Augmentation of Tissue Perfusion in PAD with Ultrasound-mediated Cavitation

超声介导的空化增强 PAD 中的组织灌注

• 批准号: 9005245
• 负责人: Jonathan R Lindner
• 金额: $ 59.47万
• 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 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9005245
• 关键词: 3-Dimensional; Acoustics; Acute; Acute myocardial infarction; Adenosine; Animal Model; Animals; Applications Grants; Biomedical Research; Biopsy; Blood; Blood Vessels; Blood capillaries; Blood flow; Canis familiaris; Cardiovascular Diseases; Clinical Engineering; Contrast Media; Coronary artery; Custom; Data; Detection; Development; Diagnostic; Eicosanoids; Encapsulated; Endothelial Cells; Exposure to; Family suidae; Frequencies; Gases; Gene Targeting; Generations; Healed; Hindlimb; Hour; Human; Image; Injury; Ischemia; Isolated limb perfusion; Leg; Limb structure; Maps; Measurement; Mediating; Mediator of activation protein; Medicine; Microbubbles; Microbubbles Ultrasound Contrast Medium; Microspheres; Modeling; Motion; Mus; Muscle; Myocardial; NOS3 gene; Necrosis; Nitric Oxide; Pathway interactions; Patients; Pattern; Perfusion; Peripheral; Peripheral arterial disease; Physiologic pulse; Physiological; Physiology; Positioning Attribute; Pre-Clinical Model; Production; Rattus; Research Project Grants; Role; Safety; Signal Transduction; Skeletal Muscle; Techniques; Technology; Testing; Therapeutic; Tissue Viability; Tissues; Transducers; Ultrasonography; Vasodilation; Vasodilator Agents; Vasomotor; angiogenesis; artery stenosis; contrast enhanced; femoral artery; healing; human subject; improved; inhibitor/antagonist; intravital microscopy; multidisciplinary; novel therapeutic intervention; pre-clinical; pressure; public health relevance; response; safety study; shear stress; volunteer

 DESCRIPTION (provided by applicant): Ultrasound (US) is used for a variety of therapeutic applications and has been proposed for increasing tissue perfusion in ischemic cardiovascular disease. The most important non- thermal bioeffect by which US can increase perfusion is convective motion which increases shear mechanotransduction. Microbubble (MB) contrast agents used in patients to enhance the blood pool can potentially augment shear through microstreaming during acoustic cavitation. We have recently demonstrated that US-mediated MB cavitation can augment limb tissue perfusion by up to 10-fold and that this effect can persist for greater than 24 hours. The overall aim of this proposal is to assemble a multidisciplinary team to optimize the technology of US- mediated MB cavitation and transition it from pre-clinical models to the treatment of patients with severe symptomatic peripheral artery disease (PAD). In Aim 1 preclinical small animal models will be used to define optimal conditions for augmenting limb perfusion with regards to acoustic pressure, frequency, MB concentration, and pulsing interval which governs the vascular level at which cavitation occurs. Contrast ultrasound perfusion imaging will be used to assess effect and the type of cavitation (stable versus inertial) will be determined from frequency-power spectra in order to understand the physical determinants for flow augmentation. In Aim 2 we will use large animal models of PAD to spatially characterize and quantify changes in limb perfusion in relation to the volume of tissue in which cavitation is produced. In both of the first two Aims, data will also be generated to define the safety profile for microbubble cavitation. Understanding the biologic determinants for acute and long-term (>24 hour) flow augmentation will be the subject of Aim 3 where we will examine the role of shear- and pressure-dependent mediators of vascular tone. Potential candidate mediators will include NO, adenosine, eicosanoids, and ATP. In Aim 4, an existing 3-D with optimized acoustic conditions for MB cavitation will be applied to evaluate limb tissue perfusion in (a) healthy human subjects, and (b) patients with PAD and critical limb ischemia. These studies represent the translational steps for development of a non-invasive therapy for severe PAD that can be used to achieve meaningful and immediate increases in perfusion, and that can maintain limb tissue viability in situations where immediate revascularization is either not immediately possible or available.

 描述（由申请人提供）：超声（US）用于多种治疗应用，并且已被提议用于增加缺血性心血管疾病中的组织灌注。超声可以增加灌注的最重要的非热生物效应是对流运动，其增加了对流运动。在患者中使用微泡（MB）造影剂来增强血池可能会通过声空化期间的微流增强剪切力。我们最近证明，超声介导的 MB 空化可以增强剪切力。肢体组织灌注增加高达 10 倍，并且这种效果可以持续超过 24 小时。该提案的总体目标是组建一个多学科团队来优化 US 介导的 MB 空化技术并将其从临床前过渡。治疗严重症状性外周动脉疾病 (PAD) 患者的模型 In Aim 1 临床前小动物模型将用于确定在声压、频率、MB 浓度和声学方面增强肢体灌注的最佳条件。控制空化发生的血管水平的脉冲间隔将用于评估空化的效果和类型（稳定与惯性）。 将根据频率功率谱确定，以便了解流量增强的物理决定因素。在目标 2 中，我们将使用 PAD 的大型动物模型来空间表征和量化肢体灌注相对于空化发生的组织体积的变化。在前两个目标中，还将生成数据来定义微泡空化的安全性，了解急性和长期（>24 小时）流量增加的生物决定因素将是该目标的主题。在图 3 中，我们将研究血管张力的剪切和压力依赖性介质的作用。潜在的候选介质包括 NO、腺苷、类二十烷酸和 ATP。在目标 4 中，将使用具有优化的 MB 空化声学条件的现有 3-D。用于评估（a）健康人类受试者和（b）患有 PAD 和严重肢体缺血的患者的肢体组织灌注，这些研究代表了开发严重肢体缺血的非侵入性疗法的转化步骤。 PAD 可用于实现有意义且立即的灌注增加，并且可以在无法立即进行或无法立即进行血运重建的情况下维持肢体组织的活力。