Design of Noninvasive Therapies Utilizing Nonlinear Focused Ultrasound With Shocks

项目总结 肾癌和肝细胞癌是两种最常见的腹部实体瘤 年，美国器官恶性肿瘤新增病例近10万例，死亡近4万例 2015年[思高2015年]。随着最近成像技术的进步导致了早期诊断，医疗实践正在发生变化 使用微创局部疗法(例如，射频消融、冷冻疗法)进行治疗 肿瘤。然而，这些治疗方法有局限性：它们需要侵入性部署，并依赖于热疗。 控制不佳的影响，特别是在可用作散热片的血管结构附近。此外, 实时治疗监测能力很低，因为热损伤不容易在 标准成像技术。高强度聚焦超声(HIFU)提供了一种替代的焦点治疗方法 这可以非侵入性地交付。目前，临床上的HIFU治疗包括热消融， 然而，沸腾组织镜检查(BH)是最近一种无创性的HIFU检查方式 由我们团队发明，可以通过提供高幅度冲击来潜在地克服这些限制 电波机械地消融组织。与现有的病灶相比，BH具有许多潜在的临床优势 治疗，包括热HIFU：1)产生精确、可控的边缘锐利的病变，同时 保留关键结构；2)通过基于超声的治疗定位和实时监测 成像，这利用了气泡的强声波反射率；以及3)液化的潜在更快的吸收 BH损害。在NIH支持的前几年，我们开发了用于表征HIFU场的计量工具 利用电击，发明了BH方法并阐明了其物理机制，确定了有效脉冲 序列，实现了治疗的实时B型成像，并设计了优化的HIFU阵列 腹部BH应用。然而，为了可靠地提供安全和安全的服务，仍然存在两个科学挑战 人类BH的有效治疗：首先，组织不均质性对休克形成的影响尚不清楚 从数量上理解。第二，剂量指标和相应的治疗策略尚未得到 确定并验证用于消融包括多个靶点的组织体积。这其中的前两个目标 项目寻求通过以下方式解决这些挑战：1)扩展我们的非线性计量工具以包括建模 异质组织预测原位休克形成，以及2)进行体外实验研究 肝和肾组织，以确定用于设计容积式BH治疗的剂量度量。第三个目标 涉及使用原型系统进行严格的临床前研究，以治疗猪肾脏和 活体肝脏。这些目标的成功完成将有助于BH治疗的设计和实施， 提供进行肾癌和肝细胞癌临床试验所需的框架。超越具体的 临床目标，这些研究将促进BH在其他临床应用中的进展，如 以及利用电击的基于超声波的新疗法的开发。

PROJECT SUMMARY Renal carcinoma (RCC) and hepatocellular carcinoma (HCC) are two of the most common abdominal solid organ malignancies in the US, accounting for nearly 100,000 combined new cases and nearly 40,000 deaths in 2015 [Siegel 2015]. With recent imaging advances leading to early diagnosis, medical practice is shifting toward the use of minimally invasive focal therapies (e.g., radiofrequency ablation, cryotherapy) for treating tumors. However, these treatments possess limitations: They require invasive deployment and rely on thermal effects that are poorly controlled, especially near vascular structures that can act as heat sinks. In addition, real-time treatment monitoring capabilities are minimal because thermal lesions are not easily visualized on standard imaging techniques. High intensity focused ultrasound (HIFU) offers an alternative focal therapy that can be delivered noninvasively. At present, clinical HIFU treatments involve thermal ablations that are subject to these same limitations; however, boiling histotripsy (BH) is a noninvasive HIFU modality recently invented by our group that can potentially overcome these limitations by delivering high-amplitude shock waves to mechanically ablate tissue. BH has many potential clinical advantages over existing focal therapies, including thermal HIFU: 1) generation of precise, controllable lesions with sharp margins while sparing critical structures; 2) targeting and real-time monitoring of treatments through ultrasound-based imaging, which utilizes the strong acoustic reflectivity of bubbles; and 3) potentially faster resorption of liquefied BH lesions. In previous years of NIH support, we have developed metrology tools for characterizing HIFU fields with shocks, invented the BH method and elucidated its physical mechanisms, identified effective pulse sequences, implemented real-time B-mode imaging of treatments, and designed a HIFU array optimized for abdominal BH applications. However, two scientific challenges remain in order to reliably deliver safe and effective BH treatments in humans: First, the impact of tissue inhomogeneities on shock formation is not yet quantitatively understood. Second, dose metrics and corresponding treatment strategies have not been defined and validated for ablating tissue volumes comprising multiple target sites. The first two aims in this project seek to address these challenges by 1) extending our nonlinear metrology tools to include modeling in heterogeneous tissues to predict in situ shock formation, and 2) conducting experimental studies in ex vivo liver and kidney tissue to determine dose metrics for use in designing volumetric BH treatments. The third aim involves the performance of rigorous pre-clinical studies using a prototype system to treat in pig kidney and liver in vivo. Successful completion of these aims will aid the design and execution of BH treatments, providing the framework needed to conduct clinical trials for RCC and HCC. Beyond the specific clinical targets, these studies will facilitate the advancement of BH for other clinical applications as well as the development of novel ultrasound-based therapies that utilize shocks.