Ultra-low Fouling and Nitric Oxide Releasing Intravascular Catheters for Prevention of Thrombosis and Infection

用于预防血栓形成和感染的超低污垢和一氧化氮释放血管内导管

• 批准号: 9908906
• 负责人: Sean Hopkins
• 金额: $ 14.98万
• 依托单位: INNOVETA BIOMEDICAL LLC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2021-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9908906
• 关键词: Adhesions; Adsorption; Allergic; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Anticoagulation; Antiviral Agents; Artificial Organs; Bacteria; Bacterial Adhesion; Bacterial Infections; Binding; Blood; Blood Platelets; Blood Proteins; Blood Vessels; Catheters; Clinical; Coagulation Process; Complex; Consultations; Data; Defibrillators; Development; Devices; Diagnosis; Endothelium; Engineering; Exhibits; Extracorporeal Membrane Oxygenation; Fibrin; Fibrinogen; Formulation; Goals; Growth; Health Care Costs; Heart; Hemorrhage; Hemostatic Agents; Heparin; Hospitals; Hydration status; Immobilization; In Vitro; Incidence; Infection; Inflammation; Intensive Care Units; Lead; Leukocytes; Local Anti-Infective Agents; Lung; Measures; Medical; Medical Device; Methods; Microbial Biofilms; N-acetylpenicillamine; Nitric Oxide; Nitric Oxide Donors; Nosocomial Infections; Pacemakers; Pathway interactions; Patients; Peripheral; Phase; Physicians; Platelet Activation; Play; Polymers; Postphlebitic Syndrome; Prevention; Property; Proteins; Pulmonary Embolism; Reporting; Research; Research Personnel; Risk; Role; S-nitro-N-acetylpenicillamine; Safety; Sepsis; Sinus; Small Business Innovation Research Grant; Stents; Surface; Syndrome; Technology; Testing; Thrombin; Thrombosis; Venous; Work; antimicrobial; antimicrobial drug; attributable mortality; base; chemical property; clinical application; commercialization; cooking; copolymer; hemocompatibility; heparin-induced thrombocytopenia; hydrophilicity; implantable device; improved; infection risk; inhibitor/antagonist; innovation; insight; interest; macrophage; mechanical properties; medical complication; monolayer; natural antimicrobial; neutrophil; novel; physical property; platelet function; preservation; prevent; side effect; success

ABSTRACT Despite decades of research, an ideal non-thrombogenic and antibacterial surface has yet to be identified to eliminate the need for systemic anticoagulation and risks of infection. Blood-material interactions are critical to the success of implantable medical devices including simple catheters, stents and grafts, insulation materials for electrical leads of pacemakers and defibrillators, and complex extracorporeal artificial organs, which are used in thousands of patients every day. The major limiting factors to clinical applications of blood-contacting materials are 1) platelet activation and thrombosis, 2) biofouling of surfaces with proteins and bacteria, and 3) infection. Commercial heparin-coated catheters have been shown to preserve fibrinogen levels, but it does not prevent the alternate hemostatic pathway of platelet activation and adhesion. Surface-induced thrombosis remains a significant challenge for such devices and systemic anticoagulation is required to prevent clotting but also results in a major risk of hemorrhage. In addition, catheters coated with antiseptics or antibiotics decrease the risk of bacterial infection, but do not prevent biofilm formation that shields bacteria from antibiotics. Therefore, there is a necessity and opportunity to combine strategies for preventing thrombosis and infection into single implantable device coatings for enhanced patency and safety. Recent work over the past 5 years has demonstrated that nitric oxide (NO) release from polymer surfaces can prevent platelet activation and bacterial infection. This technology is based on the fact that NO secretion by the normal endothelium prevents clotting by preventing platelet adhesion and activation. Further, NO released within the sinus cavities, and by neutrophils and macrophages, functions as a potent natural antimicrobial and antiviral agent. Recently we discovered that all of the positive effects of NO release can be achieved from polymers doped with the NO donor molecule S-nitroso-N-acetylpenicillamine (SNAP), which is nontoxic, inexpensive, and easy to synthesize. Nitric oxide release alone can inhibit platelet function locally at the polymer/blood interface, but it does not prevent fibrinogen adsorption and fibrin formation, which plays a key role in a clot formation. In contrast, zwitterionic materials have been demonstrated to resist protein adsorption down to < 0.3 ng/cm2, where a monolayer of protein coverage on a surface can be as high as 100500 ng/cm2. Zwitterionic materials have a stronger hydration ability compared with existing hydrophilic polymers; this accounts for their ultra-low fouling property. The goal of this proposal is to develop, optimize, and evaluate novel intravascular catheters that will combine agents that inhibit bacteria growth, platelet adhesion, and activation via NO release as well as inhibit biofouling (bacteria and fibrinogen adhesion) using immobilized zwitterionic top-coat. The new coatings will be applicable to any blood-contacting device; however, this proposal will focus on studying the combined effect of NO-releasing polymer and zwitterion in long-term (up to 30 d) intravascular catheter-type devices on clotting and infection. Due to high commercialization potential, leading biomedical companies including Cook Medical and MC3 have been interest in our technology.

