Heparin-free extracorporeal circulation via combined nitric oxide releasing/generating surfaces

通过组合的一氧化氮释放/生成表面进行无肝素体外循环

• 批准号: 10184748
• 负责人: Elizabeth Joy Brisbois
• 金额: $ 36.42万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10184748
• 关键词: 2019-nCoV; Address; Adhesions; Anti-Bacterial Agents; Anticoagulation; Attention; Bacteria; Bacterial Infections; Binding; Blood; Blood Coagulation Disorders; Blood Platelets; Blood Vessels; Blood-Borne Pathogens; COVID-19; COVID-19 pandemic; COVID-19 patient; Candida albicans; Cannulas; Catheters; Cells; Clinical; Coagulation Process; Complication; Critical Illness; Data; Devices; Embolism; Exhibits; Extracorporeal Circulation; Extracorporeal Membrane Oxygenation; Formulation; Generations; Goals; Heart failure; Hemodialysis; Hemorrhage; Heparin; Immobilization; In Vitro; Infection; Lead; Life; Measures; Mechanical ventilation; Microbial Biofilms; Modeling; N-acetylpenicillamine; Nitric Oxide; Nitric Oxide Donors; Nosocomial Infections; Obstruction; Oryctolagus cuniculus; Oxygenators; Patient Care; Patients; Platelet Activation; Polymers; Prevention; Property; Pseudomonas aeruginosa; Pulmonary Thromboembolism; Reporting; Research Project Grants; Respiratory Failure; Risk; S-Nitrosothiols; S-nitro-N-acetylpenicillamine; Safety; Savings; Selenium; Sepsis; Staphylococcus aureus; Staphylococcus epidermidis; Sterilization; Surface; System; Technology; Testing; Therapeutic; Thrombophilia; Thrombosis; Thrombus; Time; Translations; Vascular Endothelial Cell; Work; analytical method; antimicrobial; base; catalyst; clinical application; clinical development; covalent bond; early phase clinical trial; hemocompatibility; high risk; improved; in vitro Bioassay; infection rate; polydimethylsiloxane; prevent; success; synergism; thrombogenesis; thrombotic complications

Project Summary/Abstract The major limiting factors to clinical applications of blood-contacting materials, ranging from small catheters to large extracorporeal circulation (ECC) devices, include platelet activation leading to thrombosis and infection. Thrombus formation can further lead to obstruction of blood vessels, device malfunction, or even life-threatening situations such as embolism. Systemic anticoagulation is required to prevent clotting in the devices; however, one of the resulting major complications of this is bleeding. During the COVID-19 pandemic, extracorporeal membrane oxygenation (ECMO) has received critical attention as a therapy for patients where mechanical ventilation alone is ineffective. Significant challenges remain due to the increased risks of thrombosis in the circuitry that can be further exacerbated by hypercoagulable blood exhibited by COVID-19 patients. Therefore, there is an urgent necessity and opportunity to combine strategies for preventing thrombosis and infection into multifunctional device coatings for enhanced patency and safety. Our work and others have demonstrated that nitric oxide (NO) release from polymers prevent platelets activation and infection. This technology mimics the vascular endothelial cells lining the blood vessels, as well as other cells in our bodies, producing NO locally to prevent clotting and bacterial biofilm and subsequent infections. Recently we discovered that all of the positive effects can be achieved from polymers physically blended with the NO donor molecule S-nitroso-N-acetylpenicillamine (SNAP), which is nontoxic, inexpensive, and easy to synthesize. Active NO release from the NO donor functionalities in the polymer reduces thrombosis and bacterial infection polymer-blood interface; however, the NO-release strategy alone is limited by the finite reservoir of NO donor functionalities within the polymer that limit the duration of the NO availability at the polymer-blood interface. Our recent work has shown the potential of combining active NO-release with catalytic NO-generating mechanism in a single polymer. The goal of this proposal is to develop a polymer comprised of a NO donor covalently bonded to the polymer to provide active NO-release (without leaching) in combination with immobilized selenocystamine moieties to provide long-term NO-generation. This polymer will combine NO-release and NO-generating strategies for the first time, resulting in a new generation of polymers that possess potent broad-spectrum antimicrobial properties and reduce thrombosis by inhibiting platelet adhesion/activation. The new polymers will be applicable to any blood-contacting device; however, this proposal will focus on studying the combined NO-releasing/NO-generating strategy in vitro for antimicrobial properties and in a rabbit extracorporeal circulation model for prevention of thrombosis. Successful completion of this project will allow progression to early clinical trials and development of a new generation of extracorporeal circuits that can reduce complications while improving the success of patient care.

项目概要/摘要 血液接触材料临床应用的主要限制因素，从小型导管到 大型体外循环 (ECC) 装置，包括导致血栓形成和感染的血小板活化。 血栓形成可进一步导致血管阻塞、装置故障，甚至危及生命 栓塞等情况。需要全身抗凝以防止装置中出现凝血；然而， 由此产生的主要并发症之一是出血。在 COVID-19 大流行期间，体外 膜氧合（ECMO）作为机械性机械损伤患者的治疗方法受到了广泛关注。 仅靠通风是无效的。由于血栓形成风险增加，仍然存在重大挑战 COVID-19 患者表现出的高凝血液可能会进一步加剧这种回路。所以， 迫切需要和机会将预防血栓形成和感染的策略结合起来 多功能设备涂层可提高通畅性和安全性。 我们和其他人的工作已经证明，聚合物释放的一氧化氮 (NO) 会阻止血小板活化 和感染。该技术模仿血管内壁的血管内皮细胞以及其他细胞 我们体内的细胞，在局部产生一氧化氮，以防止凝血和细菌生物膜以及随后的感染。 最近我们发现，所有积极的效果都可以通过与以下材料物理混合的聚合物来实现： NO 供体分子 S-亚硝基-N-乙酰青霉胺 (SNAP)，无毒、廉价且易于制备 合成。聚合物中 NO 供体功能的活性 NO 释放可减少血栓形成和细菌 感染聚合物-血液界面；然而，NO 释放策略本身受到有限 NO 储存的限制 聚合物内的供体官能团限制了聚合物-血液界面处NO可用性的持续时间。 我们最近的工作表明了将活性 NO 释放与催化 NO 生成相结合的潜力 单一聚合物中的机制。该提案的目标是开发一种由 NO 供体组成的聚合物 与聚合物共价结合，提供活性 NO 释放（无浸出） 固定的硒代半胱胺部分可提供长期的 NO 生成。这种聚合物将结合 首次采用 NO 释放和 NO 生成策略，产生新一代聚合物 具有有效的广谱抗菌特性，并通过抑制来减少血栓形成 血小板粘附/激活。新聚合物将适用于任何血液接触装置；然而， 该提案将重点研究体外抗菌的 NO 释放/NO 生成组合策略 特性以及在兔体外循环模型中预防血栓形成的作用。顺利完成 该项目的进展将有助于进行早期临床试验并开发新一代体外 可以减少并发症，同时提高患者护理成功率的电路。