Thromboresistant/Bactericidal Intravascular Catheters Based on Electrochemical Nitric Oxide Generation

基于电化学一氧化氮生成的抗血栓/杀菌血管内导管

基本信息

批准号：
8981223
负责人：
Elizabeth Joy Brisbois
金额：
$ 5.24万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8981223
关键词：
Active Sites Acute Adherence Adhesions Animal Model Area Artificial Organs Bacterial Adhesion Biocompatible Biomedical Research Bioreactors Blood Blood Platelets Blood-Borne Pathogens Caring Catheters Chronic Clinical Coagulation Process Complex Data Development Devices Electrochemistry Electrodes Endothelium Enzymes Epithelial Cells Exposure to Faculty Foundations Frequencies Generations Goals Grant Health Care Costs Hour Image In Vitro Indwelling Catheter Infection Intensive Care Units Ions Lead Ligands Measures Mediating Medical Medical Device Methods Microbial Biofilms Modeling Nitric Oxide Nitric Oxide Donors Nitrite Reductase Nitrites Nose Oryctolagus cuniculus Patients Physiologic pulse Physiological Platelet Activation Platinum Polymers Prevention Process Production Research Research Personnel Research Project Grants Risk S-Nitrosothiols Scientist Shipping Ships Silicone Elastomers Site Sodium Chloride Solid Solutions Stents Surface Technology Temperature Testing Thrombosis Thrombus Training Translational Research Veins Venous Venous Thrombosis Work antimicrobial antimicrobial drug bactericide base catheter related infection clinical application commercial application cost diazeniumdiolate experience in vivo macrophage member neutrophil novel novel strategies prevent public health relevance research study sensor skills success voltage

项目摘要

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.

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，这些器械每天都在数百万患者中使用，临床有两个主要限制因素。血液接触材料的应用：1）血小板活化和血栓形成，2）正常内皮分泌的一氧化氮（NO）通过阻止血小板活化和感染来抑制凝血。此外，NO 由中性粒细胞和巨噬细胞释放，作为有效的抗菌剂，能够防止/分散生物膜。在过去的十年中，已经开发出能够从各种 NO 供体（S-亚硝基硫醇）持续分泌 NO 的新型材料。和二氮烯鎓二醇）嵌入聚合物中，以防止血小板粘附、血栓形成和许多生物医学设备（例如血管内设备）表面的微生物生物膜形成然而，迄今为止，由于制备和运输由脆弱的 NO 供体物种制成的商品装置（例如导管）的成本高昂，该技术还没有任何商业应用，该提案的目标是通过使用电化学调制的 NO 来开发和优化全新、低成本且坚固的抗血栓/杀菌血管内导管，从而克服这些障碍。从模拟亚硝酸还原酶活性 Cu(II/I) 位点的简单无机亚硝酸盐内部储存库中释放的物质，将被电化学还原为可进一步介导的 Cu(I) 络合物。电化学优化将亚硝酸盐还原为 NO，从而能够对 NO 进行详细的体外研究。此外，还将对兔子静脉内的新型电化学 NO 释放导管进行短期（8 小时）和长期（10 天）研究，目的是评估其功效。这些装置在预防体内血栓形成和细菌粘附方面的应用。该项目的成功可能会产生新一代低成本血管内导管，从而大大降低常见导管相关感染和血栓形成的风险。