Image-Guided Non-Invasive Ultrasonic Thrombolysis Using Histotripsy

使用组织解剖学进行图像引导无创超声溶栓

• 批准号: 7690225
• 负责人: Zhen Xu
• 金额: $ 52.11万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7690225
• 关键词: Accounting; Acoustics; Affect; American; Arterial Embolization; Blood Clot; Blood coagulation; Bypass; Caliber; Cardiovascular Diseases; Catheters; Cell Nucleus; Cessation of life; Clinical; Coagulation Process; Data; Deep Vein Thrombosis; Dependence; Diagnosis; Dialysis procedure; Embolism; Erythrocytes; Evaluation; Family suidae; Feedback; Fibrinolytic Agents; Fractionation; Hemorrhage; Human; Image; In Vitro; Individual; Infection; Lead; Leg; Location; Maintenance; Measurement; Medical; Methods; Microbubbles; Modeling; Monitor; Normal tissue morphology; Operative Surgical Procedures; Pathologic Processes; Patients; Physiologic pulse; Procedures; Process; Pulmonary Embolism; Resolution; Risk; Seeds; Speed; Stroke; Structure of superficial vein; System; Techniques; Testing; Therapeutic Embolization; Thrombosis; Time; Tissues; Ultrasonics; Ultrasonography; Venous Thrombosis; Work; base; clinical application; deep vein; improved; in vitro Model; in vivo; particle; pressure; prevent; prototype; public health relevance; response; soft tissue; standard of care; thrombolysis

DESCRIPTION (provided by applicant): Thrombosis is the medical term for the process of pathologic blood clot formation, the key mechanism behind many cardiovascular diseases. For example, deep vein thrombosis (DVT) is a condition which affects nearly two million Americans annually and is commonly diagnosed as thrombosis in the deep veins of the legs. To treat DVT, the blood clots need to be removed, a process generally termed thrombolysis. Current clinical thrombolysis methods include catheter-based procedures and thrombolytic drugs, both of which have significant drawbacks including invasiveness and risks of bleeding and infection. To improve the clinical standard of thrombolysis, we propose to develop an ultrasonic thrombolysis technique that is non-invasive and carries virtually no risks of bleeding and infection. Our technique, which we call "histotripsy", uses controlled ultrasound cavitation to mechanically fractionate soft tissue non-invasively, guided by high resolution imaging. By initiating and maintaining the cavitating bubble cloud with appropriate ultrasound pulse sequences, a targeted tissue can be precisely fractionated with a very narrow boundary between affected and normal tissue. As applied to thrombolysis, our preliminary data show that histotripsy can fractionate a blood clot at a speed fifty-fold faster than any current clinical thrombolysis method. Histotripsy breaks down blood clots into tiny particles that are smaller than red blood cells. As histotripsy-induced cavitating bubbles are easily detected acoustically, histotripsy thrombolysis can be guided and monitored by real-time ultrasound imaging. We propose to further improve and optimize histotripsy for safe and efficient non-invasive thrombolysis to treat DVT. We aim to further investigate the bubble-tissue interaction mechanism behind the histotripsy process. A deeper understanding of the interaction mechanism will provide a rational basis to optimize histotripsy acoustic parameters specific for thrombolysis. To reduce the embolization risk, we will develop a non-invasive embolus trap (NET) strategy by setting a secondary cavitating bubble cloud downstream of treatment location to capture and fractionate any escaping clot fragments. We will also develop real-time ultrasound imaging feedback techniques to guide and control the treatment progress and completion. These aims will be studied first in vitro and subsequently tested in an in vivo porcine venous thrombosis model. Successful completion of these specific aims will help us to develop a prototype histotripsy thrombolysis system to treat DVT in human patients, which could potentially lead to the broader application of histotripsy to other clinical conditions requiring thrombolysis, including stroke, superficial vein thrombosis, pulmonary embolism, and dialysis graft thrombosis. Public Health Relevance Statement (provided by applicant): Thrombosis is the medical term for the process of pathologic blood clot formation, the key mechanism behind many cardiovascular diseases. For example, deep vein thrombosis (DVT) is a condition which affects nearly two million Americans annually and is commonly diagnosed as clot formation in the deep veins of the legs. In up to 5% of DVT cases, clots dislodge and result in pulmonary embolism, causing at least 100,000 deaths annually in USA alone. To treat DVT, blood clots need to be removed, a process generally termed thrombolysis. Current clinical thrombolysis methods include thrombolytic drugs and catheter-based surgical procedure, both of which have significant drawbacks. For instance, thrombolytic drugs have the potential to cause excessive bleeding, which may be fatal in a small number of cases. Also, catheter-based procedures are invasive and carry risk of both bleeding and infection. We propose to develop an ultrasonic thrombolysis technique that is non-invasive and carries virtually no risks of bleeding and infection. Our first targeted clinical application will be DVT. In addition, we believe this technique could also potentially improve the standard of care for other clinical applications where thrombolysis is needed, including stroke, superficial vein thrombosis, dialysis graft thrombosis, bypass graft thrombosis or embolization, arterial embolism and pulmonary embolism.

