Events

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Friday, March 20, 2009

Department of Biomedical Engineering Final Oral Examination

"IN SITU TRANSDUCTION BY VIRUS LOCALIZATION ON BIOENGINEERING SCAFFOLDS FOR BONE REGENERATION"

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

BME500 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

BME500 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

Department of Biomedical Engineering Final Oral Examination

"ADVANCED POLYMER-BASED MICROFABRICATED NEURAL PROBES USING BIOLOGICALLY DRIVEN DESIGNS"

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

Department of Biomedical Engineering Final Oral Examination

"MITIGATION OF MOTION ARTIFACTS IN FUNCTIONAL MRI: A COMBINED ACQUISITION, RECONSTRUCTION AND POST PROCESSING APPROACH"

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

Department of Biomedical Engineering Final Oral Examination

"ON IMPROVING THE EFFECTIVENESS OF CONTROL SIGNALS FROM CHRONIC MICROELECTRODES FOR CORTICAL NEUROPROSTHESES"

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

BME500 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

BME
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

Department of Biomedical Engineering 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

Department of Biomedical Engineering Final Oral Examination

"INVESTIGATING THE EFFECTS OF EXERCISE AND AGING ON BONE COMPOSITION AND THE IMPACT OF COMPOSITION ON MECHANICAL INTEGRITY"

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

Department of Biomedical Engineering Final Oral Examination

"THE ROLE OF ADHESION STRENGTH IN HUMAN MESENCHYMAL STEM CELL OSTEOBLASTIC DIFFERENTIATION ON BIODEGRADABLE POLYMERS"

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

Department of Biomedical Engineering Final Oral Examination

"OIL-IN-WATER NANOEMULSIONS AS MUCOSAL VACCINE ADJUVANTS: CHARACTERIZATION, MECHANISM, FORMULATION, AND DEVELOPMENT OF A NANOEMULSION-BASED BURKHOLDRERIA CENOCEPACIA VACCINE"

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

Department of Biomedical Engineering 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

BME
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.

Tuesday, October 28, 2008

Department of Biomedical Engineering Final Oral Examination

NEUROPROSTHETIC DEVICES: INPUTS AND OUTPUTS

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

ENGINEERING THE HEART PIECE BY PIECE: STATE OF THE ART IN CARDIAC TISSUE ENGINEERING

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: www.bme.umich.edu/industry/rsvp.php

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: www.bme.umich.edu/industry/rsvp.php

Friday, September 19, 2008

Department of Biomedical Engineering Final Oral Examination

NEURAL MECHANISMS FOR BILATERAL FORCE ASYMMETRY DURING LOWER LIMB EXTENSIONS IN NEUROLOGICALLY INTACT INDIVIDUALS AND INDIVIDUALS WITH POST STROKE HEMIPARESIS

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

Department of Biomedical Engineering Final Oral Examination

MPROVED QUANTITATIVE METHODS FOR MULTIPLE NEUROPHARMACOLOGICAL NON-INVASIVE BRAIN PET STUDIES

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

Department of Biomedical Engineering Final Oral Examination

CELL SCAFFOLD- AND DRUG-BASED STRATEGIES FOR IMPROVING THE INTEGRATION OF NEURAL PROSTHESES INTO THE BRAIN

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

Department of Biomedical Engineering Final Oral Examination

BIOMECHANICAL ANALYSES OF ANTERIOR VAGINAL WALL PROLAPSE: MR IMAGING AND COMPUTER MODELING STUDIES

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

Department of Biomedical Engineering Final Oral Examination

THE EFFECT OF FEMTOSECOND LASER CREATED DRAINAGE CHANNELS ON THE AQUEOUS HUMOR OUTFLOW DYNAMICS OF THE EYE

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

Department of Biomedical Engineering 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

Department of Biomedical Engineering Final Oral Examination

EFFECTS OF NANO-FIBROUS SCAFFOLDING ARCHITECTURE ON BONE TISSUE DEVELOPMENT FROM EMBRYONIC STEM CELLS

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

Department of Biomedical Engineering Final Oral Examination

WIDE-FIELD TIME-DOMAIN FLUORESCENCE LIFETIME IMAGING MICROSCOPY (FLIM): MOLECULAR SNAPSHOTS OF METABOLIC FUNCTION IN BIOLOGICAL SYSTEMS

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

Department of Biomedical Engineering Final Oral Examination

DESIGN OF PEPTIDES WITH TARGETED APATITE AND HUMAN BONE MARROW STROMAL CELL ADHESION FOR BONE TISSUE ENGINEERING

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

Department of Biomedical Engineering Final Oral Examination

MECHANICALLY STABLE SOLID FREEFORM FABRICATED SCAFFOLDS WITH PERMEABILITY OPTIMIZED FOR CARTILAGE TISSUE ENGINEERING

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

Department of Biomedical Engineering Final Oral Examination

GENE REGULATORY NETWORK RECONSTRUCTION AND PATHWAY INFERENCE FROM HIGH THROUGHPUT GENE EXPRESSION DATA

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

Department of Biomedical Engineering Final Oral Examination

EFFECTS OF AGING AND DISUSE ON BONE REMODELING IN RESPONSE TO MICRODAMAGE

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

Department of Biomedical Engineering Final Oral Examination

SOLUTION AND SURFACE-MEDIATED EFFECTS OF BONE-LIKE APATITE COATED POLY(LACTIDE-CO-GLYCOLIDE) SCAFFOLD ON PROLIFERATION AND OSTEOGENIC DIFFERENTIATION OF BONE MARROW STROMAL CELLS

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

Department of Biomedical Engineering Final Oral Examination

BIOACTIVE CONDUCTING POLYMER COATINGS FOR IMPLANTABLE NEURAL AND COCHLEAR ELECTRODES

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

Department of Biomedical Engineering 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 (dkipke@umich.edu), Director & William Shain (shain@wadsworth.org), 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

Department of Biomedical Engineering Final Oral Examination

IMPROVEMENT OF IN VITRO FERTILIZATION (IVF) TECHNOLOGY THROUGH MICROFLUIDICS

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

Department of Biomedical Engineering Final Oral Examination

THE OCCURRENCE OF CONTRACTION-INDUCED LESIONS IN THE SARCOLEMMA OF SKELETAL MUSCLES: INSIGHTS FROM A MICRO-SIZED WHOLE MUSCLE MODEL

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

Department of Biomedical Engineering 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

Department of Biomedical Engineering Final Oral Examination

MICROENVIRONMENTAL CONTROL IN MICROFLUIDIC BIOREACTORS FOR LONG TERM CULTURE OF BONE MARROW CELLS

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

Department of Biomedical Engineering 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

Department of Biomedical Engineering 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

Department of Biomedical Engineering 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

Department of Biomedical Engineering 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.

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

Department of Biomedical Engineering 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

Department of Biomedical Engineering 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

Department of Biomedical Engineering Faculty Candidate Presentation Research Seminar/Chalk Talk

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

Department of Biomedical Engineering
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

Department of Biomedical Engineering Research Seminar and Chalk Talk

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 patient’s 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: sbitzer@umich.edu.

Tuesday, March 25, 2008

Department of Biomedical Engineering Research Seminar and Chalk Talk

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.

Biography

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

Department of Biomedical Engineering 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

Department of Biomedical Engineering Research Seminar

COMBINING LIGHT & SOUND:
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.