Engineering nitric oxide releasing polymer with immobilized thrombin inhibitor for blood contacting applications

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Project Summary/Abstract After decades of research, an ideal non-thrombogenic and antibacterial surface is still yet to be identified and remains an unsolved problem. Blood-material interactions are critical to the success of implantable medical devices including simple catheters, stents and grafts, insulation materials for electrical leads of pacemakers and defibrillators, and complex extracorporeal artificial organs, which are used in thousands of patients every day. There are two major limiting factors to clinical application of blood contacting materials: 1) platelet activation and thrombosis, and 2) infection. Over the last five years we have demonstrated that surface nitric oxide (NO) release can prevent platelet activation and bacterial infection. This technology is based on the fact that NO secretion by the normal endothelium prevents clotting by preventing platelet adhesion and activation. Further, NO released within the sinus cavities, and by neutrophils and macrophages, functions as a potent natural antimicrobial and antiviral agent. Recently we discovered that all of the positive effects of NO release can be achieved from polymers doped with the NO donor molecule S-nitroso-N-acetylpenicillamine (SNAP), which is nontoxic, inexpensive, and easy to synthesize. Nitric oxide release alone can inhibit platelet function locally at the polymer/blood interface, but it does not prevent fibrin formation, which plays a key role in a clot formation. Argatroban is a direct thrombin inhibitor that prevents fibrin formation. Argatroban is synthetic, easily available, non-allergenic, and FDA approved for intravenous administration. Recently we have also shown that immobilizing the thrombin inhibitor, argatroban, to NO-releasing surfaces preserves platelets and reduces clot formation in a 4 h animal model significantly better than the NO-releasing surfaces alone. The goal of this proposal is to develop, optimize, and evaluate a novel polymer coating that will combine agents that inhibit platelet adhesion and activation via NO release as well as inhibit the fibrin formation using the immobilized argatroban. The new coatings will be applicable to any blood-contacting device; however, this proposal will focus on studying the combined effect of NO release and argatroban in long-term (up to 30 d) intravascular catheter-type devices.