues and organs. Of critical importance is whether engineered tissues, specifically EVPOME (ex vivo produced oral mucosal equivalent) matches the mechanical properties of native tissues. If the oral tissues structural and physical functions are similar, it is possible that they are compatible for surgical implantation to replace/repair damaged or missing uterine and vaginal tissues. Scanning acoustic microscopy (SAM) has been shown to effectively image the surface characteristics and mechanical properties of tissues at the micrometer range. Using the SAM to study both natural and engineered tissues their morphologies and elastic properties is a significant step in determining whether such tissues are transplantable to other areas of the body and successfully incorporate into the these regions. Using a compression mechanism in conjunction to the SAM - a known method to test for elasticity in tissues - this study aims to determine the elastic properties of soft tissues: oral mucosa, vaginal mucosa, uterine. In addition, the same tests will be performed on a commercially available acellular cadaveric dermal tissue (AlloDerma®) EVPOME engineered tissues to compare their elastic properties.

Thursday, December 2, 2010

BME 500 Seminar Series

Nanotheranostics for Tumor Imaging and Targeted Drug Delivery

Duxin Sun, Ph.D.
Department of Pharmaceutical Sciences
College of Pharmacy
University of Michigan

Thursday, December 2, 2010, 12:00 pm - 1:00 pm
1200 EECS

Nanotheranostics integrates both imaging probe and therapeutic compounds into one nanoparticle for disease diagnosis, targeted drug delivery and therapy, and imaging-guided drug delivery. This presentation will discuss antibody- and fluorescence-labeled superparamagnetic iron oxide nanoparticle (SPIO) nanotheranostics for tumor targeting, magnetic resonance imaging (MRI), fluorescence imaging, and pH-dependent intracellular drug release.

Thursday, November 18, 2010

BME 500 Seminar Series

Intrinsic Fluorescence to Guide Characterization and Purification of Stem Cells

Brenda Ogle, Ph.D.
Biomedical Engineering
University of Wisconsin - Madison

Thursday, November 18, 2010, 12:00 pm - 1:00 pm
1200 EECS

Advances in cell research and cell therapies, such as repair of cardiac tissue following infarction, depend on technologies that accurately and non-invasively assess cell state, both as single cells and as 3D entities, with the potential to sort populations based on this assessment. Defining intrinsic biomarkers that characterize stem cell state advances this goal by reducing the need for extrinsic labels. Several pieces of evidence suggest that pluripotent cells are metabolically different than differentiated cells. Therefore, we propose that endogenous fluorophores, which are often involved in key metabolic processes and are noninvasively detectable by advanced optical methods, would exhibit different fluorescent properties in pluripotent cells than in their differentiated counterparts, thereby serving as a unique, intrinsic indicators of differentiation state. Indeed, we have identified changes in the fluorescent properties of stem cells during differentiation, utilizing multiphoton optical analysis, with its ability to probe deep within multicellular aggregates, and Fluorescence Lifetime Imaging. Using a wavelength to excite nicotinamide adenine dinucleotide (NADH) we found that the fluorescence lifetime of NADH decreases during the initial timecourse of differentiation, in both mouse and human embryonic stem cells. Furthermore, cardiomyocytes developed from human embryonic stem cells exhibit longer fluorescence lifetimes than non-beating cells. We are currently combining these observations with a modular, stage-mounted multiphoton flow cytometry system that could ultimately sort cellular aggregates, such as embryoid bodies or engineered constructs, based on such endogenous fluorescence signatures.

Thursday, November 11, 2010

BME 500 Seminar Series

"Drug Delivery Carriers mimicking Listeria Cytosol-Invasion Mechanism"

Kyung-Dall (KD) Lee, Ph.D.
Department of Pharmaceutical Sciences
Center for Molecular Drug Targeting (CMDT)
College of Pharmacy - University of Michigan

Thursday, November 11, 2010, 12:00 pm - 1:00 pm
1200 EECS

Macromolecular therapeutic agents have emerged as a powerful class of drugs that can provide solutions to many patho-physiological problems in medicine. While these therapeutic macromolecules possess enormous potential to replace or complement conventional pharmaceuticals, their full efficacy can be achieved only when combined with appropriate delivery carriers that are tailored to target and deliver to relevant cells and/or subcellular compartments. Consistent with this strategy, drug carriers of submicron dimensions (i.e., nano-carriers) also have been receiving much attention due to their favorable pharmacokinetic and pharmacodynamic properties.

A unique, targeted cytosolic delivery strategy involving nano-carriers for macromolecule drugs has been developed utilizing the cell-invasion mechanism of an intracellular bacterium, Listeria monocytogenes, to mediate escape from the endocytic compartment into the cytosol of target cells. The cytosol-targeting mechanism of Listeria has been incorporated into existing nano-delivery platforms such as liposomes or polymeric particles. Delivery of exogenous proteins, oligonucleotides and plasmid DNA using this non-viral, non-bacterial vector-based strategy, in combination with nano-particulate drug carriers, has been investigated and characterized both in cell culture systems and in mice to assess the utility of subcellular targeting in macromolecular drug delivery.

Wednesday, November 10, 2010

Final Oral Examination

Non-Cartesian Parallel Image Reconstruction for Functional MRI

Yoon Chung Kim
Chair: Dr. Douglas C. Noll

Wednesday, November 10, 2010, 3:00 PM
2203 Lurie Biomedical Engineering Building

Functional MRI (fMRI) is a widely preferred imaging modality to detect the regional brain activation associated with a task. However, the current fMRI techniques can suffer from performance degradation due to low spatial or temporal resolution from the hardware limitations, noise from systematic or measurement errors, and image distortions or artifacts from insufficient or inaccurate data.

Fortunately, parallel imaging technique can address these problems by reducing readout time, thus, improving spatial or temporal resolution or suppressing susceptibility artifacts. However, due to the reduced number of samples, current parallel imaging technique experiences problems such as aliasing artifact and low SNR. Therefore, our goal was to improve the parallel image reconstruction method to create truly effective solution for current limitation for fMRI for brain studies by alleviating its problems.

Specifically, this dissertation describes investigation and analysis of methods for updating calibration data, such as the sensitivity map or GRAPPA coefficients, as well as by improving image reconstruction methods for non-Cartesian SENSE.

For improving the image reconstruction algorithms, we focused on improving spiral SENSE with an iterative CG algorithm. This includes developing a joint estimation method of image and coil sensitivity map with a quadratic regularization on the estimation of sensitivity map, and developing an improved regularization technique which controls edge effects. Joint estimation of the image and sensitivity map resulted in much more robust performance compared to non-joint estimation approach when the initial sensitivity map is inaccurate. Selection of image support region method suppressed aliasing artifact more successfully when using a softening function with a proper mask size.

For determination of the calibration data, we analyzed several self-calibrated sensitivity map estimation methods and investigated the effect of smoothing on time series fMRI data. We also compared several updating methods of calibration data on fMRI data. Proper selection of estimation and updating technique for calibration data improved image quality, time series SNR and brain activation.

Our studies show the impact of improving and optimizing spiral SENSE and spiral GRAPPA, which may produce more effective solutions for parallel imaging in functional MRI.

Thursday, November 4, 2010

BME 500 Seminar Series

“History of Progress Towards Painless Defibrillation”

Igor R. Efimov, Ph.D.
Department of Biomedical Engineering
Washington University in St. Louis, MO

Thursday, November 4, 2010, 12:00 pm - 1:00 pm
1200 EECS

Heart rhythm disorders are the leading cause of morbidity and mortality in the developed world. Despite a profound difference in physiological mechanisms, anatomic and genetic determinants, and etiology of various arrhythmias, there are only two predominant treatments: bioelectric and ablative therapies. Pharmacological therapy has been mostly ineffective or hampered by side effects. Atrial and ventricular tachyarrhythmias are particularly challenging to prevent and treat by pharmacological therapy. Ablative therapy for both atrial and ventricular tachyarrhythmias is growing in acceptance. However, the procedure is complex and time-consuming, so the limited throughput provided by the existing clinical electrophysiology community does not meet the demands of an aging patient population that is increasing rapidly.

Electrotherapy has been effective in preventing sudden cardiac death due to ventricular tachycardia and fibrillation, and in arresting atrial tachycardia and fibrillation. However, the current bioelectric therapy paradigm has numerous limitations. Antitachycardia pacing is the most desirable approach due to its low energy requirement, which makes it painless and easy to implement in an implantable device. However, it is not effective in atrial and ventricular fibrillation (AF and VF); and its efficacy is limited to slow atrial and ventricular tachycardias (AT and VT). High-voltage biphasic shock defibrillation has evolved over the last 60 years as the dominant and highly effective therapy against both atrial and ventricular fibrillation, saving countless lives. However, the energy requirements for both atrial and ventricular fibrillation are less than optimal. Atrial fibrillation could be safely and effectively terminated by a biphasic shock with energy in the range of 1-3J. Unfortunately, such energy is painful and cannot be tolerated by the majority of patients. Ventricular defibrillation energy requirements range from 7 to 41J for a biphasic shock. While saving lives, such shocks cause myocardial damage and contribute to the progression of heart failure, conduction abnormalities, and increase hospitalization and mortality.

We present a novel approach to defibrillation: multi-stage phased bioelectric therapy. This approach will advance bioelectric therapy of cardiac arrhythmias by (1) reducing high-voltage shock induced myocardial damage and post-shock conduction abnormalities secondary to this damage, (2) reducing pain associated with termination of tachyarrhythmias, and (3) reducing energy consumption in the implantable devices. Reduction of defibrillation energy requirement below 0.1J is likely to make implantable atrial defibrillation possible for millions of AF patients. Reduction of ventricular energy requirement is likely to extend battery life of the implantable device, improve safety and efficacy of the therapy, and reduce patient hospitalization, morbidity, and mortality, and reduce healthcare costs.

Thursday, October 28, 2010

BME 500 Seminar Series

“Magnetic Glyco-Nanoparticles: A Tool for in vitro and in vivo Detection”

Xuefei Huang, Ph.D.
Department of Chemistry
Michigan State University

Thursday, October 28, 2010, 12:00 pm - 1:00 pm
1200 EECS

Carbohydrates are ubiquitous in nature. Many cellular interactions involve the binding of carbohydrates and glyco-conjugates. In this talk, we present our work in combining biological recognitions of carbohydrates with the properties of magnetic nanoparticles for in vitro and in vivo detections.

Our in vitro studies were focused on profiling of cancer cells. The development of simple and effective techniques to delineate the fine characteristics of cancer cells can have great potential impacts on cancer diagnosis and treatment. We will discuss the results of using a magnetic glyco-nanoparticle (MGNP) based nanosensor system not only to detect and differentiate cancer cells but also to quantitatively profile their carbohydrate binding abilities by magnetic resonance imaging (MRI). Using an array of MGNPs, a range of cells including closely related isogenic tumor cells, cells with different metastatic potential and malignant vs normal cells can be readily distinguished based on their respective “MRI signatures”. Furthermore, the information obtained from such studies helped guide the establishment of strongly binding MGNPs as anti-adhesive agents against tumors. As the interactions between glyco-conjugates and endogenous lectins present on cancer cell surface are crucial for cancer development and metastasis, the ability to characterize and unlock the glyco-code of individual cell lines can facilitate both the understanding of the roles of carbohydrates play as well as the expansion of diagnostic and therapeutic tools for cancer.

For our in vivo studies, we aimed at developing MGNPs for detection of vascular inflammation and atherosclerosis. Cardiovascular diseases, often associated with inflammation and atherosclerosis, are the leading cause of death and disability in the world. Despite the significant progress in recent years, there remain large unmet needs to detect vulnerable atherosclerotic plaques, which are prone to ruptures subsequently causing heart attacks and strokes. CD44 is a cell surface receptor expressed on three major cell types present in the atherosclerotic plaques, i.e., vascular endothelial cells, macrophages and smooth muscle cells. Multiple studies have suggested that CD44 promotes atherosclerosis by mediating inflammatory cell recruitment and vascular cell activation. Moreover, the expression of CD44 is up-regulated more than ten folds at rupture prone vascular sites, thus presenting an attractive target for molecular imaging of vulnerable plaques. In order to detect the presence of CD44 in atherosclerotic plaques in vivo, we have synthesized magnetic nanoparticles with hyaluronic acid (HA) immobilized on the external surface. These particles are highly mono-dispersed in water and colloidal stable even in the presence of serum. Moreover, the HA attached on the surface maintained binding with CD44 as determined through ELISA and flow cytometry. The magnetic nanoparticles prepared have high relaxivities, which are suitable contrast agents for magnetic resonance imaging (MRI). The in vitro and in vivo imaging of atherosclerotic plaques using the HA immobilized magnetic nanoparticles will be presented.

Thursday, October 21, 2010

BME 500 Seminar Series

"From Simulation to Surgery and Back Again: Dialogues in Translational Research"

Wendy M. Murray, Ph.D.
Biomedical Engineering
Northwestern University

Thursday, October 21, 2010, 12:00 pm - 1:00 pm
1200 EECS

Biomechanical models are frequently used to simulate surgical procedures in order to gain insight into clinical outcomes. For example, computer simulations have been applied to investigate the consequences of muscle re-attachment and tendon transfer procedures in the upper limb. In my lab, we have performed numerous simulation studies to gain understanding of how orthopaedic surgical reconstructions of the upper limb influence hand and arm function. This research has been received enthusiastically by clinicians; most perceptibly because many of our results resonate with anecdotal clinical experience. In addition, our simulations have generated hypothesis-driven experimental studies, including a multi-center clinical trial, aimed at providing data that both add to evidence-based medical practice and improve the accuracy of the biomechanical models that we build. In this context, I will highlight simulation and experimental findings describing the outcomes of tendon transfer surgeries performed following cervical spinal cord injury. This work illustrates the potential impact biomechanical modeling can have on clinical practice as well as our overall understanding of the role of the mechanics of the musculoskeletal system in human movement.

Friday, October 15, 2010

BME Alumni Merit Award Seminar: Michigan Engineering Homecoming Weekend

Methods for fast MRI

James G. Pipe, Ph.D.
Director, Neuroimaging Research
Director, Keller Center for Imaging Innovation
Barrow Neurological Institute

Friday, October 15, 2010, 1:30 - 2:30 PM
1123 LBME

The first part of the talk will briefly cover different methods for speeding up MR scans, with an emphasis on Non-Cartesian sampling. The ability to retain image SNR while speeding up scans (without additional hardware) will be discussed as an alternative to the general paradigm that SNR is proportional to the square root of scan time. The last part of the talk will introduce a new 3D sampling trajectory which has many unique properties, and may lead to further improvements in rapid scanning. This work will introduce (but not yet test) the hypothesis that current healthcare costs for MRI (roughly $10 billion per year in the US) could be cut by a factor of 2-4 with no loss of information or image quality.

Thursday, October 14, 2010

BME 500 Seminar Series

Multifunctional Imaging with Ultrashort Optical Pulses

Alvin T. Yeh, Ph.D.
Biomedical Engineering
Texas A & M

Thursday, October 14, 2010, 12:00 pm - 1:00 pm
1200 EECS

Advances in nonlinear and multimodal microscopy utilizing properties of sub-10-femtosecond pulses will be presented. Recent results of our development efforts will be discussed that were motivated by applications in live cell studies of tissue biomechanical responses and of complex molecular and cellular processes in vertebrate development. Utilizing the ultrashort coherence length of sub-10-fs pulses, integration of nonlinear and optical coherence microscopy was developed for characterizing depth-dependent microstructural and mechanical responses of the cornea. The combination of spectrally broad two-photon excitation with multispectral detection was motivated by multimolecular and cellular imaging of zebrafish embryogenesis. These efforts highlight our interests in the development of optical microscopy based on ultrashort optical pulses to study complex biological systems.

Thursday, October 7, 2010

BME 500 Seminar Series

“Mechanisms of Polymer Translocation Across Cell Plasma Membranes: Applications in Drug and Gene Delivery”

Mark Banaszak Holl, Ph.D.
Department of Chemistry
University of Michigan

Thursday, October 7, 2010, 12:00 pm - 1:00 pm
1200 EECS

Research describing the mechanism(s) by which polymers disrupt cell plasma membrane will be presented. The primary class of polymers discussed will be poly(amines) such as poly(amidoamine) dendrimers, poly-L-lysine, and poly(ethyleneimine). We have demonstrated by a variety of techniques that these polycationic polymers induce the formation of nanoscale holes in cell plasma membranes. Methods applied to the problem include solution and solid-state NMR, isothermal titration calorimetry, atomic force microscopy, whole cell patch-clamp, computer simulation, fluorescent activated cell sorting, and confocal laser scanning microscopy.

Thursday, September 30, 2010

BME 500 Seminar Series

"Synthesis and Biological Applications of Complex Glycoconjugates"

Zhongwu Guo, Ph.D.
Professor, Department of Chemistry
Wayne State University

Thursday, September 30, 2010, 12:00 pm - 1:00 pm
1200 EECS

Abstract: All of the cells are covered by a thick layer of hydrophilic biomolecules, including proteins, glycoproteins, polysaccharides, proteoglycans and so on, forming the cell surface matrix that plays an important role in many biological processes. These polar biomolecules are attached to the cell membrane through a number of mechanisms, among which glycosylphosphatidylinositol (GPI)-anchoring is one of the most common. GPIs are a class of complex glycolipids having 2-3 lipid chains and a carbohydrate chain linked to an inositol residue, and the GPI-anchored proteins and glycoproteins are attached to the carbohydrate chain. The lipid chains of GPIs can insert into the cell membrane, thereby to anchor proteins and glycoproteins onto the cell surface. Up to date, more than 30 GPI anchors and numerous GPI-anchored proteins and glycoproteins have been characterized. However, structural and functional studies of these molecules are almost impossible, because of the difficulty to obtain them in sufficient purity and quantity. To deal with this problem, our group is working on the development of both chemical and chemoenzymatic methods for the synthesis of structurally well-defined GPIs and GPI-linked peptides, glycopeptides and proteins. These molecules can be designed to contain specific molecular tags to facilitate various biological and biomedical investigations, such as to study GPI-bacterial toxin interactions and GPIomics for the identification of novel molecular targets for diseases.

Another important property of cell surface matrix is that it is cell-specific. For example, each cell type may have its unique glycans, and these glycans can be used as molecular targets or templates for the design and development of new therapeutic and diagnostic methods for diseases. Thus, another research project of our group is to develop cancer immunotherapies based on the unique carbohydrates expressed by cancer cells, known as tumor-associated carbohydrate antigens (TACAs). To overcome the immunotolerance problem associated with TACAs, we developed a novel strategy that combines cancer vaccines made of chemically modified TACAs and glycoengineering of cancer cells for the expression of the modified form of TACAs. The strategy was demonstrated to result in highly specific and efficient cancer immunotherapies.

The third project to be discussed in the talk will be the development of novel systems for targeted drug delivery. In specific, in collaboration with biomedical engineering scientists, we have developed liposomes that can target specific cells or tissues. These are liposomes decorated with glycans, which can take advantage of the specific binding between the glycans and their receptors on the surface of specific cells.

Friday, September 24, 2010

Final Oral Examination

Ultrasound-Triggered Drug Delivery using Acoustic Droplet Vaporization

Mario L. Fabiilli
Chair: J. Brian Fowlkes

Friday, September 24, 2010, 2:30 PM
Lurie Engineering Center, GM Conference Room

The goal of targeted drug delivery is the spatial and temporal localization of a therapeutic agent and its associated bioeffects. One method of drug localization is acoustic droplet vaporization (ADV), whereby drug-laden perfluorocarbon (PFC) emulsions are vaporized into gas bubbles using ultrasound, thereby releasing drug locally. Transpulmonary droplets are converted into bubbles that occlude capillaries, sequestering the released drug within an organ or tumor. This research investigates the relationship between the ADV and inertial cavitation (IC) thresholds ? relevant for drug delivery due to the bioffects generated by IC ? and explores the delivery of lipophilic and hydrophilic compounds using PFC double emulsions.

IC can positively and negatively affect ultrasound mediated drug delivery. The ADV and IC thresholds were determined for various bulk fluid, droplet, and acoustic parameters. At 3.5 MHz, the ADV threshold occurred at a lower rarefactional pressure than the IC threshold. These results suggest that ADV is a distinct phenomenon from IC, the ADV nucleus is internal to the droplet, and the IC nucleus is the bubble generated by ADV.

The ADV-triggered release of a lipophilic chemotherapeutic agent, chlorambucil (CHL), from a PFC-in-oil-in-water emulsion was explored using plated cells. Cells exposed to a CHL-loaded emulsion, without ADV, displayed 44% less growth inhibition than cells exposed to an equal concentration of CHL in solution. Upon ADV of the CHL-loaded emulsion, the growth inhibition increased to the same level as cells exposed to CHL in solution.

A triblock copolymer was synthesized which enabled the formulation of stable water-in-PFC-in-water (W1/PFC/W2) emulsions. The encapsulation of fluorescein in the W1 phase significantly decreased the mass flux of fluorescein; ADV was shown to completely release the fluorescein from the emulsions. ADV was also shown to release thrombin, dissolved in the W1 phase, which could be used in vivo to extend synergistically the duration of ADV-generated, microbubble embolizations.

Overall, the results suggest that PFC double emulsions can be used as an ultrasound-triggered drug delivery system. Compared to traditional drug delivery systems, ADV could be used to increase the therapeutic efficacy and decrease the systemic toxicity of drug therapy.

Thursday, September 23, 2010

BME 500 Seminar Series

“Using Biomechanics to Reduce a Variety of Unintentional Injuries”

James Ashton-Miller, Ph.D.
Director, Biomechanics Research Laboratory
Professor, Department of Mechanical Engineering
University of Michigan

Thursday, September 23, 2010, 12:00 pm - 1:00 pm
1200 EECS

The BME 500 Seminar Series is open to the public.

Thursday, September 16, 2010

BME 500 Seminar Series


James B. Grotberg, Ph.D.
Professor, Department of Biomedical Engineering
University of Michigan

Thursday, September 16, 2010, 12:00 pm - 1:00 pm
1200 EECS

BME 500 Seminar

Thursday, September 9, 2010

BME 500 Seminar Series

"Functional Brain Imaging Using MRI"

Douglas C. Noll, Ph.D.
Ann and Robert H. Lurie Professor of Biomedical Engineering
Chair of Biomedical Engineering
Co-Director, Functional MRI Laboratory
University of Michigan

Thursday, September 9, 2010, 12:00 pm - 1:00 pm
1200 EECS

BME 500

Wednesday, September 8, 2010

Final Oral Examination

"Image-Based Hybrid Scaffold Design for Multiple Tissue Regeneration Application in Periodontal Engineering"

Chan Ho Park
Chair: William V. Giannobile

Wednesday, September 8, 2010, 2:00 PM
Room G-390, School of Dentistry

The prediction and quantification of periodontal disease progression has been a challenge. The novel methodological approach, micro-computed tomography (micro-CT) image analysis can provide accurate and reproducible tooth-supporting alveolar bone loss or regeneration with significant reliability and reproducibility. As a standard of assessment of both periodontal disease progression and regeneration, effective 3-D image analysis of the complicated topology, bone-tooth interface was performed with natural reference-points to create a region-of-interest. Due to high reproducibility and reliability of the methodology, the wide applications have also addressed more feasibility for the pre-clinical predictions in various periodontal therapies as well as evaluation of dental implant stability.

The other challenge in periodontics is the control of periodontal tissue neogenesis due to the micron-scale multi-interfaces and functionalized architectures. Using the precise 3-D medical image dataset, a customized, periodontal defect-fit hybrid scaffold was designed with the cell/tissue guidable micro-architecture. To prove the geometry, the multi-layered polymeric hybrid scaffold assembling human tooth dentin slice was performed in the experimental ectopic model system with human cell transplantations. In spite of non-biomechanical conditions, the topological design approach resulted in perio-structural similarity; the perpendicular orientation of the fibrous connective PDL cells/tissues to the dentin surface and mineralized tissue formation without the ankylosis at 3 and 6 weeks. Using the micro-architecture, an image-based, customized hybrid scaffold was designed for periodontal fenestration defect healing. A surgical-created defect on the rat mandible was scanned by micro-CT and CAD/CAM system contributed to design an anatomical defect-fit and micro-architecture-incorporated hybrid scaffold. Compared to conventional salt-leaching scaffolds, the hybrid scaffold was found to control bone ingrowth and maintain the PDL-interfacial geometry. Using 3-D topological analysis, micro-CT demonstrated that this customized hybrid scaffold design approach influences the organization and control of spatiotemporal multiple tissue regeneration such as appropriate mineralized tissue formation and PDL tissue organization under the masticatory biomechanical loading condition. This dissertation study has the potential for valuable applications within regenerative medicine such as the tissue interface neogenesis for functional restoration, pre-clinically and clinically.

The other challenge in peirodontics is the control of periodontal tissue neogenesis due to the micron-scale complicated multi-interfaces and functionalized architectures. Using the precise 3-D medical image dataset, the customized, periodontal defect-fit hybrid scaffold was designed with the cell/tissue guidable micro-architecture. To prove the geometry, the multi-layered polymeric hybrid scaffold assembling human tooth dentin slice was performed in the experimental ectopic model system with human cell transplantations. In spite of non-biomechanical conditions, the topological design approach resulted in perio-structural similarity; the perpendicular orientation of the fibrous connective PDL cells/tissues to the dentin surface and mineralized tissue formation without the ankylosis at 3 and 6 weeks. Using the proved micro-architecture, image-based, customized hybrid scaffold was designed for periodontal fenestration defect healing. Surgical-created defect on the rat mandible was scanned by micro-CT and CAD/CAM system contributed to design anatomical defect-fit and micro-architecture-incorporated hybrid scaffold. Compared to the conventional salt-leaching scaffolds, the hybrid scaffold improved to control bone ingrowth and maintain the PDL-interfacial geometry without ankylosis. 3-D topological analysis, micro-CT demonstrated that customized hybrid scaffold design approach influences the organization and control of spatiotemporal multiple tissue regeneration such as the appropriate mineralized tissue formation and PDL tissue organization under the masticatory biomechanical loading condition. This dissertation study has the potential for immensely various and commercially valuable applications within translational regenerative medicine such as the tissue interface neogenesis for functional restoration, pre-clinically and clinically.

Wednesday, July 7, 2010

Final Oral Examination


Sumedha P. Sinha
Chair: Paul L. Carson

Wednesday, July 7, 2010, 9:00 AM
Forum Auditorium, Palmer Commons Building (4th Floor)

X-ray mammography is the gold standard for detecting breast cancer while B-mode ultrasound is employed as its diagnostic complement. This dissertation aimed at acquiring a high quality, high-resolution 3D automated ultrasound image of the entire breast at current diagnostic frequencies, in the same geometry as mammography and its 3D equivalent, digital breast tomosynthesis, and to extend and help test their utility with co-localization.

The first objective of this work was to engineer solutions to overcome some challenges inherent in acquiring complete automated ultrasound of the breast and minimizing patient motion during scans. Automated whole-breast ultrasound that can be registered to X-Ray imaging in the same geometry eliminates the uncertainty associated with hand-held ultrasound. More than 170 subjects were imaged using superior coupling agents tested during the course of this study. At least one radiologist rated the usefulness of X-Ray and ultrasound co-localization as high in the majority of our study cases.

The second objective was to accurately register tomosynthesis image volumes of the breast, making the detection of tissue growth and deformation over time a realistic possibility. It was found for the first time to our knowledge that whole breast digital tomosynthesis image volumes can be spatially registered with an error tolerance of 10% compared with the average size of cancers in a screening population.

The third and final objective involved the registration and fusion of 3D ultrasound image volumes acquired from opposite sides of the breast in the mammographic geometry, a novel technique that retains the resolution of high frequency ultrasound but poses unique problems. To improve the accuracy and speed of registration, direction-dependent artifacts should be eliminated. Further, it is necessary to identify other regions, usually at greater depths, that contain little or misleading information. Machine learning, principal component analysis and speckle reducing anisotropic diffusion were tested in this context. We proved that machine learning classifiers can identify regions of corrupted data accurately on a custom breast-mimicking phantom, and also that they can identify specific artifacts on in-vivo breast images. Initial registrations of the phantom image sets with many regions of artifacts removed provided good results.

Monday, May 10, 2010

Final Oral Examination


Taegyun Moon
Chair: Daryl R. Kipke

Monday, May 10, 2010, 4:00 PM
GM Conference Room - 4th Floor Robert H. Lurie Engineering Center

The limited lifetime of neural implants continues to frustrate the progress of neuroscience research. Despite extensive research into the inflammatory process and the encapsulation cascade, there has been little attention to when functional degradation of the neural probe actually begins. However, the initiation point is critical in determining the optimal time to intervene in the encapsulation process. If onset of signal degradation occurs at the very early stages of encapsulation, inhibition agents could be introduced to prevent glial activation. On the other hand, if onset occurs later in the encapsulation process it might be more advantageous to interrupt the inflammatory process before the formation of scar tissue. To answer these questions, we developed in vitro models for injury (thrombin/scratch) and acute inflammatory response (lypopolysaccride, LPS) to investigate the correlation between increasing signal impedance and the activation of glial cells. Using these in vitro models to monitor the impedance of the activated cells, we were able to demonstrate the increased impedance of activated glial cells compared to inactivated cells. This finding suggests that once an optimal strategy to intervene in encapsulation is developed, it should be possible to get stable long term recording/stimulation by controlling encapsulation at acceptable levels. We proved this concept of dynamic control, testing sequential activation/deactivation of glial cells to investigate: 1) if controlling glial activation levels over a short period of time is possible, and 2) the effect of the change of the activation levels on probe functionality by monitoring impedance. The critical implications of our results are that glial activation can be controlled in short periods of time and, hence, the impedance of the probe can be controlled by controlling the activation of the glial cells surrounding the probe.

Tuesday, May 4, 2010

Final Oral Examination

"Design and Fabrication of Integrated Microfluidic Circuits Using Normally-Closed Elastomeric Valves"

Bobak Mosadegh
Chair: Shuichi Takayama

Tuesday, May 4, 2010, 1:00 PM
1123 Lurie Biomedical Engineering Building

Microfluidics and other fluid-handling technologies are valuable tools both for biochemical assays and for patterning biomolecules and cells to better mimic in vivo microenvironments. However, many of these techniques are not widely utilized because they require the user to perform many tasks that often are not in a familiar platform. Currently most microfluidic devices capable of performing fluid switching operations require external control systems that are expensive and cumbersome. This dissertation has two parts, the first will present networks of normally-closed elastomeric valves as a novel control system to perform automated switching operations in microfluidic devices. Since all functionality can be embedded into the architecture of the device, the user is only required to plug in a fluid flow source to operate the device. Fundamental fluidic operations such as cascading and oscillatory fluid switching are demonstrated as a proof-of-principle for achieving dynamic functionality. In addition, scalable fabrication techniques of essential components for these control systems will be described. The scalable integration of many components is the first hurdle for practical fabrication of more complex devices that utilize this embedded control system. Such fluid handling technologies will be a stepping-stone for the development of user-friendly devices and methods that can be utilized by non-specialized users outside the field.

