Advanced Thromboresistant/Bactericidal Catheters via Electromodulated NO Release

通过电调节 NO 释放的先进抗血栓/杀菌导管

• 批准号: 9405609
• 负责人: MARK E MEYERHOFF
• 金额: $ 60.81万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9405609
• 关键词: Active Sites; Adhesions; Amines; Animal Model; Anti-Bacterial Agents; Antibiotics; Applications Grants; Arteries; Bandage; Bioreactors; Blood Platelets; Blood flow; Blood-Borne Pathogens; Caliber; Catheters; Centers for Disease Control and Prevention (U.S.); Chemicals; Chemiluminescence assay; Clinical; Coagulation Process; Complex; Data; Development; Devices; Dimensions; Electrochemistry; Electrodes; Electrons; Elements; Endothelium; Enzymes; Evaluation; Exhibits; Extracorporeal Circulation; Frequencies; Generations; Goals; Hand; Hour; Howard Temin Award; In Vitro; Infection; Ions; Klebsiella pneumonia bacterium; Lead; Length; Ligands; Mediating; Mediator of activation protein; Methods; Microbe; Microbial Biofilms; Microprocessor; Mirabilis; Modeling; Nitric Oxide; Nitric Oxide Donors; Nitrite Reductase; Nitrites; Organism; Oxidation-Reduction; Periodicity; Phase; Physiological; Platelet Activation; Polymers; Polyurethanes; Prevention; Property; Pseudomonas aeruginosa; Reaction; Research; Risk; S-Nitrosothiols; Sheep; Shipping; Silicone Elastomers; Site; Sodium Chloride; Spectrum Analysis; Staphylococcus aureus; Staphylococcus epidermidis; Structure; Surface; Technology; Temperature; Testing; Thrombosis; Thrombus; Time; Vascular Graft; Veins; Wound Healing; antimicrobial; antimicrobial drug; awake; bactericide; base; catheter associated UTI; catheter related infection; commercial application; cooking; cost; diazeniumdiolate; experimental study; in vitro testing; in vivo; in vivo evaluation; miniaturize; new technology; novel; novel strategies; portability; prevent; programs; purge; sensor; simulation; success; triazacyclononane; urinary; voltage

Abstract: ! 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 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 yet been any commercial applications of this technology owing to the high cost of preparing and shipping commodity devices made with the fragile NO donors species, which are often sensitive to moisture and increased temperature. To overcome this hurdle, we now propose a completely new, low cost and robust alternate method to create a new generation of thromboresistant/bactericidal intravascular and urinary catheters, as well as other biomedical devices. This approach is based on the use of electrochemically modulated NO release from an inner reservoir of a simple inorganic nitrite salt. The most promising approach toward this goal is to utilize 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) species that further mediate the one electron reduction of nitrite to NO. Substantive preliminary data are already in hand (based on a R-56 bridge award) demonstrating the ability of such electrochemical NO release catheters to prevent and/or disperse microbial biofilm formation in vitro and also substantially decrease thrombus formation in vivo. Further optimization of the electrochemistry, especially identifying new Cu(II)-ligand complexes that have high efficiency in mediating the reduction of nitrite to NO, and modeling/testing the NO release profiles of this approach in a dual-lumen catheter configuration is needed to enable extensive in vitro and in vivo studies. In vitro testing will focus on examining the antimicrobial activity of the basic technology, especially with respect to activity against microbes commonly associated with intravascular and urinary catheter induced clinical infections. Additionally, the proposed research will include studies of the new electrochemical NO release catheters within the veins/arteries sheep (14 d) with the goal of evaluating the efficacy of these devices in preventing thrombosis and microbial biofilm formation in vivo. An in vivo comparison study of the intravascular antimicrobial activity of the new electrochemical NO release catheters vs. commercial antibiotic impregnated catheters will also be conducted. A miniaturized battery powered circuitry will be developed to aid in the 14 d studies in fully awake sheep. Success of this project could lead to a new generation of low-cost catheters (both intravascular and urinary) that will dramatically reduce the risk of common catheter related infections as well as thrombosis. !

摘要： ! 正常内皮细胞分泌的一氧化氮（NO）通过阻止血小板活化和血小板活化抑制凝血， 粘连一氧化氮也是一种有效的抗微生物剂，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了新的材料， 从包埋在聚合物内的各种NO供体中分泌NO，以防止血小板粘附、血栓形成 以及在许多生物医学装置的表面上形成微生物生物膜（例如，血管内 导管/传感器、体外循环回路等）和伤口愈合绷带。然而，迄今为止， 由于制备成本高， 和运输用易碎的NO供体物质制成的商品装置，其通常对 湿度和温度升高。为了克服这一障碍，我们现在提出一种全新的、低成本的 和稳健的替代方法来创建新一代抗血栓/杀菌血管内和 导尿管以及其他生物医学设备。这种方法是基于使用 电化学调节的NO从简单无机亚硝酸盐的内部储存器释放。最 实现这一目标的一种有前途的方法是利用可溶性Cu（II）-配体络合物， 亚硝酸盐还原酶的Cu（II/I）位点。这些配合物可被电化学还原为Cu（I） 进一步介导亚硝酸盐的一个电子还原为NO的物种。实质性的初步数据是 已经在手（基于R-56桥梁奖）证明这种电化学NO 释放导管以防止和/或分散体外微生物生物膜形成，并且还基本上 减少体内血栓形成。进一步优化电化学，特别是鉴定 新的Cu（II）-配体络合物，其在介导亚硝酸盐还原成NO中具有高效率，和 需要在双腔导管配置中对这种方法的NO释放曲线进行建模/测试 以实现广泛的体外和体内研究。体外测试将重点检查抗菌剂 基础技术的活性，特别是在对通常相关的微生物的活性方面 引起的血管内和导尿管临床感染。此外，拟议的研究将 包括研究新的电化学NO释放导管内的静脉/动脉羊（14天）， 目的是评价这些器械在预防血栓形成和微生物生物膜形成方面的有效性 in vivo.新型电化学抗菌药物血管内抗菌活性的体内比较研究 还将进行NO释放导管与市售抗生素浸渍导管的比较。一 将开发小型化电池供电的电路，以帮助在完全清醒的绵羊中进行14天研究。 该项目的成功可能导致新一代低成本导管（血管内和泌尿） 这将显著降低常见的导管相关感染以及血栓形成的风险。 !