There is no small-diameter (< 5mm internal diameter) vascular prosthesis approved for clinical use in small vessel reconstruction. Current prostheses are not capable of emulating the biological and physical properties of the normal arterial wall, resulting in high failure rates. In phase I, a nanofibrous biocomposite small-diameter vascular graft comprised of Dacron and Type IV collagen (ESDC) was synthesized, with kinkresistance created within the graft structure. This novel thin-walled graft had minimal water permeation and excellent physical properties. The potent antithrombin agent recombinant hirudin (rHir) and endothelial cellspecific mitogen Vascular Endothelial Growth Factor (VEGF) were then covalently bound to the ESDC surface (ESDC-rHir-VEGF). These surface bound agents were biologically active as determined via specific in vitro assays and showed stability under simulated arterial flow conditions. Lastly, the ESDC graft showed excellent handling characteristics when implanted into a canine femoral artery in a preliminary in vivo evaluation of the graft. The goal of this Phase II proposal is to assess blood permeation and graft patency/healing of the ESDC-rHir-VEGF graft using a canine arterial grafting model. Our hypothesis is that the next generation of prosthetic arterial grafts will have to possess multiple structural and biological properties that mimic some of those processes inherent to native arteries in order to prevent complications such as thrombosis from occurring. The specific objectives of Phase II are to: 1) synthesize ESDC vascular grafts for implantation studies, 2) develop an automated graft synthesis process, 3) evaluate physical and chemical properties of the ESDC graft, 4) covalently immobilize rHir and VEGF to ESDC surface, 5) assess in vivo acute and chronic implantation periods, and 6) examine macroscopically/microscopically explanted grafts. Phase III of this project will continue long-term assessment of this novel ESDC-rHir-VEGF graft in the canine femoral arterial grafting model employed in Phase II. Development of a bioactive small-diameter vascular graft would have a significant impact on small vessel repair and replacement. These grafts could be utilized in peripheral bypass as well as for coronary artery bypass, which have some 500,000 grafts implanted annually in the United States. Potentially, the annual market value for an """"""""off-the-shelf"""""""" synthetic arterial bypass graft could exceed $1.5 billion.
