Microbubble-Medicated Ultrasonic Therapy for Microvascular Obstruction

微泡超声治疗微血管阻塞

• 批准号: 9100904
• 负责人: John J Pacella
• 金额: $ 64.2万
• 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/9100904
• 关键词: Accounting; 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; Health; Heart; Hindlimb; Image; In Vitro; Infarction; Left; Limb structure; Liquid substance; Mechanics; Mediating; Methodology; Microbubbles; Microscopy; Microvascular Dysfunction; Modeling; Myocardial; Nitric Oxide; Obstruction; Outcome; Patients; Penetration; Perfusion; Phenotype; Preparation; Property; Rattus; Reperfusion Therapy; Residual state; Resolution; Risk; Rodent; Role; Safety; Series; Site; Speed; Surface; Syndrome; System; Testing; Therapeutic; Therapeutic Embolization; Thrombectomy; Thromboembolism; Thrombosis; Thrombus; Translating; Translations; Ultrasonic Therapy; Ultrasonography; Vascular Smooth Muscle; Venous; biological systems; clinical efficacy; clinically relevant; comparative efficacy; design; effective therapy; feeding; imaging system; improved; improved outcome; in vitro Model; in vitro testing; in vivo; in vivo Model; innovation; insight; microscopic imaging; novel; novel strategies; percutaneous coronary intervention; prevent; research study; 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（由申请人提供）：尽管急性心肌梗死（AMI）的经皮冠状动脉介入治疗（PCI）取得了进展，但由于来自PCI部位的动脉粥样硬化血栓碎片的远端微栓塞而导致的缺血后微血管阻塞（MVO）通常会发生并导致再灌注失败。PCI术后MVO与较差的临床结局相关，缺乏有效的治疗方法。超声（US）诱导的静脉注射微泡（MB）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“声再灌注”（SRP）。虽然SRP已显示出治疗大血管中静脉样血栓的潜力，但其在微血管系统内的作用以及对由AMI中观察到的动脉型微血栓和动脉粥样硬化碎片组成的MVO的作用尚不清楚。此外，美国的空化机制是最有效的-稳定，惯性，或两者的组合-是未知的。因此，在本提案中，我们将开发、优化和转化SRP疗法，最终在可能是最具临床可转化性的AMI和MVO大型动物模型中测试最佳SRP方案。 我们将首先使用动脉MVO的体外血流模型（目标1a）测试候选SRP平台的相对有效性，其中我们将操纵包含3种方案的US变量：（1）稳定空化;（2）惯性空化;或（3）两者的顺序组合。为了了解成功方案的作用机制，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（目的1b）。在测试这个“机械假说”时，我们将首先使用 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方案引起的物理现象。目标1b的见解将为SRP方案的进一步改进提供信息-在目标1a中进行体外迭代测试-从中将出现3个平台（每个空化类别的最佳表现者），用于在目标2a中的动脉MVO的新大鼠后肢模型中进行体内测试。在此，除了有效性之外，还将评估每个SRP平台的临床安全性，并将其作为最终选择单个SRP平台的因素-平衡获益与风险-用于目标3。由于目标1a中的体外模型排除了可能介导给定SRP平台疗效的生物效应研究，我们还将使用大鼠后肢模型研究US-MB相互作用的生物效应（目标2b）：我们将检验“生物学假设”，即MB振动诱导的内皮剪切应力调节治疗性NO释放和内皮源性超极化因子活性增加。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AMI和MVO猪模型中使用目标2中出现的“最佳”SRP方案，以评估微血管挽救。这种系统性方法将最终形成临床上可翻译的SRP方案，并阐明作用机制，这将为优化疗效和安全性的策略提供信息。