Project Summary/Abstract The major limiting factors to clinical applications of blood-contacting materials, ranging from small catheters to large extracorporeal circulation (ECC) devices, include platelet activation leading to thrombosis and infection. Thrombus formation can further lead to obstruction of blood vessels, device malfunction, or even life-threatening situations such as embolism. Systemic anticoagulation is required to prevent clotting in the devices; however, one of the resulting major complications of this is bleeding. During the COVID-19 pandemic, extracorporeal membrane oxygenation (ECMO) has received critical attention as a therapy for patients where mechanical ventilation alone is ineffective. Significant challenges remain due to the increased risks of thrombosis in the circuitry that can be further exacerbated by hypercoagulable blood exhibited by COVID-19 patients. Therefore, there is an urgent necessity and opportunity to combine strategies for preventing thrombosis and infection into multifunctional device coatings for enhanced patency and safety. Our work and others have demonstrated that nitric oxide (NO) release from polymers prevent platelets activation and infection. This technology mimics the vascular endothelial cells lining the blood vessels, as well as other cells in our bodies, producing NO locally to prevent clotting and bacterial biofilm and subsequent infections. Recently we discovered that all of the positive effects can be achieved from polymers physically blended with the NO donor molecule S-nitroso-N-acetylpenicillamine (SNAP), which is nontoxic, inexpensive, and easy to synthesize. Active NO release from the NO donor functionalities in the polymer reduces thrombosis and bacterial infection polymer-blood interface; however, the NO-release strategy alone is limited by the finite reservoir of NO donor functionalities within the polymer that limit the duration of the NO availability at the polymer-blood interface. Our recent work has shown the potential of combining active NO-release with catalytic NO-generating mechanism in a single polymer. The goal of this proposal is to develop a polymer comprised of a NO donor covalently bonded to the polymer to provide active NO-release (without leaching) in combination with immobilized selenocystamine moieties to provide long-term NO-generation. This polymer will combine NO-release and NO-generating strategies for the first time, resulting in a new generation of polymers that possess potent broad-spectrum antimicrobial properties and reduce thrombosis by inhibiting platelet adhesion/activation. The new polymers will be applicable to any blood-contacting device; however, this proposal will focus on studying the combined NO-releasing/NO-generating strategy in vitro for antimicrobial properties and in a rabbit extracorporeal circulation model for prevention of thrombosis. Successful completion of this project will allow progression to early clinical trials and development ...