Ultra-low Fouling and Nitric Oxide Releasing Intravascular Catheters for Prevention of Thrombosis and Infection

摘要 尽管经过几十年的研究，理想的非血栓形成和抗菌表面仍未确定 消除全身抗凝的需要和感染的风险。血液与物质的相互作用对 植入式医疗设备的成功，包括简单的导管，支架和移植物，绝缘材料 起搏器和除颤器的电导线，以及复杂的体外人造器官，用于 每天都有成千上万的病人。血液接触材料临床应用的主要限制因素 1)血小板活化和血栓形成，2)表面蛋白质和细菌的生物污垢，以及3)感染。 商业肝素涂层导管已被证明可以保持纤维蛋白原水平，但它不能防止 血小板活化和黏附的交替止血途径。表面诱导的血栓形成仍然是一种 对这种装置和全身抗凝需要巨大的挑战，以防止凝血，但结果也是 有很大的出血风险。此外，在导管上涂上防腐剂或抗生素可降低罹患 细菌感染，但不能阻止保护细菌免受抗生素侵害的生物膜的形成。因此，有 将预防血栓形成和感染的策略结合到单一植入物中的必要性和机会 增强透明度和安全性的设备涂层。 最近在过去5年的研究表明，从聚合物表面释放的一氧化氮(NO)可以 防止血小板活化和细菌感染。这项技术是基于这样一个事实，即细菌不会分泌 正常的内皮细胞通过阻止血小板黏附和激活来防止凝血。此外，在此期间没有释放 鼻窦腔以及中性粒细胞和巨噬细胞是一种有效的天然抗菌剂和抗病毒药物。 探员。最近我们发现，NO释放的所有积极效应都可以从聚合物中实现 掺入NO供体分子S-亚硝基-N-乙酰青霉胺，无毒，廉价， 易于合成。仅一氧化氮释放就能抑制聚合物/血液界面的局部血小板功能， 但它不能阻止纤维蛋白原的吸附和纤维蛋白的形成，而纤维蛋白在血栓形成中起着关键作用。在……里面 相比之下，两性离子材料已经被证明可以抵抗蛋白质的吸附，最低可达0.3 ng/cm2，其中 表面的单层蛋白质覆盖率可高达100cm2/500ngcm2。两性离子材料有一种 与现有的亲水性聚合物相比，水化能力更强；这就是它们超低污垢的原因 财产。该提案的目标是开发、优化和评估新型的血管内导管。 这将结合抑制细菌生长、血小板黏附和通过释放NO而激活的药物作为 以及使用固定化两性离子面层来抑制生物污垢(细菌和纤维蛋白原黏附)。这个 新的涂层将适用于任何血液接触设备；然而，这项提案将集中研究 长期(长达30d)血管内导管置入术中NO释放聚合物与两性离子的联合作用 关于凝血和感染的设备。由于商业化潜力很大，领先的生物医药公司 包括库克医疗和MC3在内的公司一直对我们的技术感兴趣。

ABSTRACT Despite decades of research, an ideal non-thrombogenic and antibacterial surface has yet to be identified to eliminate the need for systemic anticoagulation and risks of infection. 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. The major limiting factors to clinical applications of blood-contacting materials are 1) platelet activation and thrombosis, 2) biofouling of surfaces with proteins and bacteria, and 3) infection. Commercial heparin-coated catheters have been shown to preserve fibrinogen levels, but it does not prevent the alternate hemostatic pathway of platelet activation and adhesion. Surface-induced thrombosis remains a significant challenge for such devices and systemic anticoagulation is required to prevent clotting but also results in a major risk of hemorrhage. In addition, 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. Recent work over the past 5 years has demonstrated that nitric oxide (NO) release from polymer surfaces 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 fibrinogen adsorption and fibrin formation, which plays a key role in a clot formation. In contrast, zwitterionic materials have been demonstrated to resist protein adsorption down to < 0.3 ng/cm2, where a monolayer of protein coverage on a surface can be as high as 100500 ng/cm2. Zwitterionic materials have a stronger hydration ability compared with existing hydrophilic polymers; this accounts for their ultra-low fouling property. The goal of this proposal is to develop, optimize, and evaluate novel intravascular catheters that will combine agents that inhibit bacteria growth, platelet adhesion, and activation via NO release as well as inhibit biofouling (bacteria and fibrinogen adhesion) using immobilized zwitterionic top-coat. The new coatings will be applicable to any blood-contacting device; however, this proposal will focus on studying the combined effect of NO-releasing polymer and zwitterion in long-term (up to 30 d) intravascular catheter-type devices on clotting and infection. Due to high commercialization potential, leading biomedical companies including Cook Medical and MC3 have been interest in our technology.