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: 10608084
• 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/10608084
• 关键词: 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; Cell Line; Cells; Clinical; Coagulation Process; Complication; Critical Illness; Data; Devices; Embolism; Exhibits; Extracorporeal Circulation; Extracorporeal Membrane Oxygenation; Formulation; Generations; Goals; Heart failure; Hematological Disease; Hemodialysis; Hemorrhage; Heparin; Immobilization; In Vitro; Infection; Lead; Legal patent; Life; Measures; Mechanical ventilation; Microbial Biofilms; Modeling; N-acetylpenicillamine; Nitric Oxide; Nitric Oxide Donors; Nosocomial Infections; Obstruction; Oryctolagus cuniculus; Oxygenators; Patient Admission; Patient Care; Patients; Platelet Activation; Polymers; Prevention; Property; Pseudomonas aeruginosa; Pulmonary Thromboembolism; Reporting; Research Project Grants; Respiratory Failure; Risk; S-Nitrosothiols; Safety; Selenium; Sepsis; Staphylococcus aureus; Staphylococcus epidermidis; Sterilization; Surface; System; Technology; Testing; Therapeutic; Thrombophilia; Thrombosis; Thrombus; Time; Translations; Tube; Vascular Endothelial Cell; Work; analytical method; antimicrobial; 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; 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; Cell Line; Cells; Clinical; Coagulation Process; Complication; Critical Illness; Data; Devices; Embolism; Exhibits; Extracorporeal Circulation; Extracorporeal Membrane Oxygenation; Formulation; Generations; Goals; Heart failure; Hematological Disease; Hemodialysis; Hemorrhage; Heparin; Immobilization; In Vitro; Infection; Lead; Legal patent; Life; Measures; Mechanical ventilation; Microbial Biofilms; Modeling; N-acetylpenicillamine; Nitric Oxide; Nitric Oxide Donors; Nosocomial Infections; Obstruction; Oryctolagus cuniculus; Oxygenators; Patient Admission; Patient Care; Patients; Platelet Activation; Polymers; Prevention; Property; Pseudomonas aeruginosa; Pulmonary Thromboembolism; Reporting; Research Project Grants; Respiratory Failure; Risk; S-Nitrosothiols; Safety; Selenium; Sepsis; Staphylococcus aureus; Staphylococcus epidermidis; Sterilization; Surface; System; Technology; Testing; Therapeutic; Thrombophilia; Thrombosis; Thrombus; Time; Translations; Tube; Vascular Endothelial Cell; Work; analytical method; antimicrobial; 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.

项目摘要/摘要 从小导管到血液接触材料的临床应用的主要限制因素 大型体外循环（ECC）设备包括血小板激活，导致血栓形成和感染。 血栓形成可以进一步导致血管阻塞，装置故障甚至威胁生命 栓塞等情况。需要全身性抗凝治疗以防止设备凝结。然而， 由此产生的主要并发症之一就是出血。在19日期间，体外的大流行期间 膜氧合（ECMO）已受到批评的关注，作为一种机械患者的治疗 仅通风就无效。由于血栓形成的风险增加，仍然存在重大挑战 COVID-19患者表现出的高凝血血液可能会进一步加剧电路。所以， 迫切需要和机会结合防止血栓形成和感染为 多功能设备涂层，可提高通畅和安全性。 我们的工作和其他工作表明，一氧化氮（NO）从聚合物中释放出来阻止血小板激活 和感染。该技术模仿血管内衬里的血管内皮细胞以及其他 我们体内的细胞在本地产生，以防止凝结和细菌生物膜以及随后的感染。 最近，我们发现从物理混合的聚合物中可以实现所有积极效果 无供体分子S-硝基-N-乙酰苯胺（SNAP），无毒，廉价且易于 合成。主动在聚合物中无供体功能的释放可降低血栓形成和细菌 感染聚合物血界；但是，仅无释放策略就受到否的有限水库的限制 聚合物内限制了聚合物血界面无可用性持续时间的供体功能。 我们最近的工作表明，将主动无释放与催化无生成结合起来的潜力 单一聚合物中的机理。该提议的目的是开发由无捐赠者组成的聚合物 与聚合物共价键合，以提供主动的无释放（不浸出）与 固定的硒渴stamine部分提供了长期无代。这个聚合物将结合 首次发行和无生成策略，导致新一代聚合物 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接触式血液接触装置；然而， 该提案将重点研究在体外研究抗菌剂的联合无释放/无生成策略 特性和兔子外循环模型，用于预防血栓形成。成功完成 这个项目将允许发展新一代的早期临床试验和发展 可以减少并发症的电路，同时改善患者护理的成功。