Spotlight

Building better blood vessels could advance tissue engineering

ANN ARBOR—One of the major obstacles to growing new organs—replacement hearts, lungs and kidneys—is the difficulty researchers face in building blood vessels that keep the tissues alive, but new findings from the University of Michigan could help overcome this roadblock.

“It’s not just enough to make a piece of tissue that functions like your desired target,” said Andrew Putnam, U-M associate professor of biomedical engineering. “If you don’t nourish it with blood by vascularizing it, it’s only going to be as big as the head of a pen.

“But we need a heart that’s this big,” he added, holding up his fist.

More immediately, doctors and researchers believe figuring out how to grow working blood vessels might offer treatments for diseases that affect the circulatory system such as diabetes. Perhaps the right drug or injection could save patients’ feet from amputation.

Putnam and his colleagues have revealed why one of the leading approaches to building blood vessels isn’t consistently working: It’s making leaky tubes. They also demonstrated how adult stem cells could solve this problem. A paper on the findings is published online in Tissue Engineering Part A, and will appear in a forthcoming print edition.

Today, biomedical researchers are taking two main approaches to growing new capillaries, the smallest blood vessels and those responsible for exchanging oxygen, carbon dioxide and nutrients between blood and muscles or organs.

One group of researchers is developing drug compounds that would signal existing vessels to branch into new tributaries. These compounds—generally protein growth factors—mimic how cancerous tumor cells recruit blood vessels.

The other group, which includes the U-M team, is using a cell-based method. This technique involves injecting cells within a scaffolding carrier near the spot where you want new capillaries to materialize. In Putnam’s approach, they deliver endothelial cells, which make up the vessel lining and supporting cells. Their scaffolding carrier is fibrin, a protein in the human body that helps blood clot.

“The cells know what to do,” Putnam said. “You can take these things and mix them and put them in an animal. Literally, it’s as easy as a simple injection and over a few days, they spontaneously form new vessels and the animals’ own vasculature connects to them.”

But it turns out these vessels don’t always thrive. The U-M team aimed to figure out why. In reading previously published findings, Putnam noticed that researchers used “a mishmash of support cells,” and the field had paid little attention to which ones work best. So that’s where he and his colleagues focused.

In their experiments, they mixed three recipes of blood vessel starter solutions, each with a different commonly used supporting cell type: lung fibroblasts, adult stem cells from fat and adult stem cells from bone marrow. They also made a version with no supporting cells at all. They injected each solution under the skin of mice, and allowed the new blood vessels to form over a period of two weeks. At various points in time, they injected a tracer dye into the animals’ circulation to help them see how well the engineered capillaries held blood, and whether they were connected to the animals’ existing vessel networks.

The researchers found that the solution with no support cells and the one with the lung fibroblasts produced immature, misshapen human capillaries that leaked. They could tell because the tracer dye pooled in the tissue around the new vessels. On the other hand, the solutions with both types of adult stem cells gave rise to robust human capillaries that kept blood and dye inside them.

The paper notes that one popular method biomedical engineers use to check the success of their efforts—counting blood vessels—might not be an ideal measure. The adult stem cell solutions produced fewer blood vessels than the others, in one case less than half. But the vessels they did build were stronger. And upon further analysis, the researchers found evidence that the adult stem cells may be able to differentiate into the kind of mature, smooth muscle cells that support larger blood vessels.

“The adult stem cells from fat and bone marrow both work equally well,” Putnam said. “If we want to use this clinically in five to 10 years, I think it’s crucial for the field to focus on a support cell that actually has some stem cell characteristics.”

Down the road, Putnam envisions that doctors could get these support cells from individual patients themselves—either from their bone marrow or fat—and then inject them near the site where the new blood vessels are needed.

The paper is titled, “Stromal Cell Identity Influences the In Vivo Functionality of Engineered Capillary Networks Formed by Co-delivery of Endothelial Cells and Stromal Cells.” The research was funded by the National Institutes of Health (Grant Numbers R01-HL085339 and R01-HL085339-03).

