Augmentation of Tissue Perfusion with Ultrasound-mediated Cavitation

用超声介导的空化增强组织灌注

• 批准号: 10188594
• 负责人: Jonathan R Lindner
• 金额: $ 77.72万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-12 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10188594
• 关键词: 3-Dimensional; 3D ultrasound; Acoustics; Acute; Address; Adenosine; Adenosine A2B Receptor; Affect; Age; Animal Model; Antiinflammatory Effect; Area; Atherosclerosis; Award; Blood Vessels; Blood flow; Caliber; Cardiovascular Diseases; Catheters; Chronic; Chronic Disease; Clinical Trials; Clinical Trials Design; Coagulation Process; Complication; Contrast Media; Convection; Coronary Arteriosclerosis; Coronary artery; Cytolysis; Development; Diabetes Mellitus; Diagnostic Imaging; Diffuse; Disease; Distal; Dose; Elements; Encapsulated; Endothelial Cells; Endothelium; Erythrocytes; Foundations; Frequencies; Funding; Gene-Modified; Grant; Health Care Costs; Heart; Heart failure; Human; Human Biology; Hyperlipidemia; Infarction; Inflammation; Ischemia; Isolated limb perfusion; Knowledge; Left Ventricular Dysfunction; Leg; Leg Ulcer; Limb structure; Lung; Maps; Mediating; Mediator of activation protein; Methods; Microbubbles; Microcirculation; Modeling; Morbidity - disease rate; Motion; Mus; Muscle; Muscle relaxation phase; Myocardial Ischemia; Myocardial perfusion; Myocardium; Pathway interactions; Patients; Perfusion; Peripheral; Peripheral arterial disease; Physiologic pulse; Pilot Projects; Pre-Clinical Model; Primates; Prostaglandins; Protocols documentation; Pulmonary Embolism; Pulmonary Vascular Resistance; Receptor Signaling; Regional Perfusion; Reperfusion Therapy; Rest; Risk; Risk Factors; Role; Scheme; Signal Transduction; Skeletal Muscle; Smooth Muscle; Syndrome; System; Techniques; Testing; Therapeutic; Thrombosis; Tissue Preservation; Tissue Viability; Tissues; Ultrasonic Therapy; Ultrasonography; United States; Vascular Diseases; Vascular resistance; Vasodilation; Vasospasm; acute coronary syndrome; atherosclerosis risk; base; clinical diagnostics; clinical effect; contrast enhanced; critical limb Ischemia; design; frailty; improved; inhibitor/antagonist; limb ischemia; mortality; mouse model; necrotic tissue; nonhuman primate; novel; novel therapeutic intervention; preconditioning; pressure; prevent; receptor; sex; thrombotic; volunteer; wound healing

