Augmentation of Tissue Perfusion in PAD with Ultrasound-mediated Cavitation

 描述（由申请人提供）：超声（US）用于各种治疗应用，并已被提议用于增加缺血性心血管疾病的组织灌注。超声可以增加灌注的最重要的非热生物效应是对流运动，其增加剪切力传导。在患者体内使用微泡（MB）造影剂以增强血池，可能会在声空化期间通过微流增强剪切。我们最近证明，超声介导的MB空化可以使肢体组织灌注增加10倍，并且这种作用可以持续超过24小时。本提案的总体目标是组建一个多学科团队，以优化超声介导MB空化技术，并将其从临床前模型过渡到重度症状性外周动脉疾病（PAD）患者的治疗。在目的1中，临床前小动物模型将用于定义关于声压、频率、MB浓度和脉冲间隔的增强肢体灌注的最佳条件，所述脉冲间隔控制发生空化的血管水平。将使用造影超声灌注成像评估效应和空化类型（稳定与惯性） 将从频率功率谱中确定，以便了解流量增加的物理决定因素。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与产生空化的组织体积相关的肢体灌注变化。在前两个目标中，还将生成数据以定义微泡空化的安全性特征。了解急性和长期（>24小时）血流增强的生物学决定因素将是目标3的主题，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、类花生酸和ATP。在目标4中，将应用现有的具有MB空化的优化声学条件的3-D来评价（a）健康人类受试者和（B）PAD和严重肢体缺血患者的肢体组织灌注。这些研究代表了开发重度PAD非侵入性治疗的转化步骤，该治疗可用于实现有意义的即时灌注增加，并可在即时血运重建不可能或不可用的情况下维持肢体组织活力。

 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.