Friday, April 30, 2010

Final Oral Examination


Andreja Jovic
Chair: Shuichi Takayama

Friday, April 30, 2010, 10:30 AM
1180 Duderstadt Center (Conference Room)

Orchestration of cellular operations often requires faithful conversion of chemical signals from the environment into intracellular messages that cells must decipher with their internal protein machinery. Intracellular messages are conveyed by chemical messengers, such as calcium. Signals from the environment and chemical messengers are regularly frequency-encoded: biological information is stored in the periodicity, not just the amplitude, of signals. Despite the wealth of mathematical models available for predicting and interpreting the mechanisms mediating the conversion of extracellular signals into messenger signals, there is a paucity of experimental setups enabling manipulation and further elucidation of this crucial conversion process. These limitations were overcome by developing a microfluidic platform able to deliver periodic extracellular chemical signals to mammalian cells and amenable to real-time imaging of messenger signal dynamics.

While microfluidic-mediated periodic chemical stimulation afforded greater control over the timing of calcium messenger signals, compared to continuous chemical stimulation, fidelity was compromised; however, this deficiency was surmounted to a degree by modulating periodic stimulation parameters. These results provided concrete strategies for effectively manipulating intracellular calcium signals, using physiologically-relevant stimulant concentrations and periodicities. Our theoretical results predicted that minuscule changes in cellular components could yield precipitous changes in calcium response fidelity, showing that fidelity can be highly sensitive to both stimulation and intrinsic parameters. By demonstrating experimentally that these cellular components can dramatically modulate the fidelity of intracellular signals, a new approach for counteracting potentially detrimental effects of compromised fidelity in the body is presented.

Compromised fidelity of intracellular signals, while potentially harmful, provided valuable insight into the chemical mechanisms mediating the conversion of extracellular signals into calcium signals. Several existing mathematical models of calcium signaling were unable to predict these limitations, nor predict the effects of altering periodic stimulation parameters on the calcium response fidelity. Simple revisions to model mechanisms were able to account for all our experimental results, demonstrating that this approach is powerful for evaluating models and elucidating signaling mechanisms. Collectively, this thesis research delineated that by theoretically and experimentally analyzing cells' abilities to convert periodic chemical signals into intracellular chemical messengers, manipulation and elucidation of cellular signaling mechanisms was achieved.

Wednesday, April 28, 2010

Final Oral Examination


Joseph E. Olberding
Co-Chairs: Krishnakumar R. Garikipati and Karl Grosh

Wednesday, April 28, 2010, 10:00 AM
Johnson Rooms B & C, Lurie Engineering Center

Left to their own devices, tendons and ligaments repair slowly due to low blood flow and cell content. An engineered tissue contruct (ETC) approach using multipotent bone marrow stromal cells (MSCs) without an exogenous scaffold promises a robust autologous intervention strategy. From a biomechanical perspective, two physical processes govern the development of ETCs in vitro: growth, such as protein deposition or cell proliferation, and remodeling, such as fiber reorientation or cell differentiation. This dissertation describes the development and analysis of biomechanical models of growth and remodeling critical to scaffold-less soft tissue engineering.

Firstly, the thermodynamics of a common class of fiber remodeling laws were investigated in detail. It was found that purely mechanical formulations of remodeling that stiffen tissue are thermodynamically inadmissible. This dissipation imbalance was quantified in a finite-element model of tendon undergoing fiber reorientation and was found to be positive under both constant displacement and constant load boundary conditions.

Next, a novel image processing algorithm was developed to quantify directionality in planar and volumetric image data for incorporation into continuum mechanical models. With a single input parameter, the method was validated in 2D against representative synthetic images of known fiber distributions and was able to distinguish in 3D between isotropic and fibroblast-aligned collagen gels imaged using confocal microscopy.

To optimize the ETC culture system for tendon and ligament, the effects of gaseous oxygen content were studied on the early growth and fibroblastic differentiation of rat MSCs and tendon fibroblasts (TFbs). MSCs exhibited a significantly shorter population doubling time under hypoxic conditions (5% O2) compared to normoxia (18% O2). Moreover, collagen I mRNA and protein levels increased significantly up to 2 d in hypoxic MSC culture. Both cell types demonstrated elevated mRNAs encoding the tendon and ligament-associated transcription factor scleraxis under hypoxia.

Besides the individual contributions of these studies, the ability to model and simulate complex cell and tissue behaviors both computationally and experimentally portends not only patient-specific engineered tissue therapies using computer-aided tissue engineering, but also enables the testing of hypotheses related to important biological questions not directly approachable via conventional experiments.

Wednesday, April 28, 2010

BME Research Seminar

"Biophotonic Tools for the Studying of Vascular Mechanobiology"

Dr. Elliot Botvinick
Assistant Professor
University of California, Irvine

Wednesday, April 28, 2010, 12:00 - 1:00 PM
1123 LBME

The Botvinick BEAMS lab develops and deploys biophotonic tools in the study of mechanobiology. In my seminar I will focus on two of our projects. The first uses laser tweezers in the study of Notch-ligand interactions, and the second uses photonic tools to measure mechanical properties at the scale of single molecules and single cells within engineered tissues. The Notch pathway is a signaling system critical to life that allows cells to directly communicate with and respond to their neighbors during the development of multi-cellular organisms. In angiogenesis it plays a role in tip cell - stalk cell maintenance. Notch signaling induced by ligand involves a series of proteolytic cleavage events that release the Notch intracellular domain (NICD) from the plasma membrane, allowing Notch to move to the nucleus where it directly induces a transcriptional response. In collaboration with the Weinmaster lab (UCLA) we have used laser tweezers to test and support the hypotheses that mechanical force produced during endocytosis of ligand-bound Notch physically dissociates Notch to release the Notch extracellular domain (NECD) from the intact receptor thus exposing proteolytic cleavage sites. Furthermore, we have tested and cast doubt on the standing 'recycling' hypothesis that suggests inactive ligand must be endocytosed and returned to the membrane to generate an avid notch ligand. Together, our evidence supports a mechanical role of endocytosis in the Notch signaling pathway.

Our lab is also studying the role of local mechanics in the guidance and control of new vessels during angiogenesis. In recent studies it has been demonstrated that the growth rate and maintenance of capillaries in engineered fibrin gels are correlated to changes in extracellular matrix (ECM) density and bulk substrate mechanical properties. However, because changes in matrix density simultaneously alter the number of integrin binding sites available to endothelial and stromal cells, the roles, if any, of changes in local ECM stiffness and architecture are yet to be understood. In 3D culture systems, an increase in fibrin concentration not only modulates local stiffness, but directly decreases the mean pore size, increases cell confinement and decreases matrix permeability to diffusing signals. Here we have constructed and utilized a laser based microrheology system to both characterize the microstructure of pores within fibrin matrices at physiologically relevant concentrations and to investigate the mechanics of the interaction between growing capillaries and the ECM. This passive and active microrheological method complements and adds to video based particle tracking techniques by providing both viscous and elastic measurements of the microenvironment around cells.

About the speaker:

Elliot Botvinick is an Assistant Professor at the University of California at Irvine. He has appointments in the Beckman Laser Institute, the Department of Biomedical Engineering, the Department of Surgery, and the Edwards Lifescience Center for Advanced Cardiovascular Technologies. Dr. Botvinick received his PhD in Bioengineering at the University of California at San Diego, and was awarded the Arnold and Mabel Beckman Fellowship for his postdoctoral research. He is the PI of the laboratory for Bioengineering of Advanced Mechanobiology Systems (BEAMS), which studies the roles of mechanics in the regulation of cells and tissue

Monday, April 26, 2010

Final Oral Examination

Exploring the Mechanics of Transcriptional Control through DNA Looping with Optical Tweezers

Yih-Fan Chen
Chair: Jens-Christian D. Meiners

Monday, April 26, 2010, 3:00 PM
General Motors Room, Lurie Engineering Center (4th floor, LEC)

The interior of a cell is a crowded and constantly fluctuating environment, where DNA and other biomolecules are highly constrained and subject to various kinds of mechanical forces. To unravel the role of mechanics in gene regulation, it is necessary to quantitatively understand the effects of mechanical tension and constraints on protein-mediated DNA looping, which is a ubiquitous theme in the regulation of the expression of prokaryotic and eukaryotic genes.

We have used the lac system in Escherichia coli as the model system to study how mechanical tension and constraints affect the formation and breakdown of regulatory protein-DNA complexes. The lac repressor-mediated DNA loop, which is formed when a lac repressor protein binds to two operator sites on a DNA molecule simultaneously, is the paradigm for protein-mediated DNA looping and is crucial to the repression of the lac genes.

To study the effects of mechanical constraints on the elasticity of DNA, we have developed the constant-force axial optical tweezers to manipulate submicron DNA molecules that are as short as -250 bp in length. The force-extension curves of short DNA molecules measured using the optical tweezers show that, because of the entropic boundary effects, the persistence length of a DNA molecule is contour length-dependent and that the excluded-volume force is significant when the molecule is short. In addition, by measuring the formation and breakdown of lac repressor-mediated DNA loops under static tension and fluctuating forces respectively, we have shown that the loop formation rate is sensitive to static tension on the order of only a hundred femtonewtons and to fluctuations of only a fraction of kBT. The loop disruption rate, however, is found to be insensitive to either small static tension or small fluctuations. Moreover, our data show that the sensitivity of the loop formation rate to fluctuations is insensitive to the mean applied tension in the DNA. Our findings suggest not only that tension could be used as a means of regulating the gene transcription but that the hypothetical genetic switch can function robustly even in a noisy in vivo environment.

Wednesday, April 14, 2010

BME 500 Seminar Series

"Biomechanical Control of Stem Cell Behavior and Fate"

Michael Cho, Ph.D.
Professor, Department of Bioengineering
University of Illinois at Chicago

Wednesday, April 14, 2010, 12:00 - 1:00 PM
1303 EECS

Biomechanics is known to play an important role in the cell metabolism. Cell phenotype, tissue-specific functions, and fate critically depend on the extracellular mechanical environment. The mechanical properties of the cell itself such as the cytoskeleton elasticity, membrane tension, adhesion strength may also play an important role in the cell homeostasis and differentiation. For pluripotent bone marrow-derived human mesenchymal stem cells, the cellular biomechanical properties are significantly altered during stem cell specification to a particular phenotype. However, the complexity of events associated with transformation of these precursor cells leaves many questions unanswered about morphological, structural, proteomic, and functional changes in differentiating stem cells. A thorough understanding of stem cells' behaviors would allow development of more effective approaches to expansion of stem cells in vitro and regulation of their commitment to specific phenotypes. Control of cell behaviors might be feasible through manipulation of the cellular biomechanical properties using various external physical stimuli, including electric fields, mechanical stimulus, and genetic expression. Biomechanical regulation of stem cell differentiation can greatly minimize the number of chemicals and growth factors that would otherwise be required for composite tissue engineering. Determination and appropriate use of the known physicochemical cues will undoubtedly facilitate the current research effort towards designing and engineering functional tissue constructs.

Wednesday, April 14, 2010

Final Oral Examination

"The Effects of Designed Scaffold Architecture and Biodegradable Material on Chondrogenesis in vitro and in vivo"

Claire G. Jeong
Chair: Scott J. Hollister

Wednesday, April 14, 2010, 2:00 PM
2203 LBME

Poly (1, 8-octanediol-co-citric acid) (POC) is a synthetic biodegradable biocompatible elastomer that can be processed by solid freeform fabrication into 3D scaffolds for cartilage tissue engineering. We investigated the effect of designed porosity on the mechanical properties, permeability, and degradation profiles of the POC scaffolds. Increased porosity was associated with increased degradation rate, increased permeability, and decreased mechanical stiffness that also became less nonlinear.

One goal of this work was to examine the effects of pore shape and permeability of two different POC scaffold designs on matrix production, mRNA gene expression, and differentiation of chondrocytes in both in vitro and in vivo models and the consequent mechanical property changes of the scaffold/tissue constructs. We also examined the effects of collagen I gel concentration on chondrogenesis as a cell carrier and found that a lower collagen gel concentration provides a favorable microenvironment for chondrocytes. With regards to scaffold design, low permeability with a spherical pore shape better enhanced the chondrogenic performance of chondrocytes in terms of matrix production, cell phenotype, and mRNA gene expression in vitro and in vivo compared to the highly permeable scaffold with a cubical pore shape. There were higher mRNA expressions for cartilage specific proteins and matrix degradation proteins in the high permeable design in vivo, resulting in overall less sGAG retained in the high permeable scaffold compared with the low permeable scaffold.

In order to determine the scaffold material effects on cartilage regeneration, three dimensional polycaprolactone (PCL), poly (glycerol sebacate) (PGS), and POC scaffolds of the same design were physically characterized and tissue regeneration was compared to find which material would be most optimal for cartilage regeneration in vitro. POC provided the best support for cartilage regeneration while PGS was seen as the least favorable material based on mRNA expressions. PCL still provided microenvironments suitable for chondrocytes to be active, yet it seemed to cause de-differentiation of chondrocytes inside the scaffold while growing cartilage outside the scaffold.

Scaffold architectures and materials characterization and analysis in this work will provide design guidance for scaffolds to meet the mechanical and biological parameters needed for cartilage regeneration.

Wednesday, April 7, 2010

BME 500 Seminar Series

"Engineering Away Disease with Deep Brain Stimulation"

Parag Patil, M.D., Ph.D.
Assistant Professor of Neurosurgery and Biomedical Engineering
University of Michigan

Wednesday, April 7, 2010, 12:00 - 1:00 PM
1303 EECS

Some of the most fascinating applications of biomedical engineering in medicine today are found in the clinical neurosciences. Deep Brain Stimulation (DBS) therapy involves the precise placement of electrical pacemakers into the brains of patients, to provide relief from otherwise medically incurable diseases. For two decades, DBS has been successfully applied to the treatment of Parkinson's Disease, Essential Tremor, and Dystonia. More recently, DBS technologies have been applied in psychiatric conditions such as obsessive-compulsive disorder and depression. DBS offers a tremendous opportunity to engineer away disease, and though this therapy, to better understand how the brain functions in normal and diseased states.

Wednesday, March 31, 2010

BME 500 Seminar Series

"Application of Knockout Mice in Elucidating the Significance of Transport Proteins on Drug Kinetics and Dynamics"

David E. Smith, Ph.D.
John G. Wagner Collegiate Professor and Chair
Department of Pharmaceutical Sciences
University of Michigan

Wednesday, March 31, 2010, 12:00 - 1:00 PM
1303 EECS

Pharmaceutical scientists have become increasingly aware of the need to integrate drug transport studies in the drug discovery and drug development process. Of the 27,000 genes in the human genome, about 1,100 have been classified as transport proteins. However, only a fraction of these candidate transporters have been functionally characterized at the present time. We believe it is essential for the pharmaceutical sciences to facilitate the progress and implementation of drug transport research. Innovations in technology are major factors in facilitating the progress of scientific knowledge. With this in mind, my seminar will address the use, advantages and disadvantages, and development and validation of knockout mice. Examples of their application in transport pharmacokinetics and pharmacodynamics will be discussed.

Wednesday, March 24, 2010

BME 500 Seminar Series

"Bisphosphonates: Their colorful history, and a multi-spectral approach to study the effects of drug delivery and retention in the skeleton"

Ken Kozloff, Ph.D.
Assistant Professor, Departments of Orthopaedic Surgery
and Biomedical Engineering
University of Michigan

Wednesday, March 24, 2010, 12:00 - 1:00 PM
1303 EECS

The skeleton is a dynamic system constantly optimizing its structure, organization, and strength to meet the metabolic and mechanical demands imposed upon it. In conditions of low bone mass, such as osteoporosis, disuse osteopenia, and osteogenesis imperfecta, changes in hormonal, mechanical, or genetic factors can disrupt this balance, placing the skeleton at risk for fracture. The bisphosphonate class of drugs were first identified for their anti-scaling ability as a drain cleaning agent, but over the past fourty years have been adapted to become the number one drug for the treatment of osteoporosis. Recent expansion of these drugs off-label to treat pediatric low bone mass has led to some concern for the long-term implications of reducing bone turnover in a growing skeleton. This presentation will describe the effects of bisphosphonate treatment in several models of pediatric low bone mass, and will present a molecular imaging strategy to visualize and quantify local drug delivery to the skeleton, and determine its long-term implications for bone tissue repair.

Monday, March 22, 2010

Final Oral Examination


Congxian Jia
Chair: Matthew O'Donnell

Monday, March 22, 2010, 2:00 pm
GM Room, Lurie Engineering Center (LEC)

Ultrasound (US) and photoacoustic (PA) imaging, as coherent imaging modalities, are characterized by the appearance of speckle. Speckle formation is related to the specifics of the imaging system and underlying tissue microstructure. Speckle tracking (ST) is a technique to measure speckle motion, providing a foundation for non-invasive and quantitative image-based disease diagnosis. This dissertation has demonstrated ST's application to cardiac strain imaging in US imaging and contrast enhancement in PA imaging.

In cardiac strain imaging, the accuracy of tissue Doppler imaging (TDI) and 2-dimentional (2-D) ST estimates of instantaneous axial normal strain and accumulated axial normal strain were compared using a simulated heart model. An isolated rabbit heart model of acute ischemia produced by left anterior descending (LAD) artery ligation was used to evaluate the performance of the two methods in detecting abnormal cardiac wall motion.

A well-controlled 2-D cardiac elasticity imaging technique was then introduced using two coplanar and orthogonal linear probes simultaneously imaging an isolated retroperfused rabbit heart. Acute ischemia was generated by LAD artery ligation. Single probe detection demonstrated that directional changes in the in-plane principal deformation axes can locate an ischemic cardiac wall bulging area due to LAD ligation, and strains based on principal stretches can characterize heart muscle contractility. These two findings were further validated using symmetric displacement accuracy derived from two probe data.

To evaluate 3-D ST on controlled complex 3-D heart motion, a left ventricular (LV) phantom was constructed using Polyvinyl alcohol cryogel and integrated with a pulsatile pump in combination with a pressure meter. A commercial 2-D phased array (Sonos 7500, Philips) was used to acquire 3-D radiofrequency data with increased effective frame rate. 2-D and 3-D ST algorithms were tested on this 3D data set. LV contraction and out-of-plane motion were also simulated and tracked using a computer model of cardiac imaging.

In PA imaging, ST can be used to increase specific contrast by identifying regions moved by manipulating magnetomotive Au-shell-encapsulated magnetic nanoparticles and suppressing unwanted background PA signals without motion. Magnetomotive PA imaging can potentially also be used for tissue elasticity imaging, such as measuring the relaxation time of tissue.

Wednesday, March 17, 2010

BME 500 Seminar Series

"Functional Near-infrared Spectroscopy (NIRS) of the Human Brain: Theory and Applications"

Theodore Huppert, Ph.D.
Assistant Professor of Radiology and Bioengineering
University of Pittsburgh

Wednesday, March 17, 2010, 12:00 - 1:00 PM
1303 EECS

Near-infrared spectroscopy (NIRS) is a non-invasive brain imaging technique that uses light to record changes in the oxygen content of blood in the brain. By recording changes in the optical absorption of light as it passes through the brain, NIRS provides information about blood volume and oxy- and deoxy-hemoglobin changes at a temporal resolution of several hertz. Diffuse nIR light penetrates into the brain to a depth of around 5-8mm of the cortex, allowing imaging of brain activity at the cortical surface. Over the last thirty years, NIRS has been applied to a wide variety of cognitive, sensory, and motor tasks. In addition. unlike other methods such as functional MRI, this technique is portable and allows measurements of activity during tasks such as walking and balance. In this presentation, I will describe this technology and how it relates to other modalities including fMRI and MEG (magnetoencephalography). I will also present our recent advancements to develop real-time imaging and biofeedback paradigms based on NIRS which we are applying to study learning-based attention and motor-learning paradigms. Finally, I will highlight several of the unique studies in which we have applied NIRS.

Wednesday, March 10, 2010

BME 500 Seminar Series

"Engineering a Brain-controlled Robotic Lower Limb Exoskeleton"

Daniel P. Ferris, Ph.D.
Associate Professor of Kinesiology, School of Kinesiology
Associate Professor of Biomedical Engineering, College of Engineering
and Adjunct Associate Professord of Medicine, Medical School
University of Michigan

Wednesday, March 10, 2010, 12:00 - 1:00 PM
1303 EECS

Robotic technologies have greatly advanced in recent years, making robotic exoskeletons feasible as real devices instead of being limited to science fiction. However, prototype devices are making it clear that current designs often end up with human and machine fighting each other rather than operating as an integrated system. The University of Michigan Human Neuromechanics Laboratory has designed robotic exoskeletons for assisting human locomotion and identifying principles of neuromechanical control. We are now working on incorporating mobile brain imaging techniques into our research with the eventual goal of building a brain-controlled robotic lower limb exoskeleton.

Wednesday, February 24, 2010

BME 500 Seminar Series

"Direct Observation of Failing Fibres Provides Mechanistic Insight into Muscular Dystrophy"

Susan V. Brooks, Ph.D.
Assistant Professor, Biomedical Engineering
Associate Professor, Molecular and Integrative Physiology
Research Associate Professor, Institute of Gerontology
University of Michigan

Wednesday, February 24, 2010, 12:00 - 1:00 PM
1303 EECS

Duchenne muscular dystrophy is caused by the absence of the protein dystrophin. Dystrophin's function is not known, but its cellular location and associations with both the force-generating contractile core and membrane-spanning entities suggest a role in mechanically coupling force from its intracellular origins to the fiber membrane and beyond. We report here the presence of destructive contractile activity in lumbrical muscles from dystrophin-deficient (mdx) mice during nominally quiescent periods following exposure to mechanical stress. The ectopic activity, which was observable microscopically, resulted in longitudinal separation and clotting of fiber myoplasm and was absent when calcium (Ca2+) was removed from the bathing medium. Separation and clotting of myoplasm were also produced in dystrophin-deficient muscles by local application of a Ca2+ ionophore to create membrane breaches in the absence of mechanical stress, whereas muscles from control mice tolerated ionophore-induced entry of Ca2+ without damage. These observations suggest a failure cascade in dystrophin deficient fibers that 1) is initiated by a stress-induced influx of extracellular Ca2+, causing localized activation to continue after cessation of stimulation, and 2) proceeds as the persistent local activation, combined with reduced lateral mechanical coupling between the contractile core and the extracellular matrix, results in longitudinal separation of myoplasm in non-activated regions of the fiber. This mechanism invokes both the membrane stabilization and the mechanical coupling functions frequently proposed for dystrophin and suggests that, whereas the absence of either function alone is not sufficient to cause fiber failure, their combined absence is catastrophic. The links between fiber damage and the progression of the dystrophic process remains an active area of investigation.

Wednesday, February 17, 2010

BME 500 Seminar Series

"Functional Conjugated Polymers for Self-signaling and Signal-amplifying Biosensors and Sensor Arrays"

Jinsang Kim, Ph.D.
Associate Professor, Departments of Materials Science & Engineering,
Chemical Engineering, Biomedical Engineering,
& Macromolecular Science and Engineering
University of Michigan

Wednesday, February 17, 2010, 12:00 - 1:00 PM
1303 EECS

The need of biosensors has been raised rapidly for implicating particular proteins in diseases and for fast and reliable detection of diagnostically important biological molecules. However, low cost and reliable biosensors and sensor arrays remain a significant challenge especially given the difficulty in devising an effective label-free and sensitive detection strategy. Conjugated polymers (CPs) have become emerging materials for many useful applications due to the tunability of their properties by variation of chemical structure. Particularly the biosensor application of CPs has gain much interest recently because CP-based sensors can provide large signal amplification. The concept, design principles, and applications of conjugated polymers for self-signal amplifying biosensors and sensor arrays will be discussed. We have developed conjugated polymer-based biosensors to detect clinically important biological materials such as DNA and proteins. Our signal amplifying sensors are designed to achieve high sensitivity by means of the energy harvesting property and highly emissive property of conjugated polymers. Receptors are rationally designed to provide specificity toward a target analyte to realize high selectivity. Signal amplifying DNA microarrays, PDA liposome arrays for selective potassium detection and mercury detection, prostate specific antigen sensors, bioconjugated emissive organic nanoparticles for immunofluorescence labeling, and warfare agent detection sensors will be discussed.

Wednesday, February 10, 2010

BME 500 Seminar Series

"The Effect of Therapeutic Ultrasound on Nanoparticles Penetration into Breast Cancer Spheroids"

Mohamed El-Sayed, Ph.D.
Assistant Professor, Biomedical Engineering
University of Michigan

Wednesday, February 10, 2010, 12:00 - 1:00 PM
1303 EECS

Solid tumors, including breast cancer, are characterized by a leaky vasculature that allows the extravasation of therapeutic macromolecules such as liposomes, polymeric micelles, particles, and polymer-drug conjugates from the systemic circulation into the tumor tissue. However, these macromolecular drugs typically accumulate in the tumor's vascular surface and fail to diffuse into the central hypoxic and necrotic layers of the cancer tissue. The heterogeneous distribution of these polymeric systems minimizes their efficacy and contributes to the development of drug resistance and cancer recurrence. In this seminar, I will discuss our approach to utilize therapeutic ultrasound (US) as a mechanism to enhance the penetration of nanoparticles into breast cancer spheroids, which is a 3D in vitro model of breast cancer. I will summarize our results showing the effect of particle's size, surface chemistry, and charge on their penetration profile in response to different US intensities and exposure time.

Wednesday, February 3, 2010

BME 500 Seminar Series

"Femtosecond Nanomachining: Theory and Applications in Biomedical Research and Analysis"

Alan J. Hunt, Ph.D.
Associate Professor, Biomedical Engineering
Assistant Research Scientist, Institute of Gerontology
University of Michigan

Wednesday, February 3, 2010, 12:00 - 1:00 PM
1303 EECS

The nonlinear mechanisms of femtosecond laser damage allow tight control of ablation to precisely remove very small amounts of material, leaving holes as small as tens of nanometers wide. By serially targeting laser pulses in glass, a host of three dimensional nano- and microfluidic structures can be formed including nozzles, mixers, and separation columns. Recent advances allow the formation of high aspect ratio nanochannels from single pulses, thus helping address fabrication speed limitations presented by serial processing. Femtosecond nanomachining is enabling for a variety of applications including nanoscale devices for analytic separations, chemical analysis, and biomedical diagnostics.

Wednesday, January 27, 2010

BME 500 Seminar Series

"Protein-Based Biomaterials for Regenerative Medicine"

Jan P. Stegemann, Ph.D.
Associate Professor in the Department of Biomedical Engineering
University of Michigan

Wednesday, January 27, 2010, 12:00 - 1:00 PM
1303 EECS

Our laboratory studies how cells interact with the 3D protein environment that surrounds them in tissues, and uses this knowledge to design protein-based biomaterials to direct cell function. The biologically-derived proteins collagen and fibrin are of particular interest, due to their role as structural proteins in tissues and the range of effects they can have on cell function. We are developing composite biomaterials that combine the structural and biochemical features of these polymers, in order to direct the function of adult stem cells toward desired lineages. These materials are designed to mimic key features of the cellular environment in specific tissues, and can also be used to deliver cells in a minimally invasive manner. This talk will give an overview of our work and will highlight applications in orthopaedic and cardiovascular tissue repair.

Wednesday, January 13, 2010

BME 500 Seminar Series

"Biomedical Microfluidic Technology"

Shuichi Takayama, Ph.D.
Associate Professor in the Department of Biomedical Engineering and the Macromolecular Science and Engineering Program
University of Michigan

Wednesday, January 13, 2010, 12:00 - 1:00 PM
1303 EECS

The gap between the cellular microenvironment in vivo and in vitro poses challenges for obtaining physiologically relevant responses from cells used in basic biological studies or for drawing out the maximum functional potential from cells used therapeutically. One of the reasons for this gap is because the fluidic environment of mammalian cells in vivo is 3D, microscale and dynamic whereas typical in vitro cultures are 2D, macroscopic and static. This presentation will give an overview of the evolution of microfluidic technology in our laboratory to enable spatio-temporal control of both the chemical and fluid mechanical environment of cells in both 2D and 3D, as well as to perform bioassays. The technologies and methods close the physiology gap to enhance cellular performance in therapeutic applications and provide biological information otherwise unobtainable. Specific biomedical topics that will be discussed include microfluidic studies of cell signaling, high-throughput cancer and stem cell environment engineering, and clinical applications of microfluidics in in vitro fertilization.

Wednesday, January 6, 2010

BME 500 Seminar Series

"Structure/Function Studies of Ion Channels Through Computer Simulations"

David S. Sept, Ph.D.
Associate Professor, Department of Biomedical Engineering
University of Michigan

Wednesday, January 6, 2010, 12:00 - 1:00 PM
133 Chrysler

Ion channels play an important role in producing and transducing electrical signals across the cell membrane. Some channels facilitate the passage of ions in response to mechanical or electrical stimuli, however others are controlled by the binding of intracellular ligands. The large conductance K(Ca) or BKCa channels fall into this latter class since they regulate the K+ current passing through the membrane in response to intracellular Ca2+. Through many years of mutagenesis studies, two high affinity Ca2+ binding sites have been identified in the channel structure, and one of the sites is the DRDD loop in the N-terminus of the cytoplasmic domain. This motif is highly conserved, however mutations to some of these amino acids have little phenotype while others give rise to particular forms of epilepsy. Here I will present a series of experimental and computational studies on the details of the Ca2+ binding site and the mechanism of Ca2+ gating. I will start with general presentation of BKCa channel function and the etiology of channelopathies, followed by a general discussion of the computational methods used in this study. Finally, I will present our findings and the allosteric model of calcium activation that results from these studies.

Tuesday, December 22, 2009

Final Oral Examination


Gregory J. Gage
Co-Chairs: Joshua Berke and Daryl R. Kipke

Tuesday, December 22, 2009, 3:00 PM
GM Room, Lurie Engineering Center (LEC)

The basal ganglia (BG) has been proposed as a possible neural substrate for action selection in the vertebrate brain. This hypothesis has been developed primarily through pathological observations. Human neurological disorders of the basal ganglia can result in movements that are slowed or eliminated (bradykinesia/akinesia in Parkinson's Disease) or conversely, uncontrolled or unwanted (e.g. in Huntington's Disease and Tourette Syndrome). However, the precise mechanisms by which BG circuits influence behavior remain to be understood. In this thesis, I have focused on determining the role of BG circuits in selection of well-trained actions, and how these findings can be applied for use in neuroprosthetic devices.

