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

项目总结/文摘

Project Summary/Abstract Currently, clinical applications of intravascular catheters suffer from major challenges: 1) platelet activation and surface-induced thrombosis, 2) biofouling of surfaces with proteins and bacteria, and 3) infection. Thrombus formation can further lead to obstruction of blood vessels, catheter malfunction, or even life-threatening situations such as embolism. Bacterial contamination of catheters causes more than 28,000 deaths per year in the United States, as well as costing the healthcare industry a staggering $2.3 billion. Commercial catheters with heparin- bonded surfaces are available to prevent clotting, but do little to prevent infections. In additions, catheters coated with antiseptics or antibiotics decrease the risk of bacterial infection, but do not prevent biofilm formation that shields bacteria from antibiotics. Therefore, there is a necessity and opportunity to combine strategies for preventing thrombosis and infection into single implantable device coatings for enhanced patency and safety. Our work and others have demonstrated that nitric oxide (NO) release from polymer surfaces can prevent platelet activation and bacterial 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 impregnated 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 and inability to prevent fibrin formation on the surface. 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 impregnated in the polymer to provide active NO-release in combination with immobilized selenocystamine-heparin moieties to provide long-term NO- generation and resist fibrin formation, 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, catalytic NO generation, and immobilized heparin strategy in long-term (up to 30 d) intravascular catheters on clotting and infection. Successful completion of this project will allow progression to early clinical trials and development of a new generation of catheters that can reduce complications while improving the success of patient care.