Design of Noninvasive Therapies Utilizing Nonlinear Focused Ultrasound With Shocks

项目摘要 肾癌和肝细胞癌是两种最常见的腹部实性肿瘤 器官恶性肿瘤在美国，占近100，000合并新病例和近40，000死亡， 2015年[Siegel 2015]。随着最近成像技术的进步导致早期诊断，医疗实践正在转变 趋向于使用微创局部治疗（例如，射频消融术，冷冻疗法）治疗 肿瘤的然而，这些治疗具有局限性：它们需要侵入性部署并且依赖于热效应。 控制不佳的影响，特别是在可能作为散热器的血管结构附近。此外，本发明还提供了一种方法， 实时治疗监测能力是最低限度的，因为热损伤不容易在 标准成像技术。高强度聚焦超声（HIFU）提供了一种替代的聚焦治疗 可以非侵入性地输送。目前，临床HIFU治疗涉及热消融， 然而，沸腾组织摧毁术（BH）是最近的一种非侵入性HIFU方式 由我们的团队发明，可以通过提供高振幅冲击来克服这些限制 波来机械地消融组织。BH与现有的病灶相比具有许多潜在的临床优势 治疗，包括热HIFU：1）产生精确的，可控的病变与尖锐的边缘， 保留关键结构; 2）通过基于超声的治疗靶向和实时监测 成像，其利用气泡的强声反射性;以及3）液化的 BH病变。在前几年的NIH支持下，我们已经开发了用于表征HIFU场的计量工具 发明了BH法，阐明了BH法的物理机制， 序列，实现了治疗的实时B模式成像，并设计了一个优化的HIFU阵列， 腹部BH应用。然而，为了可靠地提供安全和可靠的药物， 在人类中有效的BH治疗：首先，组织不均匀性对休克形成的影响还没有 量的理解。第二，剂量度量和相应的治疗策略尚未被确定。 定义并验证用于消融包括多个目标部位的组织体积。这其中的前两个目标 项目寻求解决这些挑战，1）扩展我们的非线性计量工具，包括建模， 异种组织来预测原位休克形成，以及2）在离体中进行实验研究 肝和肾组织，以确定用于设计体积BH治疗的剂量度量。第三个目标 涉及使用原型系统在猪肾中进行严格的临床前研究， 体内肝脏。这些目标的成功完成将有助于BH治疗的设计和执行， 为开展RCC和HCC临床试验提供了必要的框架。超越具体 临床目标，这些研究将促进BH在其他临床应用中的发展， 以及利用电击的新型超声波疗法的发展。

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.