In the first study, I investigated one proposed mechanism to help resolve competition between actions in the BG: feedforward inhibition of striatal medium spiny cells (MSNs) by fast-spiking interneurons (FSIs). I recorded single unit activity from presumed MSNs and FSIs together with motor cortex and globus pallidus (GP), in rats performing a simple choice task. My findings support the idea that FSIs contribute to action selection processes within striatal microcircuits, but suggest that the feedback pathway from GP to FSIs may be particularly important for the suppression of highly trained yet unwanted actions.

In my second study, I examined the role of large neuronal ensembles of the BG and motor cortex during two variations on a simple action selection task. Analysis of local field potential (LFP) oscillations revealed that ~20Hz rhythms (Beta) were prominent during the hold period, but only if subjects were instructed on which direction to move during the hold period. This finding is consistent with the hypothesis that Beta is involved with withholding specific selected actions, and agrees with pathological observations of increased Beta in Parkinson's Disease.

In my final study, I examined how action selection circuitry can be exploited to help solve a perpetual problem of neural engineering: how to bypass injured non-regenerating central nervous system neurons to allow for direct motor control from non-injured neurons. I developed an algorithm that observes the pattern of activity in cortical ensembles and allows both the subjects and control system to co-adapt their behavior to allow naive rats to use a neuroprosthetic device. The results of this study show that subjects can learn to select discrete actions in real-time using the neural activity of the cortex.

By developing a deeper understanding of the mechanisms behind selecting motor actions, at the single-unit, multi-unit network, neural ensemble and across structure analysis, we will provide further insight into such neurological diseases as Parkinson's Disease or Tourette Syndrome. Further knowledge in this field will also yield more sophisticated, yet more natural control of neuroprosthetic devices which will rely on native BG and cortical roles in action selection.

Thursday, December 17, 2009

Final Oral Examination


Shin-Yuan Yu
Chair: Bernard J. Martin

Thursday, December 17, 2009, 10:30 AM
1602 IOE

Reaching is a basic component of human movements requiring the coordination of the eyes and multiple body segments including the hand, forearm, arm and torso. This movement has been studied extensively. However, the theory bridging the explicit reaching behavior (coordinated movement of body segments) and the implicit reaching strategy (control mechanisms) is limited. Hence, modeling multi-functional reach movements as a result of coordination remains a difficult task.

The coordination of reach movements can be divided into two components, which relate to body segment kinematics and control mechanisms respectively. The aims of the present study were to investigate the relationships defining the coordination pattern, movement control phase composition and phase transition in order to develop a model of coordinated reach movements. This work focuses more particularly on the characterization of body segment kinematics in relation to visual information, and the role of visual feedback in movement phase transitions. Our results indicate that changes in curvature of the elbow swivel angle combined with gaze orientation seem to be a good indicator of control phase transition in reach movements. The relative durations of movement control phases were therefore determined and modeled as a function of reaching requirements. In addition, the use of the swivel angle enables the reduction of the degrees of freedom and contributes to a simplification of arm movement models. Two strategies of movement execution were observed as a function of the availability of the visual information. In absence of vision, the movement variability was significantly reduced in order to constrain the system degrees of freedom. Furthermore, the orientation of the movement errors strongly support that in the present context, movements are planned in a local coordinate system and the head is the origin of that frame of reference.

A coordination model was developed to describe the timing and kinematics of three-dimensional reach movements. This model also includes the relationship between the eyes and body segment movements. With a generalized hand trajectory, the proposed model generates the sequence of movement phases and drives a multi-linkage system as a function of target locations.

Monday, December 14, 2009

Final Oral Examination


Jeffrey A. Meganck
Chair: Steven A. Goldstein

Monday, December 14, 2009, 2:00 PM
1170A, BSRB

This dissertation includes a series of studies into bone imaging and healing. One of the main outcomes utilizes non-destructive micro-computed tomography (μCT) based imaging, so the accuracy of this imaging modality is investigated. The results indicate that proper use of filtration can avoid the beam hardening artifacts that are attributed to changes in material thickness and radiodensity. These artifacts can affect bone densitometry, but the effects can be minimized at the expense of image contrast, noise and scan throughput. The subsequent experiments build on this knowledge and use μCT as a modality in broader investigations of bone fracture healing and regeneration of structural bone allografts. An animal model of osteogenesis imperfecta (OI), a disease which results in a high incidence of bone fractures for the afflicted pediatric patients, is employed in both healing scenarios. OI patients are normally treated with antiresorptive therapies to reduce fracture risk, so the effect of these therapies on the healing of a subsequent fracture is also investigated. The results indicate that these anti-resorptives have a strong affect on fracture healing if they are present in the circulation, but if treatment is stopped at the time of fracture the effect is very minimal. Furthermore, collagen organization in the healing and intact bone are drastically different, resulting in structure biomechanical properties for the healing bone that are markedly improved in comparison to intact OI bone. This collagen matrix serves as the initial conditions in healing of a structural bone allograft, so the final study investigates this healing paradigm. A model of mouse internal fixation was developed to test grafts both with and without mineral because the presence of mineral complicates effects of matrix alterations in bone. In this case, there was variability in the graft healing between animals, between limbs of the same animal, and even within a single limb. The nature of the healing between grafts with and without mineral is quite different, but the chaotic nature of the healing process may indicate that subtleties in matrix alterations are less important than efforts to improve the healing process at all.

Monday, December 14, 2009

Final Oral Examination


Helen Fuller
Co-Chairs: Yili Liu and Matthew P. Reed

Monday, December 14, 2009, 2:00 PM
2869 IOE

Driver distraction is a topic of increasing concern. A factor in many motor vehicle accidents, it can occur when a driver performs an in-vehicle task, such as tuning a radio, entering coordinates into a GPS system, or operating a communications device in a military vehicle. Most distraction-inducing activities have physical as well as cognitive components, so it is difficult to simulate them in the predominantly cognitive existing models of driving.

The goal of this research was to integrate a physical human model (HUMOSIM Framework running in the Jack human modeling environment) with a computational cognitive model (QN-MHP) to study complex human-machine interactions during driving. A driving simulator experiment was conducted to generate data that was used to tune and validate the integrated model. The study varied the visual and physical difficulty of the secondary in-vehicle task. Driving behavior and secondary task performance results were collected, along with strategies that subjects used to share resources between the two tasks.

The Virtual Driver model that was developed is able to replicate the driving behavior and secondary task behavior displayed in the simulator study. It demonstrates the resource-sharing strategies that subjects used and provides a new way to study driver distraction. In the future, the model could be used to design in-vehicle interfaces and make predictions about staffing requirements and performance.

Friday, December 11, 2009

Final Oral Examination


Danese M. Joiner
Chair: Steven A. Goldstein

Friday, December 11, 2009, 9:00 AM
1170A, BSRB

one is a specialized connective tissue system which is able to regulate its own bone mass and architecture to meet the daily demands of its external environment. Mechanical loading directly or indirectly influences the activity of cell populations to deposit, maintain, or remove bone tissue as appropriate, which is integral to skeletal adaptation of load. With advancing age there are alterations in bone structure and mineralization which are often associated with an increase in osteoporotic fracture risk. The transduction of mechanical cues affects bone structure and mineralization and could be altered with advancing age. Current in vivo and in vitro data suggest age may affect the capacity of bone cells to respond to mechanical stimulation; however the effect of age on transduction in the regenerative skeleton and on osteocytes, which are thought to be the primary mechanical sensors, is unknown. In this study regenerative specimens primarily composed of osteocytes were produced in young and old animals. Their response to mechanical loading via nitric oxide (NO), prostaglandin E2 (PGE2), connexin 43 (Cx43), MAP Kinase, and c-fos signaling was assessed and compared to the response of age matched mature bone. Regenerative specimens from young animals had a higher net increase in NO, PGE2, Cx43 and c-fos subsequent mechanical stimulation than regenerative specimens from old animals. The mechanical stimulation of regenerative tissue resulted in a higher net increase of mechanical response molecules than mature bone in both age groups. This was observed at an earlier time point of regeneration in specimens produced in young animals which could initiate earlier remodeling and thus maintain a mean tissue age that is fairly constant and less susceptible to brittle fracture. Progenitor cells from old animals exhibited delayed mineralization and a decrease response to mechanical stimulation throughout differentiation. The data form this study suggests primary cells from old donors with appropriate differentiation time and mechanical stimulus may promote bone formation, which could make them useful for tissue engineering applications. In addition, key differences in mechanical response were highlighted which have the potential for further investigation to develop therapeutics for bone loss in aging populations.

Wednesday, December 9, 2009

Final Oral Examination


Constance Pagedas Soves
Chair: Steven A. Goldstein

Wednesday, December 9, 2009, 2:00 PM
1170A, BSRB

Maintenance of bone mass and geometry is heavily dependent upon mechanical stimuli. Current paradigms suggest that osteocytes, embedded within the mineralized matrix, and osteoblasts on the bone surfaces, are the primary responders to physical forces. However, other cells within the marrow cavity are subject to a mechanically active environment as well. Megakaryocytes (MKs), cells which give rise to platelets, may physiologically be exposed to fluid shear forces. Recent studies have highlighted the potent effects these cells have on osteoblast proliferation as well as bone formation in vivo. We hypothesize that MKs are capable of responding to physical forces and that the interactions between these cells and osteoblasts can be influenced by mechanical stimulation.

We have demonstrated that two MK cell lines respond to fluid shear stress in culture. Furthermore, we isolated MKs from histologic sections of murine tibiae that were exposed to controlled compressive loads in vivo using laser capture microdissection. C-fos, a transcription factor shown to be upregulated in response to load in various tissue types, was increased in MKs from loaded relative to non-loaded limbs at a level comparable to that of osteocytes from the same limbs.

To assess the functional outcomes of this mechanoresponsiveness, we first set out to determine whether animals with elevated numbers of MKs demonstrated altered adaptation to mechanical loading. GATA1low mice, a transgenic mouse model with arrested MK maturation leading to an elevated number of immature MKs within the marrow, were shown to have a minimally altered response to load compared to wild-type littermates. Mice injected with thrombopoietin, a potent inducer of MK proliferation and differentiation, showed no difference in response to load compared with vehicle-injected mice.

Finally, we developed a co-culture system to address whether mechanical stimulation of MKs in culture would impact osteoblast proliferation and differentiation. The presence of MKs in culture, but not conditioned media, has dramatic effects on osteoblast proliferation. Our data suggests a minimal, but non-significant, decrease in proliferation as well as an increase in mineralization capacity of osteoblasts co-cultured with MKs exposed to shear compared to co-cultures with unstimulated MKs. However, further studies are required to confirm the significance of these observations.

Wednesday, December 9, 2009

BME 500 Seminar Series

"Cell: Extracellular Matrix Remodeling in 2-D Versus 3-D Space"

Stephen J. Weiss, Ph.D.
Professor, Internal Medicine - Molecular Medicine and Genetics
Upjohn Professor of Medicine and Oncology
University of Michigan

Wednesday, December 9, 2009, 3:30 - 4:30 pm.
White Auditorium - Rm G906 Cooley Building

Normal as well as neoplastic cells proteolytically remodel the surrounding extracellular matrix during events ranging from branching morphogenesis to cancer metastasis (e.g, Cell 125:577, 2006; PNAS 106:20318, 2009). In vivo, cells interface with the surrounding extracellular matrix under either 2-dimensional (2-D) or 3-dimensional (3-D) conditions (e.g, epithelial cells abut a subjacent sheet of extracellular matrix, termed the basement membrane while fibroblasts are surrounded by a 3-D stroma comprised largely of type I collagen; J Trends Cell Biol 18:560, 2009). Though the genome encodes more than 500 proteinases, increasing evidence suggests that a small group of membrane-anchored metalloproteinases, termed the MT-MMPs, confer normal and neoplastic cells with the ability to remodel the extracellular matrix and regulate cell function (Ann Rev Cell Dev Biol 25:567, 2009). Mechanisms which imbue these proteinases with the ability to effectively remodel the pericellular extracellular matrix and transmit changes in matrix structure to the nuclear compartment and beyond.

Friday, December 4, 2009

Final Oral Examination


Woonghee Lee
Co-Chairs: Erdogan Gulari and Shuichi Takayama

Friday, December 4, 2009, 3:30 pm
1044 FXB (McDivitt)

The conventional gene synthesis methods, chemical or PCR, usually require over 2 weeks because of the separate executions of the different procedures. An integrated microfluidic chip system was designed to reduce this processing time to only 2 days with much less reaction volumes, and experimental reagent and solvent requirements. This fast high throughput gene synthesis method considerably minimizes contamination and simplifies material handling procedures. Our overall aim in this project is using the above-mentioned advantages of this system to synthesize long genes of arbitrary sequence with high purity, and cut the lead times and cost per base from the current values by at least one order of magnitude. In order to do this, four different steps are included in the microfluidic chip system: oligonucleotide synthesis and amplification on solid phase, on-chip purification, long DNA assembly, and gene transformation. The designed oligonucleotides to form the long DNAs were synthesized via light-directed phosphoramidite chemistry, and amplified on solid phase. The amplified products were treated by on-surface hybridization using complementary probes to make single strands and purification. The purified oligonucleotides were assembled into long DNAs on chip, and amplified with polymerase chain reaction in a separate microfluidic chip chamber. Finally, the synthetic target gene was transformed on a chip for gene expression. Our results showed these individual steps in bringing the system capability to a simultaneous production level of tens of double stranded oligonucleotides of lengths ranging from 0.2 to 1kb and the potential of microfluidic gene and protein synthesis system.

Friday, December 4, 2009

Final Oral Examination


David Lorch
Chair: Alan J. Hunt

Friday, December 4, 2009, 1:00 pm
1504 G.G. Brown

Flagella and cilia play critical roles in mammalian and other eukaryotic life by providing propulsion for swimming cells and moving fluids across tissue surfaces. Flagellar/ciliary bending is caused by the sliding of doublet microtubules (MTs) past each other due to a molecular motor called dynein attached to one doublet MT walking along an adjacent doublet MT. Due to these doublet MTs being fixed at the same end, this translocation produces a bend in the whole structure. While it is clear how the dynein molecules cause a bending of the doublet MTs, the mechanism underlying the generation of propagated waves of flagellar/ciliary motion has yet to be fully understood, especially with regard to the magnitude and regulation of the forces produced by dynein. Our proposed experiments are guided by one of the most powerful and widely cited models for predicting flagellar/ciliary motion: the Geometric Clutch Model (GCM). This model proposes that a transverse force produced by the flagellar bending causes a separation of the doublet MTs, which disengages sections of dynein, thereby alternating which side of the flagella is active to produce cyclical flagellar bending; first one way, then the other. Several outside studies have shown that some of dynein's mechanical properties such as velocity of MT gliding and force generation seem to be regulated by its multiple nucleotide binding sites. Our main goal is to characterize force generation by mammalian axonemal dynein to model the regulation of this molecule as well as its role in the process of propagated flagellar bending.

To better understand dynein's role in coordinated flagellar and ciliary motion, we developed two in situ assays: one in which polymerized single microtubules glide along doublet microtubules extruded from disintegrated bovine sperm flagella at a pH of 7.8 and an optical tweezers assay which is identical in geometry and environment except the single MT is held in an optical trap to measure displacements and forces rather than velocities. The exposed, active dynein in each assay remain attached to their respective doublet microtubules, allowing translocation of individual microtubules to be observed in an environment that allows direct control of chemical conditions. In the gliding assay, in the presence of ATP, translocation of microtubules by dynein exhibits Michaelis-Menten type kinetics, with Vmax = 4.7 +/- 0.2 um/sec and Km = 124 +/- 11 uM. The character of microtubule translocation is variable, including smooth gliding, stuttered motility, oscillations, buckling, complete dissociation from the doublet microtubule, and occasionally movements reversed from the physiologic direction. The gliding velocity is independent of the number of dynein motors present along the doublet microtubule, and shows no indication of increased activity due to ADP regulation. In the optical tweezers assay, average force was found to be independent of the concentrations of ATP and ADP used and durations of these forces indicates that mammalian, axonemal dynein is non-processive. These combined results reveal fundamental properties underlying cooperative dynein activity in flagella, differences between mammalian and non-mammalian flagellar dynein, and establish the use of natural tracks of dynein arranged in situ on the doublet microtubules of bovine sperm as a system to explore the mechanics of the dynein-microtubule interactions in mammalian flagella.

Wednesday, December 2, 2009

BME 500 Seminar Series

"Toward Multiscale Optical Imaging Approaches for Soft and Hard Tissue Characterizations"

Young L. Kim, PhD, MSCI
Assistant Professor of Biomedical Engineering
Weldon School of Biomedical Engineering
Purdue University

Wednesday, December 2, 2009, 3:30 - 4:30 pm.
White Auditorium - Rm G906 Cooley Building

Tissue characterizations often require non-destructive imaging of large areas with high resolution/sensitivity. However, because of the trade-off between resolution/sensitivity and field of view in imaging systems, it is challenging to obtain a detailed physical image over a large tissue area. In addition, high-resolution imaging systems rely on spatial gating such as mechanical pinhole scanning, which in turn allows imaging at discrete locations. We will introduce simple, but intriguing, imaging approaches to take advantage of intrinsic properties of low spatial coherence illumination, enhanced backscattering of light, and high anisotropic biological tissue. The wavelength dependence of light elastically backscattered from tissue can also be used to probe internal structures and tissue architectures as small as a fraction of the wavelength. Thus, these key characteristics have the potential for rapid and sensitive imaging a relatively large area over a wide range of scales from nanoscales to mesoscopic scales. We will discuss a few applications using our imaging approaches for tissue characterizations, including spectroscopic detection of field cancerization and prefailure damage analysis in bone. We envision that such imaging methods may facilitate understanding how an invasive cancer arises from a large altered carcinogenesis field and how the bone nanostructure controls bone characteristics.

Monday, November 23, 2009

Final Oral Examination


Divya Srinivasan
Chair:Bernard J. Martin

Monday, November 23, 2009, 2:00 PM
2869 IOE

Eye-hand coordination is fundamental to performing any motor activity, from the simplest everyday tasks to skilled operations required of professionals in sports or industry. While coordination of concurrent motor responses has been studied extensively, the factors that drive specific patterns of coupling of the two hand movements have not yet been clearly understood. The pattern of movement initiations, movement durations, spatio-temporal coupling of the two hand movements and how one task demand affects performance of the other task are open questions concerning the organization of bimanual coordination. Answers to these questions may lie in understanding how the competing visual demands of the two hand systems could be met within the constraints of the visual system.

The present study investigates the role of visual feedback in mediating control of bimanual movements using two reach tasks, one with each hand, to targets with different accuracy constraints. A strong tendency to temporally synchronize the movements of both hands was observed. However, although synchronized until peak velocity (regardless of task conditions), the pattern of coordination of the terminal phases of movements varied as a function of task difficulty. Furthermore, spatial symmetry was compromised in favor of temporal symmetry. The patterns of spatial coupling were pre-planned (before movement initiation) based on the central nervous system?s expectations about the time of availability of visual feedback for completion of the secondary task.

With practice, different eye-hand coordination strategies emerged as a function of task accuracy levels. Although both movements were being performed simultaneously, feedback resources were prioritized to process movement corrections of only one task at a time. In symmetric task conditions (task demand of each hand is similar), the left hand task consistently received visual attention first (primary), and performance of the right hand task was secondary, dependent on the successful performance of the primary task. This indicates an asymmetry in the feedback requirements of the two hand systems.

A control model of the visual and left & right manual subsystems has been developed to schedule movement components and simulate self-paced bimanual tasks with only high-level inputs. This model sequences the movement phases as a function of task parameters and mediates the optimal allocation of resources common to the different subsystems.

Wednesday, November 18, 2009

BME 500 Seminar Series

"Engineering Human Functional Blood Vessels in Mice as a Tool for Cancer Research"

Jacques E. Nor, D.D.S., M.S., Ph.D.
Professor of Dentistry, U-M Dental School
Professor of Otolaryngology, U-M Medical School
Professor of Biomedical Engineering, U-M College of Engineering
University of Michigan

Wednesday, November 18, 2009, 3:30 - 4:30 pm.
White Auditorium - Rm G906 Cooley Building

In this seminar, we will discuss the development and characterization of the SCID Mouse Model of Human Angiogenesis. We will also discuss the use of this model in our studies on the impact of the crosstalk between endothelial cells and tumor cells on tumor progression.

Wednesday, November 11, 2009

BME 500 Seminar Series

"The Regulation of Stem Cell Self-Renewal"

Sean Morrison, Ph.D.
Director, Center for Stem Cell Biology, Life Sciences Institute
Henry Sewall Professor in Medicine
Investigator, Howard Hughes Medical Institute
Professor, Cell and Developmental Biology
Professor, Department of Internal Medicine, Division of Medical Genetics
Research Professor, Life Sciences Institute
Research Professor, Molecular and Behavioral Neuroscience Institute
University of Michigan

Wednesday, November 11, 2009, 3:30 - 4:30 pm.
White Auditorium - Rm G906 Cooley Building

Self-renewal is the process by which stem cells divide to make more stem cells, perpetuating the stem cell pool throughout life. Self-renewal is division with maintenance of the undifferentiated state. This requires cell cycle control and maintenance of multipotentiality or pluripotentiality, depending on the stem cell. Self-renewal programs involve networks that balance proto-oncogenes (promoting self-renewal), gate-keeping tumor suppressors (limiting self-renewal) and care-taking tumor suppressors (maintaining genomic integrity). These cell-intrinsic mechanisms are regulated by cell-extrinsic signals from the niche, the microenvironment that maintains stem cells and regulates their function in tissues. In response to changing tissue demands, stem cells undergo changes in cell cycle status and developmental potential over time, requiring different self-renewal programs at different stages of life. Reduced stem cell function and tissue regenerative capacity during aging are caused by changes in self-renewal programs that augment tumor suppression. Cancer arises from mutations that inappropriately activate self-renewal programs.

Wednesday, November 4, 2009

BME 500 Seminar Series

"Electrical Turbulence and Vortex-Like Reentry in the Mammalian Heart"

Omer Berenfeld, Ph.D.
Assistant Professor of Internal Medicine and Biomedical Engineering
Center for Arrhythmia Research
Department of Internal Medicine
University of Michigan

Wednesday, November 4, 2009, 3:30 - 4:30 pm.
White Auditorium - Rm G906 Cooley Building

Cardiac electrical turbulence known as ventricular fibrillation (VF) is the major cause of sudden and unexpected death. We take an integrative approach to study the manner in which nonlinear electrical waves that were originally thought of being random organize to result in VF. The presentation centers on data derived from models of stable VF that demonstrate distinct patterns of excitation organization. Analysis of optical mapping data reveals that VF excitation frequencies are distributed throughout the ventricles in clearly demarcated domains with the highest frequency domains found where a sustained reentrant activity that drives the arrhythmia is present. Using numerical and cellular electrophysiology approaches we further study how certain transmembrane potassium currents determine the rotor stability and frequency. Computer simulations and analytical procedures then predict that the filaments of those reentrant waves (scroll waves) adopt a non-random configuration depending on fiber organization within the ventricular wall.

Wednesday, October 28, 2009

BME 500 Seminar Series

"Biomechanics of Native and Engineered Heart Valve Tissues"

Michael S. Sacks, Ph.D.
J.A. Swanson Endowed Chair in Bioengineering
Department of Bioengineering
University of Pittsburgh

Wednesday, October 28, 2009, 3:30 - 4:30 pm.
White Auditorium - Rm G906 Cooley Building

On the most basic functional level, heart valves are essentially simple-check valves that serve to prevent retrograde blood flow. This seemingly simple function belies the structural complexity, elegant solid-fluid mechanical interaction, and durability necessary for normal valve function. For example, valves are capable of withstanding 30-40 million cycles per year, resulting in a total of ~3 billion cycles in single lifetime. Passive in nature, heart valves react to the inertial forces exerted by blood flow. Pressure differences operate on the valve leaflets to initiate rapid opening and closure of the valve. Functionally the leaflet is required to exhibit diverse mechanical properties under varied states and modes of deformation. Robust constitutive models provide the fundamental framework for computational modeling of heart valve function. The complex multi-modal nature of valvular leaflet deformation warrants a treatment focused on the prediction of response to generalized mechanical stimuli. A complex interaction of constituents influences the structural response of the tissue. Structural proteins (collagen and elastin) and other extracellular matrix (ECM) components react to mechanical stimuli in varied modes to produce a highly nonlinear anisotropic tissue level response unique to the tissue type and tailored to specific physiological conditions. In general, the robust nature of a model can be characterized by the ability to capture the underlying physiologic function. Our laboratory has pioneered morphological based constitutive models that considers a broad range of strain and deformation modes, including the impact of low strain and bending response.

The staggering level of valve performance can be cut short by aortic valve disease, the most common form being stenosis resulting from calcification. Currently, the treatment of valve disease is usually complete valve replacement. First performed successfully in 1960, surgical replacement of diseased human heart valves by valve prostheses is now commonplace and enhances survival and quality of life for many patients. However, they continue to have significant clinical problems and there is a profound need for new approaches to valve therapies based on sound scientific and engineering principals. Tissue engineering represents a spectrum of cross-disciplinary technologies aimed toward the repair, replacement, or enhancement of native valve function. The scaffolds amenability to tissue development, however, belies their intricate microstructure and the concomitant complexity of mechanical interactions occurring between scaffold, cellular, and extracellular matrix constituents in an engineered tissue construct. Mathematical models that simulate the composite mechanical behavior of the scaffold and the developing tissue could potentially facilitate the design of engineered tissues and mechanical conditioning regimens. Such models could thus play a pivotal role in the design and development of an engineered heart valve.

Wednesday, October 21, 2009

BME 500 Seminar Series


William Giannobile, D.D.S., D.Med.Sc.
William K. & Mary Anne Najjar Professor of Dentistry
Professor of Biomedical Engineering
Director, Michigan Center for Oral Health Research

Wednesday, October 21, 2009, 3:30 - 4:30 pm.
White Auditorium - Rm G906 Cooley Building

Repair of alveolar bone and soft defects caused by chronic periodontal disease is a major goal of oral and craniofacial reconstructive therapy. The field of periodontal tissue engineering combines advances in materials science and biology to repair tooth-supporting structures and for whole tooth engineering. This presentation will discuss some of the challenges faced in the restoration of tooth/implant-bone interfaces for regeneration including microbial, host response and tissue engineering concepts. Future applications for the repair of tissues will be presented including the use of protein, cell and gene therapy to target biomimetic molecules to oral and craniofacial defects. Recent data on the use of growth factor technologies that have received recent FDA clearance for the dental arena will also be discussed.

Wednesday, October 7, 2009

BME 500 Seminar Series

"Image Registration: Warping Without Folding"

Jeff Fessler, PhD.
Nuclear Medicine / Radiology,
Biomedical Engineering, and EECS
University of Michigan

Wednesday, October 7, 2009, 3:30 - 4:30 pm.
White Auditorium - Rm G906 Cooley Building

Image reconstruction of moving objects (such as breathing patients) is challenging due to inconsistencies between measurements acquired at different phases of the motion. Compensating for motion during image reconstruction requires tools similar to those used in nonrigid image registration. In this talk I will discuss an approach for nonrigid image registration based on B-spline deformation models. The key feature of this approach is that it provides a simple way to ensure that the estimated deformation is invertible (diffeomorphic). This constraint is important for the registration to be physically plausible. (Work based on the dissertation work of Se Young Chun.) For more in depth information see the background paper.

Wednesday, September 30, 2009

BME 500 Seminar Series

"Regulation of the Blood Brain Barrier During Ischemic Stroke: Implications for the Use of Thrombolytic Therapy"

Daniel A. Lawrence, PhD.
Department of Internal Medicine, Division of Cardiovascular Medicine,
University of Michigan Medical School

Wednesday, September 30, 2009, 3:30 - 4:30 pm.
White Auditorium - Rm G906 Cooley Building

The use of tissue plasminogen activator (tPA) as a thrombolytic treatment in ischemic stroke is limited largely due to concerns for hemorrhagic complications. This talk will discuss recent data demonstrating that that in addition to its well established thrombolytic activity, tPA also interacts with key regulators of the neurovascular unit (NVU), and that these interactions appear to contribute to the undesirable side effects associated with the use of tPA in ischemic stroke. Understanding these connections and tPA's normal function within the NVU may offer new insights into future therapeutic approaches for the treatment of stroke and other CNS disorders.

Wednesday, September 23, 2009

BME 500 Seminar Series

"Physicochemical Regulation of Cell Function and Tissue Morphogenesis"

Andrew Putnam, Ph.D.
Assoc. Professor, Department of Biomedical Engineering
University of Michigan

Wednesday, September 23, 2009, 3:30 - 4:30 pm.
White Auditorium - Rm G906 Cooley Building

The responses of cells to chemical inputs, such as growth factors and hormones, have been widely studied in the cell biology community for decades. Independently, many investigators in the bioengineering community have focused on the responses of cells and tissues to externally applied mechanical forces. Increasing evidence suggests that cells are also sensitive to the intrinsic mechanical properties of their microenvironment, specifically the extracellular matrix (ECM), and that these properties can influence tissue patterning and morphogenesis. However, the impact of ECM mechanics on morphogenesis in 3D remains unclear, due in part to the fact that substrate mechanical properties, adhesion ligand density, and proteolytic sensitivity are intimately linked in native biopolymers systems. To decouple these effects, many research groups (ours included) have explored the use of synthetic hydrogels, based on the argument that their bulk moduli can be tuned independent of changes in biological recognition motifs. However, altering cross-link density to change bulk mechanical properties simultaneously alters the micro- and nanostructure of most hydrogels, which in turn profoundly influences cell shape. Macromolecular diffusive transport is also significantly slowed, which thereby impacts the delivery of soluble chemical cues to cells. Further complicating interpretations is the fact that the bulk mechanical properties of many systems may change significantly with time, due to either passive hydrolysis, cell-mediated proteolysis, or both. Given such limitations, will we ever understand how chemistry and mechanics conspire to influence cell fate in 3D, and thereby perhaps derive constitutive equations that govern material design for tissue engineering applications? Is all hope lost? On the contrary, new methods to measure microscale mechanics on length scales relevant to cells are enabling us to discern exactly how cell-generated tractional forces, and the ability of the ECM to resist those forces, control cell decision-making processes in 3D gels. These approaches can be further integrated with microscale, multicellular 3D culture systems capable of providing controlled growth factor gradients and externally applied forces. Understanding the integration of these inputs will ultimately impact the design of ex vivo stem cell niches, biomaterials for tissue engineering applications, and in vitro platforms for fundamental mechanistic studies of normal and pathologic morphogenesis.

Wednesday, August 12, 2009

Final Oral Examination


Sheereen Majd
Chair: Michael Mayer

Wednesday, August 12, 2009, 1:00 PM
General Motors Conference Hall, 4th Floor Lurie Engineering Center

Many cellular processes involve molecular interactions at the cell membrane. Due to the complexity of living cells, these interactions are usually studied on model membranes. This thesis introduces two platforms based on model membranes for studying biological interactions and processes on cell membranes.

