Atherosclerotic vascular disease, in the form of coronary artery and peripheral vascular disease, is the leading cause of mortality in the United States. Despite vast improvements in the field of biomaterials, a useful biocompatible material is still not available for the production of small vascular grafts largely because of blood clotting/thrombosis. To overcome this problem, Dr. David B. Masters, Gel-Del Technologies, Inc., has developed a patented fabrication process that uses purified proteins, water, and other biochemicals to produce biomimetic material in the shape of tubes that can mimic the wall structure of blood vessels (Gel-Del VasoGraft(tm)). Type I collagen and elastin proteins, along with the anti-clotting factor, heparin, are processed together and coated onto a cotton mesh scaffolding to create a tubular conduit (VasoGraft(tm)). Completed SBIR Phase I studies demonstrate excellent bio- and hemocompatibility, anti-clotting, and host tissue integration and in vivo patency out to at least 32 days in a porcine femoral artery model. While the lumen within the graft itself remained open, significant intimal hyperplasia occurred at the anastomosis sites, suggesting that the surgical injury created an adverse repair response. Because the graft itself functioned well, it is hypothesized that reduction of the anastomotic intimal hyperplasia will allow greater long term function and patency. The studies proposed within this Phase II application will utilize the proven Bravo(tm) Drug Delivery Polymer system from Surmodics, Inc., currently utilized in the Cypher(tm) drug (Sirolimus)- eluting stent (produced by Cordis, Inc.), to release Sirolimus, an inhibitor of smooth muscle cell proliferation, from the ends of the VasoGraft, creating VasoGraft-S(tm). In vitro studies will analyze the release kinetics and bioactivity of Sirolimus released from these VasoGraft-S(tm) constructs, and long-term porcine studies will test its function in vivo out to 300 days, with the ultimate goal of developing the VasoGraft-S(tm) for human trials. These studies will be executed as follows:
Aim 1 : Measure the release kinetics of different doses of Sirolimus(tm) from VasoGraft(tm) in vitro to determine optimal drug incorporation strategy;
Aim 2 : Assess optimal dose of Sirolimus(tm) for reducing stenosis in 30 and 60 day porcine femoral artery grafts;
and Aim 3 : Evaluate the patency rates of Gel-Del Vasograft(tm) with Sirolimus(tm) release in long term (i.e., 120 and 300 day) porcine femoral artery grafts. ? ?
