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

项目总结/摘要 经过几十年的研究，理想的非血栓形成和抗菌表面仍有待确定， 仍然是一个未解决的问题。血液-材料相互作用对于植入式医疗器械的成功至关重要。 包括简单导管、支架和移植物在内的器械，起搏器电导线的绝缘材料 以及复杂的体外人造器官，这些器官每年都被用于成千上万的病人。 天血液接触材料临床应用的主要限制因素有两个：1）血小板 激活和血栓形成，和2）感染。 在过去的五年里，我们已经证明，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NO分泌正常 内皮通过防止血小板粘附和活化来防止凝血。此外，NO在 窦腔，中性粒细胞和巨噬细胞，作为一种有效的天然抗菌剂和抗病毒剂 剂最近，我们发现，NO释放的所有积极作用都可以从聚合物中实现 掺杂有NO供体分子S-亚硝基-N-乙酰青霉胺（SNAP），其无毒，廉价， 且易于合成。单独的一氧化氮释放可以抑制聚合物/血液中的血小板功能 界面，但它不能阻止纤维蛋白形成，这在凝块形成中起着关键作用。阿加曲班是一种 直接凝血酶抑制剂，防止纤维蛋白形成。阿加曲班是合成的，容易获得，无过敏性， 并且FDA批准用于静脉内施用。最近，我们还表明， 凝血酶抑制剂阿加曲班在4小时内保护血小板并减少凝块形成 动物模型显著优于单独的NO释放表面。本提案的目的是 开发、优化和评估一种新型聚合物涂层，该涂层将结合联合收割机抑制血小板的药物 粘附和激活通过NO释放以及抑制纤维蛋白形成使用固定化 阿加曲班新涂层将适用于任何血液接触器械;然而，该提案将 重点研究长期（长达30天）血管内NO释放和阿加曲班的联合作用 导管型器械。

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.