In the first part of this thesis, we employed planar lipid bilayers to develop a novel, label-free, and sensitive assay for monitoring the activity of phospholipases D and C that are critical for cell signaling. The activities of these enzymes typically change the surface charge of the membrane. The present assay employs the ion channel-forming peptide gramicidin A to probe these changes and, hence, to monitor the activity of these phospholipases /in situ/ and in real-time. Quantitative results from this assay, allowed us to investigate the kinetics of the heterogeneous catalysis of these enzymes.

In addition we applied this gramicidin-based sensor to monitor the binding of two therapeutic drugs to various bilayers. Quinine, an anti-malaria agent, and imipramine, an anti-depressant, are positively-charged under physiological conditions and, once bound to a membrane, alter the membrane surface charge. The present assay probes these changes and makes it possible to quantify these binding events.

In the second part of this work, we developed a technique that employs topographically-patterned hydrogel stamps to fabricate arrays of membranes and membrane proteins for screening of membrane interactions. This method takes advantage of the porous, hydrated, and biocompatible nature of hydrogels to print spatially-addressable arrays of membranes in a rapid and parallel fashion. We employed this method for two distinct approaches; one approach takes advantage of the storage capability of agarose stamps and minimizes the required time and amount of membrane preparations by generating multiple copies of a membrane array. The other approach takes advantage of on-stamp preconcentration of cellular membrane fragments to generate arrays of multilayered-membranes with high contents of proteins and enhances detection sensitivity. We used these arrays for screening the interactions of a protein (annexin V) and an anti-inflammatory drug (nimesulide) with various bilayers. We also carried out ligand-binding assays on these arrays and showed that the stamped membrane proteins retained their binding activity.

Thursday, July 30, 2009

BME Research Seminar

"Doppler Spectral Domain Optical Coherence Tomography (OCT) used to Measure Feline Retinal Vascular Parameters"

Glenn Myers, Ph.D
Bioptigen, Inc.

Thursday, July 30, 2009, 10:00 AM
1123 LBME

When we go to a doctor's office, one of the first and most important things they do is to measure our blood pressure (BP). However, when we take a pet to the veterinarian, they usually cannot measure BP. This is especially problematic in cats, who will not tolerate BP cuffs on their limbs. Even if a cuff could be made robust enough to resist the cat's efforts to remove it-the effort alone would elevate BP, and hence invalidate the test. Bioptigen was contracted by a leading veterinary medical systems supplier to investigate the feasibility of measuring BP in cats in a noninvasive, noncontact manner using Optical Coherence Tomography (OCT).
OCT is a relatively new method to image living tissue in greater detail than medical ultrasound, and with more depth of penetration than light microscopy. Thus OCT 'fills the gap' between these two imaging modalities, and is sometimes called 'optical biopsy'. OCT is conceptually similar to ultrasound, in that it uses interferometry (of light-rather than sound) to form images.
In OCT, superluminescent diodes (SLDs) or the more expensive femtosecond lasers, supply light at one of several near infrared wavelengths (e.g. 840, 1064 or 1310 nm). We used an 840 nm SLD with a bandwidth of 50 nm (which together yield a coherence length of 6 um). It is possible to achieve coherence lengths (which ultimately limit axial resolution) of 1 um or less using multiplexed SLDs. Depth of penetration is limited by the signal to noise ratio (SNR) of returned light, which is limited in turn by absorption and scattering. Use of Spectral Domain (vs. Time Domain) OCT allows us to further improve SNR and ultimately to increase the rate of image capture, which allows us to measure moment-to-moment fluctuations in all these parameters simultaneously for the first time. Illumination was less than the 'eye safe' limit for humans.
Doppler Spectral Domain OCT was used to measure the instantaneous size of blood vessels in retinas of anesthetized cats, and the direction and rate of blood flow in these vessels, while BP was monitored invasively and manipulated pharmacologically. We experienced significant experimental difficulty with drug-drug interactions (the anesthetic isoflurane partially blocked the vasopressor effect of phenylephrine), nevertheless, our measurements suggest that, in conjunction with a simple linear model of BP vs. rate of flow and vessel size (each of which fluctuates on a moment-to-moment basis), it is feasible to estimate BP in a noninvasive, noncontact manner using Doppler Spectral Domain OCT. Additional, preliminary measurements in awake ('behaving') cats suggest that this method could be used routinely in veterinary clinics.

Monday, July 13, 2009

Final Oral Examination


Jungwoo Lee
Chair: Nicholas Kotov

Monday, July 13, 2009, 10:00 AM
GM Room, Lurie Engineering Center

Effective early stage toxicity testing of drug compounds is imperative to minimize failures in the late clinical phase. 2D cell cultures have been dominantly used in preclinical drug testing, but it is becoming apparent that they are far limited in emulating 3D human tissues. As a potential solution to improve the predictive power of in vitro screening procedures, this dissertation explored a new opportunity of in vitro tissue engineering as a part of the drug development process.

Besides the biological significance in functional tissue formation, here the scaffold should be transparent and support homogenous tissue growth. Inverted colloidal crystal (ICC) hydrogel scaffolds having standardized 3D structure and materials as well as retaining a high analytical capability were developed for this purpose. Uniform size spherical pore arrays prepared with cell repulsive polyacrylamide promoted uniform size HepG2 liver tissue spheroid formation, while the transparent hydrogel matrix allowed convenient characterization of cell aggregation process. The established standardized spheroid culture model was successfully applied to the in vitro toxicity testing of nanoparticles. Significantly reduced toxic effects were observed in the 3D culture compared to the conventional 2D culture. Tissue-like morphology and cell phenotypic change in the spheroid culture were two distinguished factors.

In addition, ICC scaffolds combined with a layer-by-layer (LBL) surface modification technique served as a platform for engineering primary lymphoid tissues, i.e. bone marrow and thymus. Under dynamic culture condition, floating hematopoietic stem cells (HSCs) could travel deep into the scaffold via interconnecting channels, while they were temporarily entrapped due to limited channel size and number. As a result, HSCs extensively interacted with stromal cells growing along the LBL coated pore surface. Such intimate cell-cell and cell-matrix interaction is the key process in HSCs survival and differentiation that was substantiated by ex vivo expansion and B-/T-cell differentiation of HSCs.

Overall this thesis introduces a promising application of in vitro tissue engineering as a practical and valuable early stage toxicity testing tool. Standardized in vitro tissue models prepared in ICC scaffolds manifested the capability to extend current cellular level cytotoxicity to the tissue level.

Friday, July 3, 2009

Final Oral Examination


Karen A. Esmonde-White
Chair: Michael D. Morris

Friday, July 3, 2009, 10:00 AM
1706 Chemistry

Vibrational spectroscopic methods are minimally invasive, and are appropriate for use in clinical contexts. Methods were developed in this dissertation for evaluating joint damage and disease using Raman spectroscopy. The goal of this research is to develop Raman spectroscopic methods for the examination of joint tissue and biological fluids, for monitoring and detecting molecular alterations associated with osteoarthritis. Subtle molecular changes in joint tissue and synovial fluid provide markers for early detection of joint damage. We identified Raman spectroscopic markers of early-stage osteoarthritis in cartilage, subchondral bone and relevant biological fluids. Using Raman spectroscopy the chemical composition of joint tissues was measured, and the results were compared to the results from micro computed tomographic and histopathologic analysis. Reduced bone mineralization was observed in Raman measurements of subchondral bone from a mouse model of early-onset osteoarthritis. A fiber-optic Raman probe for arthroscopic measurements was developed to demonstrate the feasibility of measuring the molecular composition of joint tissue with clinically-relevant instrumentation. In addition to cartilage and subchondral bone, the composition of synovial fluid is a key factor in maintaining healthy joint function. Synovial fluid from normal and diseased joints was examined using a novel drop deposition/Raman spectroscopic method. Results from drop deposition/Raman spectroscopy correlated with radiographic evidence of osteoarthritis. These studies show that Raman spectroscopic measurements of joint tissue and synovial fluid correlate with established techniques for osteoarthritis detection and Raman spectroscopy may potentially provide early detection of joint damage.

Monday, May 11, 2009

Final Oral Examination


Helen J. Huang
Chair: Daniel P. Ferris

Monday, May 11, 2009, 11:00 AM
Bickner Auditorium, CCRB/Kines Room 3735

Humans naturally coordinate upper and lower limb movements during rhythmic tasks. This innate coupling between upper and lower limbs has a neural basis that may be advantageous for gait rehabilitation. Adding upper limb effort to lower limb stepping could improve lower limb muscle recruitment during therapy.

I developed a computer controlled recumbent stepping device with mechanically coupled handles and pedals to test principles of neural coupling of the arms and legs. Subjects drove the stepping motion using different combinations of upper and lower limb effort (active or passive). The first study demonstrated that upper limb effort increased passive lower limb muscle activation proportionally in neurologically intact individuals. These results indicated an excitatory neural coupling between the upper and lower limbs during rhythmic stepping movements. I then studied neurologically intact subjects performing maximal effort, velocity-controlled recumbent stepping. The results revealed that neural coupling between the upper and lower limbs is bidirectional and ipsilaterally biased.

For the next study, I examined neural coupling in individuals with incomplete spinal cord injury to determine if adding upper limb effort enhanced muscle recruitment of volitionally maximally active lower limbs. The data indicated that maximal upper limb effort did not increase active lower limb muscle recruitment in individuals with incomplete spinal cord injury. Similar to neurologically intact individuals, spinal cord injured individuals also demonstrated increased passive lower limb muscle activation with greater upper limb effort.

Lastly, I used computer simulations to examine potential neural mechanisms behind the upper and lower limb neural coupling. These models showed that excitatory sensory feedback, excitatory ipsilateral pathways, and supraspinal drive were all possible specific neural mechanisms explaining my empirical results. Future studies can use more sophisticated neural techniques such as transcranial magnetic stimulation to test the specific neural mechanisms shown in the simulations.

Overall, my findings provide a better understanding of interlimb neural coupling and have specific implications for the design of exercise therapies for gait rehabilitation after neurological injury.

Thursday, April 30, 2009

Final Oral Examination


Yao-Kuang Chung
Chair: Shuichi Takayama

Thursday, April 30, 2009, 10:00 AM
1180 Duderstadt Center Conference Room

This project investigates effects of flow and CXC chemokine ligand-12, CXCL12 stimuli on prostate cancer PC3 cell adhesion and migration by using microfluidics. Prostate carcinoma (PCa) is the most frequently diagnosed cancer in men and the second leading cause of cancer death in American males. Bone metastasis, known to be exacerbated by CXC chemokine receptor 4 (CXCR4) signaling pathways, is a major cause of high morbidity and mortality rates.

Although inhibition of CXCR4 is known to modulate cancer metastasis in vivo, the detailed mechanisms are still ambiguous. In vitro studies are useful but lack many physiological features and may not reveal the full range of cancer cell behaviors. For example, the temporal patterns of CXCR4 stimulation by CXCL12 in vivo may be pulsatile rather than continuous as is the case in many in vitro studies. The pulsatile exposure to CXCL12 is expected due to pulsatile release, active degradation by proteases, scavenging by CXCR7 expressing cells, binding to extracellular matrix, and by presence of interstitial flows. Active scavenging by CXCR7 has been shown to be critical for cell directed sensing and polarizing toward CXCL12 stimuli in vivo further reinforcing the potentially important role of temporal patterns of stimulation. Pulsatile stimulation makes mechanistic sense also since CXCR4 is a G-protein coupled receptor (GPCR) and continuous stimulation would simply lead to receptor desensitization.

Experiments by microfluidics demonstrate that pulses of CXCL12 rather than continuous stimulation induce significantly enhanced directed migration of PC3 cells. And as expected, CXCR4 knockdown PC3 cells migrated with significantly lower speed and directionality under CXCL12 stimulation compared with normal PC3 cells. During the course of studying the effect of temporal patterns of CXCL12 stimulation it was unexpectedly discovered that PC3 cells showed significantly better adhesion and migration behavior under pulsatile flow than under steady flow even in the absence of chemical stimulation. The technology helps clarify some of the biophysical effect of CXCR4 that may be important for physiological function of malignant prostate cancer cells.

Wednesday, April 29, 2009

Final Oral Examination

Functional Assessment of Adenovirus-mediated Platelet-Derived Growth Factor Gene Delivery on Accelerating Oral Implant Osseointegration

Po-Chun Chang
Chair: William V. Giannobile

Wednesday, April 29, 2009, 10:00 AM
G550 School of Dentistry

The main purpose of dental implants is to restore the function of the dentition. Despite utilizing structural analyses to investigate treatment outcome, the therapeutic effect is sometimes unclear due to a lack of direct relevance to the biomechanical function of the peri-implant tissue. While the effective function of tissue depends on the growth pattern, maturation, and load bearing situation of the apparatus, in this dissertation I homogenized the peri-implant tissue parameters under simulated loading situations to generate functional bone apparent modulus (FBAM) and functional composite tissue apparent modulus (FCAM) through the finite element (FE) optimization process. Both FBAM and FCAM were correlated to the structural parameters, and FCAM was determined to be more relevant to interfacial biomechanical characteristics with a pre-existing extraction defect, whereas FBAM within a 200 um peri-implant concentric layer was more relevant to the circumstance without surrounding defects.

Platelet-derived growth factor (PDGF) has been utilized for dental tissue regeneration based on its effects on chemotaxis and mitogenesis, which are also key events which occur during early osseointegration. However, the bioactivity of the recombinant growth factor application may be significantly reduced due to its rapid degradation and diffusion in vivo. To ensure the efficiency of PDGF expression, we delivered PDGF to peri-implant osseous defects using adenovirus gene therapy vectors (AdPDGF-B) and evaluated the treatment outcome histologically, radiographically, and functionally. The results demonstrated that AdPDGF-B significantly accelerated the defect fill and promoted early bone-implant contact (BIC) in a dose-dependent manner. AdPDGF-B also facilitated favorable functional implant support in the early stages of osseointegration.

Presently, there exist some considerations regarding the potential of adenovirus-mediated gene therapy to induce virus-related pathologic changes. Thus, the local and systemic safety profile of AdPDGF-B was thoroughly examined in this dissertation in order to alleviate concerns about future gene therapy applications for clinical use. AdPDGF-B was eliminated within two weeks without significant dissemination in vivo, and no histopathologic changes or alterations of systemic parameters were noted. Taken together, this dissertation contributes a novel methodology to functionally evaluate the dynamics of osseointegration and demonstrates the feasibility of AdPDGF-B for accelerating osseointegration while maintaining an acceptable safety profile.

Wednesday, April 29, 2009

Final Oral Examination


Ming-Tse Kao
Chair: Edgar Meyhofer

Wednesday, April 29, 2009, 9:30 AM
1690 CSE

Kinesin motors are nanometer-scale biological motor proteins that evolved for a range of biological transport functions in cells. In cells they move along microtubules, long filaments that are part of the cytoskeleton, by hydrolyzing ATP. The small in size and robustness of movement in vitro provides tremendous advantage for engineering application compared to many artificial motors. Moreover, kinesins efficiency and ability to readily utilize chemical energy from their ambient environment, simplifies microdevice designs and eliminates the requirement of large external power supplies. In this dissertation, I present three micro- and nano-devices into which kinesin motors are integrated. Two of the devices efficiently rectify the mechanical power produced by multiple kinesins into designated directions by directing the movement of microtubules with micro- and nano-structures. The third device leverages the previously developed techniques of direction the motion of microtubules and integrates antibody to achieve highly sensitive bio-molecule sorting. These devices demonstrate that the kinesin-powered devices are practical and have significant potential for future application in modern microfluidic devices.

To enhance future technological application, it is important to understand the molecular mechanisms of kinesin. Kinesin has been intensively studied for decades; however, many of detailed molecular mechanisms remain poorly understood. One major gap in our understanding relates to the mechanism(s) that control the direction of movement of kinesin motors along microtubules. Regardless of the structural similarity of the head domain, the major domain for force production and energy transduction, kinesins with head domain in N-terminus (N-terminal kinesins) are microtubule plus-end directed motors. C-terminal kinesins on the other hand, which have their head domain at the C-terminal end, are minus-end directed kinesins. Here, I use mutagenesis to investigate which structural domains determine the directionality of conventional kinesin and Ncd, the two major kinesin models for directionality studies. The result shows that both kinesins use structural components close to their head domains to control their directionality: the structural components that control kinesins direction are neck-linker and C-terminal neck domain for plus-end directed kinesin and minus-end directed kinesin, respectively.

An important physiological property of conventional kinesin is its ability of a single motor molecule to take a large number of uninterrupted, sequential steps along the surface lattice of the microtubule without detachment. This processive hand-over-hand motion is believed to be based on a coordinated, alternate catalysis of the two head domains. One frequently cited hypothesis postulates that this coordination is based on intra-molecular mechanical strain. However, little work has directly investigated in this intra-moleculer strain coordination for kinesins processive movement. To test this intra-molecular strain hypothesis I inserted a set of flexible residues at the junction between kinetins neck domain and neck-linker. The single molecular motor gliding assays show that the wild-type and mutated kinesins have the same velocity, but the run lengths of mutants decrease. These biophysical properties of these kinesin mutants suggest that the strain coordination mechanism may be not essential and kinesins may use different mechanism(s) other than the mechanical strain to coordinate their processive movement.

Tuesday, April 28, 2009

Final Oral Examination


Yi Wang
Co-Chairs: Larry E. Antonuk and W. Leslie Rogers

Tuesday, April 28, 2009, 10:00 AM
Conference Room, Argus I Building

Electronic portal imaging devices (EPIDs) based on active matrix, flat-panel imagers (AMFPIs) have been widely used for patient set-up verification, and are being investigated for megavoltage (MV) cone-beam computed tomography (CBCT). However, the performance of conventional AMFPI-based EPIDs is limited by their relatively low detective quantum efficiency (DQE) at radiotherapy energies, ~1% for 6 MV X rays. Consequently, MV CBCT carried out with these inefficient EPIDs requires impractically high doses to achieve soft-tissue visualization. In order to significantly improve DQE, this research work examined thick mercuric iodide (HgI2) photoconductors in the form of particle in binder (PIB) and thick, segmented scintillators consisting of 2D matrices of scintillating crystals separated by septal walls.

Through simulation of radiation transport, quantum efficiency (QE), modulation transfer function (MTF) and DQE were studied as a function of the thickness of PIB-HgI2 photoconductors. Simulations of radiation and optical transport were carried out to investigate how various geometric and optical properties affect the DQE for segmented CsI:Tl and BGO scintillators. Four prototype EPIDs, employing three CsI:Tl scintillators (11.4, 25.6 and 40.0 mm thick) and one BGO scintillator (11.3 mm thick), were empirically evaluated using a 6 MV photon beam. Finally, the potential MV CBCT performance provided by segmented scintillators was investigated by simulation of radiation transport.

Compared to conventional EPIDs, PIB-HgI2 photoconductors up to 6 mm thick have the potential to provide up to a factor of ~5 improvement in DQE. Segmented CsI:Tl and BGO scintillators up to 40 mm thick can provide DQE improvement of up to a factor of ~29 and 42, respectively, through optimization of optical properties. The three CsI:Tl prototypes demonstrated DQE improvement of up to a factor of ~25 at low spatial frequencies, while the BGO prototype exhibited an improvement of a factor of ~20 at zero frequency and over a factor of ~10 at the Nyquist frequency. The simulation results indicate that CsI:Tl and BGO scintillators up to 40 mm thick can provide dose reduction for MV CBCT of up to a factor of ~51 and 59, respectively, creating the possibility of providing soft-tissue visualization at clinically acceptable doses.

Tuesday, April 21, 2009

Final Oral Examination


Shawn M. O'Connor
Chair: Art Kuo

Tuesday, April 21, 2009, Reception: 10:40 AM Defense: 11:00 AM
Baer Room, Cooley Building

The traditional view of motor control predicates that the central nervous system dictates the motions of the body through muscle activation. An alternative view suggests that movement may be governed by body dynamics alone without need for neural control. Both philosophies have merits, but neither represents a complete solution for robust and efficient behavior. We propose an integrated view of control and dynamics and investigate how the natural dynamics of the limbs influence control strategies used to pattern and stabilize walking. We explore how features of human walking, traditionally absent in passive walking models, are gained by adding compliance. This compliant behavior essentially models work performed by muscle and tendon and predicts energetic costs measured in human walking. We also counter the notion that walking and running can best described by stiff and compliant leg behavior, respectively. We show that the amount and proportion of mechanical energy in the legs distinguishes between gaits much more so than leg compliance or other properties. However, some control is needed to provide spring-like actuation and could be afforded by reflex loops and neural oscillators located in the spinal cord. We use a compliant walking model to study how the feedforward and feedback nature of central pattern generators (CPGs) can be optimally combined to produce steady walking motions. Our findings suggest that CPGs serve a primary role to filter sensory information rather than to simply generate motor commands. Finally, three-dimensional passive walkers suggest that the fore-aft component of walking may be self stable, whereas lateral motion remains unstable and requires control, as through active foot placement. We tested whether healthy humans exhibit such direction-dependent control by applying low-frequency perturbations to the visual field and measuring foot placement during treadmill walking. We found step variability to be nearly ten times more sensitive to lateral perturbations than fore-aft, suggesting that the central nervous system gains fore-aft stability through uncontrolled behavior. Our results may have implications for the development of novel prosthetics, more energy efficient robots, and the rehabilitation of a broad set of neuromuscular and physical disorders that cause locomotor impairment.

Thursday, April 16, 2009

Final Oral Examination

Gas Embolotherapy: Bubble Evolution in Acoustic Droplet Vaporization and Design of a Benchtop Microvascular Model

Zheng Zheng Wong
Chair: Joseph Bull

Thursday, April 16, 2009, 10:45 AM
Lurie Engineering Center, GM Conference Room

This work is motivated by our ongoing development of a potential embolotherapy technique to occlude blood flow to tumors using gas bubbles selectively formed by in vivo acoustic droplet vaporization (ADV) of liquid perfluorocarbon droplets. The mechanics of bubble evolution is one of the interesting topics in our research.

Post-ADV bubble evolution in a rigid tube, under physiological and body temperature conditions, was observed via an ultra-high speed camera. For bubble evolution at physiological temperature, a radial expansion ratio of 5.05 was attained, consistent with the value predicted by theory. The initial growth rate of the bubble was linear at 3.56 m/s; from about 7 microseconds onwards, the growth rate increased proportionally with square root of time. Eventually growth became asymptotic. The assumption of phase change being completed before bubble expands was challenged by some of the experimental observations.

A new theoretical model was derived from a modified Bernoulli equation and compared with the experimental results. A computational model by Ye & Bull (2004) was also compared with the results. Initial growth rates were predicted correctly by both models. The experimental results showed heavy damping of growth rate as bubble grows towards the wall, whereas both models predicted an overshoot followed by multiple oscillations in the expansion ratio. The theoretical model would break down near the wall; the computational model would give a reasonable bubble shape near the wall but would require correct initial pressure values to be accurate.

At room temperature, the expansion ratio shot to 1.43 initially and oscillated down to 1.11. Failure of the bubble to expand fully could be due to unconsumed liquid perfluorocarbon or re-condensation under thermodynamically unfavorable conditions.

A new fabrication method via non-lithographic means was devised to make a circular-lumen microchannel out of PDMS, with a diameter as small as 80 microns to mimic the size of a medium arteriole. When endothelialized, the microchannel became a feasible benchtop model of a microvessel. Cell viability assays confirmed the viability of cells maintained in the microchannel. Simple bubble motion experiments were performed with the benchtop microvascular model to demonstrate its feasibility.

Wednesday, April 15, 2009

BME 500 Seminar Series

"Experimental and Computational Analysis of Cancer Signaling Networks"

Pamela Kreeger, Ph.D.
Assistant Professor, Department of Biomedical Engineering
University of Wisconsin - Madison

Wednesday, April 15, 2009, 4:30 - 5:30 PM
1303 EECS

Recent studies of the cancer genome have shown that tumors are enriched for coordinated mutations in pathways that regulate key functions such as the cell cycle. My lab seeks to understand the impact of these altered pathways on the cellular signaling network and cell phenotype, using a variety of experimental and mathematical techniques. In this talk, I will discuss recent work examining mutated K-RAS or N-RAS, GTPases that lay in the center of a variety of signaling cascades within the cell. Although K-RAS and N-RAS have similar biochemical activities, it has been demonstrated that K-RAS mutations, much more than N-RAS mutations, sensitize cells to apoptosis following treatment with the inflammatory cytokine, TNF?. Our results indicate that the different RAS mutants affect both positive feedback loops such as autocrine signals and negative feedback mechanisms including phosphatases. These studies may help improve our understanding of how oncogenic mutations alter the inflammatory response to promote tumor growth. I will also discuss ongoing studies to use these approaches to address priorities in women's health, including breast and ovarian cancer.

Wednesday, April 8, 2009

BME 500 Seminar Series

"Bio-Responsive Materials That Mimic Nature's Mechanisms"

William Murphy, Ph.D.
Assistant Professor, Depts. of Biomedical Engineering and Pharmacology
University of Wisconsin

Wednesday, April 8, 2009, 4:30 - 5:30 PM
1670 CSE

Control over the molecules that cells encounter in their local environment is a common theme in natural tissue development. Similarly, schemes to mimic development and "engineer" functional tissues are likely to benefit from control over the cell's local signaling environment. This concept is particularly important in stem cell applications, in which local signaling can dictate cell fate. We are interested in assembling biomaterials that are capable of actively communicating with stem cells. We use specific, reversible interactions to build biomaterials with new capabilities, including bioresponsiveness and regulated soluble signaling. Approaches highlighted in this talk will include noncovalent assembly of biological molecules on engineered surfaces and within synthetic hydrogels.

Tuesday, April 7, 2009

Final Oral Examination

Improving Accuracy and Precision in FLIM Applications: Well-Controlled Gated FLIM with Temporal and Spatial Optimizations

Ching-Wei Chang
Chair: Mary-Ann Mycek, Ph.D.

Tuesday, April 7, 2009, 2:00 PM
2203 LBME (Lurie Biomedical Engineering)

To propose potential molecular targets for treatments of diseases such as cancers, the quantitative understanding of living cells has received high attention. Fluorescence lifetime imaging microscopy (FLIM) can quantitatively measure cellular and molecular responses in living cells, produces spatially resolved images of fluorescence lifetime, and has advantages over intensity-based measurements. However, in live-cell FLIM applications with high-energy source such as lasers, maintaining biological viability has been a critical issue. High-speed time-gated FLIM can reduce light perturbation to live cells, but making measurements at low light levels remains a challenge that affects quantitative FLIM results.

In this study, we significantly improve accuracy and precision in live-cell gated FLIM applications. We first demonstrate that fluorescence resonance energy transfer (FRET) can be better detected with FLIM than with intensity. With FLIM, the use of a better fluorophore and environmental controls can improve FRET results with higher consistency, better statistics, and less non-specific FRET. In our temporal approach, several lifetime determination methods are investigated in search of optimal gating schemes. We show a reduction in relative standard deviation (RSD) from 52.57% to 18.93% resulting from optimal gating in an example. In our spatial approach, we conclude that significant improvements of the two novel total variation (TV) image denoising algorithms developed in this study, FWTV (f-weighted TV) and UWTV (u-weighted TV), can be achieved for a real imaging system. With live-cell images, they can improve the precision of local lifetime determination without significantly altering the global mean lifetime values (< 5% of lifetime changes). Finally, with our novel combined approach, even low-light excitation can achieve precision better than that in high-light cases (RSD = 12.76% at total photon counts, or TC, = 100 vs. RSD = 23.03 % at TC = 400). Therefore, high-energy excitation can be avoided when unfavorable. The notable five-fold improvements in precision (RSD from 49.90% to 11.94%) can be easily observed in our extreme low-light example.

This study, for the first time, overcomes the challenges in quantitative measurements of cellular responses, by enabling fluorescence lifetime map construction for better quantification of molecular interactions and sub-cellular environmental changes in live cells.

Friday, April 3, 2009

Department of Biomedical Engineering

Midwest Biomedical Engineering Conference

Biomedical Engineering and The BME Career Alliance
Friday, April 3, 2009, All Day
School of Public Health

The University of Michigan Department of Biomedical Engineering is honored to host the 2009 Midwest Biomedical Engineering Conference (MBEC) "Showcasing the Future of Biomedical Engineering" on Friday, April 3rd at the University's School of Public Health. Please visit the conference website to learn more about the experts and topics included on the agenda and to register. Early registration ends March 27 and all participants must register.

MBEC is a great opportunity to learn about industrial and academic careers for BMEs as well as current research in the areas of Biomaterials, Nanotech/MEMS and Imaging. The conference provides an opportunity to network with faculty, industry representatives, and other students from throughout the Midwest. The keynote speaker is Dr. Walt Olson, Vice President of CRDM Research at Medtronic. MBEC featured speakers are Dr. George Truskey, President of BMES, and Dr. James Baker, a physician entrepreneur from the University of Michigan. A Career Networking Session will be held at the conclusion of the conference.

Friday, April 3, 2009

Final Oral Examination

"Biophysical Determinants of Notch Signaling"

Jeongsup Shim
Co-Chairs: John B. Lowe and Alan J. Hunt

Friday, April 3, 2009, 1:00 PM
1180 Duderstadt Center Conference Room

Notch signaling is involved in many biological contexts such as cancer, stem cell development, and neural cell development. Because of the importance of Notch function in health and disease, the Notch signaling pathway has emerged as a potential therapeutic target.

Mammalian Notch receptors are single-pass transmembrane glycoprotein receptors, which contain 29-36 EGF like repeats. The fucosyltransferase termed Pofut1 transfers fucose to the serine or threonine residue of the O-fucose consensus sequence on some EGF domains of Notch receptors. The glycosyltransferases termed Fringe can elongate O-fucose moieties by adding N-Acetylglucosamine, which may be subsequently modified by galactose and sialic acid. These O-fucosylated glycans play key roles in modulating Notch-mediated signal transduction events.

Here, we have observed how O-fucosylated glycan modifications modulate Notch receptor-ligand interactions using surface plasmon resonance techniques. A biphasic binding and dissociation pattern was observed, suggesting a two-state receptor-ligand interaction model characterized by initial formation of a transient receptor-ligand complex followed by a conformational change that leads to a more stable receptor-ligand complex. Primary and secondary on and off-rates for the four binding-competent Notch1-Notch ligand pairs were observed to be distinct and characteristic for each Notch ligand. The overall association constants observed when Dll-1 or Dll-4 interacted with Fringe-modified Notch1 were significantly greater than when these ligands interacted with unmodified Notch1, with enhancement likely due to Fringe modifications of fucose moieties within EGF domains 16-36. By contrast, Fringe modification of Notch1 did not significantly modulate interactions with Jag-1 or Jag-2. Mutational analyses confirm prior observations that the O-fucosylation site within EGF repeat 12 dictates much, if not all of the binding between Notch1 and its ligands. Finally, we observe that Fringe modification of Dll-4 enhances its ability to bind to Notch1.