SUMMARY Ultrasound (US) is used for a variety of therapeutic applications. Over a range of different frequencies and powers, US has been shown to produce to produce modest increases in arterial diameter and tissue perfusion in animal models of limb and myocardial ischemia. In the initial funding period for this award, we described how the combination of US with microbubble (MB) contrast agents that undergo inertial cavitation during high-power contrast-enhanced US (CEU) produces much greater augmentation of limb skeletal muscle perfusion (up to 10-fold) than US alone. Brief CEU cavitation protocols were found to reverse limb ischemia for >24 hrs in animal models, and a clinical trial in patients with peripheral artery disease (PAD) confirmed that MB cavitation increases limb perfusion by several fold. In the course of our studies, optimal conditions for these bioeffects were investigated which mandated us to design novel US pulse schemes and 3-D exposure capability. From a mechanistic standpoint, we carefully mapped pathways responsible for cavitation-induced flow augmentation which rely on shear-mediated ATP release from endothelial cells and erythrocytes, with secondary purinergic vasodilation through downstream mediators (NO, prostaglandins, adenosine). Knowledge of the optimal conditions and mechanistic underpinnings is critical for our current efforts to apply cavitation and activation of ATP channels to treat ischemic disease by augmenting flow or by other potentially beneficial anti-thrombotic and anti-inflammatory effects of purinergic signaling. The overall aim of this renewal is to leverage knowledge from the first funding period in order to explore the therapeutic role of cavitation and non-cavitation US for acute and chronic ischemic syndromes. In Aim 1 preclinical models will be used to determine whether limb flow-augmentation from MB cavitation using previously-optimized pulse schemes can: (a) prevent tissue necrosis in acute ischemia, with a particular focus on the effect of clinical variables (age, sex, hyperlipidemia, diabetes), and (b) improve wound healing and limb function in chronic disease. The functional role of purinergic vascular signaling will be evaluated by using inhibitor strategies or gene--modified models. In Aim 2 we will determine whether MB cavitation directly augments myocardial perfusion in acute MI using murine models that allow us to manipulate purinergic pathways, and in primate models that more closely resemble human biology. We will also study how US-mediated ATP release has the potential to mitigate inflammation, and microvascular thrombosis upon reperfusion. In Aim 3 we will test whether US energy from multi-element high-power intra- arterial catheters increases downstream perfusion through shear-mediated purinergic pathways. This Aim is based on evidence that therapeutic US catheters used in patients with pulmonary embolism can reduce pulmonary vascular resistance even without clot lysis. Our proposal represents the translational steps for development of non-invasive therapies for acute and chronic vascular diseases and will form the basis for the design of clinical trials that we plan to initiate as the key unsolved issues are addressed.

概括 超声波（美国）用于多种治疗应用。在一系列不同的频率和 美国已被证明可以适度增加动脉直径和组织灌注 在肢体和心肌缺血的动物模型中。在该奖项的初始资助期间，我们描述了如何 US 与微泡 (MB) 造影剂的组合，在高功率期间经历惯性空化 对比增强超声 (CEU) 可以更大程度地增强肢体骨骼肌灌注（高达 10 倍）比仅美国就高。研究发现，简短的 CEU 空化方案可逆转肢体缺血 >24 小时 动物模型和外周动脉疾病 (PAD) 患者的临床试验证实，MB 空化 使肢体灌注增加数倍。在我们的研究过程中，这些生物效应的最佳条件 进行了调查，要求我们设计新颖的 US 脉冲方案和 3D 曝光能力。来自一个 从机械的角度来看，我们仔细绘制了导致空化引起的流动增强的路径 依赖于内皮细胞和红细胞剪切介导的 ATP 释放，具有次级嘌呤能 通过下游介质（NO、前列腺素、腺苷）舒张血管。最优知识 条件和机械基础对于我们当前应用空化和激活的努力至关重要 ATP 通道通过增加血流或其他潜在有益的抗血栓药物来治疗缺血性疾病 和嘌呤能信号的抗炎作用。此次更新的总体目标是利用知识 从第一个资助期开始，为了探索空化和非空化超声的治疗作用 急性和慢性缺血综合征。在目标 1 中，将使用临床前模型来确定肢体是否 使用先前优化的脉冲方案通过 MB 空化增强流量可以： (a) 防止组织 急性缺血坏死，特别关注临床变量（年龄、性别、高脂血症、 糖尿病），以及（b）改善慢性疾病的伤口愈合和肢体功能。嘌呤能的功能作用 将通过使用抑制剂策略或基因修饰模型来评估血管信号传导。在目标 2 中，我们将 使用小鼠模型确定 MB 空化是否直接增加急性 MI 中的心肌灌注 使我们能够在更接近人类生物学的灵长类动物模型中操纵嘌呤能途径。 我们还将研究 US 介导的 ATP 释放如何具有减轻炎症和微血管的潜力 再灌注时血栓形成。在目标 3 中，我们将测试美国能源是否来自多元素高功率内部 动脉导管通过剪切介导的嘌呤能途径增加下游灌注。这个目标是 基于证据表明，用于肺栓塞患者的治疗性美国导管可以减少 即使没有血栓溶解，肺血管阻力也会增加。我们的建议代表了转化步骤 开发针对急性和慢性血管疾病的非侵入性疗法，并将成为以下领域的基础： 我们计划在解决关键的未解决问题后启动临床试验的设计。