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: 8125002
• 负责人: Zhen Xu
• 金额: $ 50.18万
• 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/8125002
• 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(申请人提供)：血栓形成是病理性血液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，需要去除血栓，这一过程通常被称为溶栓。目前临床上的溶栓方法主要有导管溶栓和药物溶栓，但两者都存在着侵袭性大、出血和感染风险大等缺点。为了提高临床溶栓水平，我们建议开发一种无创、携带 几乎没有出血和感染的风险。我们的技术，我们称之为“组织摩擦”，使用受控超声空化，在高分辨率成像的引导下，非侵入性地机械分割软组织。通过用适当的超声脉冲序列启动和保持空化气泡云，可以在受影响组织和正常组织之间以非常窄的边界精确地分割目标组织。应用于溶栓，我们的初步数据显示，组织摩擦可以分离血栓的速度比目前的任何临床溶栓方法快50倍。组织学将血液凝块分解成比红细胞更小的微小颗粒。由于组织摩擦诱发的空化气泡很容易在声学上被检测到，组织摩擦溶栓可以通过实时超声成像来指导和监测。我们建议进一步改进和优化组织摩擦学，以安全有效的无创溶栓治疗DVT。我们的目标是进一步研究组织摩擦过程背后的气泡-组织相互作用机制。对相互作用机制的深入理解将为优化组织摩擦学溶栓特异性声学参数提供合理的依据。为了减少栓塞风险，我们将开发一种非侵入性栓子捕捉器(Net)策略，在治疗位置下游设置二次空化气泡云以捕获。 并分离出任何逃逸的血块碎片。我们还将开发实时超声成像反馈技术，以指导和控制治疗过程和完成。这些目标将首先在体外进行研究，然后在活体猪静脉血栓模型中进行测试。这些特定目标的成功完成将有助于我们开发用于治疗人类患者DVT的组织摩擦溶栓系统原型，这可能导致组织摩擦溶栓技术在其他临床需要溶栓治疗的疾病中得到更广泛的应用，包括中风、浅静脉血栓形成、肺栓塞和透析移植物血栓形成。 公共卫生相关声明(由申请人提供)：血栓形成是病理性血液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。在多达5%的DVT病例中，血栓移位并导致肺栓塞，仅在美国每年就导致至少10万人死亡。为了治疗DVT，需要清除血栓，这一过程通常被称为溶栓。目前临床溶栓方法主要有溶栓药物和导管外科手术。 程序，这两种方法都有很大的缺陷。例如，溶栓药物有可能导致大量出血，这在少数病例中可能是致命的。此外，以导管为基础的手术是侵入性的，同时存在出血和感染的风险。我们建议开发一种超声溶栓技术，这种技术是非侵入性的，几乎没有出血和感染的风险。我们的第一个有针对性的临床应用将是DVT。此外，我们相信，这项技术还可能提高其他需要溶栓治疗的临床应用的护理标准，包括中风、浅静脉血栓形成、透析移植物血栓形成、搭桥血栓形成或栓塞、动脉栓塞和肺栓塞。