Published on Apr 04, 2013
Contact Nicole Casal Moore

Related Links:
Original U-M News Service article: http://www.ns.umich.edu/new/multimedia/videos/21358-building-better-blood-vessels-could-advance-tissue-engineering
Full text of paper: http://online.liebertpub.com/doi/pdf/10.1089/ten.tea.2012.0281
Andrew Putnam: www.sitemaker.umich.edu/cset/home

Tags: Andrew Putnam, Blood vessels, build blood vessels, cell engineering, College of Engineering, engineering alumni, engineering topics, engineering video, healthcare, mconnex, michepedia, michigan alumni, Michigan Engineering, Professor Putnam, Putnam, replacement organs, Stem Cells, Tissue Engineering, u-m, u-m alumni, UM, University of Michigan, uofm
Posted in All News, Faculty News, Spotlight

Targeting Disease With Nanoparticles

“Nanoparticles, which are popular candidates for ferrying drugs to target locations in the human body, have been shown to evade the immune system and infiltrate tissues and cells. This makes them effective in delivering medication for conditions such as cardiovascular disease and cancer.

But, Michigan Engineering Professor Lola Eniola-Adefeso and her team has discovered they’re no good at leaving the bloodstream, getting trapped instead by red blood cells. To combat that, researchers are exploring the possibility of different shapes for these nanoparticles, to help them more effectively navigate to their targets.”

Professor Lola Eniola-Adefeso, who also holds a joint appointment in the Department of Biomedical Engineering along with her position in Chemical Engineering, is featured in the latest MconneX MichEpedia video. Check it out here!

Tags: arteriosclerosis, biomedical engineering, blood cells, Cancer, cardiovascular disease, Chemical Engineering, College of Engineering, drug carriers, engineering alumni, engineering topics, engineering video, lola eniola-adefeso, mconnex, michepedia, michigan alumni, Michigan Engineering, nano drug carriers, nano engineering, nano spheres, nanoparticles, professor eniola, red blood cells, u-m, u-m alumni, UM, University of Michigan, uofm
Posted in All News, Faculty News, Spotlight

Professor Alan Hunt Memorial

It is with profound sadness that U-M BME shares news of the death of Alan J. Hunt, professor of biomedical engineering in the College of Engineering.  Professor Hunt died on October 28, 2012 at the age of 49, after a courageous battle with cancer.

Professor Hunt received his B.A. degree in Biochemistry and Cell Biology in 1986 from the University of California, San Diego and his Ph.D. in Biophysics in 1993 from the University of Washington.  He was a postdoctoral fellow at the University of Colorado from 1994 through 1998.  He began his career in Ann Arbor as an assistant professor in 1998, was promoted to associate professor with tenure in 2004 and was promoted to professor in 2010.

Professor Hunt was a truly talented and inspiring teacher.  He helped to design a modern biomedical engineering curriculum with a strong focus on principles of cellular and molecular engineering. Among the courses he has developed and taught are “Molecular and Cellular Biomechanics” (graduate), and “Quantitative Cell Biology” (undergraduate). These courses will have a lasting and significant impact on the biomedical engineering education at the University of Michigan and beyond.  He served as caring and supportive mentor to 10 Ph.D. students who have gone on to distinguished careers in academia and industry.

