 | | | (Reprinted with permission from the Fall 2007 issue of Ward Rounds, the quarterly magazine of Northwestern University's Feinberg School of Medicine, article written by Michael Nyquist) Senyei Award winner Samuel I. Stupp, PhD, is applying nanotechnology to repair the damage caused by heart attacks. “Our work aims to improve the outcome after myocardial infarction by inducing revascularization in the ischemic tissue,” says Dr. Stupp, Board of Trustees Professor of Materials Science, Chemistry, and Medicine and director of the Institute for BioNanotechnolgy in Medicine. “Heart muscle dies because the blood supply is compromised. By jumpstarting angiogenesis—the growth of new blood vessels—we can rescue, or if we are very optimistic, regenerate, the myocardium.” Dr. Stupp’s lab team developed synthetic molecules that self-assemble into a tubular nanostructure displaying heparin molecules on its outer surface. “Heparin is one of many sulfated polysaccharides that exist in the human body’s extracellular space,” he explains. “Important proteins, such as growth factors responsible for either differentiation or proliferation of cells, have heparin binding domains. When these growth factors bind to heparin on the nanostructure, they are oriented in a way that increases their signaling capacity.” The system uses a “cocktail” of the synthetic molecules, heparin, and growth factors injected into the target tissue. The heparin combined with electrolytes in the tissue triggers the self-assembly of the nanostructures, providing a stable substrate binding both the injected proteins and those present in the tissue. “Self-assembly occurs in seconds to minutes, freezing the proteins in place,” says Dr. Stupp. “Binding to heparin also protects them from the normal enzymatic degradation that occurs when they are free floating. It’s a way of efficiently using the proteins already there. For example, if you tried to use angiogenic growth factors as a therapy, you would need such a massive quantity of them that the therapy would be unaffordable and infeasible. Our system uses only nanoquantities of them.” Earlier research showed that within seven days of injecting the cocktail into a rat cornea, blood vessels appeared. Other in vitro experiments showed the nanotechnology system promoted the formation of endothelial cells into tube-like structures, the precursors to blood vessels.  | New blood vessel growth
Dr. Sam Stupp developed synthetic molecules that self-assemble into nanotubes displaying heparin on their surfaces. Angiogenic growth factors bind to the heparin oriented in a way that increases their signaling capacity. The growth of new blood vessels in the rat cornea (above, left) induced by his system far outstrips that induced by growth factors alone (right). |
In the first animal studies, Dr. Stupp collaborated with Jon W. Lomasney, MD, associate professor of pathology, using a mouse model of myocardial infarction. “We inject the cocktail directly into the myocardium,” explains Dr. Stupp. “Thirty days later, we went in with a catheter to measure the left ventricular contractility of the heart, which showed distinct improvement.” However, he continues, “We don’t have clear evidence yet of new blood vessel growth. In the heart it is much more difficult to visualize new growth because so many blood vessels already exist, whereas in the cornea none exist, so you see new blood vessels easily. It may be that our system has effects that we have not anticipated that account for the tremendous improvement in heart function.” For example, certain proteins critical to cell survival bind to heparin, such as fibronectin, which is involved in tissue repair, blood clotting, and cell migration and adhesion. In another mouse experiment, Dr. Lomasney created a model of peripheral ischemia in the leg. Says Dr. Stupp, “We injected our cocktail into four spots in the leg muscle, then quantified the angiogenic response using angiography. We clearly saw that branches had sprouted.” Advanced peripheral arterial disease in humans can lead to lower-leg amputations. The next step is implementing the system in a pig model. Dr. Stupp and co-investigators Nirat Beohar, MD, assistant professor of medicine, and Charles J. Davidson, MD, professor of medicine, both interventional cardiologists, developed a protocol for injecting the system into heart muscle via a catheter threaded through the femoral artery. “This is closer to what would happen in humans,” notes Dr. Stupp. “We induce an infarct, then verify the ischemia in the myocardium using magnetic resonance imaging. We’re determining the right amount of protein to use in this animal model to achieve the same therapeutic effects we saw in the mouse.” Dr. Stupp will collaborate with William H. Pearce, MD, Violet and Charles Baldwin Professor of Vascular Surgery and chief of the Division of Vascular Surgery, once the evidence for safety and efficacy is strong enough to warrant moving into human clinical trials. | |
