We will develop a thromboresistant, small diameter prosthetic arterial graft for use in the clinical setting. Currently there are no acceptable prostheses which can be utilized for vascular repair or replacement in situations which require a conduit with an internal diameter of less that 4mm due to prompt thrombosis.The research objectives to be accomplished in Phase I are1) chemical modification of a urethane-based polymer;2) immobilization of the potent, thrombin-specific anticoagulant hirudin to the modified biomaterial;3) determination of surface reactivity.The polyurethane graft surface will be modified such that carboxyl or amine groups will be present on the surface without varying the biostability of the polymer. Recombinant hirudin will then be immobilized on the graft surface. The amount of recombinant hirudin bound to the surface will be evaluated and there will be studies on binding optimization. The immobilized recombinant hirudin will be assayed for surface biologic activity using static and flow conditions. Static assay will focus on surface thrombin inhibition, thrombin release pharmacokinetics, and in vitro clotting times of bound recombinant hirudin. In vitro flow assays will be utilized to evaluate immobilized recombinant hirudin's thrombin binding and structural stability as well as blood protein deposition on the material surface. The mechanical characteristics of the novel biomaterial will also be determined.National Heart, Lung, and Blood Institute (NHLBI)
