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.

项目总结/摘要 心肌梗塞由缺血事件引起，并且通常导致心肌损伤， 可能死亡。在美国，每年约有15万人死于急性心肌梗死。 梗塞和类似数量的人继续遭受由于梗塞而导致的衰弱性心力衰竭。主 治疗心肌梗塞的临床目标是尽快恢复心肌的血流 可能然而，矛盾的是，再灌注可对心肌造成显著损害。的 可能高达50%的总梗塞体积可归因于再灌注而不是局部缺血。的 再灌注损伤的发生部分是由于缺血组织将新发现的氧供应转化为 活性氧物质。活性氧能显著损伤细胞并导致细胞死亡。这 该项目将开发一种基于超声波的氧气清除方法，以实现受控的低氧血症 再灌注以减少活性氧引起的细胞死亡。这项技术依赖于一个过程 被称为声学液滴蒸发，其中液滴相变成气体微泡 当暴露于超声波时。微泡在全血中充当氧气的水槽，有效地隔离 微泡内的氧气，使得更少的氧气扩散到组织中。反过来，组织中的氧气减少 可以减少氧化应激和细胞死亡。我们的核心假设是超声波介导的氧气 在缺血事件之后的再灌注期间的清除增加了细胞和组织的生存力。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。我们的原理证明数据表明，氧清除可以完成 使用血管内超声装置，这简化了体内超声靶向， 经皮方法，可以集成到现有的经皮治疗。我们还 证明了通过改变液滴性质、液滴性质和液滴浓度来调节氧清除量的能力。 浓度和超声辐照参数。我们将通过以下研究来验证这一假设： 体外、离体和体内氧清除的效率和功效。第一个目标是调整我们的 将当前的技术融入到相关的工作系统中。研究将调查液滴制造 和超声波治疗方法。第二个目标将调查的规模和持续时间如何 氧清除作用再灌注损伤，使用具有Langendorff制剂的离体全心脏， 能够测量梗死面积和心室功能。这些协议将被翻译成一个 缺血-再灌注损伤的体内猪模型。该模型中的主要结局将包括梗死 尺寸测量和血氧测定。这些实验的进展将确保彻底了解 以及如何对该方法进行修改以提高治疗效果。