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，并已被建议用于增加缺血性心血管疾病的组织灌注量。超声能增加血流灌注的最重要的非热生物效应是对流运动，它增加了剪切力传导。用于患者增强血池的微泡(MB)造影剂可以潜在地通过声空化过程中的微流来增强剪切力。我们最近已经证明，超声引导的MB空化可以将肢体组织的灌注量增加10倍，并且这种效果可以持续24小时以上。这项建议的总体目标是组建一个多学科团队，以优化美国介导的MB空化技术，并将其从临床前模型过渡到治疗严重症状性外周动脉疾病(PAD)的患者。在目标1中，临床前的小动物模型将被用来定义关于声压、频率、MB浓度和控制空化发生的血管水平的脉冲间隔的最佳条件来增加肢体灌注量。超声造影灌注成像将用于评估效果和空化的类型(稳定与惯性)。 将根据频谱-功率谱确定，以便了解流量增大的物理决定因素。在目标2中，我们将使用PAD的大型动物模型来描述和量化与产生空洞的组织体积相关的肢体血流灌注的变化。在前两个目标中，还将生成数据来定义微泡空化的安全概况。了解急性和长期(24小时)血流增加的生物决定因素将是目标3的主题，在那里我们将研究剪切和压力依赖的血管张力介质的作用。潜在的候选介质将包括一氧化氮、腺苷、二十烷基类化合物和三磷酸腺苷。在目标4中，现有的具有优化的MB空化声学条件的3-D将用于评估(A)健康人和(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一种非侵入性治疗重度PAD的转化步骤，该方法可用于实现有意义的立即增加灌注量，并可在无法立即进行血管重建的情况下维持肢体组织的存活。

 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.