Thromboresistant/Bactericidal Intravascular Catheters Based on Electrochemical Nitric Oxide Generation

 描述（由申请人提供）：血液/材料相互作用对于植入式医疗器械（包括导管、支架、移植物和体外人工器官）的成功至关重要，这些器械每天用于数百万患者。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。正常内皮分泌的一氧化氮（NO）通过阻止血小板活化和粘附来抑制凝血。此外，NO由嗜中性粒细胞和巨噬细胞释放，其用作有效的抗微生物剂并且能够防止/分散生物膜。在过去的十年中，已经开发了新型材料，其从嵌入聚合物中的各种NO供体（S-亚硝基硫醇和二醇二氮烯鎓）连续分泌NO，以防止血小板粘附、血栓形成和许多生物医学装置（例如，血管内导管/传感器、ECC回路等）。然而，迄今为止，由于制备和运输商品装置（例如，导管），其由易碎的NO供体物质制成，所述NO供体物质对水分和升高的温度敏感。该提案的目标是通过开发和优化一种全新的、低成本的和稳健的抗血栓/杀菌血管内导管来克服这些障碍，该血管内导管通过使用从简单无机亚硝酸盐的内部储存器释放的电化学调制的NO。模拟亚硝酸盐还原酶的活性Cu（II/I）位点的可溶性Cu（II）-配体络合物将被电化学还原为Cu（I）络合物，该Cu（I）络合物可以进一步介导亚硝酸盐还原为NO。 新导管的释放和抗菌活性。此外，还将对新型电化学NO释放导管在家兔静脉内进行短期（8 h）和长期（10 d）研究，目的是评价这些器械在体内预防血栓形成和细菌粘附的有效性。该项目的成功可能会导致新一代低成本血管内导管，这将大大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.