Our data reveals that the molecular basis of glycan-dependent Notch-Notch ligand binding. We propose the two-state binding model with triple stranded structure for Notch-Notch ligand complex arrangement. Here, O-fucose and Fringe modification of Notch receptors play a key role in both the binding and the conformational change step.

Wednesday, April 1, 2009

BME 500 Seminar Series

"In Vivo Diffuse Optical Tomography and Spectroscopy of Cancer"

Regine Choe, Ph.D.
Postdoctoral Researcher of Physics
University of Pennsylvania

Wednesday, April 1, 2009, 4:30 - 5:30 PM
1670 CSE

Diffuse optical techniques derive unique physiological information about tissues such as oxygenated and deoxygenated hemoglobin, water, lipid concentration, tissue scattering, and blood flow. These tissue properties are often substantially different in rapidly growing cancers compared to normal tissues due to angiogenesis, hyper-metabolism, and vessel leakiness. Diffuse optical techniques thus hold great potential to be implemented in the clinic as both an imaging and a treatment monitoring device for cancer; they utilize non-ionizing radiation, are non-invasive, and are technologically simple and fast. In addition, diffuse optical techniques are versatile tools in multi-disciplinary settings which can connect animal model studies and human translational studies.

At the University of Pennsylvania, I have developed diffuse optical tomography/spectroscopy instruments and image reconstruction algorithm for cancer characterization and therapy monitoring. Using human breast cancer as an example case, I will present the translational capability of diffuse optical techniques to distinguish benign and malignant tumors, to track changes induced by chemotherapy, and to image fluorescence of contrast agent in vivo. Then I will discuss how diffuse optical techniques can fit in the multi-disciplinary effort to connect microscopic and macroscopic understanding of cancer mechanism and development of therapy.

Wednesday, March 25, 2009

The UM Department of Biomedical Engineering is sponsoring Susan Rowinski who will present on proactive reimbursement planning.

Proactive Reimbursement Planning based on Product Development Cycles

Susan Rowinski, MSE
Principal, Sue Rowinski Group LLC
Reimbursement & Marketing Consulting for the Life Sciences
Wednesday, March 25, 2009, 5:30 PM - 7:00 PM
Lurie Biomedical Engineering Building-atrium
1101 Beal AVE
Ann Arbor, MI 48109

Sue has a broad experience base in medical device reimbursement planning, specifically with imaging systems, CLIA-based IVD-MIAs, hospital-based diagnostics, therapeutics (catheter-based, surgical implants, laparoscopic and other MIS techniques).

She will present a reimbursement planning model that is based on three specific phases of the product development cycle. These phases are; Safety and Feasibility, Pivotal Trial and Market Launch.

Starting reimbursement planning well before product launch may help to improve the probability of obtaining payer approvals after FDA approval.

Sue will also present a case study and reference material reinforcing the presentation's goal.

While the presentation will focus on medical device reimbursement, those in the other life science sectors such as pharma, biopharma, and biotech will find the presentation's planning concepts and methodologies useful.

To register visit the registration page.

Friday, March 20, 2009

Final Oral Examination


Wei-Wen Hu
Chair: Dr. Paul Krebsbach

Friday, March 20, 2009, 9:30 AM
G390 Dental School

Different gene delivery systems were developed in this dissertation to promote tissue regeneration by regenerative in vivo gene therapy. A local virus delivery method was developed using a lyophilized adenovirus formulation to restrict viral vector delivery in and around biomaterials. This strategy may reduce the dispersion of virus to avoid unwanted systemic infection and decrease the viral concentration within scaffolds. We also determined that virus bioactivity can be preserved for long-term storage using this method, which allows freeze-dried adenoviruses to be incorporated with biomaterials as a pre-made construct to be use at the time of surgery. This delivery has been applied to successfully repair not only critical-sized craniofacial defects, but also osteonecrosis caused by radiation therapy.

To enhance the spatial control of gene delivery, two different strategies were established to effectively bind viral vectors on scaffold surfaces. Avidin-biotin and antibody-antigen interactions were used to mediate virus immobilization. By binding viral vectors to biomaterials, only cells that adhered and proliferated on scaffolds would be transduced to express bioactive signals. Furthermore, a wax masking technique was introduced to control the bioconjugation on defined regions of biomaterials for spatially controlling transgene expression.

In order to broadly apply the immobilized gene delivery methods to different biomaterial scaffolds, chemical vapor deposition (CVD) polymerization was applied to functionalize biomaterials surfaces for immobilization of cell-signaling viruses. This surface modification was able to be performed on 2-D and 3-D structures. Through these controlled gene delivery systems, bioactive factors may be precisely expressed to engineer distinct tissue interfaces.

Wednesday, March 18, 2009

BME 500 Seminar Series

"Vascular Microbubbles for Therapy"

Joseph L. Bull, Ph.D.
Associate Professor, Department of Biomedical Engineering and Department of Surgery
University of Michigan

Wednesday, March 18, 2009, 4:30 - 5:30 PM
1670 CSE

Embolotherapy involves the occlusion of blood flow to tumors to treat a variety of cancers, including renal carcinoma and hepatocellular carcinoma. The accompanying liver cirrhosis makes the treatment of hepatocellular carcinoma by traditional methods difficult. Previous attempts at embolotherapy have used solid emboli, such as blood clot, gelatin sponge, particulates, balloons and streamers. A major difficulty in embolotherapy is restricting delivery of the emboli to the tumor, i.e. minimizing ischemia of healthy tissue, without extremely invasive procedures. We are developing a novel minimally invasive gas embolotherapy technique that uses gas bubbles rather than solid emboli. The bubbles originate as encapsulated liquid perfluorocarbon droplets that are small enough to pass through capillaries. The droplets can be selectively vaporized in vivo by focused high intensity ultrasound to form gas bubbles, which are then sufficiently large to lodge in the tumor vasculature. Understanding the potential bioeffects from acoustic droplet vaporization and the mechanisms of emboli transport and lodging are essential to designing treatment strategies that achieve highly selective delivery of the gas emboli to the tumor. Therefore, we are investigating the biofluid dynamics of microbubbles for therapy using a combination of experimental and theoretical approaches. Our work on acoustic droplet vaporization, microbubble transport, and microbubble lodging will be discussed.

Wednesday, March 11, 2009

BME 500 Seminar Series

"From Biomaterials and Stem Cells to Regenerative Medicine: A Bioengineering Perspective"

Xuejun Wen, M.D., Ph.D.
Associate Professor of Bioengineering, Cell Biology & Anatomy, Orthopaedic Surgery,
Neuroscience, and Hollings Cancer Center
Clemson University

Wednesday, March 11, 2009, 4:30 - 5:30 PM
1670 CSE

My research program is aimed at developing clinically applicable strategies for tissue and organ regeneration based upon tissue engineering and regenerative medicine principles to enhance human health. The specific areas of my research cover novel biopolymer syntheses/nanostructured biomaterials development, scaffold design and fabrication, stem cell biology and engineering, tissue engineering and regenerative medicine, in vitro and in vivo models for translational research, and proteomics, genomics, biosensors, and biomedical imaging. Recent progresses in my lab in some these areas will be discussed. Examples of using bioengineering approaches for the central nervous system (CNS) repair (e.g., spinal cord injury, Parkinson's disease, traumatic brain injury, and brain stroke), sensory protection and functional restoration (hearing loss), cardiovascular tissue engineering, lung tissue regeneration, and orthopedic tissue regeneration will be discussed. Finally, the novel concept of in vivo tissue engineering based upon the manipulation of endogenous stem cells that are resident in the tissues for cell replacement and tissue regeneration will be introduced.

Wednesday, March 4, 2009

BME 500 Seminar Series

Peripheral Nerve Stimulation: Identifying the Correct Neural Target for Therapeutic Outcome

Paul B. Yoo, Ph.D.
Postdoctoral Research Associate in the Dept. of Biomedical Engineering
Duke University

Wednesday, March 4, 2009, 4:30 - 5:30 PM
1670 CSE

Electrical stimulation of the nervous system offers a viable alternative to conventional modes of therapy (e.g., pharmacological) that either exhibit low patient compliance or are otherwise clinically ineffective. One of the main challenges facing the development of this technology, however, is our incomplete understanding of the effects of electrical stimuli on the underlying neural substrate. As a consequence, the development of neural prostheses for the peripheral nervous system and the clinical translation of such devices have been limited, despite the comparatively simple neuroanatomical characteristics of this part of the nervous system (cf. the basal ganglia for deep brain stimulation).

In this talk, I will present my recent efforts in trying to bridge this gap between the laboratory model and the clinical patient. The presentation will highlight the development of neural prosthesis-based therapies for (1) the restoration of bladder function in persons with spinal cord injury and (2) the treatment of obstructive sleep apnea. The current hypotheses for pathogenesis, recent advances in our understanding of the neuroanatomy and physiology, and a glimpse into the future direction of these therapies will be discussed.

Tuesday, March 3, 2009

Final Oral Examination


John Paul Seymour
Chair: Dr. Daryl Kipke

Tuesday, March 3, 2009, 11:00 AM
GM Conference Room, Lurie Engineering Center (4th Floor)

This oral defense will present new designs and materials for neural recording and stimulation technology. A higher density of electrodes is enabling neuroscientists to study larger neuronal populations, but even greater signal stability and electrode density are needed. Addressing these issues is critically important for neuroprostheses in the treatment of spinal cord injury, ALS, or limb loss. Stimulating electrodes have already improved quality of life for those with Parkinson's and dystonia and this technology has many new indications on the horizon. Smaller stimulating electrodes with reduced glial encapsulation would reduce the power requirements of these applications. I will discuss how our research impacts neurotechnology by enabling reduced glial encapsulation, greater design options, and improved electrical insulation.

Our first study introduced a novel neural probe with reduced chronic cellular encapsulation. We hypothesized that if a structural feature size is smaller than a reactive cell body (<7 m), the resulting encapsulation would be mitigated by the prevention of cellular spreading. We investigated this relationship between size and tissue reactivity using a microfabricated parylene structure. Probes were implanted in the rat neocortex for four weeks followed by histological analysis. We found the non-neuronal density around the sub-cellular feature was less than half of that around the probe shank.

The objective of our second study was to identify a parylene process that would enable long-term bioelectrical insulation. We contrasted parylene-C with an alternative parylene material using electrical and mechanical tests. We present a reactive parylene (complementary layers of PPX-CHO and PPX-CH2NH2) that can be used in conjunction with parylene-C but has improved electrical insulation and wet metal adhesion.

In our third study, a new parylene-based microfabrication process is presented for neural recording, stimulation, and drug delivery applications. We introduce a large design space for electrode placement and structural flexibility with a six mask process. By using chemical mechanical planarization, electrodes may be created top-side, back-side, or on edge having three sides. Poly (3,4-ethylenedioxythiophene) (PEDOT) modified edge electrodes having an 85 m2 footprint (smallest reported to date) resulted in an impedance of 200 k at 1kHz. Edge electrodes successfully recorded single unit activity in acute animal studies.

Friday, February 20, 2009

Final Oral Examination


Kiran Kumar Pandey
Chair: Dr. Douglas C. Noll

Friday, February 20, 2009, 10:00 AM
GM Conference Room, Lurie Engineering Center (4th Floor)

Head motion limits the accuracy, specificity and sensitivity of fMRI. Rigid body registration of fMRI data only corrects for bulk movements while leaving secondary motion artifacts from spin history effects, dynamic field inhomogeneity changes and interpolation errors untouched. Secondary artifacts reduce accuracy of image registration, increase variance in fMRI time-series and reduce sensitivity of detection of active voxels. In this thesis, some approaches to increase robustness of fMRI to head motion have been presented. These involve explicit optimization of acquisition parameters, use of image acquisition and reconstruction methods that reduce secondary motion artifacts and better isolation and removal of residual motion artifacts that remain after image realignment.

Specifically, methods used to mitigate motion artifacts include use of thinner slices and slices of variable thickness during image acquisition for better signal recovery in brain regions with large intra-voxel dephasing induced signal loss. Combined forward and reversed spiral k-space trajectory was used to reduce susceptibility artifacts in presence of motion. Iterative image reconstruction with dynamically updated fieldmaps was used to correct temporally changing field inhomogeneity from motion and susceptibility interactions. Results demonstrated that these corrective measures increased the overall robustness of fMRI to susceptibility induced field inhomogeneity, head motion, and dynamic interactions between them. Consequently, better quality of fMRI images also improved the quality of motion correction, reduced variance in the time-series and increased sensitivity of detection of active voxels during fMRI experiments with head movement.

Constrained Independent Component Analysis (cICA) was used for modeling, isolation and removal of residual motion artifacts that remain in fMRI time series despite image registration. cICA was found to be better able to isolate the residual errors compared to the prevalent General Linear Model (GLM) methods. Further, cICA automated the identification and removal of erroneous components and eliminated human errors during this process. Using a combined approach i.e. by optimizing acquisition parameters, acquisition methods, and reconstruction methods during data collection to improve image quality and motion correction and, by better modeling, isolation and removal of residual motion artifacts using cICA, the impact of head motion on fMRI studies can be vastly reduced if not completely eliminated.

Friday, February 20, 2009

Final Oral Examination


Hirak Parikh
Chair: Dr. Daryl R. Kipke

Friday, February 20, 2009, 10:30 AM
East Conference Room, Rackham (4th floor)

Using microelectrodes, we can record neural signals which can eventually be used to control cortical neuroprostheses for assisting people with spinal-cord trauma, stroke deficits, amyotrophic lateral sclerosis (ALS), and motor-neuron disease. Despite recent encouraging advances, a number of fundamental issues need to be resolved for a reliable, fully-functional, long-term human neuroprosthesis. Improving cortical prostheses require further development both in neural interfaces and investigation of cortical signals for obtaining the most effective control signals. The goal of this dissertation is to investigate the effectiveness of unit activity and local field potentials(LFPs) in the motor cortex using chronic multisite microelectrodes.

In the first study, we first demonstrate a novel method to assess neural signatures across sessions and quantify neuron stability by providing a probabilistic estimate of similarity between units. This technique supports both single and multiple electrodes, and has applications in: designing appropriate neuroprosthetic control algorithms, determining recalibration parameters, investigating neural plasticity, and assessing significance of particular metrics.

Next, we investigate unit activity and LFP activity in the different layers of the motor cortex. Four rats were implanted bilaterally with multi-site single-shank silicon microelectrode arrays in the motor cortex while the animal was engaged in a movement-direction task. In the second study, we demonstrate that units in the lower layers (Layers 5,6) are more likely to encode direction information as compared to units in the upper layers (Layers 2,3) suggesting electrode sites clustered in the lower layers provide access to more salient control information.

In the third study, we investigate LFP activity to determine significant interactions in time and/or frequency across the different layers. We analyzed LFP activity in four frequency ranges: low(3-15Hz), low-gamma(15-40Hz), high-gamma(40-70Hz) and high(>70Hz) across both upper(Layers 2,3) and lower layers(Layers 5,6) of the cortex. Our analysis based on 585 LFP recordings from 39 sessions shows that the low frequency range(3-15Hz) is more likely to encode directional information as compared to other frequency ranges. We found a significant difference in LFP activity between the upper and lower layers of cortex in the high gamma(40-70Hz) range, but not in the other frequency ranges. Our results indicate that LFPs are viable alternative control signals that can be recorded from either upper or lower layers of the cortex for performance comparable to our results from unit activity.

Wednesday, February 18, 2009

BME 500 Seminar Series

"Optofluidic Ring Resonator Technology Platform for Rapid and Sensitive Biological and Chemical Sensing"

Xudong Fan, Ph.D.
Assistant Professor, Biological Engineering Department
University of Missouri

Wednesday, February 18, 2009, 4:30 - 5:30 PM
1670 CSE

The optical ring resonator is an emerging sensing technology that has recently been under intensive investigation. In a ring resonator, light propagates in the form of whispering gallery modes (WGMs), which results in a light-analyte interaction length much longer than the resonator physical size. Consequently, the ring resonator can achieve a much improved detection limit, lower sample volume, and larger integration density than the traditional waveguide or optical fiber based sensor. The optofluidic ring resonator (OFRR) is a unique technology platform developed in my lab in the past three years, which integrates microfluidics and photonics. The platform has a wide spectrum of applications, ranging from low-cost, portable, sensitive biomedical devices to highly sophisticated photonic instruments used in optical signal processing, nonlinear optics, and fundamental physics. In this talk, I will focus on three major biomedical applications of the OFRR:

1. OFRR label-free biosensors, including their working principles, performance advantages, and sensing examples (e.g., detection of protein, DNA, viruses, and cells such as MCF7 breast cancer cells and CD4+). Actual clinical applications of the OFRR for development of a portable and rapid breast cancer serological biomarker analyzer will be presented. Its potential application for high throughput proteomics will also be discussed;
2. OFRR based micro-gas chromatography for chemical vapor sensing and its potential biomedical applications as a portable and sensitive breath analyzer;
3. OFRR microfluidic lasers and their applications in development of novel molecular beacon with ultrahigh sensitivity and ultralow sample volume.

Wednesday, February 11, 2009

BME 500 Seminar Series

"Hemodynamic Monitoring for the 21st Century"

Ramakrishna Mukkamala, Ph.D.
Associate Professor, Department of Electrical and Computer Engineering
Michigan State University

Wednesday, February 11, 2009, 4:30 - 5:30 PM
1670 CSE

The projected growth of the elderly population and shortage of clinical staff underscores the need for effective and easy-to-use patient monitoring systems at the beginning of the 21st century. This need is especially apparent in the context of hemodynamic monitoring of cardiovascular disease. Today, hemodynamic monitoring often entails the convenient measurement and display of blood pressure waveforms mostly from peripheral arteries but also from the right heart and pulmonary artery. Indeed, catheters are broadly utilized in clinical practice and non-invasive commercial systems and implantable devices are available for automated and safe monitoring of blood pressure waveforms from these circulatory sites. On the other hand, it is well known that cardiac output (total blood flow rate), left atrial pressure (cardiac preload), ejection fraction (cardiac function), and central arterial blood pressure (cardiac afterload) are more effective in predicting patient outcome and guiding therapy. However, the conventional methods for measuring these central hemodynamic variables either require an operator or are highly invasive and risky. Thus, the use of these difficult methods is limited today and likely to be even more so hereafter due to the evolving demographics. In this talk, we introduce a set of novel physiologic-based signal processing techniques to estimate cardiac output, left atrial pressure, ejection fraction, and central arterial blood pressure from the temporal variations in more readily available blood pressure waveforms. We demonstrate the validity of these techniques with respect to independent reference measurements from animals and humans over a wide physiologic range. With further development and successful testing, the techniques may ultimately be employed for automated and less invasive monitoring of central hemodynamic variables of clinical significance in hospitals with existing catheters, outpatient environments and at home with non-invasive commercial systems, and the ambulatory setting with implantable devices so as to help meet the patient monitoring demands of the 21st century.

Wednesday, February 4, 2009

Department of Biomedical Engineering

Winter Career Event

Wednesday, February 4, 2009, 12:00 PM - 5:00 PM
Lurie Biomedical Engineering Building

The University of Michigan Chapter of the Biomedical Engineering Society and The Department of Biomedical Engineering is hosting a half-day Winter BME Career Event on Wednesday, February 4, 2009. This networking event is designed to provide employers with an opportunity to advertise their companies and interact with undergraduate and graduate biomedical engineers.

Event Schedule:
Noon - 1pm Panel discussion on BME careers and lunch
1:15 - 1:30 Concurrent presentations by companies
1:30 - 3:00 10 minute sessions with students
3:10 - 3:25 Concurrent presentations by companies
3:30 - 5:00 10 minute sessions with students

Wednesday, February 4, 2009

BME 500 Seminar Series

"Engineering Scaffold Structure-Function Behavior: Influence on Soft and Hard Tissue Regeneration"

Scott Hollister, Ph.D. Professor of Biomedical Engineering and Mechanical Engineering, College of Engineering
and Associate Professor of Surgery, Medical School
University of Michigan

Wednesday, February 4, 2009, 4:30 - 5:30 PM
1670 CSE

It is widely hypothesized that the effective properties and material of tissue engineering scaffolds can influence the success of tissue regeneration. However, a key component of testing this hypothesis is engineering scaffolds with controlled structure-function characteristics, that is, porous architecture/material combinations that give desired effective mechanical and mass transport characteristics. This seminar will examine how we design scaffold architectures to achieve desired structure-function attributes, how we actually manufacture these scaffolds, and lastly, how these engineered structure-function attributes affect both soft and hard tissue regeneration.

Wednesday, January 28, 2009

BME 500 Seminar Series

"Smart" Delivery Systems for Macromolecular Therapeutics

Mohamed E.H. El-Sayed, Ph.D.
Assistant Professor, Biomedical Engineering
University of Michigan

Wednesday, January 28, 2009, 4:30 - 5:30 PM
1670 CSE

Recent advances in drug design have led to the development of several classes of novel therapeutic macromolecules including peptides, proteins, monoclonal antibodies, immunotoxins, lysozymes, plasmid DNA, antisense oligodeoxynucleotides, and short interfering RNA. Despite the established potential of these macromolecules, their development into stable and clinically-active drugs with defined dosage regimens remains a significant challenge. To transform these promising drug candidates into actual therapeutic or diagnostic agents, we have to develop effective strategies to improve drug stability, control spatial and temporal drug release in the body, increase drug absorption across epithelial and endothelial barriers, allow selective drug accumulation in diseased tissues, and achieve drug targeting at cellular and sub-cellular levels. In this seminar, I will discuss our research efforts to develop "smart" pH-sensitive, membrane-destabilizing polymeric carriers that can effectively deliver therapeutic nucleic acids past the endosomal membrane and into the cytoplasm of targeted cells to successfully suppress the expression of targeted genes.

Wednesday, January 21, 2009

BME 500 Seminar Series

"Microfluidic Assay Chip and Polymer-Based Artificial Robot Skin "

Euisik Yoon, Ph.D.
Associate Professor, Electrical Engineering and Computer Science
University of Michigan

Wednesday, January 21, 2009, 4:30 - 5:30 PM
1670 CSE

In this talk, application of polymers in microfluidic assay chips and flexible artificial robot skins will be presented. Stacked polymer layers will be introduced for high-throughput cellular manipulation using a microfluidic chip with multiple micro-wells in two-dimensional arrays. The chip performs single cell positioning, specific reagent injection, and secretion monitoring for high-throughput cell analysis and drug screening. A cell capture experiment has been performed using myoblast stem cells, and the successful positioning of single cells on micro-wells was achieved. Also, the selective injection of various growth factors into specific target cells has been demonstrated and its effects on cell proliferation and differentiation have been monitored. A 16 x 16 tactile sensor array with 1mm spatial resolution, similar to that of human skin, has been fabricated by stacking multiple layers of PDMS elastomer. Tactile response of a cell has shown a sensitivity of 3%/mN within the full-scale range of 40mN (250kPa). Expandability has been demonstrated by using ACP to tile up the modular arrays. Various tactile images have been successfully captured by one sensor module, as well as the expanded 32 x 32 modular array sensor.

Wednesday, January 14, 2009

BME 500 Seminar Series

"Genetic Engineering of Cardiac Myocytes: Insights into Heart Failure"

Margaret Westfall, Ph.D.
Assoc. Professor of Surgery and Assoc. Professor of Molecular and Integrative Physiology
Medical School
University of Michigan

Wednesday, January 14, 2009, 4:30 - 5:30 PM
1670 CSE

Heart failure results from a variety of alterations in the heart's structure and function. Therapies to treat heart failure are primarily palliative in nature and transplantation is currently the only available cure. Hearts experiencing contractile failure often show derangements in signaling, Ca2+ cycling, and contractile proteins. My laboratory utilizes adenovirus to genetically engineer cardiac myocytes to understand how signaling cascades and sarcomeric proteins influence both sarcomere structure and myocyte contractile function. This seminar will begin with a broad overview of cardiac myocyte physiology and pathophysiology, and show how genetic engineering provides insights into heart failure and future therapeutic treatment strategies.

Wednesday, January 7, 2009

BME 500 Seminar Series

Micro- and NanoFluidics for Cellular Physiology Studies

Shuichi Takayama, Ph.D.
Departments of Biomedical Engineering and Macromolecular Science and Engineering University of Michigan

Wednesday, January 7, 2009, 4:30 - 5:30 PM
1670 CSE

Many biological studies, drug screening methods, and cellular therapies require culture and manipulation of living cells outside of their natural environment in the body. The gap between the cellular microenvironment in vivo and in vitro, however, poses challenges for obtaining physiologically relevant responses from cells used in basic biological studies or drug screens and for drawing out the maximum functional potential from cells used therapeutically. One of the reasons for this gap is because the fluidic environment of mammalian cells in vivo is microscale and dynamic whereas typical in vitro cultures are macroscopic and static. This presentation will give an overview of efforts in our laboratory to develop microfluidic systems that enable spatio-temporal control of both the chemical and fluid mechanical environment of cells. The technologies and methods close the physiology gap to provide biological information otherwise unobtainable and to enhance cellular performance in therapeutic applications. Specific biomedical topics that will be discussed include, in vitro fertilization on a chip, microfluidic tissue engineering of small airway injuries, micropatterned gene delivery and knockdown, and development of tuneable nanofluidic systems towards applications in single molecule DNA analysis.

Thursday, December 18, 2008

Final Oral Examination

Nanoscale Protein Patterning via Nanoimprint Lithography and Ultrafast Laser Irradiation

Jeremy Damon Hoff
Chair: Alan J. Hunt

Thursday, December 18, 2008, 11:00 AM - 12:30 PM
2203 Lurie Biomedical Engineering Building

The diverse biological roles of proteins include catalysis, force generation, mechanical support, signaling and sensing. Beyond their central importance to biology, proteins are of interest because these nano-machines have potential to be integrated into micro- fabricated devices to create low-cost, robust technologies of unprecedented small scale and high efficiency. Applications include biosensors, actuation of micro-electromechanical systems (MEMS), and tissue engineering, as well as screening tools for proteomics and pharmacology, and basic biological research. However, both the study and application of proteins has been challenged by the inherent difficulties associated with positioning these tiny objects. Thus, a primary enabling technology is the ability to immobilize biomolecules in well-defined patterns while retaining their functionality.

Towards achieving this goal, we have developed two approaches capable of producing high resolution protein patterns. First, we immobilized proteins in patterns defined by nanoimprint lithography, which offers the advantages of high throughput, high reproducibility, and low cost. We demonstrate patterning of bioactive antibodies with sub-100nm feature resolutions.

The second technique uses tightly focused ultrafast laser pulses which, through a non-linear damage mechanism, are known to be capable of ablating features far smaller than the diffraction-limited spot size. We find that proteins can be removed from a glass surface at intensities considerably below the ablation threshold, cleaning the surface without damaging the underlying substrate. AFM and epifluorescent analyses indicate near-total removal of proteins from a glass surface with well-defined nanoscale features. We describe potential mechanisms for the damage and/or removal of proteins from the surface based on the photolytic generation of free electrons.

Glass surfaces irradiated at these low intensities exhibit marked changes in surface chemistry. We characterize the adsorption of several model proteins as well as small charged fluorophores. Based on the adsorptive behaviors of these molecules, we describe a sub-threshold damage mechanism which alters the long-term chemical state, surface charge, and adsorptivity of irradiated glass surfaces.

Finally, we made use of the laser-based protein removal technique described above to selectively remove fibronectin from the path of motile fibroblasts. We demonstrate that we are able to guide movement by this in situ modification of the cells microenvironment.

Friday, December 5, 2008

Final Oral Examination


Nadder David Sahar
Chair: David H. Kohn

Friday, December 5, 2008, 8:00 AM
East Conference Room, Rackham (4th floor)

Fractures are the most frequent health problem associated with bone and represent a significant clinical and economic burden. Clinically, fracture risk is diagnosed by low bone mass and interventions to reduce fractures are intended to increase mass. However, aging and interventions, like exercise, influence fracture risk by more than what changes in mass predict, indicating that exercise and aging alter skeletal integrity by altering tissue quality, not just quantity. Currently, there is no clear understanding of how tissue quality contributes to skeletal integrity or how it can be altered by external influences. Therefore, this study examined the hypothesis that exercise and aging in adult mice would alter bone composition leading to altered mechanical competence, even when adjusting for changes to bone size and shape.

Exercise in young mice significantly improved strength and resistance to fatigue-induced damage, but had no measured benefit in old mice. The mechanical improvements in young mice were accompanied by increased mineralization and decreased carbonate substitution. Aging significantly reduced structural and tissue-level mechanical properties and increased mineral crystal size, carbonate substitution, and microcracking. Compositional changes with exercise and aging occurred in pre-existing bone (determined by micro-CT analysis and calcein labeling) and mechanical improvements were observed without significant increases in bone size, demonstrating that bone can adapt to external stimuli by altering tissue quality without the processes of modeling or remodeling. Further, colocalization of compositional and mechanical measurements by Raman microspectroscopy and nanoindentation provided corroborative evidence compositional changes contributed significantly to changes in mechanical competence, but in an age dependent manner.

This work challenges conventional theories about bone adaptation and the influence of bone composition on mechanical integrity. It was demonstrated for the first time that exercise and aging can modulate bone composition, and therefore tissue-level mechanical properties, even in the absence of bone formation or remodeling. Therefore, changes in tissue quality may often be overlooked because they can occur without significant changes in bone mass. This work also illustrates the potential utility of using compositional markers in diagnosing skeletal fragility but warns against making sweeping conclusions about the consequences of compositional changes in bone.

Friday, December 5, 2008

Final Oral Examination


Sylva Jana Krizan
Chair: David H. Kohn and Kurt D. Hankenson

Friday, December 5, 2008, 11:00 AM
G550 Dental School

Human mesenchymal stem cells (hMSC) are promising candidates for promoting bone growth on biodegradable polymer scaffolds however little is known about early hMSC-polymer interactions. Adhesion is highly dynamic and during adhesive reinforcement, numerous proteins form adhesion plaques linking the cell's cytoskeleton with the extracellular matrix. These proteins are known to affect cellular function but their role in hMSC differentiation is less clear. Adhesion plaques are associated with adhesive force, still a detachment force of hMSC on polycaprolactone (PCL), poly-lactide-co-glycolide (PLGA) or alginate has never been described or shown to affect downstream function.

We demonstrate that hMSC attached to PCL, PLGA and alginate exhibit different adhesion strengths (tau50) as determined by both fluid shear and spinning disk systems, with PLGA demonstrating the greatest tau50. Elastic modulus and hydrophobicity were characterized for these surfaces and correlated positively with tau50 to an optimum. Attachment studies of hMSC showed that adhesion plateau timespans were independent of cell line and surface but both morphology and focal adhesion expression varied by polymer type. Differentiation studies of hMSC on PLGA and PCL showed a strong association between markers of differentiation (alkaline phosphatase activity and mineral content) and tau50 within polymer groups, but a poor relationship was found between tau50 and differentiation across polymer groups, suggesting that other polymer properties may be important for differentiation.

