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

项目摘要/摘要 目前，血管内导管的临床应用面临着主要挑战：1)血小板活化和 表面诱导的血栓形成，2)表面蛋白质和细菌的生物污损，以及3)感染。血栓 形成可进一步导致血管阻塞、导管故障，甚至危及生命的情况 比如栓塞症。在美国，导管的细菌污染每年导致超过2.8万人死亡 各州，以及医疗保健行业损失了惊人的23亿美元。使用肝素的商用导管- 粘合表面可以防止凝血，但对预防感染作用很小。此外，导管被涂上了 使用防腐剂或抗生素可降低细菌感染的风险，但不能防止生物被膜的形成 保护细菌免受抗生素的侵害。因此，有必要也有机会将战略结合起来，以 防止血栓形成和感染进入单一的植入性设备涂层，以增强通透性和安全性。 我们和其他人的工作已经证明，从聚合物表面释放的一氧化氮(NO)可以防止血小板 激活和细菌感染。这项技术模拟血管内皮细胞衬里血管， 以及我们体内的其他细胞，局部不产生任何物质来防止凝血和细菌生物膜以及随后的 感染。最近我们发现，所有的积极作用都可以通过浸渍聚合物来实现。 与NO供体分子S-亚硝基-N-乙酰青霉胺(SNAP)，无毒，廉价，容易 来合成。聚合物中NO供体官能团的活性NO释放可减少血栓形成和 细菌感染聚合物-血液界面；然而，NO释放策略本身受到有限的限制 聚合物内的NO给体官能团的储存库，其限制了在聚合物处NO可用性的持续时间- 血液界面和无法阻止表面纤维蛋白的形成。我们最近的工作显示了这种潜力 将活性NO释放和催化NO生成机制结合在单一聚合物中。这样做的目的是 建议开发一种由NO供体组成的聚合物，浸渍在聚合物中以提供活性 NO的释放与固定化的硒半胱胺-肝素部分相结合，提供长期的NO- 产生并阻止纤维蛋白的形成，导致新一代聚合物具有强大的 广谱抗菌性能和通过抑制血小板减少血栓形成 黏附/活化。新的聚合物将适用于任何血液接触设备；然而，这 提案将重点研究NO释放、催化NO生成和固定化肝素的组合 长期(长达30天)血管内导管对凝血和感染的防治策略。成功完成这项工作 该项目将使早期临床试验和开发新一代导管能够 减少并发症，同时提高患者护理的成功率。

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.