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

项目摘要/摘要 限制血液接触材料临床应用的主要因素从小导管到 大型体外循环(ECC)设备，包括导致血栓形成和感染的血小板激活。 血栓形成可进一步导致血管阻塞、设备故障，甚至危及生命 例如血栓等情况。需要全身抗凝来防止设备中的凝血；然而， 由此产生的主要并发症之一是出血。新冠肺炎大流行期间，体外循环 膜氧合(ECMO)作为一种治疗机械性疾病的方法受到了高度重视。 仅靠通风是无效的。由于血栓形成的风险增加，仍然存在重大挑战 新冠肺炎患者表现出的高凝血液可进一步加剧电路。因此， 迫切需要和机会将预防血栓形成和感染的战略结合到 多功能设备涂层，可增强透明度和安全性。 我们和其他人的工作表明，从聚合物中释放的一氧化氮(NO)可以阻止血小板的激活 和感染。这种技术模拟血管内皮细胞衬里血管，以及其他 我们体内的细胞，不会在局部产生任何物质，以防止凝血和细菌生物膜以及随后的感染。 最近我们发现，所有的积极作用都可以通过与聚合物物理混合而实现。 无毒、价廉、易得的NO供体分子S-亚硝基-N-乙酰青霉胺 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NO的有限储存量的限制 聚合物内的供体官能团，其限制了在聚合物-血液界面的NO可用性的持续时间。 我们最近的工作表明，将主动释放NO和催化产生NO相结合的潜力 在单一聚合物中的机理。这项提议的目标是开发一种由一氧化氮供体组成的聚合物 共价结合到聚合物上，提供活性的NO释放(不溶出)，与 固定化的硒半胱胺部分，以提供长期的NO生成。这种聚合物会结合在一起 首次提出了NO释放和NO生成策略，从而产生了新一代聚合物 具有强大的广谱抗菌特性，并通过抑制血栓形成 血小板黏附/激活。新的聚合物将适用于任何血液接触设备；然而， 本提案将重点研究体外联合NO释放/NO生成策略的抗菌剂。 性质和用于预防血栓形成的兔体外循环模型。成功完成 该项目的实施将使早期临床试验和新一代体外技术的发展成为可能。 电路可以减少并发症，同时提高患者护理的成功率。

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.