Advanced Thromboresistant/Bactericidal Catheters via Electromodulated NO Release

描述（由申请人提供）：正常内皮分泌一氧化氮（NO）通过阻止血小板活化和粘附抑制凝血。一氧化氮也是一种有效的抗菌剂，能够阻止/分散生物膜。在过去的十年里，包括我们在内的几个研究小组已经开发出了一种新型材料，这种材料可以从嵌入聚合物中的各种NO供体（s -亚硝基硫醇和重氮二元酸酯）中持续分泌NO，以防止血小板粘附、血栓形成和微生物生物膜在许多生物医学设备（例如，血管内导管/传感器、体外循环回路等）和伤口愈合绷带表面形成。然而，到目前为止，由于制备和运输商品设备（例如，导管，绷带等）的成本很高，这种技术还没有任何商业应用，这些设备由易损坏的NO供体物种制成，对湿气和温度升高敏感。为了克服这一障碍，我们现在提出了一种全新的、低成本的、强大的方法来制造新一代抗血栓/杀菌血管内导尿管和导尿管，以及其他生物医学设备，通过从简单无机亚硝酸盐的内部储存器中使用电化学调节的NO释放。一种方法依赖于电化学还原稳定的亚硝酸盐离子，通过金属铜线电极电化学生成瞬态Cu(I)离子，将亚硝酸盐还原为NO。另外，我们还将探索使用可溶性Cu（II）配体复合物来模拟亚硝酸盐还原酶的活性Cu（II/I）位点。这些配合物可以电化学还原为Cu(I)配合物，进一步介导亚硝酸盐还原为NO。初步数据已经证明电化学NO释放导管能够在体外阻止和/或分散微生物生物膜的形成，并显著减少体内血栓的形成。进一步的电化学优化将使基础技术的抗菌活性在体外进行详细的研究。此外，它将允许短期（8小时）和长期（7和30天）研究新的电化学NO释放导管在兔子静脉内，目的是评估这些装置在预防的功效

DESCRIPTION (provided by applicant): Nitric oxide (NO) secretion by the normal endothelium inhibits clotting by preventing platelet activation and adhesion. Nitric oxide is also a potent antimicrobial agent and is capable of preventing/dispersing biofilms. Over the past decade, several groups, including ours, have developed novel materials 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, extracorporeal circulation loops, etc.) and wound healing bandages. 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, bandages, etc.) made with the fragile NO donors species, which are sensitive to moisture and increased temperature. To overcome this hurdle, we now propose a completely new, low cost and robust method to create a new generation of thromboresistant/bactericidal intravascular and urinary catheters, as well as other biomedical devices, via use of electrochemically modulated NO release from an inner reservoir of simple inorganic nitrite salt. One approach relies on electrochemically reducing the stable nitrite ions via electrochemical generation of transient Cu(I) ions from a metallic copper wire electrode that reduce nitrite to NO. Alternatively, we will also explore the use of soluble Cu(II)-ligand complexes that mimic the active Cu(II/I) site of nitrite reductase enzymes. These complexes can be electrochemically reduced to Cu(I) complexes that further mediate the reduction of nitrite to NO. Preliminary data already demonstrate the ability of electrochemical NO release catheters to prevent and/or disperse microbial biofilm formation in vitro and also dramatically decrease thrombus formation in vivo. Further optimization of the electrochemistry will enable detailed in vitro studies on the antimicrobial activity of the basic technology. Additionally, it will allow shrt- term (8 h) and long-term (7 and 30 d) studies of the new electrochemical NO release catheters within the veins of rabbits with the goal of evaluating the efficacy of these devices in preventing thrombosis and microbial biofilm formation in vivo. Miniaturized battery powered circuitry will be developed to aid in the longer-term studies in freely moving animals. Success of this project could lead to a new generation of low- cost catheters (both intravascular and urinary) that will dramatically reduce risk of common catheter related infections and thrombosis, and it may also provide a novel technology for creating planar NO release patches that can readily employed to promote wound healing.