IMPACT

Research at the University of Virginia School of Engineering & Applied Science

Volume 11 Number 1

fall 2010

Engineering a Healthier World

Developing Leaders of Innovation

IMPACT

Research at the U.Va. Engineering School

Contents

Healthy Innovations T

3 4 6 8

Reducing Death and Injury on Our Highways Innovations in Biomedical Engineering Medical Research Across the School Exploring Treatments for Alzheimers Disease

On the cover: The Center for Applied Biomechanics uses a variety of test dummies to measure the effects of side and front impacts on drivers and passengers.

Writer and Editor Charlie Feigenoff Contributing Editors Josie Pipkin Zak Richards Graphic Design Travis Searcy Mountain High Media Photography Tom Cogill
IMPACT is published by the University of Virginia School of Engineering and Applied Science. An online version of the magazine is available at www.seas.virginia.edu/impact.

he faculty members at the School of Engineering and Applied Science conduct research not simply because they are driven to figure out how things work, but also because they are determined to harness that knowledge for the good of humanity. There is no more direct way to help others than to improve their health and for faculty researchers that means focusing on how the human body works. In laboratories around the School, faculty members are learning how the body responds to the trauma of injury so they can devise better safety systems for automobiles. They are improving on the bodys own mechanisms for healing, helping surgeons mend bones and reconnect nerves more efficiently. And they are learning how cells and tissues function, so they can develop ways to halt the progress of diseases like cancer, diabetes and Alzheimers. Health-related research is the primary focus of the Department of Biomedical Engineering, but there are groundbreaking programs in virtually every department in the School. The Engineering School faculty almost doubled its research funding from the National Institutes of Health in fiscal year 2010. We could not have achieved these gains on our own. What makes these programs successful is our close partnership with the School of Medicine. The Department of Biomedical Engineering is a joint program of our two schools, but a significant number of our faculty have joint appointments in departments like emergency medicine or orthopaedic surgery. We understand that the road to innovation in the 21st century lies on the border between disciplines.

Address corrections should be sent to the University of Virginia School of Engineering and Applied Science, P.O. Box 400259, Charlottesville, VA 22904-4259, or call 434-924-1383.

Barry W. Johnson
Senior Associate Dean Associate Dean for Research U.Va. School of Engineering and Applied Science
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Center researchers (L to R) Jeff Crandall, Costin Untaroiu and Richard Kent are shown with Buster, a biofidelic sideimpact test dummy.

REDUCING HIGHWAY FATALITIES I

n 2009 the National Highway Traffic Safety Administration reported 33,000 motor vehicle deaths, the lowest since it began counting more than three decades ago. Researchers at the Engineering Schools Center for Applied Biomechanics are determined to reduce that figure even further and they have the expertise, facilities and record of achievement to play a leading role in this effort. Since it was founded 21 years ago, the center has grown dramatically, thanks to support from the Engineering School and the School of Medicine. It currently has 30 full-time researchers and 20 graduate students and is poised to expand further. It just moved to a new building at the University Research Park, giving it 25,000 square feet of laboratory and office space. The center is now the largest University-based impact biomechanics laboratory in the world. The highlight of the new facility is a second state-of-the-art sled system, this one designed to analyze the vehicle rollovers that account for one-third of all highway fatalities. The centers sleds are highly instrumented. During a typical crash test, researchers can collect 10,000 data points every second from each of 250 to 300 channels of information. We film at more than 1,000 frames a

second and can track the motion of a person during an impact with submillimeter resolution, says Jeff Crandall, the centers director and a professor in the Departments of Mechanical and Aerospace Engineering, Biomedical Engineering, and Emergency Medicine. The center currently has projects under way in virtually every area needed to reduce traffic fatalities and injuries. It is helping to develop more accurate criteria for preventing lower extremity and thoracic injury, testing advanced vehicle passenger restraint systems and studying the biomechanics of aging as part of the Engineering Crash Injury Research and Engineering Network. It is a partner in the Global Human Body Modeling Consortium and is also evaluating next-generation crash dummies. Many of the injuries that occur during a crash inevitably are fatal, notes Richard Kent, a professor in the Departments of Mechanical and Aerospace Engineering and Emergency Medicine and the leader of the Automobile Safety Research Group at the center. The only way to treat them is to prevent them. Thats what this center does.
READ MORE: www.centerforappliedbiomechanics.org/

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innovations in biomedical engineering

Edward Botchwey is developing new techniques to amplify and manage natural processes to mend shattered bones and reconnect severed nerves.

