Scar Detection and Treatment with Droplet Activation

项目摘要 可商购的磷脂包封的全氟丙烷微泡可以被压缩成 亚微米大小的液滴，即使在体温下也能在壳内保持液态。 我们已经证明，这些带壳的液滴具有明显不同的声学特性， 它们是由微泡形成的，并且可以积聚在正在形成的心肌瘢痕区内。 此外，我们已经蒸发这些液滴与诊断高机械指数（MI）经胸 超声在小型和大型心肌缺血和再灌注（I/R）动物模型中的应用。我们现在已经 证实了在血管外位置包括肌浆内存在液滴， I/R后静脉注射。选择性激活/空化的诊断和治疗潜力 本应用将探索正在形成的疤痕区（DSZ）内的液滴。核心假设 该项目的一个重要特点是，静脉注射的全氟丙烷液滴在DSZ内可以蒸发， 高MI诊断超声以及随后背景扣除强度将与 液滴浓度此外，我们预计，这些形成的微泡的活化和空化 将增加组织一氧化氮的产生，从而缩小DSZ的尺寸。这项建议 旨在解决必须克服的重大知识差距，以充分检验这一假设。的 必须确定液滴汽化的诊断超声阈值，以及 所形成的微泡表现为聚结、空化或再冷凝 汽化我们将采用超高速（>106兆赫帧速率）摄像机来检测激活 （蒸发）阈值并检查所形成的微泡行为。我们将利用体外流动系统 使用无源空化检测器来确定微血管中的激活和空化阈值， 血管血流条件。我们将分析微滴的微血管位置（血管或血管外） 在正常条件下和大鼠提睾肌I/R后。然后我们将选择性地 在心肌I/R的大鼠模型中，对DSZ的激活/空化脉冲。硝酸的选择性活化 也将验证疤痕区域内的氧化物活性，以及它如何受到施加时间的影响。 与再灌注相关的激活/空化脉冲。然后我们将评估选择性 在心肌I/R的大型动物模型中，通过激活/空化来量化梗死面积。最后，我们将评估 静脉注射后DSZ选择性激活/空化成像的长期治疗效果 在猪I/R模型中，在再灌注后的不同时间点注射全氟丙烷液滴。 该项目将确定选择性液滴激活和空化的潜力，以检测正在发展的 瘢痕区，以及这种激活/空化过程如何改变损伤后的左心室重塑。

Project Summary Commercially available phospholipid encapsulated perfluoropropane microbubbles can be compressed into droplets that are submicron in size and remain in a liquid form within their shell even at body temperatures. We have demonstrated that these shelled droplets have significantly different acoustic properties than the microbubbles they are formed from, and can accumulate within a developing myocardial scar zone. Moreover, we have vaporized these droplets with diagnostic high mechanical index (MI) transthoracic ultrasound in small and large animal models of myocardial ischemia and reperfusion (I/R). We have now demonstrated droplet presence within extravascular locations including the sarcoplasm following intravenous injection after I/R. The diagnostic and therapeutic potential of selective activation/cavitation of droplets within the developing scar zone (DSZ) will be explored in this application. The central hypothesis of this project is that intravenously injected perfluoropropane droplets within the DSZ can be vaporized with high MI diagnostic ultrasound, and that subsequent background-subtracted intensities will correlate with droplet concentration. Furthermore, we project that activation and cavitation of these formed microbubbles will increase tissue nitric oxide production, resulting in a reduction in the size of the DSZ. This proposal seeks to address significant knowledge gaps that must be overcome to adequately test this hypothesis. The diagnostic ultrasound thresholds for droplet vaporization must be determined, and what specific behavior the formed microbubbles exhibit in terms of coalescence, cavitation, or re-condensation following vaporization. We will employ an ultra-high speed (>106 Megahertz frame rate) camera to detect activation (vaporization) thresholds and examine the formed microbubble behavior. We will utilize in vitro flow systems with passive cavitation detectors to determine activation and cavitation thresholds in microvascular and vascular flow conditions. We will analyze the microvascular location of droplets (vascular or extravascular) under normal conditions and following I/R in the rat cremaster muscle. We will then apply selective activation/cavitation pulses to the DSZ in a rat model of myocardial I/R. The selective activation of nitric oxide activity within the scar zone will also be verified, and how it is affected by the timing of the applied activation/cavitation impulses in relation to reperfusion. We will then assess the ability of selective activation/cavitation to quantify infarct size in a large animal model of myocardial I/R. Finally, we will assess the long-term therapeutic effect of selective activation/cavitation imaging of the DSZ following intravenous injections of perfluoropropane droplets at different time points following reperfusion in porcine models of I/R. This project will determine the potential for selective droplet activation and cavitation to detect the developing scar zone, and how this activation/cavitation process may alter left ventricular remodeling following injury.