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

项目摘要/摘要 经过几十年的研究，理想的无血栓和抗菌表面仍有待确定和 仍然是一个悬而未决的问题。血液与物质的相互作用是植入式医疗成功的关键 起搏器电气导线的绝缘材料，包括简单导管、支架和移植物 和除颤器，以及复杂的体外人造器官，每年都有成千上万的患者使用这些设备 天。血液接触材料的临床应用有两个主要限制因素：1)血小板 激活和血栓形成；2)感染。 在过去的五年里，我们已经证明了表面一氧化氮(NO)的释放可以防止血小板 激活和细菌感染。这项技术是基于这样一个事实，即正常情况下没有分泌 内皮细胞通过阻止血小板黏附和激活来防止凝血。此外，没有在 鼻窦腔、中性粒细胞和巨噬细胞是一种有效的天然抗菌剂和抗病毒药物。 探员。最近我们发现，NO释放的所有积极效应都可以从聚合物中实现 掺入无毒、价廉的NO供体分子S-亚硝基-N-乙酰青霉胺， 而且很容易合成。一氧化氮的单独释放可以抑制聚合物/血液中的局部血小板功能 但它不能阻止纤维蛋白的形成，纤维蛋白在血栓形成中起着关键作用。阿加曲班是一家 直接凝血酶抑制物，可防止纤维蛋白形成。阿加曲班是人工合成的，容易获得，不会过敏， FDA批准静脉给药。最近，我们还表明，将 凝血酶抑制剂阿加曲班到NO释放表面，在4小时内保存血小板并减少血栓形成 动物模型明显优于单纯NO释放表面。这项提议的目标是 开发、优化和评估一种新型聚合物涂层，该涂层将结合抑制血小板的药物 通过释放NO进行黏附和活化，以及使用固定化的 阿加曲班。新的涂层将适用于任何血液接触设备；然而，这项提议将 重点研究长期(长达30d)血管内应用NO释放和阿加曲班的联合作用 导管型装置。

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.