Engineering Healing
As Edward Botchwey sees it, the human body is like a promising undergraduate. It needs a little assistance to help reach its potential. Although the body has the means to heal wounds, Ive never been truly happy with the time it takes or, in many cases, the results, he says. My goal is to find ways to more effectively engineer healing.
Botchwey, an associate professor of biomedical engineering and orthopaedic surgery, specializes in the musculoskeletal tissue, which includes muscles, tendons, bones and nerves. One area in which he thinks the body could do better is bone. When someone shatters a bone, surgeons take bone from a tissue bank and use it to piece together the fragments. Although this bone allograft has many of the biological components needed for bone healing, it is poorly vascularized, Botchwey notes. This sometimes causes the allograft to crack and fail, which inevitably means additional surgery. Working with graduate student Cynthia Juang, he coats the allograft with a synthetic, degradable polymer. The polymer releases a drug that targets S1P receptors in the bone tissue, which when activated will promote vascularization, enhance integration with host bone and remodel the allograft.
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Botchwey is also developing new techniques to promote healing of peripheral nerves, bundles of nerve fibers that carry information to and from the spinal cord. When these nerves are severed, surgeons can repair them by delicately stitching together the ends. If they have to stretch them, however, the outcome is usually poor. With Botchweys guidance, graduate student Rebekah Neal has developed a completely novel method of connecting them without strain. She turned to a process called electrospinning to produce nanoscale fibers that combine a biodegradable polymer with collagen and laminin, two substances necessary for nerve growth. The fibers serve as a scaffold connecting the nerve endings, and the laminin encourages the nerve cells on each side of the severed nerve to grow toward the target organ.
READ MORE: www.bme.virginia.edu/lct/
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Over the past 18 months, Kevin Janes research has attracted more than $2.9 million in funding.

a knock-out combination for cancer

The new kinase assay system that Karin Holmberg (pictured above) is developing will be put to use immediately, thanks to her collaboration with Michael Weber, a professor of microbiology and director of the U.Va. Cancer Center. Weber is developing treatments for melanoma, a deadly form of skin cancer in which kinase signaling is often deregulated. He has found that certain combinations of drugs have an effect on melanoma cells that is greater than the sum of their individual effects, but he is not sure why. The assay were developing can track the activity of multiple kinases at the same time, Holmberg says. It will provide the data we need to understand cell signaling at the network level, helping us understand why certain drug combinations are synergistic. This knowledge will help us choose drug combinations that will inhibit the growth of melanoma cells even more efficiently.

decoding the language of

cell signaling

ne way to describe a human cell is as a very sophisticated circuit board. It constantly receives inputs from the world around it and processes them into chemical or electrical signals that generate cellular outputs. Depending on what is happening in a cells microenvironment, these signals might cause the cell to migrate, divide, or differentiate into another cell type. This information processing, called signal transduction, is the theme of Kevin Janes laboratory. In recent years scientists have made great progress understanding how each individual circuit works. The next challenge is to understand what happens when clusters of circuits are activated, as is typically the case. We dont really understand how pathways work together on a systems level, Janes says. Its a problem that engineers are ideally suited to solve. One roadblock is that existing methods of analyzing the activities of groups of pathways are slow and cumbersome and permit only a general qualitative assessment. Working with graduate student Karin Holmberg, Janes is designing a bioassay that is more efficient at producing quantitative results. He is focusing on circuits that use kinase and phosphatase enzymes, because these chemical signals often lose their regulation and get stuck on or off in cancer and in inflammatory diseases like atherosclerosis and rheumatoid arthritis. By combining our knowledge of enzyme biochemistry with newly introduced instrumentation, we are developing a much more sensitive, high-throughput method to quantitatively analyze samples for half a dozen kinases at a time, he says.
READ MORE: www.bme.virginia.edu/janes/
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medical research across the school

AUTOMATING DIABETES TREATMENT

ticking yourself with a lancet is no fun, yet thats exactly what people with Type 1 diabetes have to do four or more times a day. Because their bodies have lost the ability to produce insulin, they have to continually monitor their blood sugar and inject the hormone when blood sugar levels rise too high. While the technology for doing this has become much more convenient there are now glucose monitors that help people interpret these pinpricks and insulin pumps that replace syringes these blood sugar snapshots provide only a rough assessment of a persons insulin needs. As Stephen Patek, an associate professor of systems engineering, notes, There are thousands of small events during the day from eating a doughnut with your 10 oclock coffee to going for a jog that can cause dramatic swings in blood sugar levels. Patek is part of a multidisciplinary international team that is developing an automatic continuous system for blood sugar control. Their challenge is to develop algorithms that take all these daily variables into account. The ultimate goal of the team, which includes Professors Boris Kovatchev and Marc Breton from the School of Medicine, is to link glucose monitors with insulin pumps in a closedloop system they call the artificial pancreas. This research is funded by the Juvenile Diabetes Research Foundation, the National Institutes of Health, the National Science Foundation and industry groups. Pateks specialties include the optimization of random events, but the consequences of eating a meal are hardly random. Food ingestion will always elevate blood sugar levels, just as exercise lowers them. Typical models used to describe random disturbances dont work for people, he notes. Another issue is the lag-time of up to 45 minutes associated with using the continuous glucose monitor and the insulin pump. It takes time for the changes in the blood to reach the fluids that the monitor samples, and it takes even more time for insulin delivered by the pump under the skin to reach the bloodstream. Patek is building mathematical models that enable him to bridge that gap. This is a fascinating project to be involved with, Patek says. The path to having a positive impact on peoples lives is commercialization, but its a complicated process.
READ MORE: http://web.sys.virginia.edu/stephen-d-patek.html
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Stephen Patek is contributing his systems engineering expertise to a global effort that one day will make the artificial pancreas a reality.

