Developing Methods for Precise, Safe and Target-location Specific Histotripsy of Liver Tumors

项目总结 这笔赠款的目标是优化肝脏组织检查，以创建安全有效的消融 定位于大型动物，人体大小的模型。肝癌是主要的死亡原因， 消融是特定患者有限的治疗选择之一。不幸的是，目前可用 消融手术的局部失败率可变，约为10%-40%。另外，肿瘤位于附近 重要的结构，如胆管和肠道，通常不会像热疗那样得到根治。 消融会增加受伤的风险。组织诊断学是第一个非侵入性、非侵入性的 热的和非电离的消融方式，使用聚焦的超声波能量来产生空化， 导致机械性组织破裂。在初步研究中，组织试验显示出一种能力 造成组织破坏，使某些具有胶原结构的结构幸免于难，包括 胆管和肠道，并在治疗和正常之间创建边缘较窄的消融区 纸巾。催化组织摩擦学的临床翻译，并潜在地增加 有多少患者有资格接受根治治疗，一个关键问题需要得到回答： 我们能否在保持疗效的同时利用组织尿道学的潜在安全优势 这样更多的肿瘤才有资格接受根治？第一，缓解危机的战略 高频喷射换气或应用减少肝脏运动对呼吸运动的影响 用于模拟肝脏运动和修改处方的内置式锥束CT将在Aim 1中进行试验。 目的2我们将确定治疗切除的肝癌的剂量阈值，同时保留关键结构以 为任何部位的肿瘤确定安全、有效的治疗剂量，然后在 一种存活的活体猪肝脏模型。最后，在目标3中，我们将提出一种类似SCID的肝细胞癌猪 肝脏肿瘤模型，这将使我们能够将这些策略应用于位于特定区域的肿瘤 以确认安全性和有效性，最终证明了我们的假设 这种组织检查可以安全地治疗任何肝脏部位的肿瘤。这三个具体目标是 跟在后面。目标1：确定减轻呼吸运动影响的最佳策略 提高组织学消融的精确度和安全性。目标2：确定药物的剂量阈值 肝癌和体外关键结构，允许试验安全、有效的治疗参数 用于关键部位的活体治疗。目的3：建立高度相关的大动物肝细胞癌 用于医疗器械的模型，并在这个大型动物模型中确认安全性和有效性。这个项目 将产生关键的临床前数据，在广泛采用之前是必要的 组织学在非手术肝细胞癌治疗中的应用

PROJECT SUMMARY The goal of this grant is to optimize hepatic histotripsy to create safe and effective ablation in any location in a large animal, human-scale model. Liver cancer is a leading cause of death with ablation one of the limited curative options in select patients. Unfortunately, currently available ablation procedures have a variable local failure rate of ~10-40%. Also, tumors located near critical structures, such as bile ducts and bowel, often do not receive curative treatment as thermal ablation is associated with increased risk of injury. Histotripsy is the first non-invasive, non- thermal, and non-ionizing ablation modality, using focused ultrasound energy to create cavitation, resulting in mechanical tissue disruption. In preliminary studies, histotripsy has shown an ability to cause tissue disruption that spares certain structures with collagenous architecture, including bile ducts and bowel, and to create ablation zones with a thin margin between treated and normal tissues. To catalyze the clinical translation of histotripsy and potentially increase the number of patients eligible for curative treatment, a key question needs to be answered: Can we leverage the potential safety advantages of histotripsy while maintaining efficacy such that more tumors will be eligible for curative treatment? First, strategies to mitigate the effects of respiratory motion by decreasing liver motion with high-frequency jet ventilation or using in-suite cone-beam CT to model liver motion and modify prescriptions will be trialed in Aim 1. In Aim 2 we will determine dose thresholds to treat excised HCC while sparing critical structures to identify a safe, effective treatment dose for tumors of any location and then validate this dose in a survival, in vivo swine liver model. Finally, in Aim 3 we will advance a SCID-like HCC porcine liver tumor model, which will allow us to apply these strategies to tumors located within specific high-risk locations of the liver to confirm safety and efficacy, ultimately, proving our hypothesis that histotripsy can treat tumors in any liver location safely. The three Specific Aims are the following. Aim 1: Determine the best strategy to mitigate the effects of respiratory motion to increase the precision and safety of histotripsy ablation. Aim 2: To determine dose thresholds for liver cancer and critical structures ex vivo, allowing a trial of safe, effective treatment parameters for in vivo treatment in critical locations. Aim 3: Advance a highly relevant large animal liver HCC model for medical devices and confirm safety and efficacy in this large animal model. This project will yield critical preclinical data which will be necessary before the widespread adoption of histotripsy to treat patients with non-surgical hepatocellular carcinoma.