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

项目总结/摘要 目前，血管内导管的临床应用遭受主要挑战：1）血小板活化和血小板聚集。 表面诱导的血栓形成，2）蛋白质和细菌对表面的生物污染，以及3）感染。血栓 形成可进一步导致血管阻塞、导管故障或甚至危及生命的情况 例如栓塞。在美国，导管的细菌污染每年导致超过28，000人死亡 美国，以及成本医疗保健行业惊人的23亿美元。市售肝素导管- 粘合表面可用于防止凝血，但对防止感染作用不大。此外，涂层导管 使用防腐剂或抗生素可降低细菌感染的风险，但不能防止生物膜的形成， 保护细菌免受抗生素的侵害。因此，有必要和机会进行联合收割机战略， 防止血栓形成和感染到单个可植入装置涂层中，以增强开放性和安全性。 我们的工作和其他人已经证明，从聚合物表面释放的一氧化氮（NO）可以防止血小板聚集。 激活和细菌感染。这项技术模拟了血管内皮细胞， 以及我们体内的其他细胞，局部产生NO以防止凝血和细菌生物膜以及随后的 感染.最近，我们发现，所有的积极影响，可以实现从聚合物浸渍 与NO供体分子S-亚硝基-N-乙酰青霉胺（SNAP），这是无毒，廉价，容易 合成。聚合物中NO供体官能团的活性NO释放减少了血栓形成， 细菌感染聚合物-血液界面;然而，单独的NO释放策略受到有限的 - 聚合物内的NO供体官能团的储存器，其限制聚合物处的NO可用性的持续时间; 血液界面且无法防止表面形成纤维蛋白。我们最近的研究表明 在单一聚合物中结合活性NO释放和催化NO生成机制。这个目标 一个提议是开发一种聚合物，该聚合物包含浸渍在聚合物中的NO供体，以提供活性 NO-释放与固定的硒代胱氨酸-肝素部分组合以提供长期的NO- 产生并抵抗纤维蛋白形成，从而产生新一代聚合物， 广谱抗菌特性，通过抑制血小板减少血栓形成 粘附/活化。新的聚合物将适用于任何血液接触装置;然而， 建议将重点放在研究组合NO释放，催化NO生成和固定化肝素 长期（长达30天）血管内导管中凝血和感染的策略。成功完成本 该项目将允许进展到早期临床试验和新一代导管的开发， 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.