Professor Hunt has made numerous outstanding scientific contributions with significant impact in three main areas: 1) microtubule self-assembly and mitosis, 2) nanofabrication via ultrafast laser machining, and 3) asymmetric stem cell division. In the area of microtubule self-assembly and mitosis, he published the first computational model of mitosis, the process by which a replicated genome is segregated into two complete sets of chromosomes during cell division.  This article stands as possibly the best description of the molecular mechanical basis of mitosis.  Professor Hunt’s group has pioneered the use of optical tweezers to measure single microtubule self-assembly at the nanometer-scale, giving molecular mechanistic framework with which to understand how microtubule-directed anticancer drugs exert their therapeutic influence.  In the area of nanofabrication via ultrafast laser machining, Professor Hunt’s group applied femtosecond laser pulsing to create nanoscale features that can be created with high precision and accuracy, for example, the development of liquid glass electrodes where electrical current through a nanofluidic channel is controlled by reversibly inducing dielectric breakdown in a glass wall within the channel. Related to asymmetric stem cell division, Professor Hunt in collaboration with stem cell biologists, found that centrosome mis-orientation reduces the ability of stem cells to divide.  Professor Hunt’s expertise in the dynamics of microtubules, which are anchored to and nucleated from centrosomes, was vital in establishing this important link between the cytoskeleton and stem cell division.   Professor Hunt was a highly respected scientist and was selected as associate editor of the journal Cellular and Molecular Bioengineering.

Professor Hunt is survived by his wife Karen, daughters Sarah and Deanna, parents Mary Lou and Earl, brothers Bob and Steve, sister Susan, and many loving relatives and friends.  His friendship and inspiring intellect will be missed by his colleagues, friends and family.

Tags: Alan Hunt, Memorial
Posted in All News, Faculty News, Spotlight

Understanding Alzheimer’s: Study gives insights into how disease kills brain cells

Article by: Nicole Casal Moore

ANN ARBOR—Exactly how Alzheimer’s disease kills brain cells is still somewhat of a mystery, but University of Michigan researchers have uncovered a clue that supports the idea that small proteins prick holes into neurons.

The team also found that a certain size range of clumps of these proteins are particularly toxic to cells, while smaller and larger aggregates of the protein appear to be benign.

The findings, which appear in the journal PLOS ONE, add important detail to the knowledge base regarding this disease that affects 5.4 million Americans in 2012 but remains incurable and largely untreatable. The results could potentially help pharmaceutical researchers target drugs to the right disease mechanisms.

The U-M findings strongly support the idea that amyloid peptides damage the membrane around nerve cells and lead to uncontrolled movement of calcium ions into them. Calcium signaling is an important way that cells communicate and healthy cells regulate its flow precisely. The toxic mechanism implicated in the new study could act on its own or together with the other proposed courses and ultimately lead to a loss of brain cells in patients, the researchers say.

“There’s a good chance Alzheimer’s is caused, at least in part, by four- to 13-peptide aggregates that punch holes in cells and kill them gradually after prolonged exposure,” said Michael Mayer, an associate professor of biomedical engineering and chemical engineering who led the research.

“The size range of amyloid clumps that we identified as the most pore-forming was also the most toxic. The correlation is staggering. In the conditions of the culture dish, these results strongly suggest that pore formation by amyloid-beta is responsible for neuronal cell death.”

Using observation and sophisticated statistical analysis, the team explored whether the peptides’ tendency to poke holes in cell membranes correlated with the death of actual cells under the same conditions.

To conduct the experiment, Panchika Prangkio, a Ph.D. student in Mayer’s lab, formed amyloid-beta aggregates in water over 0, 1, 2, 3, 10 and 20 days. She measured how well amyloid clumps of various sizes punched pores in a lipid bilayer that mimicked a cell membrane. And, separately, but with the same amyloid samples, the team observed how many cells died and determined which size amyloids were in the sample at each time point. The researchers used cells from a human nerve cell cancer line.

Their finding that mid-size amyloid clumps are most toxic supports recent theories that individual peptides as well as longer amyloid fibers might be protective, rather than harmful, the researchers say. The smallest and largest aggregates were negatively correlated with cell death, which suggests they may bind with the dangerous mid-length clumps and trap them in a nontoxic form.

