Research Supplement to Promote Diversity Supplement for the ECMO without Anticoagulation

研究补充促进无抗凝 ECMO 的多样性补充

• 批准号: 10712181
• 负责人: Robert H. Bartlett
• 金额: $ 4.32万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10712181
• 关键词: Anticoagulation; Blood; Blood Platelets; Blood Vessels; Blood coagulation; Cardiovascular system; Chemicals; Devices; Enzymes; Failure; Funding; Gases; Goals; Half-Life; Hemorrhage; Homeostasis; In Vitro; Individual; Ions; Life; Measures; Membrane Oxygenators; Mentors; Modeling; Molecular Weight; NOS3 gene; National Heart, Lung, and Blood Institute; Nitric Oxide; Nitric Oxide Donors; Nitrites; Partial Pressure; Polymers; Research; Risk; Sulfhydryl Compounds; Surface; Thrombus; Training; Tube; Work; analytical method; biomaterial compatibility; divalent metal; graduate student; pre-doctoral; prevent; programs; side effect

PROJECT SUMMARY/ABSTRACT Nitric Oxide (NO) is a gaseous radical continuously produced by the endothelial nitric oxide synthase (eNOS) enzyme within the walls of the blood vessels and is an essential molecule to maintain homeostasis and prevent blood clot formation. NO is an extremely reactive molecule with only 2 ms half-life and can form various metabolites in the blood. The artificial surfaces of blood contacting devices can activate platelets and induce thrombus formation. This is a not desired side effect of Extracorporeal Life Support (ECLS) circuits and is typically prevented by systemic anticoagulation, which however increases the risk of hemorrhagic complications. Hence, there is an effort to create more biocompatible artificial surfaces that obviate the need for systemic anticoagulation. NO emitting artificial surfaces offer attractive solution to this problem. However, the NO payload of such surfaces is inherently limited. In this research supplement we would like to explore an alternative approach, where the available NO payload is circulating within the blood in the form of NO metabolites (e.g., nitrite, small and large molecular weight S-nitroso thiols) as reservoirs and is released upon contact with the chemically modified artificial surface of the biomedical device. We would like to achieve this goal through the following aims: Aim 1: Develop analytical methods to measure circulating NO donors in the blood. Selective analytical methods will be developed to quantify potential circulating NO donors (nitrite, small and large molecular weight S-nitroso thiols) in the blood. Aim 2: Modulate concentration of circulating NO reservoirs in the blood. This aim is to assess the effect of the delivered NO gas on the quantity of individual NO metabolites within the blood. NO gas will be delivered to pre-conditioned blood via an in vitro membrane oxygenator setup. This will allow for precise control of the delivery of NO to the blood (partial pressure of NO and O2, flow rate of sweep gas and blood). Aim 3: Modify EC surfaces that can induce NO release from circulating NO reservoirs. We will coat PVC tubing with a polymer coating doped/covalently modified with divalent metal ions (Cu2+) and assess its ability to induce NO release from the circulating NO reservoirs and to prevent blood clot formation in vitro in Chandler loop model.

项目摘要/摘要 一氧化氮（NO）是由内皮一氧化氮连续产生的气态自由基 血管壁内的合酶（eNOS）酶，是必需的分子 保持体内平衡并防止血凝块形成。否是一个极具反应性的分子 只有2毫秒的半衰期，可以在血液中形成各种代谢物。血液的人造表面 接触装置可以激活血小板并诱导血栓形成。这是不希望的 体外生命支持（ECLS）电路的副作用，通常由全身性阻止 但是，抗凝治疗会增加出血并发症的风险。因此，有一个 努力创建更具生物相容性的人造表面，以消除系统性的需求 抗凝。 没有发射人造表面为这个问题提供了有吸引力的解决方案。但是，没有有效载荷 这样的表面本质上受到限制。 在本研究补充中，我们想探索一种替代方法 没有有效载荷在血液中以无代谢物的形式循环（例如亚硝酸盐，小和 大分子量S-硝基硫醇作为储层，并在与 化学修饰的生物医学装置的人工表面。我们想实现这个目标 通过以下目的： 目的1：开发分析方法来测量血液中没有供体的循环。 将开发选择性分析方法来量化潜在的无捐赠者（亚硝酸盐， 小分子量S-硝基硫醇）在血液中。 AIM 2：调节血液中没有循环的水库的浓度。这个目标是 评估未交付的气体对单个无代谢产物数量的影响 鲜血。不会通过体外膜氧合将气体输送到预先调节的血液中 设置。这将允许精确地控制对血液递送的递送（NO的部分压力和 O2，清扫气体和血液的流速）。 AIM 3：修改EC表面，该表面不会引起不释放无库。 我们将用二价金属离子掺杂/共价修饰的聚合物涂层涂层PVC管 （Cu2+）并评估其诱导不释放的无储存库的能力，并防止 Chandler循环模型的体外血凝块形成。