Image-guided Non-invasive Ultrasonic Thrombolysis Using Histotripsy

描述（由申请人提供）：深静脉血栓 (DVT) 是一种以腿部深静脉中形成血栓为特征的疾病，每年影响近 200 万美国人。 DVT 的临床治疗包括溶栓药物和基于导管的外科手术，这两种方法都有显着的缺点，例如侵入性以及出血和感染的风险。在超声成像引导下，组织解剖是一种基于空化的超声疗法，可分割组织。使用我们的实验室原型，组织解剖法将体外凝块分解成比红细胞更小的碎片，其速度比当前临床溶栓方法快五十倍。使用猪体内 DVT 模型，组织解剖学无创地根除了 12 例中的 10 例的血栓。通过消除溶栓药物和导管、缩短治疗时间、维持或可能提高血栓清除功效，组织解剖学有可能真正改变血栓治疗的格局。该提案的目标是推进组织解剖溶栓的临床转化。为实现这一目标，我们提出以下三个具体目标。 1）为DVT患者设计并构建集成图像引导组织解剖溶栓系统。 2）开发两项技术创新（显微解剖和气泡诱导彩色多普勒反馈），进一步提高组织解剖溶栓的安全性和有效性。 3) 通过猪 DVT 模型的全面临床前研究，确定临床设计的组织解剖溶栓系统的体内安全性和有效性。这些目标旨在获得对于获得美国食品和药物管理局 (FDA) 批准启动首个组织解剖溶栓临床试验至关重要的结果。此外，我们提出的全面的临床前体内安全性研究将定量测量空化的所有可能的不利影响，这对于所有基于空化的溶栓技术（包括组织解剖学）的临床转化至关重要。虽然我们目前正在研究 DVT，但还有许多其他疾病可以从这种革命性的新型溶栓技术中受益，包括中风、心肌梗死、浅静脉血栓形成以及外周动脉和移植物血栓形成。每一种都提出了显着的临床问题，其中组织解剖溶栓可能会改善当前的治疗方法。

DESCRIPTION (provided by applicant): Deep vein thrombosis (DVT) is a condition characterized by the formation a blood clot in the deep veins of the legs and affects nearly two million Americans per year. Clinical treatments for DVT include thrombolytic drugs and catheter-based surgical procedures, both of which have significant drawbacks, such as invasiveness and risks of bleeding and infection. Guided by ultrasound imaging, histotripsy is a cavitation-based ultrasound therapy that fractionates tissue. Using our laboratory prototype, histotripsy fractionated in vitro clots into debris smaller than red blood cells at a speed fifty-fold faster tan current clinical thrombolysis methods. Using an in vivo porcine DVT model, histotripsy non-invasively eradicated the thrombus in 10 of 12 cases. By eliminating thrombolytic drugs and catheters, shortening the treatment time, and maintaining or possibly increasing the efficacy for clot removal, histotripsy has the potential to truly change the landscape of thrombosis therapy. The goal of this proposal is to advance the clinical translation of histotripsy thrombolysis. To achieve this goal, we propose the following three specific aims. 1) Design and build an integrated image-guided histotripsy thrombolysis system for DVT patients. 2) Develop two technical innovations (microtripsy and bubble-induced color Doppler feedback) to further improve the safety and efficacy of histotripsy thrombolysis. 3) Determine the in vivo safety and efficacy of the clinically designed histotripsy thrombolysis system through a comprehensive pre-clinical study in the porcine DVT model. These aims are designed to obtain results that are crucial towards achieving approval from the United States Food and Drug Administration (FDA) to inaugurate the first clinical trial of histotripsy thrombolysis. In addition, our proposed comprehensive preclinical in vivo safety study will quantitatively measure all the possible adverse effects of cavitation, which will be essential for clinical translation of all cavitation-bsed thrombolysis techniques including histotripsy. While we are currently studying DVT, there are many other diseases which could benefit from this revolutionary new thrombolysis technique, including stroke, myocardial infarction, superficial vein thrombosis, and peripheral arterial and graft thrombosis. Each poses a significant clinical problem where histotripsy thrombolysis may improve upon current treatment methods.