Microbubble-Medicated Ultrasonic Therapy for Microvascular Obstruction

微泡超声治疗微血管阻塞

• 批准号: 9256527
• 负责人: John J Pacella
• 金额: $ 69.27万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9256527
• 关键词: Acoustics; Acute; Acute myocardial infarction; Adverse event; Animal Model; Animal Testing; Area; Arterial Fatty Streak; Arteries; Atherosclerosis; Back; Biological; Cardiovascular Diseases; Caring; Categories; Cessation of life; Clinical; Coagulation Process; Coculture Techniques; Coronary; Coronary heart disease; Data; Distal; EFRAC; Endothelium; Equilibrium; Failure; Family suidae; Gases; Genes; Goals; Heart; Hindlimb; Image; In Vitro; Infarction; Injectable; Intravenous; Limb structure; Liquid substance; Mechanics; Mediating; Methodology; Microbubbles; Microscopy; Microvascular Dysfunction; Modeling; Myocardial; Nitric Oxide; Obstruction; Outcome; Patients; Penetration; Perfusion; Phenotype; Preparation; Rattus; Reperfusion Therapy; Residual state; Resolution; Risk; Rodent; Role; Safety; Series; Signal Recognition Particle; Site; Speed; Stents; Surface; Syndrome; System; Testing; Therapeutic; Therapeutic Embolization; Thrombectomy; Thromboembolism; Thrombosis; Thrombus; Translating; Ultrasonic Therapy; Ultrasonography; Vascular Smooth Muscle; Venous; clinical translation; clinically relevant; clinically translatable; comparative efficacy; design; effective therapy; experimental study; feeding; imaging system; improved; improved outcome; in vitro Model; in vitro testing; in vivo; in vivo Model; innovation; insight; mechanical properties; microscopic imaging; novel; novel strategies; percutaneous coronary intervention; prevent; public health relevance; shear stress; success; targeted treatment; ultrasound biological effect; vibration

 DESCRIPTION (provided by applicant): Despite advances in percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI), post ischemic microvascular obstruction (MVO) due to distal microembolization of atherothrombotic debris from the site of PCI commonly occurs and leads to failure of reperfusion. Post PCI MVO is associated with worse clinical outcomes, and effective treatments are lacking. Ultrasound (US)-induced cavitation (vibration) of intravenously injected microbubbles (MBs), offers an exciting new approach for treating MVO, which we call "sonoreperfusion" (SRP). While SRP has shown potential for treating venous-like thrombi in large vessels, its effects within the microvasculature, and on MVO comprised of arterial type microthrombi and atherosclerotic debris seen in AMI, are unknown. Furthermore, which US cavitational regime is most effective -- stable, inertial, or a combination thereof - is unknown. Accordingly, in this proposal, we will develop, optimize and translate SRP therapy, culminating in testing of the optimal SRP regime in perhaps the most clinically translatable large animal model of AMI and MVO available. We will first test the relative efficacies of candidate SRP platforms using an in vitro flow model of arterial MVO (Aim 1a), in which we will manipulate US variables that encompass 3 regimes: (1) stable cavitation; (2) inertial cavitation; or (3) a sequential combination of both. To understand mechanisms of action underlying successful regimes, we will study the physical consequences of MB vibrations on local fluid dynamics and tPA clot penetration (Aim 1b). In testing this "mechanical hypothesis," we will be the first to use an ultra-high speed microscopy system to delve into dynamics of MB-clot interactions and the resulting physical phenomena elicited by the SRP regimes tested in Aim 1a. Insights from Aim 1b will inform further refinements in the SRP regimes --to be iteratively tested in vitro in Aim 1a- from which 3 platforms (top performer for each cavitation category) will emerge for in vivo testing in a new rat hind limb model of arterial MVO in Aim 2a. Here, in addition to efficacy, the clinical safety of each SRP platform will be assessed and factored into the final selection of a single SRP platform-that balances benefit vs. risk -- for use in Aim 3. As the in vitro model in Aim 1a precludes study of bioeffects that may mediate efficacy of a given SRP platform, we will also use the rat hind limb model to study biological effects of US-MB interactions (Aim 2b): We will test the "biologic hypothesis" that MB vibration-induced endothelial shear stress modulates therapeutic NO release and increased activity of endothelial derived hyperpolarizing factor. In Aim 3, we will use the "best" SRP regime emerging from Aim 2, in a new, clinically relevant, atherosclerotic porcine model of AMI and MVO to assess for microvascular salvage. This systematic approach will culminate in a clinically translatable SRP regime and elucidate mechanisms of action which will inform strategies for optimization of efficacy and safety.

 描述(申请人提供)：尽管经皮冠状动脉介入治疗(PCI)在治疗急性心肌梗死(AMI)方面取得了进展，但由于来自PCI部位的动脉粥样硬化血栓残留物远端微栓塞术导致的缺血后微血管阻塞(MVO)经常发生，并导致再灌注失败。PCIMVO术后临床转归较差，缺乏有效的治疗方法。超声(US)诱导静脉注射微泡(MBS)的空化(振动)为治疗MVO提供了一种令人兴奋的新方法，我们称之为“声再灌流”(SRP)。虽然SRP已显示出治疗大血管中静脉样血栓的潜力，但其在微血管系统中的作用以及对由急性心肌梗死中可见的动脉型微血栓和动脉粥样硬化碎片组成的MVO的影响尚不清楚。此外，美国的哪种空泡体制是最有效的--稳定的、惯性的，还是两者的组合--是未知的。因此，在这项提案中，我们将开发、优化和翻译SRP疗法，最终在可能是最具临床可译性的急性心肌梗死和MVO大型动物模型中测试最佳的SRP方案。我们将首先使用动脉MVO(Aim 1a)的体外流动模型来测试候选SRP平台的相对效率，在该模型中，我们将操纵包括3个区域的US变量：(1)稳定空化；(2)惯性空化；或(3)两者的顺序组合。为了理解成功机制背后的作用机制，我们将研究MB振动对局部流体动力学和tPA凝块渗透的物理后果(目标1b)。在检验这一“机械假说”时，我们将率先使用 一个超高速显微镜系统，用于深入研究MB-凝块相互作用的动力学以及目标1a中测试的SRP制度引发的物理现象。来自AIM 1b的见解将为SRP方案的进一步改进提供信息--将在AIM 1a进行体外迭代测试--从中将出现3个平台(在每个空化类别中表现最好)，用于在Aim 2a的新的大鼠后肢动脉MVO模型中进行体内测试。在这里，除了疗效，每个SRP平台的临床安全性将被评估和考虑到最终选择的单一SRP平台--权衡益处和风险--用于AIM 3。由于AIM 1a中的体外模型无法研究可能介导特定SRP平台有效性的生物效应，我们还将使用大鼠后肢模型来研究US-MB相互作用的生物学效应(Aim 2b)：我们将检验MB振动诱导的内皮切应力调节治疗性NO释放和内皮衍生超极化因子活性增加的“生物假说”。在目标3中，我们将在一个新的、临床相关的、动脉粥样硬化的急性心肌梗死和MVO猪模型中，使用目标2中出现的“最佳”SRP方案来评估微血管的挽救。这一系统的方法将最终形成临床可翻译的SRP制度，并阐明其作用机制，从而为优化疗效和安全性的策略提供信息。