Subsequently, we examined the role of focal adhesion kinase (FAK) and Rho-GTPase (RhoA) on hMSC adhesion and differentiation on PLGA. hMSC were retrovirally transduced with mutant constructs of FAK and RhoA genes. Alternatively, hMSC were treated with Rho-kinase inhibitor, Y27632. Both cells transduced with mutant RhoA or FAK constructs, or those treated with Y27632 displayed aberrant cell morphology and changes in focal adhesion number. Differentiation studies demonstrated that both constitutively active RhoA and mutants of FAK increase normalized osteoblastic activity, while both dominant negative RhoA cells and hMSC treated with Y27632 exhibited a decrease in these markers. Significant effects on osteogenesis resulting from the above studies were seen on PLGA demonstrating maximal tau50 in earlier studies. This suggests that hMSC differentiation on polymers exhibiting high adhesion strength depends on FAK and RhoA signaling.

Wednesday, December 3, 2008

BME 500 Seminar Series

"Molecular Imaging, NanoBiotechnology, and MechanoBiology in Live Cells"

Yingxiao (Peter) Wang, Ph.D.
Departments of Bioengineering, Molecular and Integrative Physiology
University of Illinois, Urbana-Champaign

Wednesday, December 3, 2008, 3:30 - 4:30 PM
White Auditorium - Rm G906 Cooley Building

Signaling molecules and their activities are well coordinated in space and time to regulate cellular functions in response to mechanical and chemical microenvironment. Based on fluorescent resonance energy transfer (FRET), we have developed several genetically encoded biosensors for detecting the spatiotemporal activities of signaling molecules, including Src, Rac1, MT1-MMP, and Calcium. With a Src biosensor, local mechanical stimulation induced by laser-tweezer-traction can be observed to cause a directional wave propagation of Src activation along the plasma membrane. Different Src activities can also be observed at different subcompartments when the Src biosensor is tethered on plasma membrane in or outside of lipid raft. A Rac biosensor further revealed that the Rac activity in cells constrained on micropatterned extracellular-matrix surface is polarized with higher activity concentrated at the leading edge of migrating cells upon PDGF stimulation, whereas Src activities in these cells displayed global activation patterns without obvious polarity. With a MT1-MMP biosensor, epidermal growth factor (EGF) can be observed to induce significant FRET changes in live cancer cells expressing MT1-MMP, but not in MT1-MMP-deficient cells. Active MT1-MMP was directed to the leading edge of migrating cells along micropatterned fibronectin stripes, via a process dependent upon an intact cytoskeletal network. Most recently, our calcium biosensor revealed that there is a spontaneous Ca2+ oscillation in human mesenchymal stem cells (HMSCs) both inside the cytoplasm and endoplasmic reticulum (ER). The substrate stiffness where HMSCs are cultured can significantly affect this Ca2+ oscillation, in a fashion dependent on the RhoA signaling pathway. In summary, our novel FRET biosensors in combination with tools in nanobiotechnology and biophotonics have made it possible to monitor key signaling cascades in live cells with spatiotemporal characterization and to elucidate the underlying molecular mechanisms in Mechanobiology.

Tuesday, December 2, 2008

Final Oral Examination


Paul Edward Makidon
Chair: James R. Baker, Jr.

Tuesday, December 2, 2008, 2:30 PM
1170A and 1150B BSRB

Surface active oil-in-water nanoscale emulsions have been developed as mucosal vaccine adjuvants capable of producing robust systemic, mucosal, and cellular immune responses against diverse microbial and recombinant antigenic proteins. This dissertation examines the development of nanoemulsion (NE) as a new generation nasopharyngeal adjuvant. Part of the thesis is organized to address the characterization of NE-induced immune response and includes the pre-clinical studies of a novel NE-based recombinant hepatitis B vaccine (HBsAg-NE). Our results suggest that nasal immunization with HBsAg-NE may be a safe and effective hepatitis B vaccine. The adjuvant induces specific IgG, mucosal IgA, and a Th1-biased cellular immunity. Immunogenicity is comparable to the standard alum-based vaccine. HBsAg-NE is stable for months at elevated temperatures because of the physical association of NE and antigen and its stability was enhanced with buffered salt diluents. We also report that NE-based vaccines do not require specially engineered delivery devices. The prolonged stability and ease of delivery are direct advantages for use of NE-based vaccines in developing populations.

We also evaluate the mechanism of NE adjuvant activity. NE promotes antigen internalization in nasal epithelium and loading into mucosal DC. Trafficking of the antigen to the submandibular lymph nodes and thymus occurs within 24 hours of intranasal vaccination. Administration of NE was not associated with the typical induction of local inflammation or histopathological changes. Microarray analysis shows the upregulation of only 1.6% of genes responsible for the production of acute phase inflammatory cytokines including IL6. Hallmark inflammatory cytokines such as IL4, and INF- were not measured in nasal secretions. The role of IL6 in NE adjuvant activity was examined by evaluating immunogenicity in IL6 mutant mice.

The final component of the dissertation addresses the development of a NE-based Burkholderia cenocepacia outer membrane protein (OMP) vaccine. We demonstrate that NE is as a strong mucosal adjuvant for OMP and OMP-NE protects against experimental lung infections in mice.

Overall, these findings confirm that NE is an excellent mucosal stimulant and support the further development of nanoemulsions as nasopharyngeal adjuvants. We conclude that nanoemulsion exhibits all the major desired characteristics of an adjuvant.

Wednesday, November 19, 2008

BME 500 Seminar Series

"Three-Dimensional Sub-micron Imaging of Remodeling in Cancellous Bone"

Christopher J. Hernandez, Ph.D.
Director of Musculoskeletal Mechanics and Materials Laboratory
Department of Biomedical Engineering
Case Western Reserve University

Wednesday, November 19, 2008, 3:30 - 4:30 PM
White Auditorium - Rm G906 Cooley Building

Osteoporosis is currently diagnosed using dual-energy x-ray absorptiometry based measures of bone mineral density (BMD). Although many explanation have been proposed, it is not yet clear how the amount of bone remodeling might influence bone strength, independent of bone mass. A common explanation is that cavities formed in bone during the bone remodeling process (remodeling cavities) act as stress risers and impair bone strength, particularly in cancellous bone. Measurements of remodeling cavities in cancellous bone have so far been qualitative because of the lack of quantitative data regarding the number, size and distribution of the cavities. Here I present a three-dimensional fluorescent imaging approach based on serial milling that is capable of imaging bone and fluorescent markers at a resolution as great as 0.7 microns/pixel in plane. Images obtained using the technique can be used to visualize and measure individual remodeling cavities as well as fluorescent markers of bone formation and /or microscopic tissue damage. This approach has led to the first direct measures of the number and size individual remodeling cavities in cancellous bone. The biomechanical significance of remodeling cavities and how they may explain differences among osteoporosis drug therapies is discussed.

Wednesday, November 12, 2008

BME 500 Seminar Series

"Micromechanical Modeling of the Viscoelastic and Growth Responses of Native and Engineered Ligament and Tendon"

Ellen M. Arruda, Ph.D.
Departments of Mechanical Engineering and Macromolecular Science and Engineering
University of Michigan

Wednesday, November 12, 2008, 3:30 - 4:30 PM
White Auditorium - Rm G906 Cooley Building

Micromechanics is used to develop constitutive models of soft tissues. Multi-phasic representative volume elements of linear or non-linear constituents that are isotropic or anisotropic lend themselves readily to viscoelastic and growth phenomena modeling at various length scales. Ligament and tendon are similar connective tissue structures comprised largely of type I collagen. The viscoelastic responses of these two tissue types have been shown in the literature to be qualitatively quite different and neither tissue response is captured by the quasiviscoelastic model. Moreover, tendon and ligament display a functionally graded response that is altered by various pathologies. These examples of viscoelastic behavior as well as growth will be examined via a soft tissue micromechanical model and compared to experiments on engineered and native ligament and tendon.

Wednesday, November 12, 2008

Final Oral Examination

"Perfusion Estimation in Volumetric Imaging of Ultrasound Contrast Agents"

Nelson G Chen
Co-Chairs: J. Brian Fowlkes and Gerald L. LeCarpentier

Wednesday, November 12, 2008, 9:00 AM
GM Room, Lurie Engineering Center (LEC)

This dissertation presents research involving the investigation of perfusion measured using volumetric imaging of ultrasound contrast agents. Ultrasound contrast agents are micrometer-sized gas bubbles that track the blood circulation. They strongly reflect ultrasound; therefore, a small quantity of agent produces strong echoes, enabling the examination of microcirculation.

The development of three-dimensional ultrasound has led to entire tissue volumes being imaged. Such imaging, now even being performed with two-dimensional arrays, provides more information for diagnostic purposes. Therefore, exploration of contrast imaging in three-dimensions is needed to determine potential benefits in clinical use.

The study of blood flow using contrast agent has been dominated by the imaging of contrast refill into a volume previously cleared of contrast. First, a mechanical method of performing contrast clearance/refill in a three-dimensional volume using two one-dimensional arrays is introduced. The method generated expected volumetric contrast images in a perfused tube phantom, based on the well-known parabolic velocity profiles of laminar flow. This consistency showed that the mechanical method properly images the refill into a volume at every time after contrast clearance.

Second, the apparatus was applied to a perfused kidney phantom. Refill curves were obtained for the kidney cortex throughout the volume. Refill curves were also obtained using a modified interval imaging technique for comparison. A normalization scheme, which uses the renal artery as a measure of the instantaneous contrast signal intensity, was used to correct for contrast degradation, and to make absolute perfusion estimates. No significant difference was observed between the volumetric perfusion measurements and those obtained from the modified interval imaging, suggesting the independence of refill curves from contrast clearance volume.

Finally, a general form of the normalization scheme was developed that permits normalization from a generic large vessel. The model was tested by imaging different-sized tubes at two orientations, and examining the normalization factor derived. Comparisons were made to values obtained using simpler approaches (global mean and attenuation only models). Values obtained using the model were similar across tube sizes, and were generally larger than those obtained otherwise. Both partial voluming and contrast attenuation are shown to play substantial roles in proper normalization.

Wednesday, November 5, 2008

BME 500 Seminar Series

"Design Issues in BCI Research"

Dennis J. McFarland, Ph.D.
Wednesday, November 5, 2008, 3:30 - 4:30 PM
White Auditorium - Rm G906 Cooley Building

Dennis J. McFarland is a research scientist, Laboratory of Nervous System Disorders, Wadsworth Center, New York State Department of Health. His research interests include brain-computer interfaces and central auditory processing disorders. McFarland received a PhD in psychology from the University of Kentucky. He is a member of the Society for Neuroscience and the American Psychological Society.

Friday, October 31, 2008

Department of Biomedical Engineering

Second Annual Halloween Party

Friday, October 31, 2008, 11:30 AM - 1:00 PM
Lurie Biomedical Engineering Building Atrium

Please join us for the 2nd annual BME Halloween party and lunch, Friday October 31, 11:30 - 1:00, LBME atrium.

While not absolutely required, costumes are STRONGLY encouraged. There will be prizes for costumes in the following categories:

  • Best Impersonation of a Faculty Member
  • Best Biomedical Device or Process
  • Funniest Costume
  • Cutest Costume
  • Most Creative Costume

Also, the GSC will be organizing a Halloween Pictionary tournament. Form a team of five and compete against other BME students, faculty and staff. The top team will win a pizza party! Additional sign-up information coming soon.

Faculty, Staff, and Students are welcome to RSVP

Tuesday, October 28, 2008

Final Oral Examination


Kip Ludwig
Chair: Daryl R. Kipke

Tuesday, October 28, 2008, 11:00 AM
1014 Dow

Prior studies have demonstrated that the firing rate of cortical neurons can be volitionally modulated by a subject to generate a controllable output signal; this neural output signal can then be manipulated to direct a robotic arm, a cursor on a computer screen, or other interface device. The burgeoning field of neural control has led to a number of innovative applications, known more commonly as neuroprosthetic devices. Neuroprosthetic devices have the potential to return some degree of functionality to the over 250,000 Americans with incapacitating spinal cord injuries, or allow healthy subjects to control electronic devices in their everyday lives. The research presented here consists of three studies focused on improving the current generation of neuroprosthetic devices.

In the first study, we introduced and evaluated a Bayesian maximum-likelihood estimation (bMLE) strategy to identify optimized training data for neuroprosthetic devices. By limiting initial decoding assumptions and training only on relevant neural data, accurate neural-control was possible with as few as two neurons, using minimal training data and no a-priori movement measurements for calibration. Moreover, implanted subjects obtained useful prosthetic control using local field potentials and neurons from cingulate cortex as input.

In the second study, we refined a method to electrochemically deposit surfactant-templated ordered poly(3,4-ethylenedioxythiophene) (PEDOT) films on the recording sites of standard "Michigan" probes, and evaluated the in vivo efficacy of these modified sites in recording chronic neural activity. PEDOT sites were found to outperform control sites in terms of signal-to-noise ratio and number of viable unit potentials - thereby improving the quality of neural input sources to the neuroprosthetic device.

In the third study, we evaluated a technique known as common average referencing (CAR) to generate a more ideal reference electrode for microelectrode recordings. CAR was found to drastically outperform standard types of electrical referencing, reducing noise by more than 30 percent. As a result of the reduced noise floor, arrays referenced to a CAR yielded almost 60 percent more discernible neural units than traditional methods of electrical referencing again improving the quality of neural input sources to a neuroprosthetic device.

Wednesday, October 22, 2008

BME 500 Seminar Series

Evaluating Nanoparticles: Is C60 an Adequate Standard for Toxicological Testing Protocols

Angela Violi, Ph.D
Depts. of Mechanical Engineering, Chemical Engineering & Biomedical Engineering
University of Michigan

Wednesday, October 22, 2008, 3:30 - 4:30 PM
White Auditorium - Rm G906 Cooley Building

Scientists and toxicologists from the US, Europe and Japan have recently joined forces to develop standard protocols for testing the environmental, health and safety impacts of nanoparticles/nanomaterials. This alliance was formed because of lack of agreement among scientists over procedures for determining how nanoparticles interact with biological systems. In this talk, after describing the main sources of environmental nanoparticles, and a new computational method to determine the chemical composition and morphologies of these structures, we report on a recent study on the effects of nanoparticles interacting with lipid bilayers.

Computational simulations of cell membrane permeation frequently employ the C60 fullerene as representative nanoparticle in the size range of 1 nm. Using C60 as a point of reference, we show using computational tools, significant variability of the permeation rate and free energy potential of similarly massed nanoparticles possessing different morphologies and chemical compositions.

Wednesday, October 15, 2008

BME 500 Seminar Series

Mechanics and Energetics of Human Locomotion: Let Your Physics do the Walking

A. D. Kuo, Ph.D.
Depts. of Mechanical Engineering & Biomedical Engineering,
University of Michigan

Wednesday, October 15, 2008, 3:30 - 4:30 PM
White Auditorium - Rm G906 Cooley Building

Human walking requires considerable coordination, with the central nervous system orchestrating the activity of many muscles in the upper and lower body. The body expends effort both to control the motion and to provide energy. But just how much control is needed, and where does the energy go? To answer these questions we might consider just how little control and energy are needed. Passive walking machines are two-legged mechanisms that can walk down a gentle slope with no control whatsoever and no external energy input. They can also walk on level ground with a very small amount of power. We will consider whether humans harness the passive dynamic properties of the limbs when they walk, just as the machines do. We will use simple principles to interpret theoretical and experimental evidence that indicates that humans really heavily on the physics to do the walking. Finally, we will examine applications to robotics and prosthetics.

Wednesday, October 8, 2008

BME 500 Seminar Series

"Ionic Bases of Cardiac Fibrillation: The role of IK1"

Sandep V. Pandit, PhD
Research Assistant Professor
Center for Arrhythmia Research
Dept. of Internal Medicine-Cardiology
University of Michigan

Wednesday, October 8, 2008, 3:30 - 4:30 PM
White Auditorium - Rm G906 Cooley Building

Friday, October 3, 2008

BME Alumni Award Seminar

Advances in Neurology - The Influence of Biomedical Engineering

James W. Albers, M.D., Ph.D.
Professor of Neurology
University of Michigan

Friday, October 3, 2008, 11:00 AM 12:00 PM
1123 LBME

Biomedical engineering has influenced the advancement of neurology at many levels, including our understanding of peripheral nervous system disorders such as neuropathy. Advances include improved understanding of basic neurophysiologic mechanisms in health and disease, the development of electrodiagnostic medicine, and design of equipment used in diagnosing and treating peripheral nervous system disorders. Less well recognized is the application of the sensible and pragmatic engineering problem-solving approach to teach and improve diagnostic proficiency, particularly among medical students and residents. The recent history of such advances can be featured in the context of an engineering "grand rounds," highlighting the impact of biomedical engineering on the diagnosis and management of patients with inflammatory nerve diseases.

Wednesday, October 1, 2008

BME 500 Seminar Series


Ravi K. Birla, PhD
Artificial Heart Laboratory,
Division of Cardiac Surgery,
University of Michigan

Wednesday, October 1, 2008, 3:30 - 4:30 PM
White Auditorium - Rm G906 Cooley Building

Research at the Artificial Heart Laboratory (AHL) is focused on developing functional 3-dimensional models of heart muscle, blood vessels, tri-leaflet valves, cell based cardiac pumps and tissue engineered ventricles. In addition, we have developed bioreactors to provide electrical, mechanical, and chemical conditioning, as well as micro-perfusion systems to support long term culture of tissue constructs. In vitro testing consists of functional (twitch force, pressure, tensile) and biological (histological, western, RT-PCR, electron microscopy) characterization, while in vivo performance is evaluated in small animal injury models. Collectively, our efforts are focused on engineering the heart piece by piece, with the development of tissue engineering models and the necessary supporting technology.

There are several aspects of our research which give us with a competitive advantage in the field of functional cardiovascular tissue engineering. First, researchers at the AHL have expertise in the development of all major components of the heart, including heart muscle, blood vessels, tri-leaflet valves, cell based cardiac pumps, and tissue engineered ventricles. Therefore, we have established a foundation in bioengineering tissues for all of the major functional components of the heart. Second, we have developed several platforms to engineer cardiovascular structures in vitro, including self-organization strategies, biodegradable hydrogels, and custom fabricated biomaterials. This becomes particularly valuable, as dominant designs for bioengineered cardiovascular constructs have not been established. Finally, our core group of researchers consists of experts from the medical, engineering, and life science fields. This has equipped the AHL with the diverse skills required to advance various tissue engineering projects. Collectively, the development of various bioengineered functional cardiovascular structures, multiple platforms, and our diverse expertise have positioned our lab to undertake a diverse array of tissue engineering endeavors and have provided the necessary framework for our establishment as the AHL.

As we look into the future, we are excited about the opportunities which lie within our tissue engineering models and the potential impact of this research on patient care. In the field of functional cardiovascular tissue engineering, opportunities are tremendous, matched only by the number of scientific and technological challenges. At the AHL, motivation and enthusiasm drive our research, providing the impetus to meet these challenges.

Wednesday, September 24, 2008

BME 500 Seminar Series

Finding Ways to Keep the Bananas Dispersed in the Jell-O as it Solidifies

Brian Love, Ph.D.
Departments of Materials Science and Engineering,
Biomedical Engineering,
Biologic and Materials Science (Dentistry)
University of Michigan

Wednesday, September 24, 2008, 3:30 - 4:30 PM
White Auditorium - Rm G906 Cooley Building

Photopolymerizable resins have been commonly used in dentistry for sealants, composite restoratives, and adhesives in orthodontic appliance attachment. The formulation-dose-fluence dependence is critical to gauge rates of solidification, and overall conversion can affect residual monomer extraction potential, gradients in conversion, etc. What we have learned applying materials chemistry to dentistry has led us to consider areas where we could apply dentistry in other clinical sub-discplines in vivo. We have been focused on two relatively clinical sub-disciplines, chemotherapeutics and interventional neuroradiology. Our targeted areas of interest are tied to therapeutic embolisation procedures, self assembling scaffolds induced by light, and photopolymerizable drug delivery injectables where the solidified mass restricts the convective transport of chemotherapeutic or growth factor for example. Often it is a significant challenge to keep dispersions adequately dispersed and this can affect mass flux and dosing. In this talk, I will cover these themes in more detail, recent experimental and modeling work to characterize chemorheological advancement, and some directions for the future.

Tuesday, September 23, 2008

Department of Biomedical Engineering

Industry Reception

Tuesday, September 23, 2008, 4:00 - 6:00 p.m.
Lurie Biomedical Engineering Building

Visit the BME Department at the completion of the Career Fair. Tour the new BME facilities and meet faculty and students in a late afternoon reception. Please RSVP at:

Friday, September 19, 2008

Department of Biomedical Engineering

Donuts to Design and BME Industry Career Event

Friday, September 19, 2008, 8:30 AM - 4:00 PM
Lurie Biomedical Engineering Building

Learn about the latest activity in the BME program, design experiences. Talk with current students about your company or industry. Please RSVP at:

Friday, September 19, 2008

Final Oral Examination


Ann Simon
Chair: Daniel P. Ferris

Friday, September 19, 2008, 3:30 PM
East Hall, 4th Floor Colloquium Room, Room 4448

When individuals with post-stroke hemiparesis train with upper or lower extremity robotic devices, they increase muscle recruitment and strength specific to the joints exercised. Although current robotic devices address muscle weakness in individuals post-stroke, they do not address patients impaired force scaling abilities.

In this dissertation I have examined lower limb force production and designed and tested the use of a novel control mode (symmetry-based resistance) for improving individuals? force-scaling abilities. With symmetry-based resistance, exercise resistance increases with increasing lower limb force asymmetry. Subjects who train with symmetry-based resistance perform the least work when they produce symmetric forces.

In the first and second experiments, I investigated lower limb force production in neurologically intact and post-stroke individuals. When both subject populations were asked to produce equal isometric forces in their lower limbs, they generated less force in their weaker limb even though they believed their forces were equal. Normalizing force by each limbs? bilateral maximum voluntary contraction force revealed no significant differences between limbs. These results suggest that individuals relied primarily on sense of effort, rather than proprioceptive feedback, for gauging isometric lower limb force production. Results suggest that sense of effort is also major factor determining force production during isotonic, or dynamic, movements in subjects post-stroke. In the third experiment, I demonstrated that neurologically intact individuals can successfully use the robotic device with symmetry-based resistance to improve their force scaling abilities and increase the symmetry of their lower limb forces from ~46% to ~50% (where 50% indicates perfect symmetry). In the final experiment, individuals with post-stroke hemiparesis were able to improve their lower limb symmetry from an initial average value of ~29% to ~36% during exercise with symmetry-based resistance. Improvements in lower limb symmetry, however, were not maintained during the one day training session when the controller was turned off. Subjects who trained for four weeks showed a trend towards retention of improved symmetry as initial lower limb symmetry values were improved from Day 1 to Day 4.

Overall these studies provide information about the neural mechanisms for lower limb force generation and suggest an innovative controller for stroke rehabilitation.

Wednesday, September 17, 2008

BME 500 Seminar Series

The effect of spatial distribution and coupling of fibrosis on dynamics of impulse propagation in models of cardiac fibrillation

Omer Berenfeld, PhD
Center for Arrhythmia Research
Dept. of Internal Medicine
University of Michigan

Wednesday, September 17, 2008, 3:30 - 4:30 PM
White Auditorium - Rm G906 Cooley Building

Pathological conditions such as ischemic cardiomyopathy and heart failure result in increased fibrosis in both the ventricles and the atria. The differentiation of fibroblasts into myofibroblasts may further result in myocyte-fibroblast electrical coupling via gap junctions. Our research aims at the understanding of the consequences of such pathological conditions on the cardiac action potential propagation using a combination of approaches that include molecular biology, cell cultures, isolated hearts as well as numerical simulations. We show that myofibroblast proliferation and increased heterocellular coupling significantly alter cardiac wave propagation complexity and stability with a bi-phasic effect on conduction velocity. Overall, the results provide novel insight into the mechanisms whereby electrical myocyte-myofibroblast interactions modify wave propagation and govern arrhythmias.

Wednesday, September 10, 2008

BME 500 Seminar Series

Histotripsy: Imaging Guided Ultrasound Therapy for Non-invasive Surgery

Zhen Xu, Ph.D.
Research Scientist, Therapeutic Ultrasound Group
Biomedical Engineering
University of Michigan

Wednesday, September 10, 2008, 3:30 - 4:30 PM
White Auditorium - Rm G906 Cooley Building

Histotripsy is a new non-invasive technique that mechanically fractionates and removes soft tissue using high intensity ultrasound pulses. This technique can be viewed as soft tissue lithotripsy, which gave rise to the name "histotripsy." Using focused ultrasound pulses, histotripsy produces a cluster of energetic microbubbles within a treatment region. These microbubbles, each similar in size to individual cells, function as "mini-scalpels" to mechanically fragment and subdivide cell and tissue structures. These acoustic mini-scalpels can be clearly visualized on clinical ultrasound imaging system, which are used to guide and monitor the histotripsy treatment. Histotripsy has potential for many clinical applications where non-invasive tissue removal is desired. We have been developing histotripsy for breaking down diseased clots (thrombolysis), removing unwanted tissue and tumors inside organs including prostate, kidneys, and breasts, and heart.

Friday, September 5, 2008

Final Oral Examination


Aniket Joshi
Co-chairs: Robert A. Koeppe and Jeffrey A. Fessler

Friday, September 5, 2008, 9:00 AM
1180 Duderstadt Center (Videoconference suite)

Positron emission tomography (PET) is a medical imaging modality offering a powerful tool for brain research, brain ailment diagnosis and drug development. Brain-PET enables mapping of in vivo neurobiological functions such as blood flow, metabolism, enzyme activity, neuroreceptor binding site density and occupancy. Quantification in brain-PET can broadly be classified into: 1) the accurate quantification of radiotracer distribution such that image values are proportional to the radiotracer concentration in tissue, and 2) the accurate quantification of the pharmacological state of the system-of-interest. This thesis addresses both of these aspects for functional neuroreceptor imaging studies of the living brain.

Traditional brain PET studies have at least two primary limitations. First, they measure only a single neuropharmacological aspect in isolation, which is often insufficient for characterizing a neurological condition. Second, data acquisition is accompanied by arterial blood sampling for measuring the input function to the system-of-interest, which is invasive for the subjects. The motivation for this thesis was to address both of these limitations and has led to the developed of quantitative methods for multiple neuropharmacological PET studies performed without blood sampling. One such experimental design investigated was a dual-measurement intervention study where the system-of-interest is perturbed during data acquisition with the intent of changing the subject's pharmacological status and system parameters are estimated both pre- and post-intervention. Second was a dual-tracer study where two radiotracers targeting two different neuropharmacological systems were injected closely in time in the same study.

A major challenge in the data analysis of the multiple pharmacological PET studies is the statistical noise induced bias and variance in the parameter estimates. In this thesis, methods have been developed for improving accuracy of the neurpharmacological estimates reducing bias without a corresponding decrease in precision.

The thesis also addresses the issue of inter-scanner PET image variability, a major confound in multi-center studies used to investigate disease progression and in drug trials. Since various PET centers have different scanner models with different hardware and software; systematic differences exist in multi-center data. This thesis develops a framework to reduce the inter-scanner PET image variability before multi-center data is pooled for analysis.

Thursday, September 4, 2008

Final Oral Examination


Erin Purcell
Chair: Daryl R. Kipke

Thursday, September 4, 2008, 2:00 PM
Johnson Rooms in the Lurie Engineering Center (LEC)

Neuroprosthetic devices record extracellular cortical signals which may then be used to place exterior devices under a patient's direct control. Therefore, these systems have the potential to restore function to individuals immobilized by paralysis or neurodegenerative disease. For neuroprosthetics to be useful in clinical and research settings, long-term, stable recordings must be achieved. However, these devices are plagued by recording instability, and the reactive tissue response that occurs after insertion into the brain is a likely cause. Specifically, neuronal density is reduced surrounding devices, and glial encapsulation isolates neuroprostheses from their neuronal signal sources.

The research presented describes the development and evaluation of two strategies to improve the tissue response to neuroprostheses: a neural stem cell (NSC)-seeded scaffold and a cell cycle-inhibiting drug. NSCs were hypothesized to secrete factors, such as neurotrophins, which would improve device-tissue integration. Three studies were conducted to develop the cell-seeded device. In the first study, NSCs were seeded into an alginate hydrogel scaffold, and in vitro testing identified the material composition which provided optimal mechanical stability and support of neurotrophic factor release (a high guluronic acid alginate without poly-L-lysine (PLL) coating). In the second study, in vivo stability and biocompatibility testing showed little benefit of PLL coating. In the third study, quantitative histological examination revealed that the NSC-seeded alginate scaffold mitigated the early tissue response to an implanted prosthesis, but exacerbated it by six weeks post-implantation. The final study of the dissertation investigated the role of cell cycle re-entry in reactive gliosis surrounding neural prostheses, and the effects of a cell cycle-inhibiting drug (flavopiridol) on electrophysiology and tissue response metrics. Flavopiridol reduced the appearance of a cell cycle protein (cyclin D1) in microglia surrounding probes three days after implantation and decreased impedance over the 28 day study period. Additionally, the data revealed several novel, significant correlations between recording quality, impedance, and endpoint histology measurements.

In conclusion, the studies demonstrate significant effects of two intervention strategies on tissue response and electrophysiology measurements, characterize alginate stability and its use as a NSC scaffold, and add insight into the relationship between the tissue-device interface and recording quality.

Friday, August 22, 2008

Final Oral Examination


Luyun Chen
Co-Chairs: James A. Ashton-Miller and John O.L. DeLancey

Friday, August 22, 2008, 8:00 AM
2215 GG Brown

Pelvic organ prolapse is a distressing and debilitating condition for women. Indeed, 200,000 women will require surgery for this condition each year. Anterior vaginal prolapse (AVP), clinically referred to as cystocele, is the most common form of pelvic organ prolapse. Despite its common occurrence, its pathomechanics remains poorly understood. This dissertation is the first attempt to understand the mechanisms underlying an anterior vaginal wall prolapse from a biomechanics point of view. The goal is to develop new insights into how and why AVP develops in order to help improve treatment efficacy and improve the quality of women's health care.

In this dissertation magnetic resonance (MR) imaging and biomechanical computer modeling was used to develop anatomically accurate models that allows us to analyze the pathomechanics of AVP by examining what-if scenarios. We hypothesized that the occurrence and magnitude of AVP cannot be explained by a single failure mechanism. Rather, it can be explained by failure of more than one connective tissue site and/or levator ani muscle impairments.

In Chapters 2 & 3 static 3-D magnetic resonance imaging was used to quantitatively measure the geometry of the anterior vaginal wall and its support structures in women with and without prolapse.

