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.

项目摘要/摘要 心肌梗死是由缺血性事件引起的，通常会导致心肌损坏 潜在的死亡。由于急性心肌，美国每年大约150,000人死亡 梗塞和类似的数量仍在因梗塞引起的心力衰竭而衰弱。主要 心肌梗死治疗期间的临床目标是恢复流向心肌的血流 可能的。但是，自相矛盾的是，再灌注会对心肌造成重大损害。的 总梗塞量，可能归因于再灌注，而不是缺血。这 再灌注损伤，部分原因是缺血组织将氧气的新发现供应转化为 活性氧。活性氧可能会显着损害细胞并导致细胞死亡。这 项目将开发一种基于超声的氧气清除方法，以启用受控的低氧质量 再灌注以减少活性氧的细胞死亡。该技术依赖于一个过程 被称为声液滴汽化 当暴露于超声波时。微泡是全血的氧气水槽，有效地隔离 微泡中的氧气，因此较少的氧气扩散到组织中。反过来，组织中的氧气较少 可能会减少氧化应激和细胞死亡。我们的中心假设是超声介导的氧气 在再灌注期间，在缺血事件后清除会增加细胞和组织活力。体外细胞 培养和离体组织模型已使用用于获得初步数据 支持这一假设。我们的原理证明数据表明可以清除氧气 使用血管内超声设备，这简化了体内超声靶向，并允许 可以将经皮整合到现有经皮疗法中的经皮方法。我们也有 证明了通过修饰液滴特性（液滴）来调整氧气清除量的能力 浓度和超声调节参数。我们将通过关注的研究来检验假设 氧气在体外，体内和体内清除的效率和功效。第一个目的是适应我们的 当前技术成为翻译相关的工作系统。研究将研究液滴制造 和超声声音方法。第二个目标将调查幅度和持续时间 氧气清除效应效应再灌注损伤，使用孤立的整个心脏和兰多夫准备 可以测量梗塞大小和心室功能。这些协议将被翻译成一个 缺血再灌注损伤的体内猪模型。该模型中的主要结果将包括梗塞 尺寸测量和血氧仪。这些实验的进展将确保彻底理解 治疗以及如何对方法进行修改以提高治疗功效。