Heparin-free extracorporeal circulation via combined nitric oxide releasing/generating surfaces

项目总结/摘要 血液接触材料临床应用的主要限制因素，从小导管到 大型体外循环（ECC）装置，包括血小板活化导致血栓形成和感染。 血栓形成可进一步导致血管阻塞、器械故障，甚至危及生命 如栓塞。需要全身抗凝以防止器械内凝血;然而， 由此产生的主要并发症之一是出血。在COVID-19大流行期间，体外 膜肺氧合（ECMO）作为机械性肺损伤患者的治疗方法受到了广泛关注。 单独通风是无效的。由于血栓形成的风险增加， 这可能会因COVID-19患者表现出的高凝血液而进一步恶化。因此，我们认为， 迫切需要和机会将预防血栓形成和感染的联合收割机策略结合到 多功能器械涂层，增强通畅性和安全性。 我们的工作和其他人已经证明，一氧化氮（NO）从聚合物释放防止血小板活化 和感染这项技术模仿血管内皮细胞内衬的血管，以及其他 我们体内的细胞，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，所有的积极效果都可以从物理共混的聚合物中实现， 一氧化氮供体分子S-亚硝基-N-乙酰青霉胺（SNAP），无毒，廉价， 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和细菌感染。 感染聚合物-血液界面;然而，单独的NO释放策略受到NO的有限储存库的限制 聚合物内的供体官能团限制了NO在聚合物-血液界面处的可用性的持续时间。 我们最近的工作显示了结合活性NO释放和催化NO生成的潜力 在一个单一的聚合物的机制。该提案的目标是开发一种由NO供体组成的聚合物 与聚合物共价键合以提供活性NO释放（不浸出）， 固定的硒代胱胺部分以提供长期的NO生成。这种聚合物将联合收割机 第一次提出了释放NO和产生NO的策略，从而产生了新一代聚合物 其具有有效的广谱抗微生物特性，并通过抑制 血小板粘附/活化。新的聚合物将适用于任何血液接触装置;然而， 本文将重点研究体外NO释放/NO生成的联合策略， 性质和在兔体外循环模型中用于预防血栓形成。成功完成 这一项目的进展将允许早期临床试验和新一代体外循环的发展， 电路，可以减少并发症，同时提高病人护理的成功。

Project Summary/Abstract The major limiting factors to clinical applications of blood-contacting materials, ranging from small catheters to large extracorporeal circulation (ECC) devices, include platelet activation leading to thrombosis and infection. Thrombus formation can further lead to obstruction of blood vessels, device malfunction, or even life-threatening situations such as embolism. Systemic anticoagulation is required to prevent clotting in the devices; however, one of the resulting major complications of this is bleeding. During the COVID-19 pandemic, extracorporeal membrane oxygenation (ECMO) has received critical attention as a therapy for patients where mechanical ventilation alone is ineffective. Significant challenges remain due to the increased risks of thrombosis in the circuitry that can be further exacerbated by hypercoagulable blood exhibited by COVID-19 patients. Therefore, there is an urgent necessity and opportunity to combine strategies for preventing thrombosis and infection into multifunctional device coatings for enhanced patency and safety. Our work and others have demonstrated that nitric oxide (NO) release from polymers prevent platelets activation and 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 physically blended 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. 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 covalently bonded to the polymer to provide active NO-release (without leaching) in combination with immobilized selenocystamine moieties to provide long-term NO-generation. This polymer will combine NO-release and NO-generating strategies for the first time, 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/NO-generating strategy in vitro for antimicrobial properties and in a rabbit extracorporeal circulation model for prevention of thrombosis. Successful completion of this project will allow progression to early clinical trials and development of a new generation of extracorporeal circuits that can reduce complications while improving the success of patient care.