In Chapter 4 a 2-D, sagittal plane, lumped parameter model was developed to study the interaction between the support provided by apical connective tissues (cardinal and uterosacral ligaments) and the support provided by the levator ani muscles under peak Valsalva intra-abdominal pressure. In Chapter 5 a 3-D, subject-specific, anatomically accurate, finite element model was developed to analyze the effect on cystocele formation of different combinations of connective tissue and muscle impairments.

In Chapter 6 synchronous measurements of intra-abdominal pressure and MR-measured displacements of the most dependent bladder point were used to make the first in vivo estimates of the compliance of anterior vaginal wall support.

This dissertation provides insights into the biomechanical mechanisms underlying the development of anterior wall prolapse in women. Hopefully, these insights will help lead to improvements in the treatment of this distressing condition.

Monday, August 11, 2008

Final Oral Examination


Dongyul Chai
Co-Chairs: Alan J. Hunt and Tibor Juhasz

Monday, August 11, 2008, 10:00 AM
1180 Duderstadt Center Conference Room

Various treatments have been introduced to delay or slow the progress of glaucoma, one of the leading causes of blindness, by reducing intraocular pressure (IOP), the unique manageable factor in glaucoma. However, there are limitations to the continuous usage of these treatments. A femtosecond laser presents the potential of advanced treatment with significantly reduced damage. This dissertation will address the clinically significant problem of glaucoma and the development of a minimally invasive surgical procedure and a supporting tool to improve the efficiency of this procedure.

The experimental set up was built to scan the eye with a femtosecond laser in a predetermined pattern with adjustable parameters. The outflow rate was measured to evaluate the effect of the channel. It was demonstrated that the subsurface scleral channel that increases aqueous humor (AH) outflow rate can be created in ex vivo rabbit eyes with a femtosecond laser.

Considering that the goal of glaucoma treatment is IOP reduction into the normal range, a tool is required to predict the channel dimensions to achieve a predetermined reduction in IOP. I developed a 3D finite element model and demonstrated the potential of the 3D FEM model as a tool for estimating channel dimensions by fitting the experimental data to the model.

The experimental set up was altered to make a scan on an in vivo rabbit. It was demonstrated that the subsurface scleral channel can be created in the eyes of in vivo rabbits and IOP can be reduced with this channel. It was found that IOP can be reduced with a positive relation to the dimensions of the channel, demonstrating the potential for controlled IOP reduction by manipulating channel dimensions.

Therefore, it can be concluded that the subsurface scleral AH drainage channel can be created with a femtosecond laser, overcoming the disadvantages of current treatments. The method has the potential of controlling IOP reduction with the channel dimensions. 3D FEM has potential as a tool for glaucoma treatment by predicting the post treatment IOP and calculating channel dimensions for a required IOP reduction.

Monday, August 11, 2008

Final Oral Examination

Cerebral Blood Flow Measurement Using Dynamic Susceptibility Contrast MRI: Mathematical Regularization and Phantom Evaluation

Behzad Ebrahimi
Chair: Timothy E. Chupp

Monday, August 11, 2008, 4:00 PM
General Motors Conference Hall, 4th Floor Lurie Engineering Center (LEC)

Strokes have been the third most prevalent cause of death in developed countries and the second most prevalent cause of mortality worldwide. Ischemic strokes are by far the most common type of strokes. Verifying the extent and severity of brain damage may be the most challenging problem in the diagnosis and treatment of stroke. Magnetic resonance imaging provides important indicators, such as cerebral blood flow (CBF), cerebral blood volume (CBV) and mean transition time (MTT), for tissues at the risk for acute strokes. These perfusion-related parameters can be estimated using MR techniques, specifically as dynamic susceptibility contrast (DSC).

The DSC technique measures the change in MR signal during the passage of a non-diffusible tracer through the brain tissue. The signal change can be related to the blood flow through a mathematical convolution model, originally suggested by Meier and Zierler, based on indicator-dilution theory. There have been many attempts to find a deconvolution algorithm that overcomes the many limitations, especially, the instability issue of this ill-posed problem. We have suggested a new approach based on the framework of Tikhonov regularization which we will refer to that as "Generalized Tikhonov". Using computer simulations, this method proved promising for blood flow estimation in the presence of the major sources of error: noise, tracer delay and dispersion. In comparison to the standard Tikhonov regularization, our method showed less sensitivity to the changes in regularization parameters that determine the extent of the regularization.

To investigate the model we have designed a perfusion phantom which is very similar to actual tissues in terms of perfusion-related parameters such as blood volume, blood flow and the flow transition time. The signal to noise ratio, due to the similarity of the flow volume, is similar to that in actual perfusion measurements. The phantom has the capability of including or excluding the tracer delay and dispersion depending on the desired nature of experiments. Flow at every point of the phantom can be calculated using finite element methods. The perfusion phantom was used to verify the accuracy of the Generalized Tikhonov method and to compare it to the conventional methods.

Friday, August 8, 2008

Final Oral Examination


Laura Smith
Chair: Peter X. Ma

Friday, August 8, 2008, 2:00 PM
Dental School G390

Embryonic stem cells, isolated from the inner cell mass of blastocysts, represent a potentially unlimited cell source for tissue engineering. However, the tumorgencity of the undifferentiated cells and the heterogeneous cell population generated by current differentiation protocols impede the use of embryonic stem cells as a clinical cell source for tissue engineering applications. This thesis examines the effects of emulating the differentiation signals provided by the extracellular matrix during development with synthetic poly(L-lactic) acid nano-fibers on the differentiation of the embryonic stem cells to osteoblasts.

First, undifferentiated mouse embryonic stem cells were seeded onto two dimensional nano-fibrous thin matrices or flat (solid) films. With osteogenic supplementation the nano-fibrous architecture was found to enhance the osteogenic differentiation and mineralization of the mouse embryonic stem cells. Upon closer study, alpha 2 and alpha 5 integrin signaling were found to contribute to this osteogenic differentiation.

Next, the effects of biologically active factors and three dimensional culture were examined on mouse embryonic stem cells which were pre-differentiated through embryoid body formation prior to seeding on the materials. The nano-fibrous architecture was found to facilitate differentiation in the absence of osteogenic stimulation, while the solid film required osteogenic supplements and growth factors to support osteogenic differentiation. Three dimensional culture on nano-fibrous scaffolding was found to further enhance the osteogenic differentiation and mineralization more than two dimensional culture on either the nano-fibrous or solid architecture and three dimensional culture on the solid-walled scaffolding.

The osteogenic differentiation of human embryonic stem cells was examined next. In both two and three dimensional culture, the nano-fibrous architecture enhanced the osteogenic differentiation and mineralization of the human embryonic stem cells compared to the solid architecture eventually leading to better tissue formation on the nano-fibrous scaffolding compared to the solid-walled scaffold.

In summary, the nano-fibrous architecture enhances the osteogenic differentiation of mouse and human embryonic stem cells compared to the more traditional solid-walled architecture. Indicating that emulating the extracellular matrix with synthetic nano-fibers is advantageous in promoting osteogenic differentiation of embryonic stem cells.

Friday, August 8, 2008

Final Oral Examination


Dhruv Sud
Chair: Mary-Ann Mycek

Friday, August 8, 2008, 10:00 AM
1121 1121 Ann & Robert H. Lurie Biomedical Engineering Building (LBME)

Steady-state fluorescence imaging is routinely employed to obtain physiological information but is susceptible to artifacts such as absorption and photobleaching. FLIM provides an additional source of contrast oblivious to these but is affected by factors such as pH, gases, and temperature. Here we focused on developing a resolution-enhanced FLIM system for quantitative oxygen sensing. Oxygen is one of the most critical components of metabolic machinery and affects growth, differentiation, and death. FLIM-based oxygen sensing provides a valuable tool for biologists without the need of alternate technologies. We also developed novel computational approaches to improve spatial resolution of FLIM images, extending its potential for thick tissue studies.

We designed a wide-field time-domain UV-vis-NIR FLIM system with high temporal resolution (50 ps), large temporal dynamic range (750 ps-1 micros), short data acquisition/processing times (15 s) and noise-removal capability. Lifetime calibration of an oxygen-sensitive, ruthenium dye (RTDP) enabled in vivo oxygen level measurements (resolution = 8 microM, range = 1-300 microM). Combining oxygen sensing with endogenous imaging allowed for the study of two key molecules (NADH and oxygen) consumed at the termini of the oxidative phosphorylation pathway in Barrett's adenocarcinoma columnar (SEG-1) cells and Esophageal normal squamous cells (HET-1). Starkly higher intracellular oxygen and NADH levels in living SEG-1 vs.HET-1 cells were detected by FLIM and attributed to altered metabolic pathways in malignant cells.We validated our calibration with EPR spectroscopy, the gold standard for intracellular oxygen measurements. Differences between FLIM and EPR results were explained via cell lysate-FLIM studies. We proposed a new protocol for estimating oxygen levels by using a living reference cell line and cellular lysate analysis.

We performed FLIM studies in microfluidic bioreactors seeded with mouse myoblasts. For these systems, oxygen concentrations play an important role in cell behavior and gene expression. Oxygen levels decreased with increasing cell densities and were consistent with simulated model outcomes. In single bioreactor loops, FLIM detected spatial heterogeneity in oxygen levels as high as 20%.

Lastly, we proposed and compared two different image restoration approaches, direct lifetime vs. intensity-overlay. Both approaches improved resolution while maintaining veracity of lifetime.

Friday, August 1, 2008

Final Oral Examination


Sharon Segvich
Chair: David H. Kohn

Friday, August 1, 2008, 10:30 AM
Kellogg Building G550

The restoration and repair of orofacial and large bone defects resulting from extreme trauma, disease, or genetic inheritance is a clinical challenge in need of new solutions, as current grafting techniques can result in donor site morbidity, graft rejection, and/or inadequate bone formation and quality. Because bone is a complex organ, its hierarchical structure may only be restored in such defects if a temporary material guides tissue formation. Bone tissue engineering explores combinations of materials, biological signals, and cell sources to achieve guided tissue formation with structure-function properties matching those of native tissue.

By using nature's building blocks, or amino acids, as a design platform to synthesize multi-dimensional biomolecules in the form of peptides, biological function can be influenced. The idea is to provide specificity to induce a desired biological activity. In addition, coating a material with biomimetic bone-like mineral can provide a surface morphology and composition similar to the native hydroxyapatite in bone. While bone-like mineral can increase bone growth in vivo, the tissue formed is not uniform or spatially controlled, suggesting the need for better-designed scaffolding to spatiotemporally influence bone tissue development.

No studies have investigated the potential impact biomolecule-laden bone-like mineral has on influencing cell behavior. The work presented in this thesis is first to design dual-functioning peptides to increase in vitro cell attachment on bone-like mineral. Using a combinatorial phage library, computational modeling, and biological assays, specific peptide sequences that preferentially adsorb to bone-like mineral and attach to clonally derived human bone marrow stromal cells (hBMSCs) were identified. When combined, these sequences formed a dual-functioning peptide that exhibited an increased ability to attach hBMSCs compared to previous peptide designs. Additionally, a bioreactor was designed to coat three-dimensional porous scaffolds with uniform, continuous bone-like mineral, addressing a need for improved biomimetic coating fabrication techniques. The presented strategies can influence guided bone growth and advance the current methodologies in bone engineering. This work provides a new paradigm for peptide development linking organics to inorganics, not only for bone tissue engineered constructs, but also for any system requiring temporary or guided adhesion.

Monday, July 28, 2008

Final Oral Examination


Jessica M. Kemppainen
Chair: Scott Hollister

Monday, July 28, 2008, 1:00 PM
2203 LBME (Lurie Biomedical Engineering)

Clinical treatment options for articular cartilage repair are progressing with the incorporation of synthetic matrices alongside current autologous chondrocyte implantation techniques. This work explores mechanical properties and physical design considerations of potential matrices. Solid freeform fabrication (SFF) is used to create highly reproducible scaffolds with precise structural features in order to explore the mechanical potential of 3D designed poly(-caprolactone) (PCL) and poly(glycerol sebacate) (PGS) scaffolds, and to examine the effects of a designed physical property, permeability, for cartilage regeneration.

The first aim explores the potential of PCL and PGS scaffolds to provide temporary mechanical function within a tissue defect. We find that PCL mimics the viscoelastic nature of cartilage; however its stiffness properties cannot be changed through alterations in molecular weight or melting temperature. Fabricated into the architectures explored, it has aggregate modulus (HA) values within the correct magnitude, but higher than native cartilage. Furthermore, we demonstrate the importance of mechanically testing PCL scaffolds at physiological temperatures and we quantify their contraction in polar environments.

Poly(glycerol sebacate) has never been used for cartilage tissue engineering. We characterize how variations in the molar ratios of glycerol to sebacic acid (during pre-polymer synthesis) or variations in curing time can be used to change the stiffness of PGS, enabling fabrication of scaffolds with a wide range of architectures (designed for optimal tissue regeneration) that all support in vivo loads. Chondrocytes seeded onto PGS produce cartilaginous matrix and express cartilage specific genes similar to or better than cells cultured on PCL, showing the biocompatibility of PGS for cartilage applications for the first time.

The second aim looks at enhancing cartilage regeneration by optimizing scaffold permeability. We show that chondrocytes prefer a lower permeable scaffold that mimics the natural environment of native tissue, producing significantly more matrix and increased expression of cartilage specific markers. Bone marrow stromal cells (BMSCs) display the opposite trend, favoring a higher permeable environment for chondrogenic differentiation, as displayed through collagen 2 to collagen 1 expression, suggesting that increased access to chondrogenic induction factors in media is more important to these cells than mimicking the low permeable environment of native tissue.

Friday, July 25, 2008

Final Oral Examination


Weijun Luo
Chair: Peter J. Woolf

Friday, July 25, 2008, 9:30 AM
1150B-1170A BSRB (Biomedical Science Research Building)

Two basic motivating questions in biomedical research are: What genes regulate what other genes? What genes or groups of genes regulate a specific phenotype? Gene regulatory network (GRN) reconstruction and pathway inference are the two computational strategies addressing these two questions respectively. GRN reconstruction is to infer the components and topology of an unknown pathway, while pathway inference is to infer association between known pathways and a phenotype. This thesis focuses on gene regulatory network reconstruction and pathway inference from high throughput biological data.

In the first part of this work, I developed a novel method, MI3, for de novo GRN reconstruction using continuous three-way mutual information. MI3 addresses three major issues in previous probabilistic methods simultaneously: (1) to handle continuous variables, (2) to detect high order relationships, (3) to differentiate causal vs. confounding relationships. MI3 consistently and significantly outperformed frequently used control methods and faithfully capture mechanistic relationships from gene expression data.

In the second part of this work, I proposed another novel method, GAGE, Generally Applicable Gene Set Enrichment for pathway inference. I successfully apply GAGE to multiple microarray data sets with different sample sizes, experimental designs and profiling techniques. GAGE shows significantly better performance when compared to two other commonly used GSA methods of GSEA and PAGE. GAGE reveals novel and relevant regulatory mechanisms from both published and previously unpublished microarray studies.

In the third part of this work, we conducted a microarray study on transcriptional programs during BMP6 induced osteoblast differentiation and mineralization, and applied GAGE to recover the regulatory pathways and transcriptional signaling networks in the process. I not only showed which pathways or gene sets are significant, but also when and how they are involved in the osteoblast differentiation and mineralization. Different from common pathway analyses, our work further captures the interconnections among individual pathways or functional groups and integrate them into a whole system.

Monday, July 21, 2008

Final Oral Examination


Erik I. Waldorff
Chair: Steven A. Goldstein

Monday, July 21, 2008, 10:00 AM
3515 BSRB (Biomedical Science Research Building)

The risk of whole bone fracture in osteoporosis may be substantially increased as a result of microdamage accumulation in bone in conjunction with the associated remodeling that attempts to repair the damage. The risk may be increased as a result of age and disuse, which are hypothesized to alter remodeling in response to microdamage. Elucidating the effects of age and disuse on bone repair may provide clinically important insight into the relationship between microdamage accumulation and increased fracture risk in the elderly. The goals of this study were to experimentally determine the influence of age and mechanical usage on microdamage accumulation and repair.

A unique animal model was developed that enabled loading of distal femoral trabecular bone of rats in-vivo. Utilizing this model it was demonstrated that older rats have a reduced ability of bone to recover after damage and that removal of microdamage is altered with advancing age.

For the second series of studies a hindlimb suspension and four-point bending apparatus were developed to simulate disuse and induce tibial cortical microdamage. Utilizing these models, it was shown that disuse alters the microdamage response through a reduction in woven bone production and cessation of microdamage resorption. This suggests that elderly individuals with severe activity reductions may further accumulate microdamage. Most importantly, while many studies have proposed that microdamage repair is triggered by cell apoptosis, these results suggest this mechanism may be insufficient without the stimulus associated with mechanical usage.

Finally, it was shown that daily short-term weight-bearing during disuse rescues the lack of targeted bone remodeling normally associated with disuse. This provides support to early clinical evidence that moderate loading can reduce recovery time from stress fractures.

In aggregate, it was found that advanced age and associated disuse lead to a reduction in targeted remodeling associated with microdamage, thereby increasing the fracture risk due to potential microdamage accumulation. In addition, the importance of physiological loading to the process of microdamage repair supports the potential for altering the current clinical practice of limiting weight-bearing for the treatment of stress fractures.

Thursday, July 17, 2008

University of Michigan Center for Computational Medicine and Biology (CCMB) And Department of Biomedical Engineering Presents

Taxol and Tubulin: From Molecular Mechanism to Microtubule Mechanics

David Sept, Ph.D.
Washington University, St. Louis
Department of Biomedical Engineering

Thursday, July 17, 2008, 4:00 - 5:00 PM
Forum Auditorium, Palmer Commons Building (4th Floor)

Taxol is a commonly used antitumor agent that functions by hyperstabilizing microtubules and thereby preventing cell division. The interaction of Taxol with the microtubule has been studied extensively though a wide array of experimental techniques, however the mechanism by which Taxol stabilizes microtubules has remained elusive. Here, through the use of large-scale molecular simulations, we show that Taxol does affect the interactions between the M and H1-S2 loops of adjacent tubulin dimers, but more importantly leads to a significant increase in the dynamics and flexibility of the portion of beta-tubulin that both surrounds the bound nucleotide and makes contact with alpha-monomer of the next dimer in the protofilament. We extend these studies by implementing a mesoscopic/continuum mechanics model for the microtubule based on our atomistic simulations and show how Taxol increases the flexibility of the microtubule. We conclude that this increase in flexibility allows the microtubule to compensate for conformational changes induced by nucleotide hydrolysis and keeps the protofilaments in a straight conformation, resulting in a stable microtubule. These findings provide a basis for understanding numerous experiments which are discussed.

Tuesday, July 15, 2008

Final Oral Examination


Kyungsup Shin
Chair: David H. Kohn

Tuesday, July 15, 2008, 2:00 PM
G550 School of Dentistry

Annually, 3 million musculoskeletal and orthopedic procedures are performed in US, including those for fractures (15%), joint problems (22%), and spinal disorders (12%). The musculoskeletal diseases, disabilities and trauma necessitating these procedures cost approximately $215 billion in health care costs and loss of economic productivity. The field of bone tissue engineering has been developed in response to limitations in contemporary therapeutic strategies for these musculoskeletal and orthopedic defects.

A biomimetic approach involving the self-assembly of mineral within the pores of 3-dimensional porous polymer scaffolds is a promising strategy to integrate biological advantages (e.g. bioactivity and osteoconductivity) of an inorganic phase with desirable material functions (e.g. biodegradability) of an organic phase into a single material for mineralized tissue engineering. As cells attach and grow on the surface of this hybrid material, biological functions of the cells could be regulated by the mineral surface, which may also undergo partial dissolution affecting cell function as well. Therefore, we hypothesized that proliferation and differentiation of multipotent mesenchymal stem cells are regulated by a tandem of solution and surface-mediated signals from the biomimetically synthesized apatite materials.

To test the hypothesis, we first demonstrated that bone-like carbonated apatites were self-assembled within the pores of 3-D porous PLGA scaffolds via a biomimetic process using a simulated body fluid (SBF). By adjusting the ionic activity product (IP) of the SBF, carbonate content (7.23% to 5.42%), Ca/P molar ratio (1.63 +- 0.005 to 1.51 +- 0.002) and crystallinity (FWHM at (112): 0.147 to 1.035) were controlled in a predictable manner. The crystallinity of apatite is one of main factors determining its resorbability, and the variances in chemical composition of the apatites, along with their dissolution products, could differentially influence cell function. Therefore, we also tested the dissolution behavior of the apatites and both their solution and surface-mediated effects on cell function.

The dissolution behavior of the apatites was characterized quantitatively by measuring the chemical composition of the dissolution products and qualitatively by changes in the structure and morphology of the apatite. Lower crystalline carbonated apatites with low Ca/P ratios were more resorbable and underwent bulky erosion on the mineral surface in both PBS and serum-supplemented MEMa media, whereas higher crystalline carbonated apatites with high Ca/P ratios were less resorbable and underwent surface erosion. When immersed in PBS, only dissolution occurred and crystallinity of the apatites increased over time. Both adsorption and dissolution of Ca and P were observed in serum-supplemented MEMa and crystallinity of the apatites maintained over time.

Observing that the mineralized scaffolds significantly adsorbed Ca and P from serum-supplemented MEMa media, we next tested effects of extracellular soluble Ca and P on cell functions, and concluded that proliferation and osteogenic differentiation of mouse BMSCs were inhibited by Ca,P-deficiency. This finding was generalized, when soluble Ca,P-deficiency also inhibited functions of cells seeded on surfaces of the carbonated apatites and PLGA. However, under conditions of normal soluble Ca and P in the media, mineralized surfaces exhibited significantly enhanced osteogenic differentiation and cell-mediated mineralization relative to non-mineralized surfaces. Among groups of the biomimetic apatites, the more-resorbable carbonated apatite, whose Ca/P ratio and crystallinity were closer to those of natural bone mineral apatite, had a stimulatory effect on osteogenic differentiation compared to the less-resorbable carbonated apatite, whose Ca/P ratio and crystallinity were close to those of hydroxyapatite.

From the experiments of this thesis, we conclude that mouse BMSCs proliferate and differentiate into osteogenic phenotypes in response to combined stimuli from two extracellular environments; solution-mediated effects and surface-mediated effects of calcium phosphate biomaterials. By uncoupling mechanisms of soluble and surface-mediated signals from carbonated apatite self-assembled on a polymer, it was elucidated that, regardless of the substrate that the cells are attached to and grow on, appropriate levels of extracellular soluble Ca and P are essential for proliferation and osteogenic differentiation of the mouse BMSCs. Polymer scaffolds coated with bone-like carbonated apatites can stimulate osteogenic differentiation to a greater extent than non-coated scaffolds when normal levels of extracellular soluble Ca and P are maintained. The work of this thesis also demonstrates that signals from both the solution and the surface of biomaterials should be taken into account when trying to optimize biological performance of a material. This combination of design criteria may also advance for the development of new materials for bone tissue engineering.

Friday, July 11, 2008

Final Oral Examination


Jeffrey L. Hendricks
Chair: David C. Martin

Friday, July 11, 2008, 1:30 PM
Johnson Rooms B & C in the Lurie Engineering Center (LEC)

Neural prostheses facilitate communication with the nervous system for the diagnosis, treatment, and functional recovery from neurological illness or trauma. These devices require electrodes that can be permanently implanted, provide a stable electrical connection to the nervous system for reliable interaction, and do not produce adverse effects. Unfortunately, the immune and inflammatory reaction to implanted electrodes often leads to the formation of fibrous tissue that limits charge transfer and renders longterm performance unreliable.

This dissertation presents the development and characterization of a number of novel electrode coatings designed to promote enhanced functional integration at the tissue-electrode interface. The primary constituent of these coatings is the conducting polymer poly(3,4-ethylene dioxythiophene) (PEDOT). PEDOT is a suitable material for interfacing electrodes with tissue because it is biocompatible, conducts both electronic and ionic charge, is easily functionalized with cells and biomolecules, and mediates the mechanical mismatch often found when metallic or ceramic probes are implanted in soft tissue. In addition, PEDOT-based coatings can be rapidly and reproducibly deposited on individual electrode sites.

To form electrode coatings containing live cells or cellular components, PEDOT was deposited around living neuroblastoma and primary cortical neurons. These coated electrodes had 73 % lower 1 kHz impedance than uncoated electrodes while delivering live cells to direct the tissue response. Spongy coatings and tissue engineering scaffolds were made from PEDOT deposited in alginate hydrogel containing live cells and were capable of delivering over 25 times more current at the same voltage than an electrode without PEDOT. Laser patterning of PEDOT films was performed to produce electrode coatings capable of directing neuronal orientation and elongation. Laser interference patterning of 825 nm thick PEDOT coatings with channels of period 7.82 um resulted in the alignment of up to 87 % of neurites in the direction of the pattern without compromising the improved electrical properties of the coating.

Finally, evaluation of conducting polymer and hydrogel coatings on cochlear implants was performed. Coatings on cochlear electrodes reduced the electrode impedance by 80 and 99 % at 1 kHz and 10.7 Hz, respectively. These coated electrodes also delivered BDNF directly within the cochlea, increasing levels of the neurotrophin to 30.3 ng/ml after one week compared to 1.7 ng/ml in animals that received control implants without BDNF. When implanted into deafened guinea pigs, coated cochlear implants had reduced failure compared to uncoated implants and had a final average 1 kHz impedance of 5.9 kOhm compared to 1.2 MOhm for uncoated implants after 6 months.

Bioactive conducting polymer electrode coatings offer the ability to direct the tissue reaction and promote integration at the neuron-electrode interface while providing improved electrical transfer. Results from in vitro and in vivo testing indicate that these materials may be able to increase the specificity, reliability, and safety of clinical neural prostheses and thus enable the longterm use of next-generation neural prosthetic devices.

Monday, June 23, 2008

Final Oral Examination

High-Throughput Profiling of Ion Channel Activity in Lymphocytes for Quantifying Activity of Human Autoimmune Disease

Daniel J. Estes
Chair: Michael Mayer

Monday, June 23, 2008, 3:00 pm
1180 Duderstadt Center Conference Room

The voltage-gated potassium ion channel, Kv1.3, in human lymphocytes is a promising target for treatment of several autoimmune diseases, including multiple sclerosis (MS) and rheumatoid arthritis (RA). Despite the relevance of this ion channel for disease, current techniques to measure Kv1.3 activity are low-throughput, laborious, and require significant expertise. As a result, studying ion channels in cells of the immune system is not accessible to most clinicians and immunologists.

This thesis describes the development of a high-throughput assay to measure Kv1.3 activity in lymphocytes. The method is automated, specific for Kv1.3 channels, and able to measure Kv1.3 activity in 100-200 lymphocytes within 1 h. This throughput is at least 20-fold higher than the throughput of manual patch clamp techniques.

Using this high-throughput assay enabled profiling Kv1.3 activity in T cells from peripheral blood of patients with MS and RA. Patients with a chronic progressive (CP) form of MS exhibited significantly higher Kv1.3 activity compared to healthy controls or MS patients in remission. Developing metrics to quantify the percentage of T cells with high Kv1.3 activity made it possible to distinguish between CP-MS patients and controls with 100% sensitivity and 94% specificity. In addition, patients with an active form of RA exhibited higher Kv1.3 activity than patients with inactive RA. These results suggest that Kv1.3 activity may be a useful clinical marker for quantifying activity of inflammatory autoimmune disorders.

Moreover, the assay developed here enabled immunological experiments to study the changes in Kv1.3 activity upon T cell stimulation. The activity of Kv1.3 ion channels increased ~3-fold in T cells following stimulation. We show that this upregulation was driven by signaling through the interleukin (IL)-2 receptor. Interestingly, inflammatory cytokines (IL-2, IL-15) increased Kv1.3 activity even in the absence of signaling through T cell receptor pathways. These studies suggest that both specific activation of T cells and general inflammatory proteins lead to high Kv1.3 activity in vivo.

High-throughput electrophysiology introduces a promising new strategy for clinical applications such as diagnosis and therapeutic monitoring of autoimmune disease. This work also provides a general methodology that makes the study of ion channels in primary cell types accessible to laboratories that are not specialized in electrophysiology.

Sunday, June 15, 2008

Satellite event to the 2008 Neural Interfaces Conference

Summit Meeting on Chronic Microscale Neural Interfaces: Towards Standards and Benchmarks for an R&D Roadmap

Organizers: Daryl Kipke (, Director & William Shain (, Assoc. Director , Center for Neural Communication Technology
Sunday, June 15, 2008, 12:30 - 5:00pm
Cleveland InterContinental Hotel and Conference Center

The 2008 CNCT Summit Meeting will center on broad-based, directed discussions of the design and analysis of chronic microscale neural interface technologies for recording and stimulation and neurochemical sensing and delivery. The goals of this meeting are to (1) build an organizational framework for the formation of an open-source, collaborative knowledge-base of neural interface technologies and (2) begin directed discussions of developing design and performance guidelines of various types of microscale devices. Relevant technical areas include microelectrode technologies, materials, surgical techniques, embedded electronics and related components and subsystems. This meeting is part of the kick off an emerging "Neural Interface Technologies Initiative" organized by the CNCT that will provide an ongoing, international collaborative community forum for neural interface design, analysis, and advancement.

Engineers, neuroscientists, and physicians are invited. Early stage researchers, post-docs, and students are expressly encouraged to participate. This will be an excellent opportunity to network and get engaged in the neural interface community.

Please register here by June 1, 2008. Registration is free.

For more and updated information, please go here.

Thursday, June 12, 2008

Final Oral Examination


Yunseok Heo
Chair: Shuichi Takayama

Thursday, June 12, 2008, 1:00 p.m.
1200 EECS

Despite advances in in vitro manipulation of pre-implantation embryos, there is still a lag in the quality of embryos produced in vitro leading to lower pregnancy rates compared to embryos produced in vivo. Reducing the incidence of high-order multiple pregnancies while maintaining the overall in vitro fertilization (IVF) success rate is a holy grail of human IVF and would be greatly assisted by the ability to produce and identify the highest quality embryos. A promising new technology, microfluidics, does exist and is becoming increasingly studied. A challenge of studying embryo on microfluidic device is that preimplantation mouse embryos are highly sensitive cells and their development is affected greatly by osmolality shifts as will occur in devices with thin poly(dimethylsiloxane) (PDMS) membranes even in typical humidified cell culture incubators. Here we characterized and resolved the evaporation mediated osmolity shifts that constrain microfluidic cell culture in Poly(dimethylsiloxane) Devices. Next, we developed a dynamic microfunnel embryo culture system would enhance outcomes by better mimicking the fluid mechanical stimulation and chemical agitation embryos experience in vivo from ciliary currents and oviductal contractions. Using a mouse embryo model, average cell counts for blastocysts after 96 hours of culture in dynamic microfunnel conditions increased 70% over that of conventional static cultures. Importantly, the dynamic microfunnel cultures significantly improved embryo implantation and ongoing pregnancy rates over static culture to a level that approached that of in utero-derived preimplantation embryos. Lastly, we reported a new computerized microfluidic real time embryo culture and assay device that can perform automated periodic analyses of embryo metabolism over 24 hrs. Biochemical methods for embryo analysis based on measurement of metabolic rates do exist, but are not practical for clinical use because of difficulties in manipulating precise amounts of sample and reagents at the sub-microliter scale. The convenient, non-vasive, reliable, and automated nature of these assays open the way for development of practical single embryo biochemical analysis systems. Collectively, these results confirm that microfluidic technology can be used to properly mimic a broad range of the embryo environments seen in physiology and to assess embryo viability for in vitro fertilization clinics.

