Thromboresistant/Bactericidal Intravascular Catheters Based on Electrochemical Nitric Oxide Generation

 描述(由申请人提供)：血液/材料的相互作用对植入式医疗设备的成功至关重要，包括导管、支架、移植物和体外人工器官，每天有数百万患者使用这些设备。血液接触材料的临床应用有两个主要限制因素：1)血小板活化和血栓形成；2)感染。正常内皮细胞分泌的一氧化氮(NO)通过阻止血小板活化和黏附来抑制凝血。此外，NO由中性粒细胞和巨噬细胞释放，作为一种有效的抗菌剂，能够防止/分散生物膜。在过去的十年里，人们已经开发出一种新型材料，可以从嵌入在聚合物中的各种NO供体(S-亚硝硫醇和二氮杂二醇)中持续分泌NO，以防止血小板黏附、血栓形成和许多生物医学设备(例如血管内导管/传感器、ECC环等)表面的微生物生物膜形成。然而，到目前为止，这项技术还没有任何商业应用，因为用对湿度和温度升高敏感的脆弱的非供体物种制造的商品设备(例如导管)的准备和运输成本很高。这项建议的目标是通过开发和优化一种全新的、低成本和强大的抗血栓/杀菌血管内导管来克服这些障碍，方法是使用电化学调节的NO从简单的无机亚硝酸盐内部储存库释放NO。模拟亚硝酸还原酶活性中心的可溶性铜(II)-配体络合物将被电化学还原为能进一步催化亚硝酸根还原为NO的铜(I)络合物。电化学的优化将使NO的详细体外研究成为可能 新型导尿管的释放和抗菌活性。此外，还将在兔静脉内对新型电化学NO释放导管进行短期(8h)和长期(10d)的研究，目的是评估这些装置在体内预防血栓形成和细菌黏附的效果。该项目的成功可能导致新一代低成本的血管内导管，这将极大地降低常见导管相关感染和血栓形成的风险。

 DESCRIPTION (provided by applicant): Blood/material interaction is critical to the success of implantable medical devices including catheters, stents, grafts, and extracorporeal artificial organs, which are used in millions of patients every day. There are two major limiting factors to clinical application of blood-contacting materials: 1) platelet activation and thrombosis, and 2) infection. Nitric oxide (NO) secretion by the normal endothelium inhibits clotting by preventing platelet activation and adhesion. Further, NO is released by neutrophils and macrophages, which functions as a potent antimicrobial agent and is capable of preventing/dispersing biofilms. Over the past decade, novel materials have been developed that continuously secrete NO from various NO donors (S-nitrosothiols and diazeniumdiolates) embedded within polymers to prevent platelet adhesion, thrombosis and microbial biofilm formation on the surface of a number of biomedical devices (e.g., intravascular catheters/sensors, ECC loops, etc.). However, to date, there have not been any commercial applications of this technology owing to the high cost of preparing and shipping commodity devices (e.g., catheters) made with the fragile NO donors species, which are sensitive to moisture and increased temperature. The goal of this proposal is to overcome these hurdles by developing and optimizing a completely new, low cost, and robust generation of thromboresistant/bactericidal intravascular catheters via the use of electrochemically modulated NO release from an inner reservoir of simple inorganic nitrite salt. Soluble Cu(II)-ligand complexes, that mimic the active Cu(II/I) site of nitrite reductase enzymes, will be electrochemically reduced to Cu(I) complexes that can further mediate the reduction of nitrite to NO. Optimization of the electrochemistry will enable detailed in vitro studies of the NO release and antimicrobial activity of the new catheters. Additionally, short-term (8 h) and long-term (10 d) studies of the new electrochemical NO release catheters within the veins of rabbits will be conducted, with the goal of evaluating the efficacy of these devices in preventing thrombosis and bacterial adhesion in vivo. Success of this project could lead to a new generation of low-cost intravascular catheters that will dramatically reduce risk of common catheter related infections and thrombosis.