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the geometry of

muscle strain

hether you can sprint 100 meters in 9.8 seconds like the Olympic gold medalist Usain Bolt or are content to run a few laps around the track after work, you are likely to experience a hamstring strain sooner or later. Silvia Salinas Blemker, an assistant professor in the Departments of Mechanical and Aerospace Engineering and Biomedical Engineering, is taking a fresh look at why certain muscles like hamstrings are particularly prone to injury. The hamstrings run along the back of the thigh and attach on both sides of the knee joint. They are responsible for pulling the foot from the ground with each stride. Traditionally, researchers treat them like anatomical rubber bands, uniformly elastic along their length. Blemker is taking a closer look, relating muscle structure to its mechanical properties and ultimately to its function.

the shape of your muscles

When you take a really close look at muscle and graduate student Bahar Sharafi (pictured above) has you start noticing a variety of different tissue geometries. Sharafis challenge has been to create three-dimensional computational models that link a muscles microscopic morphology and properties to muscle function. For instance, using modeling, she has found that the shape of its fascicles, or bundles of muscle fibers or cells, gives a muscle its ability to adapt to the sheer forces that act on it. Different fascicle shapes are more appropriate for different sheer forces and are found in different muscles. She is also studying the mechanics of the myotendinous junction, the point of insertion of muscle fibers into the tendon, to explore the mechanisms that contribute to a high rate of injury in this region. Sharafi came to her research without any knowledge of biomechanics and muscle anatomy. Ive found it fascinating to apply the principles of mechanical engineering to the human body, she says.

Recreational athletes and Olympians alike may suffer fewer muscle strains in the future, thanks to research on muscle geometry by Silvia Blemker.

To determine if aponeuroses width is an important factor in injury, Blemker proposes to take magnetic resonance images of members of a sports team at the beginning of their season and then track them to see if people with narrow aponeuroses do indeed become injured more often.
READ MORE: www.mae.virginia.edu/muscle/
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Blemkers work combines computation with magnetic resonance imaging and anatomical measurements. The goal is to create a computational model of the musculoskeletal system that incorporates its complex three-dimensional architecture and geometry. In the process, she has discovered a significant marker for injury susceptibility that could be applied to all muscles. Tendons are embedded in muscle to provide a firmer attachment. These internal tendons, which vary in width, length and thickness, are called aponeuroses. Blemker found that strains occur in muscle tissues adjacent to narrow aponeuroses.

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University of Virginia Office of the Dean School of Engineering and Applied Science P .O. Box 400246 Charlottesville, VA 22904-4246 www.seas.virginia.edu/impact

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Alzheimers Disease

disrupting the Biochemistry of

Inchan Kwon is searching for a substance that could prevent the formation of amyloid plaques, a characteristic of Alzheimers disease.

nchan Kwon, an assistant professor of chemical engineering, takes the old DuPont advertising slogan Better Living through Chemistry quite literally. He is combining his expertise as a chemical engineer and his knowledge of proteins, honed in industry and university research labs, to cure neurodegenerative diseases. He is particularly interested in Alzheimers disease. One theory for the cause of the disease places the blame on a peptide called amyloid-beta. Peptides, like proteins, consist of a chain of amino acids. Individually, amyloid-beta peptides are harmless, but when they clump together they disrupt communication between neurons and cause them to die. Finding a substance that could modulate amyloid-beta aggregation is a promising strategy for preventing or treating Alzheimers, Kwon says. Kwon is screening small molecules already approved by the FDA and other peptides to search for compounds that could modulate amyloid-beta aggregation safely and effectively. He has identified a number of promising molecules and is applying to the National Institutes of Health for funding to fine-tune the characteristics of these molecules and to conduct animal studies. His research on peptides has been similarly productive. We still need to do more testing, he says, but we are hopeful that we will be able to make a difference.

READ MORE: www.faculty.virginia.edu/kwon/