Advanced Thromboresistant/Bactericidal Catheters via Electromodulated NO Release

说明(申请人提供)：正常内皮细胞分泌的一氧化氮(NO)通过阻止血小板激活和黏附来抑制凝血。一氧化氮也是一种有效的抗菌剂，能够防止/分散生物膜。在过去的十年里，包括我们在内的几个小组已经开发出新型材料，这种材料可以持续地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、体外循环回路等)表面的微生物生物膜形成。和伤口愈合绷带。然而，到目前为止，由于准备和运输商品设备(如导管、绷带等)的成本很高，这项技术还没有任何商业应用。由易碎的无供体物种制成，它们对湿度和温度上升很敏感。为了克服这一障碍，我们现在提出了一种全新的、低成本和强大的方法来创造新一代抗血栓/杀菌血管内和尿管，以及其他生物医学装置，通过使用电化学调节的NO从简单的无机亚硝酸盐的内部储存库释放。一种方法依赖于电化学还原稳定的亚硝酸根离子，方法是在金属铜线电极上电化学产生瞬时的铜(I)离子，将亚硝酸根还原为NO。或者，我们还将探索使用可溶的铜(II)-配体络合物来模拟亚硝酸盐还原酶的活性铜(II/I)位置。这些络合物可以被电化学还原为铜(I)络合物，进一步催化亚硝酸根还原为NO。初步数据已经证明，电化学NO释放导管在体外能够防止和/或分散微生物生物膜的形成，并显著减少体内血栓的形成。电化学的进一步优化将使对基础技术的抗微生物活性的详细体外研究成为可能。此外，它还将允许在兔的静脉内对新的电化学NO释放导管进行短期(8小时)和长期(7天和30天)的研究，目的是评估这些装置在预防 体内血栓形成和微生物生物膜形成。微型电池供电的电路将被开发出来，以帮助在自由活动的动物身上进行长期研究。该项目的成功可能导致新一代低成本导管(包括血管内和尿路)，将极大地降低常见导管相关感染和血栓形成的风险，并可能提供一种新的技术，用于制造平面NO释放贴片，易于用于促进伤口愈合。

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.