The work could help advance the search for Alzheimer’s treatments that would work by blocking pore formation by mid-sized amyloid-beta clumps. And they could raise questions about the potential efficacy of drugs (such as Bapineuzumab) that aim to remove large aggregates of amyloid beta

“The better the research community understands how Alzheimer’s operates, the more likely we are to develop effective treatment,” Mayer said.

The paper is titled “Multivariate analyses of amyloid-beta oligomer populations indicate a connection between pore formation and cytotoxicity.” It is a collaborative effort with the research group of Jerry Yang, an associate professor of chemistry and biochemistry at the University of California, San Diego, and David Sept, an associate professor of biomedical engineering at U-M. Funding was provided by the Wallace H. Coulter Foundation with support from the Alzheimer’s Association, the National Science Foundation and the government of Thailand.

Related Links:

• Study: www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0047261
• Michael Mayer: www.bme.umich.edu/labs/biomembrane
• Link to original News Services article: http://www.ns.umich.edu/new/releases/20884-understanding-alzheimer-s-study-gives-insights-into-how-disease-kills-brain-cells

Tags: alzheimer's, Alzheimer's Association, Brain, Coulter, David Sept, Michael Mayer, National Science Foundation, NSF, PLOS ONE, Thailand
Posted in All News, Faculty News, Spotlight

New U-Mich joint biomedical department holds promise for better healthcare technologies

Bringing engineers and physicians together under new structure will accelerate discovery and improve training

ANN ARBOR, Mich.– In an effort to develop more technologies that improve health care, the University of Michigan will established a Joint Department of Biomedical Engineering (BME) with footholds in its top-ranked College of Engineering and Medical School, in an action approved by the U-M Board of Regents today. The change takes effect Sept. 1, 2012.

The department is currently housed in engineering, though its researchers regularly collaborate with medical doctors and a number of Medical School faculty hold joint appointments there. The change in academic structure is designed to bring biomedical engineering researchers closer to the patients their technologies aim to benefit, say leaders in both schools.

“As engineers, one of our goals is to invent and develop technologies that make a difference in society,” said Douglas Noll, the Ann and Robert H. Lurie Professor of Biomedical Engineering and current department chair. “By linking ourselves in the Medical School, we will establish closer connections for our faculty and students to practicing clinicians and the health care system, which will allow us to better identify and translate our discoveries to medical care and to offer new educational opportunities for our students.”

As part of this plan, BME will expand over the next five years from approximately 20 primary faculty members to 35 Most of the new hires will be Medical School appointments. The department will retain its space on North Campus in engineering and in the North Campus Research Complex. It will also open a space at the Medical School in the future. Already at the NCRC, a new biointerfaces laboratory has opened that allows medical, engineering and physics researchers to collaborate on projects.

“Patients everywhere already benefit from the work of engineers and physicians working together, but closer cooperation will bring even greater potential to develop new devices and technologies to improve human health, while training students in a collaborative environment that maximizes exposure to both fields,” said James O. Woolliscroft, M.D., dean of the Medical School and Lyle C. Roll Professor of Medicine.
U-M provost Phil Hanlon notes, “The new department will enhance partnerships between educational programs, laboratory research and clinical medicine, leveraging the strengths of both schools and accelerating technology development.”

Noll said U-M joins about 10 other institutions across the country with similar joint set-ups, though each case is unique. In some instances, two universities collaborate to form a joint department. At Michigan, the schools are across the road from one another, and they are both ranked in U.S. News & World Report’s top ten, as is the Biomedical Engineering Department.

For more information:
Department of Biomedical Engineering: http://www.bme.umich.edu/
College of Engineering: http://www.engin.umich.edu/
Medical School: http://www.med.umich.edu/medschool/

Contacts: Kara Gavin, 734-764-2220, kevagin@umich.edu
Nicole Casal Moore, 734-647-7087, ncmoore@umich.edu

Tags: BME, engineering, Joint Department, Medical School, Top-ranked
Posted in All News, Faculty News, Spotlight