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： 好了！ 正常内皮细胞分泌一氧化氮(NO)通过阻止血小板活化和抑制凝血 粘附力。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了新的材料，不断地 从嵌入聚合物中的各种NO供体分泌NO，以防止血小板黏附、血栓形成 以及在许多生物医学装置(例如，血管内)的表面上形成微生物生物膜 导管/传感器、体外循环回路等)和伤口愈合绷带。然而，到目前为止， 由于制备成本很高，这项技术还没有任何商业应用 以及运输用脆弱的无捐赠者物种制造的商品设备，这些物种通常对 湿度和升高的温度。为了克服这一障碍，我们现在提出一种全新的、低成本的 和强大的替代方法，以创造新一代抗血栓/杀菌血管内和 导尿管，以及其他生物医学设备。此方法基于使用 电化学调制NO从简单的无机亚硝酸盐的内部储存库中释放。最多的 为了实现这一目标，有希望的方法是利用可溶的铜(II)配体络合物来模拟活性 亚硝酸还原酶的铜(II/I)位点。这些络合物可以被电化学还原为铜(I)。 进一步促进亚硝酸根的单电子还原为NO的物种。实质性的初步数据为 已经在手中(基于R-56桥梁奖)，证明了这种电化学NO的能力 释放导尿管以防止和/或分散体外微生物生物膜的形成 减少体内血栓形成。电化学的进一步优化，特别是识别 高效催化亚硝酸根还原为NO的新型铜(II)配体络合物，以及 需要在双腔导管配置中模拟/测试该方法的NO释放分布 以实现广泛的体外和体内研究。体外测试的重点将是检查抗菌剂 基础技术的活动，特别是针对通常相关的微生物的活动 有血管内和尿管引起的临床感染。此外，拟议的研究将 包括对绵羊静脉/动脉内新型电化学一氧化氮释放导管的研究(14d) 评估这些装置在预防血栓形成和微生物生物膜形成方面的效果的目标 在活体内。新型电化学材料血管内抑菌活性的体内比较研究 也将进行不释放导管与商业抗生素浸渍导管的比较。一个 微型电池供电的电路将被开发出来，以帮助对完全清醒的绵羊进行14天的研究。 该项目的成功可能导致新一代低成本导管(血管内和尿路)的出现。 这将极大地降低常见导管相关感染和血栓形成的风险。 好了！