Image-guided Non-invasive Ultrasonic Thrombolysis Using Histotripsy

描述（由申请人提供）：深静脉血栓形成（DVT）是一种以腿部深静脉血栓形成为特征的疾病，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，这两种方法都有明显的缺点，例如侵入性以及出血和感染的风险。在超声成像的引导下，组织粉碎术是一种基于空化的超声治疗，可将组织分离。使用我们的实验室原型，组织破碎法在体外将凝块分离成比红细胞小的碎片，其速度比目前的临床溶栓方法快50倍。使用体内猪DVT模型，在12例病例中的10例中，组织摧毁术非侵入性地根除了血栓。通过消除血栓溶解药物和导管，缩短治疗时间，保持或可能增加凝块清除的功效，组织碎石术有可能真正改变血栓形成治疗的前景。该提案的目的是推进组织破坏溶栓的临床翻译。为了实现这一目标，我们提出以下三个具体目标。1)设计并建立一套完整的DVT患者影像引导组织碎石溶栓系统。2)开发两项技术创新（显微碎石和气泡诱导彩色多普勒反馈），进一步提高组织碎石溶栓的安全性和有效性。3)通过在猪DVT模型中进行的全面临床前研究，确定临床设计的组织粉碎溶栓系统的体内安全性和有效性。这些目标旨在获得对获得美国食品和药物管理局（FDA）批准以启动第一次组织破坏溶栓临床试验至关重要的结果。此外，我们提出的全面临床前体内安全性研究将定量测量空化的所有可能的不良反应，这对于所有基于空化的溶栓技术（包括组织破坏术）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。每一个都提出了一个重要的临床问题，其中组织碎石术溶栓可能会改善目前的治疗方法。

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.