Thursday, June 5, 2008

Final Oral Examination


Rainer Ng
Chair: John A. Faulkner

Thursday, June 5, 2008, 2:30 p.m.
Room 1130 Seminar Room C, Biomedical Science Research Building

Muscles exposed to unaccustomed exercise or injurious contractile activities are likely to sustain mechanical damage to muscle fibers, a characteristic of contraction-induced injuries. The susceptibility of muscles to contraction-induced injury increases with age, disuse or disease. Although lesions in the sarcolemma have been implicated in the injury process, the conditions that lead to the formation of such lesions, as well as the extent to which these lesions affect muscle function remain inadequately understood. To study membrane-based events reliably, we developed a micro-sized whole muscle model that was robust, but more importantly, compatible the contemporary techniques used to study cellular function. In characterizing this muscle model in vitro, we report a level of stability and flexibility that had not been observed in previous whole muscle preparations. Utilizing this muscle model, we demonstrated that sarcolemmal lesions and overactive mechanosensitive ion channels accounted for the majority of the functional deficit observed in the diseased muscles of mdx mice, the murine model of Duchenne Muscular Dystrophy. These results provide a basis for the development of therapeutic strategies directed at stabilizing the membrane of dystrophic skeletal muscle. When wild-type muscles were subjected to an injurious protocol of lengthening contractions, the mechanical stress associated with lengthening contractions, while severe enough to cause a 30% force deficit, was found to be insufficient to elicit membrane lesions in a whole skeletal muscle. This finding diminished the role of mechanical stress as the direct cause of sarcolemmal injury and implies that contraction-induced lesions observed in wild-type muscle must result from the contributions of other factors, such as reactive oxygen species and proteolytic enzyme activity.

Friday, May 23, 2008

BME Research Seminar

Taxol and Tubulin: From Molecular Mechanism to Microtubule Mechanics

David Sept, Ph.D. Associate Professor
Biomedical Engineering and Center for Computational Biology
Washington University

Friday, May 23, 2008, 12:00 - 1:30pm
1123 LBME (Lurie Biomedical Engineering)

Taxol is a commonly used antitumor agent that functions by hyperstabilizing microtubules and thereby preventing cell division. The interaction of Taxol with the microtubule has been studied extensively though a wide array of experimental techniques, however the mechanism by which Taxol stabilizes microtubules has remained elusive. Here, through the use of large-scale molecular simulations, we show that Taxol does affect the interactions between the M and H1-S2 loops of adjacent tubulin dimers, but more importantly leads to a significant increase in the dynamics and flexibility of the portion of beta-tubulin that both surrounds the bound nucleotide and makes contact with alpha-monomer of the next dimer in the protofilament. We extend these studies by implementing a mesoscopic/continuum mechanics model for the microtubule based on our atomistic simulations and show how Taxol increases the flexibility of the microtubule. We conclude that this increase in flexibility allows the microtubule to compensate for conformational changes induced by nucleotide hydrolysis and keeps the protofilaments in a straight conformation, resulting in a stable microtubule. These findings provide a basis for understanding numerous experiments which are discussed.

Tuesday, May 20, 2008

Final Oral Examination


Geeta Mehta
Co-Chairs: Shuichi Takayama and Jennifer Linderman

Tuesday, May 20, 2008, 9:30 AM - 11:30 AM
1180 Duderstadt Center Conference

The goal of this research is to create in vitro microenvironments for long term culture of hematopoeitic stem cell (HSC) in microfluidic bioreactors. In vivo, HSCs reside in the bone marrow osteoblastic and vascular niches in adult mammals. Some of the defining features of their in vivo niche are: small number of HSCs, heterogeneous population of bone marrow cells that support HSCs, and low oxygen tension. In vivo studies with HSCs are often tedious and time consuming, while the conventional in vitro cultures do not capture the microenvironments found in vivo. We are using microfluidic tools to study and re-create the microenvironmental HSC niches in vitro. We engineer niche elements in microfluidic bioreactors by: modulation of oxygen tension in the microbioreactors, optimal attachment and growth of HSC supporting bone marrow stromal cells, and also by culturing small numbers of HSCs in their physiologically relevant ratios between HSCs and supporting cells.

By using a combination of a mathematical model and quantitative experiments, we have created a design tool to manipulate and control oxygen tension for cell culture inside the poly(dimethyl siloxane) (PDMS) microbioreactors. Dissolved oxygen concentrations in the microbioreactor are quantified in real time using fluorescence lifetime imaging of an oxygen sensitive dye. Experimental results are consistent with the mathematical model1 and give insight into the conditions under which the devices must be operated to get desired oxygen tension in cell culture regions of the microbioreactor.

We also have used microfluidic perfusion systems to develop nanocoatings made from electrostatic self assembly of PDDA (poly(diallyldimethyl ammonium chloride)), clay, type IV collagen and fibronectin to optimize attachment of primary murine bone marrow cells (support cells for HSCs) onto PDMS bioreactors. Assays for cell attachment, spreading, proliferation and cell viability were performed at regular intervals during fifteen days of culture. PDDA topped coatings were found to be cytotoxic, while coatings with two or more bilayers of proteins collagen and fibronectin were found to have highest spreading, proliferation, and viability compared to other surfaces.

Additionally, 3-D co-culture of hematopoeitic cells with supporting cells in PDMS bioreactors were undertaken to create on-chip model for erythropoiesis, to optimize the ratio of support cells to HSCs for maximum number of colony formation and also to test efficacy of our in vitro artificial HSC niches. Thus, by the combination of hypoxia (which simulates in vivo bone marrow oxygen tension), biofunctional surfaces, and 3-D co-cultures, we are moving towards a microfluidic HSC niche, in which hypothesis-driven studies about crosstalk between HSCs and stromal cells can be carried out.

Friday, May 2, 2008

Final Oral Examination

Statistical Performance Evaluation, System Modeling, Distributed Computation and Signal Pattern Matc

Li Han
Co-Chairs: W. Leslie Rogers and Neal H. Clinthorne

Friday, May 2, 2008, 10:00 AM
4419 EECS

In radionuclide treatment, tumor cells are primarily destroyed by charged particles emitted by the compound while associated high energy photons are used to image the tumor in order to determine radiation dose and monitor shrinkage. The problem is that these tracers emit high energy photons that are difficult to image with conventional collimated Anger cameras, since a trade-off between resolution and sensitivity, and increased septal penetration and scattering for detecting high energy photons. This research compares imaging system performance of the conventional camera to a Compton camera that can have improved spatial resolution and sensitivity for high energy photons because of decoupled resolution and sensitivity trade-off, and the decreased effects of Doppler broadening. The imaging system performance and comparison are analyzed using the modified uniform Cramer-Rao bound algorithms we developed and verified along with Monte Carlo calculations and system modeling. The bound calculations show that the effect of Doppler broadening is the limiting factor for Compton camera performance for imaging 364keV photons. The performance of the two systems was compared and analyzed by simulating a two dimensional disk with uniform activities for the same number of detected events. The performance of the proposed Compton imaging system is superior to the collimated Anger camera especially as the desired spatial resolution is better than 12mm FWHM. The low variance bound ratio of the two systems at 5mm and 1mm desired point source response is 1000 and 15, respectively. Meanwhile, the detection sensitivity of the proposed Compton imaging system is about 15-20 times higher than the collimated Anger camera. For both systems, images were reconstructed using MLEM. Reconstruction speed-up for the Compton system using developed distributed MLEM with parallel processors and chessboard data partition increased speed a factor of 22 with 64 processors. To address the problem of event pileup at high count rates in the second detector, a real time signal processing and pattern matching system was designed and simulated. The circuits can effectively extract energy for 85% pile-up at a count rate of 2 million per second.

Wednesday, April 30, 2008

BME Research Seminar

Femtosecond Laser Nanosurgery Shedding Light on Nerve Regeneration and Helping in the Treatment of Cancer

Adela Ben-Yakar Ph.D.
Mechanical Engineering Department, University of Texas at Austin

Wednesday, April 30, 2008, 12:00 - 1:30 pm
1123 Lurie Biomedical Engineering Building

The application of femtosecond (fs) lasers to biomedicine opens new opportunities for the study of biological systems and the diagnosis and treatment of diseases. The ultra high peak intensities of fs-lasers enable nonlinear interactions between light and tissue. These nonlinear interactions confine energy absorption to focal volumes beneath the surface enabling selective ablation inside the tissue with high resolutions. This highly efficient and non-thermal ablation mechanism allows removal of tissue using low energy pulses, reducing both mechanical and thermal damage to the surroundings of the target.

I will first present our studies on laser nanosurgery performed in vivo in the model organism, C. elegans. The high precision of fs-laser ablation allows inducing controlled axon injury inside the nematode and studying the regeneration process of severed axons in vivo. By developing a high-throughput laser nanoaxotomy platform using integrated microfluidic devices, we can now pursue rapid identification of genes and molecules that affect nerve regeneration. Next, I will discuss how we combine the focusing power of plasmonic nanoparticles to provide nano-scale ablation and how we take advantage of bright two-photon luminescence of plasmonic gold nanorods to develop bright contrast agents for molecular imaging of cancer cells. When integrated into our new miniaturized probe for laser microsurgery with two-photon imaging capabilities, these plasmonic tools will help us in the realization of an advanced "seek-and-treat" probe to aid in the early diagnosis and treatment of cancer.

We are witnessing the beginning of a new exciting field. Shaping these ultrafast laser assisted technologies with creative engineering ideas will allow promising breakthroughs in biology and medicine.

Adela Ben-Yakar is an Assistant Professor of Mechanical Engineering at the University of Texas at Austin. She obtained her Ph.D. in Mechanical Engineering from Stanford University in 2000. From 2000 to 2004, she was a postdoctoral researcher in Applied Physics at Stanford University and a visiting scholar at Harvard University. Her research interests are in femtosecond laser tissue interactions, fs-laser nano-surgery, plasmonic laser nano-surgery, two-photon imaging, and fs-laser applications for diagnosis and treatment of cancer and for in-vivo nerve regeneration studies.

Thursday, April 24, 2008

Final Oral Examination

Computer-aided Diagnosis of Pulmonary Nodules in Thoracic Computed Tomography

Ted W. Way
Co-Chairs: Heang-Ping Chan and Jeffrey A. Fessler

Thursday, April 24, 2008, 9:30am
B1C111 University Hospital

Lung cancer is the leading cause of cancer death in the United States. The five-year survival rate is only 15% because most patients present with advanced disease. If lung cancer is detected and treated at its earliest stage, the five-year survival rate has been reported to be as high as 92%. Computed tomography (CT) has been shown to be more sensitive than chest radiography in detecting abnormal lung lesions (nodules), especially when they are small. However, each thin-slice thoracic CT scan can contain hundreds of images. Large amounts of image data, radiologist fatigue, and diagnostic uncertainty may lead to missed cancers or unnecessary biopsies. We address these issues by developing a computer-aided diagnosis (CAD) system that would serve as a second reader for radiologists by analyzing nodules and providing a malignancy estimate using computer vision and machine learning techniques. To segment the nodules, we extended the active contour (AC) model to 3D by adding new energy terms. The classification accuracy, quantified by the area (Az) under the receiver operating characteristic curve, was used as the figure-of-merit to guide segmentation parameter optimization. The effect of CT acquisition parameters on 3DAC segmentation was systematically studied by imaging simulated nodules in chest phantoms. We conducted simulation studies to compare the relative performance of feature selection and classification methods and to examine the bias and variance introduced due to limited training sample sizes. We also designed new feature descriptors to describe the nodule surface, which were combined with texture and morphological features extracted from the nodule volume and the surrounding tissue to characterize the nodule. Stepwise feature selection was used to search for the subset of most effective features to be used in the linear discriminant analysis classifier. The CAD system achieved a test Az of 0.86 +/- 0.02 in a leave-one-case-out resampling scheme for 256 nodules from 152 patients. We conducted an observer study with six thoracic radiologists and found that their average Az in assessing nodule malignancy increased significantly (p<0.05) from 0.83 +/- 0.03 to 0.85 +/- 0.04. These results indicate the potential usefulness of the CAD system as a second reader for radiologists in characterizing lung nodules.

Monday, April 21, 2008

Final Oral Examination

Cardiac Activation Mapping Using Ultrasound Current Source Density Imaging

Ragnar Olafsson
Chair: Matthew O'Donnell

Monday, April 21, 2008, 11:00am
GM Conference Room - 4th Floor Robert H. Lurie Engineering Center

Intracardiac ablation procedures to correct drug-resistant arrhythmias require accurate maps of cardiac activation. Conventional methods are time-consuming and have poor spatial resolution (5- 10 mm). The goal of this dissertation was to develop a new method, Ultrasound Current Source Density Imaging (UCSDI), to map biological currents. UCSDI is based on the acousto-electric (AE) effect, a modulation of the electric resistivity by acoustic pressure. If a current passes through the focal region of an ultrasound transducer, a voltage modulated at the ultrasonic frequencies can be measured with a pair of electrodes located distant to the focal zone. By sweeping the focal zone, UCSDI can map a distributed current field.

UCSDI has several potential advantages as a technique for mapping cardiac activation currents: high spatial resolution determined by the typically sub-mm focal characteristics of the ultrasound beam, short mapping time using electronically steered ultrasonic beams, and automatic registration with B-mode ultrasound images without sophisticated mathematical algorithms. UCSDI was first validated by mapping an artificially generated 2D current distribution. It was compared to sequential electrode mapping, computer simulation as well as to an inverse algorithm. In this study it was possible to use UCSDI to locate monopolar current sources to within 1-mm of their true locations without making any prior assumptions about the source geometry. UCSDI was then used to detect and map biological currents in an isolated rabbit heart. Both UCSDI and normal low frequency electrocardiograms (ECG) were measured simultaneously by tungsten electrodes embedded in the left ventricle. The motion of the heart was significantly reduced by perfusing it with an excitation contraction de-coupler. Measured UCSDI maps showed temporal and spatial patterns consistent with a spreading activation wave and timing consistent with normal ECG signals.

UCSDI was finally combined with ultrasonic strain imaging in a new method for electromechanical imaging. This combined method was used to make localized measurements of electromechanical delay. This method could be useful in cardiac resynchronization therapy for placing pacemaker leads.

Monday, April 21, 2008

Office of the Vice President for Research

James R. Baker Jr. M.D. Named Distinguished University Innovator

James R. Baker Jr. M.D.
Monday, April 21, 2008, 4:00pm
Biomedical Science Research Building (BSRB) Auditorium

On Monday April 21, 2008 at 4:00pm Dr. Baker will present a lecture titled "Taking Nanotechnology from the Bench to the Bedside" as part of the award ceremony. The event will be held in the Biomedical Science Research Building (BSRB) Auditorium with a reception to follow. This event is open to the public and is sponsored by the Office of the Vice President for Research. For more information, visit the event page. If you have any questions, please contact the Office of the Vice President for Research at 734-763-1290.

Wednesday, April 16, 2008

Final Oral Examination

Development of Nanoparticle Based Tools for Reactive Oxygen Species Related Biomedical Applications

Gwangseong Kim
Chair: Raoul Kopelman

Wednesday, April 16, 2008, 2:00pm
1201 Chemistry Building (Central Campus)

Reactive oxygen species (ROS) are various oxygen derived intermediates produced from the reduction of molecular oxygen and highly reactive / cytotoxic byproducts of aerobic metabolisms in biology. ROS includes hydroxyl radicals (OH), superoxide anion radical (O2-), hydrogen peroxide (H2O2), and energetically excited oxygen (singlet oxygen 1O2)). ROS are capable of oxidizing various biomolecules, interrupting their cellular functions, and consequently, inducing cell death. ROS play various roles in normal and pathogenic conditions in biology. However, our understandings about ROS still largely remain in qualitative stages because their exceptionally unstable nature makes the investigations of ROS highly challenging.

This work demonstrates how to utilize nanoparticle-encapsulation to ROS related research and applications with improved properties. Three independent nanoparticle based tools have been developed using PEBBLE (Photonic Explorer for Biomedical use with Biologically Localized Embedding) technology with organically modified silicate (Ormosil) matrix. First, singlet oxygen sensitive nanoparticle probes were synthesized by encapsulating a singlet oxygen molecular probe, 1,3-diphenylisobenzofuran (DPIBF), which is the most sensitive but not appropriate for biological uses, into protective Ormosil matrix. They exhibited improved singlet oxygen sensitivity over conventional molecular probes. Based on this established sensitivity, the direct quantity of singlet oxygen generated from an in vitro photodynamic therapy (PDT) for cancer was able to be determined. Second, hydrogen peroxide detecting nanoparticle probes were also developed. The non-specific ROS detecting molecular probe, 2',7'-dichlorofluorescin diaceate (DCFDA) was embedded into Ormosil nanoparticle by post-loading technique. The DCFDA nanoprobes showed enhanced selectivity towards H2O2 by excluding the interferences from other ROS by screening effect of nanoparticle matrix based on the combination of size exclusion, lifetime exclusion, and hydrophobicity. An in vitro H2O2 production from stimulated macrophages could be quantitatively monitored by the DCFDA PEBBLE nanoprobes with low nM of resolution. Third, dual-functional nanoparticles containing near-infrared absorbing indocyanine green dye (ICG) were developed for photoacoustic imaging/diagnosis and photodynamic therapy for cancer. The ICG nanoparticles showed capability of generating singlet oxygen for PDT. Tissue mimicking phantoms containing these nanoparticles were built with diffusive agarose gels and they were successfully imaged by 2-D and 3-D photoacoustic imaging systems. ICG nanopartcies were targeted to cancer by incorporating with an antibody and displayed sufficient photoacoustic contrast effect in a prostate cancer model in vitro.

Tuesday, April 15, 2008

Final Oral Examination

Microfludic Culture and Analysis of Endothelial Cells in Relation to Cardiovascular Disease and Canc

Jonathan Wanserk Song
Chair: Shuichi Takayama Ph.D.

Tuesday, April 15, 2008, 1:00pm
1180 Duderstadt Center

Endothelial cells comprise the inner lining of the entire circulatory system and are key mediators in many aspects of vascular biology. The interaction of endothelial cells with blood-borne constituents and the mechanical forces due to blood flow regulate a broad range of diseases that originate at the vasculature. The challenges of studying endothelial cell biology in vivo is that it is highly invasive to access, experimentally manipulate, and/or observe changes inside of blood vessels. Furthermore, current in vitro-based systems do not faithfully recreate the mechanical and chemical cellular environments with the proper length scales seen in physiology. Here we show examples of using the tools of microfluidics and microfabrication in developing perfusion-based in vitro systems that mimic the in vivo environments of endothelial cells. We describe a novel, reconfigurable micro-pumping and valving system that enables the delivery of a wide range of mechanical shear stress to multiple endothelial cell compartments simultaneously. We also utilized this pumping and valving system to culture endothelial cells under continuous recirculation of sub-microliter amounts of fluid. Finally, we engineered a compartmentalized endothelium to model the intravascular adhesion events of circulating cancer cells with endothelium at metastatic and non-metastatic sites. We determined that the endothelium regulates site-specific adhesion of circulating cancer cells that is independent of the predicted metastatic abilities of the cancer cells. Collectively, these results confirm that microfluidic technology can be used to properly mimic a broad range of the endothelial cell environments seen in physiology. Furthermore, we establish microfluidics as a platform for the development of systems that have the capabilities of advancing the understanding of endothelial cell biology as it relates to vascular diseases.

Thursday, April 3, 2008

BME Research Seminar

Optical imaging of Drosophila melanogaster (fruit fly) cardiovascular physiology

Michael A. Choma, MD, PhD
Thursday, April 3, 2008, 12:00pm - 2:00pm
1121 LBME (Lurie Biomedical Engineering)

Successive generations of physicians and scientists have leveraged past discoveries in the fruit fly Drosophila melanogaster along with advances in technology to gain new insights into fundamental cardiovascular mechanisms. Recent insights into comparative genomics and embryology are highlighting important similarities between the D. melanogaster and vertebrate cardiovascular systems. In addition, advances in high-speed optical imaging technologies are greatly expanding our ability to measure wild-type and abnormal anatomic and physiologic phenotypes in the D. melanogaster cardiovascular system. This is spurring new experimental work using D. melanogaster as a model for adult and congenital heart disease.

In this talk I will cover three topics. First, I will discuss the use of structural and Doppler optical coherence tomography (OCT) in assessing in vivo adult and pre-pupal D. melanogaster cardiovascular structure and function. Second, I will discuss new contrast microangiography techniques that allow for the real-time, in vivo visualization of otherwise-transparent cardiovascular fluid flow in D. melanogaster. These techniques are used in the setting of both traditional stereomicroscopy as well as in OCT. Finally, I will discuss how these advanced imaging and biological techniques are enabling new types of experiments in D. melanogaster cardiovascular physiology and circulation-based mass transport.

Wednesday, April 2, 2008

BME 500 Seminar Series

"Dandelions as a Model for BioEngineered Tendons"

Alan S. Litsky, M.D., Sc.D.
Associate Professor of Orthopaedics and Biomedical Engineering
Director, Orthopaedics Biomaterials Laboratory
Ohio State University

Wednesday, April 2, 2008, 4:30pm - 5:30pm
Chesebrough Auditorium, Chrysler Building

Developing a secure, durable interface for transferring muscle power to a synthetic tendon would allow the harnessing of muscle force for a number of surgical applications. Current techniques, which include sutures or clamps, suffer from either insufficient stability or the need for excess compressive force resulting in tissue necrosis. Implantation of a large number of ultrafine polyester fibers parallel to the muscle fibers produces a very large surface area and permits force transmission through shear force. These fibers can be coalesced into a synthetic tendon and used to transmit the muscle pull. In vitro and in vivo testing has demonstrated the efficacy of this approach.

Tuesday, April 1, 2008

BME Research Seminar

Improving Deep Brain Stimulation in Parkinson's Disease Using Feedback Control

Sridevi Sarma, Ph.D.
Tuesday, April 1, 2008, 12:00 - 2:00 PM
1123 LBME (Lurie Biomedical Engineering)

An estimated 3 to 4 million people in the United States have Parkinson's Disease (PD), a chronic progressive neural disease that occurs when specific neurons in the midbrain degenerate, causing movement disorders such as tremor, rigidity, and bradykinesia. Currently, there is no cure to stop disease progression. However, surgery and medications are available to relieve some of the symptoms in the short term. A highly promising treatment is deep brain stimulation (DBS). DBS is a surgical procedure in which an electrode is inserted through a small opening in the skull and implanted in a targeted area of the brain. The electrode is connected to a neurostimulator (sits inferior to the collar bone), which injects current back into the brain to regulate the pathological neural activity. Although DBS is virtually a breakthrough for PD, it is necessary to search for the optimal stimulation signal postoperatively. This calibration often takes several weeks or months because the process is trial-and-error. During a post-operative visit, the neurologist asks the patient to perform various motor tasks and makes subjective observations. Based on these, he/she tweaks the stimulation parameters and asks the patient to return in hours, days or even weeks. The difficulty is that there are millions of stimulation parameters to choose from, though experience has reduced this to roughly 1000 options.

In this talk, I will describe my current research efforts, which are to 1. reduce calibration time down to days by developing a systematic testing paradigm using feedback control principles, and to 2. develop a new feedback stimulation paradigm that allows for broader classes of DBS signals to be administered. The former will allow neurologists to treat more patients with DBS and significantly cut medical costs, and the latter may result in further improving patients responses to DBS while reducing the need for replacements surgeries.

Sridevi V. Sarma received a BS (1994) from Cornell University and an MS (1997) and PhD (2006) from Massachusetts Institute of Technology in Electrical Engineering and Computer Science. Sri is now a postdoctoral fellow jointly at Harvard Medical School and MIT. Her research interests include control of constrained and defective systems (applications in neuroscience) and large-scale optimization. Sri is president and cofounder of Infolenz Corporation, a Marketing Analytics company. She is a recipient of the GE faculty for the future scholarship, a National Science Foundation graduate research fellow, and a recipient of the Burroughs Wellcome Fund Careers at the Scientific Interface Award.

Friday, March 28, 2008

Department of Biomedical Engineering

BiomedE Undergrad Student/Faculty Lunch

Department of Biomedical Engineering
Friday, March 28, 2008, 12:00 pm
LBME (Lurie Biomedical Engineering) Atrium

BiomedE Undergraduate students are invited to join the BiomedE faculty for a luncheon in the LBME atrium.

To attend the event please RSVP to:

Tuesday, March 25, 2008

BME Research Seminar

Algorithms at the Brain-Machine Interface

Lakshminarayan "Ram" Srinivasan, Ph.D.
Tuesday, March 25, 2008, 12:00 - 2:00 PM
1123 LBME (Lurie Biomedical Engineering Building)

Direct two-way interaction between brain and machine is now possible due to ongoing developments in fabrication and bioengineering. These techniques are expanding our ability to record and stimulate neural activity through better temporal and spatial resolution, with implications for neuroscience and the treatment of neurological diseases. What are the common principles of algorithm design that will drive the varied applications of the brain-machine interface?

Random processes and estimation theory, guided by neuroscience, forms a partial basis for our approach to breaking new conceptual ground in this area. As a case example, this talk will focus on one project from our work related to upper-limb neural prosthetic devices. Algorithms at this interface are intended to restore function for people that are unable to move their arms as a result of trauma, stroke, neuromuscular degeneration, or other disease processes. Specifically, we discuss the dominant and seemingly dissimilar approaches to upper-limb prosthesis design, and how these approaches were unified through estimation theory while addressing a spectrum of practical challenges.

The talk concludes with a proposal for a key revision of these concepts that expands the capabilities of neuro-medical devices.


Lakshminarayan "Ram" Srinivasan is a Research Fellow in Neurosurgery at the Center for Nervous System Repair, Massachusetts General Hospital. His research focus is the analysis and design of neural systems. Dr. Srinivasan completed his B.S. in Electrical and Computer Engineering at the California Institute of Technology (2002) with a focus on computational neuroscience, and S.M. (2003) and Ph.D. (2006) in the Department of Electrical Engineering & Computer Science at the Massachusetts Institute of Technology with a focus on estimation theory and neuroscience. He will also receive the M.D. at Harvard Medical School supported by the NIH Medical Scientist Training Program Ruth Kirschstein National Research Service Award T32 GM-07753-28. His research on principled algorithms for brain-machine interfaces draws on human electrophysiology, estimation, and stochastic control, with applications to neuroscience and neurological disease.

Wednesday, March 19, 2008

BME Research Seminar

Neural Signal Processing: Making Sense of Brain Activity

Hualou Liang, PhD
The University of Texas Health Science Center at Houston

Wednesday, March 19, 2008, 4:30pm - 5:30pm
Chesebrough Auditorium, Chrysler Building

Technological advances are making simultaneous recordings from many different neurons and/or neural assemblies a daily reality. A proper framework for analyzing and interpreting the resulting multivariate data is a key step toward understanding how the nervous system functions under normal conditions and how it fails in pathology. In this talk I will discuss a set of signal processing methods for the assessment of brain network dynamics, and their possible applications to neuroinformatics and brain dynamics imaging.

Thursday, March 6, 2008

Department of Biomedical Engineering

Chalk Talk/Lunch discussion with Faculty Candidate Dr. Shai Ashkenazi

Shai Ashkenazi, Asst. Research Scientist, Biomedical Engineering, University of Michigan
Thursday, March 6, 2008, 12:00pm - 1:30pm
1123 LBME (Lurie Biomedical Engineering)

BME will be hosting a Chalk Talk/Lunch discussion with Faculty Candidate Dr. Shai Ashkenazi on Thursday, March 6th, from 12-1:30 in 1123 LBME. Dr. Ashkenazi is currently a Research Scientist in our Biomedical Ultrasonics laboratory, and will be discussing his current and future research plans with any interested staff, faculty, and scientists. Lunch will be provided.

Wednesday, March 5, 2008

BME Research Seminar

Can ultrasound become the preferred modality for functional and molec

Shai Ashkenazi, Asst. Research Scientist, Biomedical Engineering, University of Michigan
Wednesday, March 5, 2008, 4:30pm - 5:30pm
Chesebrough Auditorium, Chrysler Building

"Ultrasound imaging is widely used in medical diagnostics. It provides tissue structure imaging with sub-millimeter resolution at a depth exceeding 10 cm. Higher frequencies increases resolution (<0.1 mm) at the expense of reduced penetration. High resolution end is limited by current transducer technology. Combining optics and ultrasound elevates the imaging in two major aspects: increasing resolution by forming high density transducer arrays and providing functional and molecular sensitivity by interaction with optical contrast agents. Clinical implementation of these techniques will have a major impact on both diagnostics and imaging assisted therapy of cardiovascular diseases and cancer. Optoacoustic transducers are based on high quality factor optical resonators for ultrasound sensing and efficient thermo-elastic materials for converting optical pulses into ultrasound emission. This alternative ultrasound technology enables high density packing of ultrasonic transducer elements in a small area, exhibiting high bandwidth operation for high resolution 3D imaging. The technology is tailored for specific medical applications such as intravascular imaging and biopsy guiding. In the second part of the seminar photoacoustic imaging will be introduced. The technique combines optical contrast with the high resolution of ultrasound for deep tissue imaging. It relies on sound generation in tissue illuminated by a pulsed laser. Optical absorption followed by heat deposition and rapid thermal expansion creates a volume distributed acoustic source. Ultrasound imaging methods are then applied to reconstruct an image of tissue optical properties. Using optical contrast agents extends the scope of photoacoustic imaging to functional and molecular imaging. We have successfully applied cancer cell targeting nanoparticles as photoacoustic contrast agents. We have also developed a pump-probe pulse scheme for photoacoustic probing of fluorophors' lifetime. Its application to measuring dissolved oxygen level in tissue will be presented. Future research plan in this field includes developing a range of functional agents for imaging of cellular metabolism, tissue pH, enzymatic activity, tissue oxygenation and other specific diagnostic markers."

BME 500, Winter 2008 lecture serise. This is the main graduate student seminar for the Department of Biomedical Engineering. We will explore various BME subdisciplines with the goal of exposing students to research going on in biomedical engineering at U-M and at other institutions and providing a view into the breadth of the field of biomedical engineering. This seminar is open to all.