摘要 尽管经过数十年的研究，理想的非血栓形成和抗菌表面尚未确定， 消除了全身抗凝治疗的需要和感染的风险。血液-物质相互作用对于 包括简单导管、支架和移植物在内的可植入医疗设备的成功， 起搏器和除颤器的电导线，以及复杂的体外人工器官， 每天都有成千上万的病人。血液接触材料临床应用的主要限制因素 是1）血小板活化和血栓形成，2）表面被蛋白质和细菌生物污染，以及3）感染。 商业肝素涂层导管已被证明可以保持纤维蛋白原水平，但它不能防止 血小板活化和粘附的替代止血途径。表面诱导的血栓形成仍然是一个 这类装置面临重大挑战，需要全身抗凝以防止凝血， 有大出血的危险此外，涂有防腐剂或抗生素的导管可降低以下风险： 细菌感染，但不能阻止生物膜的形成，保护细菌免受抗生素的侵害。因此有 将预防血栓形成和感染的联合收割机策略结合到单个植入式植入物中的必要性和机会 用于增强开放性和安全性的器械涂层。 过去5年的研究表明，从聚合物表面释放的一氧化氮（NO）可以 防止血小板活化和细菌感染。这项技术是基于这样一个事实，即NO分泌的 正常的内皮通过阻止血小板粘附和激活来防止凝血。此外，NO在 窦腔，以及中性粒细胞和巨噬细胞，作为一种有效的天然抗菌剂和抗病毒剂 剂最近，我们发现，NO释放的所有积极作用都可以从聚合物中实现 掺杂有NO供体分子S-亚硝基-N-乙酰青霉胺（SNAP），其无毒、廉价， 易于合成。单独的一氧化氮释放可以在聚合物/血液界面处局部抑制血小板功能， 但它不能阻止纤维蛋白原吸附和纤维蛋白形成，而纤维蛋白原在凝块形成中起关键作用。在 相反，两性离子材料已被证明抵抗低至<0.3ng/cm 2的蛋白质吸附，其中 表面上单层的蛋白质覆盖率可高达100 ~ 500 ng/cm 2。两性离子材料具有 与现有的亲水性聚合物相比，具有更强的水合能力;这是其超低结垢的原因 财产该提案的目标是开发、优化和评估新型血管内导管 其将结合抑制细菌生长、血小板粘附和通过NO释放活化的联合收割机试剂， 以及使用固定的两性离子表面涂层抑制生物污垢（细菌和纤维蛋白原粘附）。的 新涂层将适用于任何血液接触器械;然而，本提案将重点研究 NO释放聚合物和两性维酮在长期（长达30天）血管内导管型 凝血和感染的装置。由于具有很高的商业化潜力，领先的生物医药公司 包括Cook Medical和MC 3都对我们的技术感兴趣。