Ultrasound-guided Ultra-steerable Histotripsy Array System for Non-invasive treatment of Soft Tissue Sarcoma

超声引导超导式组织摩擦阵列系统在软组织无损治疗中的应用 肉瘤 摘要 本项目的目标是开发一种用于非侵入性治疗的新型超定向组织摩擦阵列系统 软组织肉瘤(STS)。STS是生长在脂肪、肌肉、软骨等软组织中的恶性肿瘤， 纤维组织、血管或皮下组织。美国癌症协会报告新增病例13,190例 在美国，每年有5130人死于STS。手术是STS的一线治疗方法。然而，当STS 包围或生长在关键结构(例如，主要神经、血管和骨骼)附近，手术切除 尤其具有挑战性，有时这些癌症被认为是无法切除的。放射治疗、化疗和 微创或非侵入性消融方法对STS治疗无效或具有重大缺点， 因此，它们在STS治疗中的使用非常有限。组织诊疗是一种非侵入性的超声疗法， 通过受控空化将目标组织机械液化为无细胞碎片。组织诊断学非常适合于 STS治疗，因为它可以无创地清除和缩小肿瘤，同时保留关键结构，如 作为主要的血管、神经和骨骼。组织学可用于STS的非侵入性清除，以促进或 有可能取代外科手术。尽管组织摩擦学已经被研究用于各种肿瘤的治疗 类型，性传播疾病的治疗带来了独特的挑战。1)STS可以生长得比其他类型的肿瘤大得多 (&gt；10厘米或&gt；400毫升)，需要非常快的治疗速度。2)STS通常生长在关键结构附近和/或关闭 到皮肤表面。需要制定治疗策略，以避免对关键结构和 皮肤。3)组织学治疗通常由二维B型超声成像指导，但快速治疗大型 STS需要3D监控功能。在这项提案中，我们将开发一种新型的超导向性组织摩擦 具有3D空化监测能力和超高速STS消融特殊策略的相控阵系统 以及在皮肤表面和关键结构附近进行安全治疗。我们提出了以下三个具体目标。 目的1：设计和构建一个由超导向性组织摩擦学组成的完整的组织摩擦学STS系统 具有发射-接收能力的相控阵，用于三维空化监测、超声图像制导、机器人 手臂辅助和声学耦合。目的2：优化快速(10毫升/分钟)和安全的组织摩擦学参数 接近皮肤表面和关键结构的处理以及在体外组织和离体人和犬的测试 不同组织亚型的STS标本。目的3：体内安全性和有效性的测试 组织摩擦学STS系统(目标1)和优化的参数，用于快速、安全地治疗近皮肤和危重患者 弗吉尼亚理工大学动物癌症护理和研究中心的犬性传播疾病患者的结构(目标2)。这 该项目将产生一个具有独特治疗和监测能力的人体原型组织摩擦系统，如 以及为STS治疗优化的参数。犬类患者是检验安全性的最佳大型动物模型 和组织摩擦STS治疗的有效性，以加快临床翻译，兽医治疗是 在FDA批准人类使用之前，另一项组织旅行STS治疗申请。

Ultrasound-guided Ultra-steerable Histotripsy Array System for Non-invasive treatment of Soft Tissue Sarcoma Summary The goal of this project is to develop a novel ultra-steerable histotripsy array system for non-invasive treatment of soft tissue sarcomas (STS). STS are malignant tumors that grow in soft tissues like fat, muscle, cartilage, fibrous tissues, blood vessels, or subcutaneous tissues. The American Cancer Society reports 13,190 new cases and 5,130 deaths of STS annually in the US. Surgery is the first-line treatment for STS. However, when STS encompass or grow near critical structures (e.g., major nerves, blood vessels, and bones), surgical resection is particularly challenging and sometimes these cancers are deemed unresectable. Radiation, chemotherapy, and minimally invasive or non-invasive ablation methods are not effective for STS treatment or have major drawbacks, such that they have very limited use in STS therapy. Histotripsy is a non-invasive ultrasound therapy that mechanically liquefies the target tissue to acellular debris via controlled cavitation. Histotripsy is well-suited for STS treatment because it can debulk and shrink the tumor non-invasively while sparing critical structures, such as major vessels, nerves, and bones. Histotripsy can be used for non-invasive debulking of STS to facilitate or potentially replace surgery. Even though histotripsy has been investigated for the treatment of various tumor types, STS treatment presents unique challenges. 1) STS can grow significantly larger than other types of tumors (>10 cm or >400mL), requiring very fast treatment speed. 2) STS often grow near critical structures and/or close to the skin surface. Treatment strategies need to be developed to avoid damage to critical structures and the skin. 3) Histotripsy treatment is typically guided by 2D B-mode ultrasound imaging, but fast treatment of a large STS requires 3D monitoring capabilities. In this proposal, we will develop a novel ultra-steerable histotripsy phased array system with 3D cavitation monitoring capabilities and special strategies for ultra-fast STS ablation and safe treatment near the skin surface and critical structures. We propose the following three specific aims. Aim 1: To design and construct an integrated histotripsy STS system, consisting of an ultra-steerable histotripsy phased array with transmit-receive capability for 3D cavitation monitoring, ultrasound image guidance, robotic arm assistance, and acoustic coupling. Aim 2: To optimize histotripsy parameters for fast (>10 mL/min) and safe treatment near the skin surface and critical structures and test in ex vivo tissue and excised human and canine STS samples of different histological subtypes. Aim 3: To test the in vivo safety and efficacy of the integrated histotripsy STS system (Aim 1) and optimized parameters for fast and safe treatment near the skin and critical structures (Aim 2) in canine STS patients at the Virginia Tech Animal Cancer Care and Research Center. This project will result in a human prototype histotripsy system with unique treatment and monitoring capabilities as well as parameters optimized for STS therapy. Canine patients are the best large animal model to test the safety and efficacy of histotripsy STS treatment to accelerate the clinical translation, and the veterinary treatment is another application for histotripsy STS therapy before the FDA approval of human use.