The use of endovascular bioprostheses or vascular stents is currently limited by two host responses, acute thrombotic occlusion and reparative processes following vessel wall injury that result in progressive intimal thickening and luminal obstruction. The central objective of the research program proposed in this application is to improve the biological characteristics of endovascular bioprostheses. We propose a multidisciplinary approach which attacks this problem in two general ways. First, we propose to fabricate stents with mechanical properties suitable for both surgical and catheter-based insertion from biodegradable polymers in a manner which i) permits control of porosity and hydration capacity to render them suitable for delivery of recombinant, replication-defective adenoviruses, and ii) incorporates chemical modifications which enhance endothelial attachment and thus may enhance the rate of re- endothelialization following implantation. Secondly, we propose to employ these devices as vehicles for the local delivery of recombinant adenovirus vectors to achieve local genetic modification of cells resident in the vessel wall. We intend to overexpress proteins which may enhance reendothelialization, retard smooth muscle cell proliferation, increase local fibrinolytic potential or augment the antithrombotic activity of the endothelium in a local vascular segment, and to evaluate the biological efficacy of these interventions in porcine femoral and coronary artery models. If successful, the development of vascular prostheses with i) enhanced intrinsic biocompatability, and ii) the capacity to serve as delivery vehicles for targeted gene therapy, should have broad application to both surgical and catheter-based revascularization in many circulatory beds.
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