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: 10592406
• 负责人: Jonathan R Lindner
• 金额: $ 78.17万
• 依托单位: UNIVERSITY OF VIRGINIA
• 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 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10592406
• 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; Cardiovascular Diseases; Catheters; Chronic; Chronic Disease; Clinical Trials; Clinical Trials Design; Coagulation Process; Complication; Contrast Media; Coronary Arteriosclerosis; Coronary artery; Cytolysis; Development; Diabetes Mellitus; Diagnostic Imaging; Diameter; 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; 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; United States; Vascular Diseases; Vascular resistance; Vascularization; Vasodilation; Vasospasm; acute coronary syndrome; atherosclerosis risk; clinical diagnostics; clinical effect; contrast enhanced; critical limb Ischemia; design; frailty; improved; inhibitor; limb ischemia; mortality; mouse model; necrotic tissue; nonhuman primate; novel; novel therapeutic intervention; preconditioning; pressure; prevent; receptor; sex; thrombotic; trial planning; ultrasound; 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.

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