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（由应用提供）：血液/物质相互作用对于包括导管，支架，移植物和体外人造器官在内的可植入医疗设备的成功至关重要，这些器官每天都在数百万患者中使用。接触血液接触材料的临床应用有两个主要因素：1）血小板激活和血栓形成，以及2）感染。正常内皮的一氧化氮（NO）分泌通过防止血小板激活和粘合剂抑制衣服。此外，中性粒细胞和巨噬细胞释放了NO，该嗜中性粒细胞和巨噬细胞充当潜在的抗菌剂，并能够预防/分散生物膜。在过去的十年中，已经开发出了新型材料，这些材料不断地秘密秘密，这些材料嵌入了聚合物内的各种无供体（S-硝基硫醇和重18zenimdiolates）中，以防止血小板广告，血栓形成和微生物生物膜形成在许多生物外科设备的表面上（例如，许多生物医学设备的表面）但是，迄今为止，由于准备和运输商品设备（例如，导管）用脆弱的无供体物种制成的高成本（例如导管），该技术尚无该技术的任何商业应用，这些物种对水分敏感和温度升高。该提案的目的是通过开发和优化全新的，低成本且强劲的血栓耐药性/杀菌性血管内导管来克服这些障碍，通过使用电化学调制的无释放的简单无机亚硝酸盐盐的内部储备中的释放。可溶性铜（II） - 配合物，模仿亚硝酸盐的活性Cu（II/I）位点会减少酶，从而将降低到Cu（I）络合物中，这些络合物可以进一步将硝酸盐的还原降低到NO。电化学的优化将实现NO的详细体外研究新导管的释放和抗菌活性。此外，还将进行新电化学的短期（8小时）和长期（10 d）研究，将进行兔静脉内的无释放导管，目的是评估这些设备在预防体内血栓形成和细菌粘附方面的有效性。该项目的成功可能导致新一代的低成本血管内导管，这将大大降低常见导管相关感染和血栓形成的风险。