Over 60,000 prosthetic grafts, which are comprised of either polyethylene terephthalate (polyester) or expanded polytetrafluoroethylene (ePTFE), are implanted in the United States each year. Medium (6-8mm) and small (<5mm) internal diameter (I.D.) prosthetic arterial grafts continue to have unacceptably high failure rates when used in the clinical setting. The two major complications associated with these grafts are acute thromboses and incomplete, unregulated cellular healing. The goal of this Phase I STTR grant is to develop in vitro a novel polyester vascular graft with a bioactive surface. Our hypothesis is covalent immobilization of Activated Protein C (APC), a natural anticoagulant, onto a functionalized polyester vascular graft surface will prevent surface thrombus formation via renewably inactivating FVa and FVIIIa and by preventing platelet activation. Additionally, surface bound APC would promote adherence of EPCR positive cells circulating in the blood to the polyester graft surface through a highly specific, high affinity ligand-receptor binding reaction and signal graft-adherent cells or cells from adjacent endothelium to proliferate and migrate on the surface. The specific objectives of this study are to: 1) optimize surface functional groups on the modified polyester (EDA) graft surface and immobilize APC, 2) evaluate the biostability of surface bound APC and 3) biological testing of surface immobilized APC. Development of a bioactive polyester vascular graft that would provide localized surface antithrombin properties and stimulate endothelial cell specific attachment would have a significant impact on vessel repair and replacement. These grafts could be utilized in peripheral bypass (specifically below-knee) as well as for coronary artery bypass, in which there are over 500,000 bypass grafts implanted annually in the United States. Thus, the potential annual market value for an off-the-shelf bioactive synthetic arterial bypass graft could exceed $1.5 billion. In Phase II of this proposal, EDA-APC grafts (6mm internal diameter) with covalently bound APC will undergo acute and chronic evaluation in a canine bilateral carotid grafting model in order to assess long-term patency and overall healing characteristics. ? ? ?
