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

基本信息

批准号：
10153874
负责人：
Kevin Joseph Haworth
金额：
$ 73.38万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
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/10153874
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 Ultrasonography 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 vaporization

项目摘要

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。活性氧会严重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一假设体外、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。