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: 10677544
• 负责人: Kevin Joseph Haworth
• 金额: $ 68.29万
• 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 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10677544
• 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 Separation; Cell Survival; Cells; Cessation of life; Clinical; Coronary artery; Coronary sinus structure; Data; Defect; Devices; Diffusion; 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; 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; Risk Assessment; Stains; Starvation; 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; experimental study; first-in-human; heart cell; human study; improved; in vivo; indexing; manufacture; minimally invasive; mortality; myocardial infarct sizing; myocardial injury; novel; novel therapeutics; percutaneous coronary intervention; porcine model; preservation; pressure; primary outcome; secondary analysis; sensor; success; technology platform; 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 心肌梗死是由缺血事件引起的，通常会导致心肌和 可能会死亡。美国每年约有15万人死于急性心肌梗死 脑梗塞和类似数量的人会因脑梗塞而患上衰弱的心力衰竭。初级阶段 治疗心肌梗死的临床目标是尽快恢复心肌的血流量 有可能。然而，矛盾的是，再灌注会对心肌造成显著的损害。中的 总的梗死体积，可能高达50%，可以归因于再灌注，而不是缺血。这个 再灌注损伤的发生，部分是由于缺血组织将新发现的氧气供应转化为 活性氧物种。活性氧能严重损伤细胞，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 再灌流，以减少细胞死亡的活性氧物种。这项技术依赖于一个过程 称为声学液滴汽化，即液滴转变为气体微泡。 当暴露在超声波下时。微泡充当了全血中氧气的接收器，有效地隔离了 微泡内的氧气，因此较少的氧气扩散到组织中。反过来，组织中的氧气更少 可能会减少氧化应激和细胞死亡。我们的中心假设是超声波介导的氧气 在缺血事件后的再灌流期间进行清除，可增加细胞和组织的存活率。体外细胞 使用培养和体外组织缺血再灌注损伤模型来获得初步数据 支持这一假说。我们的原理验证数据表明，氧气清除是可以进行的 使用血管内超声设备，这简化了体内超声靶向，并将允许 可集成到现有经皮治疗中的经皮途径。我们还有 展示了通过改变液滴的属性来调节氧气清除量的能力 浓度和超声辐照参数。我们将通过关注以下几个方面的研究来检验这一假说 体外、体外和体内清除氧的效率和效果。第一个目标是使我们的 将当前技术转化为与翻译相关的工作系统。研究将调查液滴制造 超声波辐射就要到了。第二个目标将调查大小和持续时间如何 朗宁多夫制剂对离体全心再灌流损伤的清除作用 可同时测量梗塞面积和心功能。这些协议将被转换为In 活体猪缺血再灌注损伤模型。该模型中的主要结果将包括脑梗塞 尺寸测量和血氧测定仪。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。

项目成果

Impact of Perfluoropentane Microdroplets Diameter and Concentration on Acoustic Droplet Vaporization Transition Efficiency and Oxygen Scavenging.

• DOI: 10.3390/pharmaceutics14112392
• 发表时间: 2022-11-05
• 期刊: PHARMACEUTICS
• 影响因子: 5.4
• 作者: Benton, Rachel P.;Al Rifai, Nour;Stone, Kateryna;Clark, Abigail;Zhang, Bin;Haworth, Kevin J.
• 通讯作者: Haworth, Kevin J.

Controlling Reperfusion Injury With Controlled Reperfusion: Historical Perspectives and New Paradigms.

• DOI: 10.1177/10742484211046674
• 发表时间: 2021-11
• 期刊: Journal of cardiovascular pharmacology and therapeutics
• 影响因子: 2.6
• 作者: Fischesser DM;Bo B;Benton RP;Su H;Jahanpanah N;Haworth KJ
• 通讯作者: Haworth KJ