描述（由申请人提供）：血栓形成是病理性血凝块形成过程的医学术语，是许多心血管疾病背后的关键机制。例如，深静脉血栓形成（DVT）是一种每年影响近200万美国人的疾病，通常被诊断为腿部深静脉血栓形成。为了治疗DVT，需要移除血凝块，这一过程通常称为血栓溶解。目前的临床溶栓方法包括基于导管的程序和溶栓药物，这两种方法都具有显著的缺点，包括侵入性以及出血和感染的风险。为提高临床溶栓水平，我们建议发展一种无创、携带药物的超声溶栓技术， 几乎没有出血和感染的风险。我们的技术，我们称之为“组织摧毁术”，使用受控的超声空化，在高分辨率成像的指导下，非侵入性地机械破碎软组织。通过用适当的超声脉冲序列启动和维持空化气泡云，目标组织可以被精确地分离，其中受影响组织和正常组织之间的边界非常窄。应用于溶栓，我们的初步数据表明，组织破碎术可以破碎血块的速度比目前任何临床溶栓方法快50倍。组织摧毁术将血块分解成比红细胞还小的微粒。由于组织破坏引起的空化气泡很容易通过声学检测到，因此组织破坏溶栓可以通过实时超声成像来引导和监测。我们建议进一步改进和优化组织碎石术，以实现安全有效的无创溶栓治疗DVT。我们的目的是进一步研究组织破坏过程背后的气泡-组织相互作用机制。深入了解其相互作用机制，将为优化溶栓声学参数提供合理依据。为了降低栓塞风险，我们将开发一种无创栓子捕获器（NET）策略，在治疗位置下游设置二次空化气泡云，以捕获 并粉碎任何逃逸的凝块碎片我们还将开发实时超声成像反馈技术，以指导和控制治疗进度和完成。这些目标将首先在体外进行研究，随后在体内猪静脉血栓形成模型中进行测试。这些特定目标的成功完成将有助于我们开发一种原型组织碎石术溶栓系统来治疗人类患者的DVT，这可能会导致组织碎石术更广泛地应用于其他需要溶栓的临床疾病，包括中风、浅静脉血栓形成、肺栓塞和透析移植物血栓形成。 公共卫生相关性声明（由申请方提供）：血栓形成是病理性血凝块形成过程的医学术语，是许多心血管疾病背后的关键机制。例如，深静脉血栓形成（DVT）是一种每年影响近200万美国人的疾病，通常被诊断为腿部深静脉中的凝块形成。在高达5%的DVT病例中，血栓脱落并导致肺栓塞，仅在美国每年就造成至少100，000人死亡。为了治疗DVT，需要去除血块，这一过程通常称为血栓溶解。目前临床溶栓方法包括溶栓药物和基于导管的外科手术 这两种方法都有很大的缺点。例如，溶栓药物有可能导致过度出血，这在少数情况下可能是致命的。此外，基于导管的手术是侵入性的，并且具有出血和感染的风险。我们建议开发一种非侵入性的超声溶栓技术，几乎没有出血和感染的风险。我们的第一个目标临床应用将是DVT。此外，我们认为该技术还可能提高其他需要溶栓的临床应用的护理标准，包括卒中、浅静脉血栓形成、透析移植物血栓形成、旁路移植物血栓形成或栓塞、动脉栓塞和肺栓塞。