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.

项目概要/摘要 一氧化氮（NO）是由内皮一氧化氮不断产生的气态自由基 血管壁内的合成酶（eNOS）是一种重要的分子 维持体内平衡并防止血栓形成。 NO 是一种极其活泼的分子 半衰期仅为2毫秒，可在血液中形成多种代谢物。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。这是一个不想要的 体外生命支持 (ECLS) 回路的副作用通常可以通过全身系统来预防 抗凝治疗，但这会增加出血并发症的风险。因此，有一个 努力创造更具生物相容性的人造表面，从而消除系统性的需要 抗凝。 不排放人造表面为这个问题提供了有吸引力的解决方案。然而，没有有效负载 这种表面本质上是有限的。 在本研究补充中，我们希望探索一种替代方法，其中可用的 NO 有效负载以 NO 代谢物（例如亚硝酸盐、小分子和小分子）的形式在血液中循环。 大分子量的S-亚硝基硫醇）作为储存库，并在与物质接触时释放 生物医学装置的化学改性人造表面。我们希望实现这个目标 通过以下目标： 目标 1：开发测量血液中循环 NO 供体的分析方法。 将开发选择性分析方法来量化潜在的循环 NO 供体（亚硝酸盐、 血液中的小分子量和大分子量 S-亚硝基硫醇）。 目标 2：调节血液中循环 NO 储存库的浓度。这个目的是为了 评估所输送的 NO 气体对内部单个 NO 代谢物数量的影响 血。 NO 气体将通过体外膜氧合器输送至预先调节的血液中 设置。这将允许精确控制 NO 向血液的输送（NO 分压和 O2，吹扫气和血液的流速）。 目标 3：修改 EC 表面，诱导 NO 从循环 NO 储存库中释放。 我们将用二价金属离子掺杂/共价改性的聚合物涂层涂覆 PVC 管 (Cu2+) 并评估其诱导 NO 从循环 NO 库中释放并防止 钱德勒循环模型中体外血凝块形成。