Ultrasound-mediated Controlled Hypoxemic Reperfusion for Inhibition of Reperfusion Injury

超声介导的控制低氧再灌注抑制再灌注损伤

• 批准号: 10391488
• 负责人: Kevin Joseph Haworth
• 金额: $ 72.21万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10391488
• 关键词: Acoustics; Acute myocardial infarction; Address; American; Animal Model; Anterior Descending Coronary Artery; Biological Markers; Blood; Blood Vessels; Blood flow; Buffers; Cardiac Myocytes; Cardiac Volume; Catheters; Cell Culture Techniques; Cell Death; Cell Survival; Cells; Cessation of life; Clinical; Coronary artery; Coronary sinus structure; Data; Defect; Devices; Diffuse; Distal; Emergency Situation; Emulsions; Ensure; Event; Exposure to; Family suidae; Fluorocarbons; Free Radicals; Frequencies; Gases; Goals; Heart; Heart Injuries; Heart failure; Hypoxemia; Hypoxia; In Vitro; Infarction; Interruption; Ischemia; Lead; Left; Life; Ligation; Liquid substance; Measurement; Measures; Mechanics; Mediating; Microbubbles; Microfluidics; Modeling; Modification; Morbidity - disease rate; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardium; Outcome; Oxidative Stress; Oxygen; Oxygen saturation measurement; Partial Pressure; Patients; Perfusion; Phase Transition; Physiologic pulse; Physiological; Preparation; Process; Production; Property; Protocols documentation; Rattus; Reactive Oxygen Species; Reperfusion Injury; Reperfusion Therapy; Risk; Savings; Stains; Stuttering; System; Techniques; Technology; Testing; Tetrazolium; Therapeutic; Therapeutic Embolization; Time; Tissue Model; Tissue Viability; Tissues; Translating; Treatment Efficacy; Troponin; United States; Ventricular; Ventricular Function; Whole Blood; base; experimental study; first-in-human; heart cell; human study; improved; in vivo; indexing; minimally invasive; mortality; myocardial infarct sizing; myocardial injury; novel; novel therapeutics; percutaneous coronary intervention; porcine model; preservation; pressure; primary outcome; secondary analysis; sensor; success; ultrasound; vaporization

PROJECT SUMMARY/ABSTRACT Myocardial infarction is induced by an ischemic event and often leads to damage of the myocardium and potentially death. Approximately 150,000 deaths occur each year in the United States due to acute myocardial infarction and a similar number go on to suffer from debilitating heart failure due to the infarction. The primary clinical goal during treatment of myocardial infarction is to restore blood flow to the myocardium as quickly as possible. However, paradoxically, the reperfusion can cause significant damage to the myocardium. Of the total infarcted volume, potentially up to 50% can be attributed to reperfusion and not ischemia. The reperfusion injury occurs, in part, due to the ischemic tissue converting the newfound supply of oxygen into reactive oxygen species. Reactive oxygen species can significantly damage a cell and lead to cell death. This project will develop an ultrasound-based oxygen scavenging approach to enable controlled hypoxemic reperfusion in order to reduce cell death from reactive oxygen species. The technique relies on a process known as acoustic droplet vaporization, where a liquid droplet is phase-transitioned into a gas microbubble when exposed to ultrasound. The microbubble acts a sink for oxygen in whole blood, effectively sequestering the oxygen within the microbubble so that less oxygen diffuses into the tissue. In turn, less oxygen in the tissue may reduce oxidative stress and cell death. Our central hypothesis is that ultrasound-mediated oxygen scavenging during reperfusion, following an ischemic event, increases cell and tissue viability. In vitro cell culture and ex vivo tissue models of ischemia-reperfusion injury have been used to obtain preliminary data supporting this hypothesis. Our proof-of-principle data demonstrates that oxygen scavenging can be done using intravascular ultrasound devices, which simplifies in vivo ultrasound targeting and would allow for a percutaneous approach that can be integrated into existing percutaneous treatments. We have also demonstrated the ability to tune the amount of oxygen scavenging by modifying droplet properties, droplet concentrations, and ultrasound insonation parameters. We will test the hypothesis through studies focusing on the efficiency and efficacy of oxygen scavenging in vitro, ex vivo, and in vivo. The first aim is to adapt our current technology into a translationally relevant working system. Studies will investigate droplet manufacturing and ultrasound insonation approaches. The second aim will investigate how the magnitude and duration of oxygen scavenging effect reperfusion injury using an isolated whole heart with Langendorff preparation that enables measurement of both infarct size and ventricular function. These protocols will be translated to an in vivo porcine model of ischemia-reperfusion injury. The primary outcomes within that model will include infarct size measurement and oximetry. The progression of these experiments will ensure a thorough understanding of the therapy and how modifications to the approach can be made to improve therapeutic efficacy.

项目概要/摘要 心肌梗塞是由缺血事件引起的，通常会导致心肌和心肌的损伤。 潜在的死亡。美国每年约有 15 万人因急性心肌梗塞死亡 梗塞和类似数量的人继续遭受因梗塞而导致的衰弱性心力衰竭。初级 心肌梗死治疗的临床目标是尽快恢​​复心肌血流 可能的。然而，矛盾的是，再灌注会对心肌造成严重损害。的 总梗塞体积可能高达 50%，可归因于再灌注而非缺血。这 再灌注损伤的发生部分是由于缺血组织将新发现的氧气转化为 活性氧。活性氧可以显着损害细胞并导致细胞死亡。这 该项目将开发一种基于超声波的除氧方法，以实现控制低氧血症 再灌注以减少活性氧造成的细胞死亡。该技术依赖于流程 称为声学液滴汽化，其中液滴相变为气体微泡 当暴露于超声波时。微泡充当全血中氧气的接收器，有效隔离 微泡内的氧气，从而减少扩散到组织中的氧气。反过来，组织中的氧气减少 可以减少氧化应激和细胞死亡。我们的中心假设是超声波介导的氧气 缺血事件后再灌注期间的清除可增加细胞和组织的活力。体外细胞 缺血再灌注损伤的培养和离体组织模型已用于获得初步数据 支持这一假设。我们的原理验证数据表明可以进行除氧 使用血管内超声设备，这简化了体内超声定位并允许 经皮方法可以整合到现有的经皮治疗中。我们还有 证明了通过改变液滴特性来调节氧清除量的能力，液滴 浓度和超声声波参数。我们将通过研究来检验这个假设 体外、离体和体内除氧的效率和功效。第一个目标是适应我们的 将当前技术转化为可转化的相关工作系统。研究将调查液滴制造 和超声波方法。第二个目标将调查影响的幅度和持续时间 使用带有 Langendorff 制剂的离体全心来清除氧对再灌注损伤的影响 能够测量梗塞面积和心室功能。这些协议将被翻译成一个in 猪体内缺血再灌注损伤模型。该模型中的主要结果将包括梗塞 尺寸测量和血氧测定。这些实验的进展将确保彻底理解 治疗方法以及如何修改该方法以提高治疗效果。