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: 8916211
• 负责人: MARK E MEYERHOFF
• 金额: $ 55.39万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8916211
• 关键词: Active Sites; Acute; Adhesions; Animal Model; Animals; Anti-Bacterial Agents; Applications Grants; Bacterial Infections; Bandage; Blood Platelets; Blood-Borne Pathogens; Caliber; Catheters; Chemiluminescence assay; Chemistry; Chronic; Clinical; Coagulation Process; Complex; Copper; Data; Development; Devices; Diffuse; Electrochemistry; Electrodes; Electrons; Elements; Endothelium; Enzymes; Epithelial Cells; Evaluation; Exhibits; Extracorporeal Circulation; Frequencies; Generations; Goals; Health; Hour; In Vitro; Infection; Ions; Klebsiella pneumonia bacterium; Lead; Length; Ligands; Longitudinal Studies; Marketing; Mediating; Methods; Microbial Biofilms; Microprocessor; Modeling; Nitric Oxide; Nitric Oxide Donors; Nitrite Reductase; Nitrites; Nose; Oryctolagus cuniculus; Physiologic pulse; Platelet Activation; Polymers; Prevention; Property; Pseudomonas aeruginosa; Research; Risk; S-Nitrosothiols; Sepsis; Shipping; Ships; Silicone Elastomers; Site; Sodium Chloride; Solutions; Staphylococcus aureus; Surface; Technology; Temperature; Testing; Thrombosis; Thrombus; Time; Vascular Graft; Veins; Work; Wound Healing; antimicrobial; antimicrobial drug; bactericide; catheter related infection; commercial application; cost; diazeniumdiolate; in vivo; killings; macrophage; miniaturize; new technology; novel; novel strategies; prevent; research study; sensor; simulation; success; urinary; voltage

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.

描述（由申请人提供）：正常内皮细胞分泌的一氧化氮（NO）通过阻止血小板活化和粘附来抑制凝血。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。在过去的十年中，包括我们在内的几个研究小组已经开发出新型材料，这些材料可以从嵌入聚合物中的各种NO供体（S-亚硝基硫醇和二醇二氮烯鎓）中持续分泌NO，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，由于制备和运输商品装置（例如，导管、绷带等）用易碎的NO供体物质制成，其对水分和升高的温度敏感。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建新一代的抗血栓/杀菌血管内和导尿管，以及其他生物医学设备，通过使用电化学调制NO释放从简单的无机亚硝酸盐的内部水库。一种方法依赖于电化学还原稳定的亚硝酸根离子，通过电化学产生的瞬态铜（I）离子从金属铜线电极，减少亚硝酸根NO。或者，我们也将探索使用可溶性铜（II）-配体配合物，模拟活性铜（II/I）的亚硝酸还原酶位点。这些络合物可以电化学还原为Cu（I）络合物，其进一步介导亚硝酸盐还原为NO。初步数据已经证明电化学NO释放导管能够防止和/或分散体外微生物生物膜形成，并且还显著减少体内血栓形成。电化学的进一步优化将使详细的体外研究的基础技术的抗微生物活性。此外，它将允许在家兔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和30天）研究，目的是评价这些装置在预防和治疗急性心肌梗死方面的有效性。 体内血栓形成和微生物生物膜形成。将开发微型电池供电电路，以帮助在自由活动动物中进行长期研究。该项目的成功可能导致新一代低成本导管（血管内和泌尿两者），其将显著降低常见导管相关感染和血栓形成的风险，并且其还可能提供用于产生平面NO释放贴片的新颖技术，该贴片可以容易地用于促进伤口愈合。