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）：尽管针对急性心肌梗塞（AMI）的经皮冠状动脉介入治疗（PCI）取得了进展，但由于 PCI 部位动脉粥样硬化血栓碎片的远端微栓塞引起的缺血后微血管阻塞（MVO）经常发生，并导致治疗失败。 PCI 后 MVO 与较差的临床结果相关，并且缺乏超声（US）引起的静脉内空化（振动）的有效治疗。注射微泡 (MB) 为治疗 MVO 提供了一种令人兴奋的新方法，我们称之为“声灌注”(SRP)，虽然 SRP 已显示出治疗大血管中静脉样血栓的潜力，但它对微脉管系统和 MVO 的影响包括在内。 AMI 中出现的动脉型微血栓和动脉粥样硬化碎片的情况尚不清楚。此外，哪种超声空化方案最有效（稳定、惯性或两者的组合）也是未知的。因此，在本提案中，我们将开发、优化和转化 SRP 疗法，最终在可能是临床上最具可转化性的 AMI 和 MVO 大型动物模型中测试最佳 SRP 方案，我们将首先测试候选药物的相对疗效。 SRP 平台使用动脉 MVO 的体外流动模型（目标 1a），其中我们将操纵包含 3 个状态的 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机制的作用机制，我们将研究 MB 振动对局部流体动力学和 tPA 凝块渗透的物理影响（目标 1b）。成为第一个使用的人 一个超高速显微镜系统，用于深入研究 MB 与血块相互作用的动力学以及 Aim 1a 中测试的 SRP 方案所引发的物理现象，Aim 1b 中的见解将为 SRP 方案的进一步改进提供信息——将在 Aim 1a 中进行迭代测试。 Aim 1a- 中的体外试验将出现 3 个平台（每个空化类别的最佳表现），用于 Aim 中新的大鼠后肢动脉 MVO 模型的体内测试2a. 此处，除了功效之外，还将评估每个 SRP 平台的临床安全性，并将其纳入最终选择单一 SRP 平台的因素（平衡效益与风险）以用于目标 3。在目标 1a 中排除了可能介导给定 SRP 平台功效的生物效应的研究，我们还将使用大鼠后肢模型来研究 US-MB 相互作用的生物效应（目标 2b）：我们将测试“生物”假设“MB 振动诱导的内皮剪切应力调节治疗性 NO 释放并增加内皮衍生超极化因子的活性。在目标 3 中，我们将在一种新的、临床相关的动脉粥样硬化猪中使用从目标 2 中出现的“最佳”SRP 方案AMI 和 MVO 模型来评估微血管挽救，这种系统方法将最终形成可临床转化的 SRP 方案并阐明其作用机制。将为优化功效和安全性的策略提供信息。