Accelerated Low Dose Thrombolytic Catheter Directed Sonothrombolysis

摘要 静脉血栓栓塞（VTE）包括深静脉血栓形成（DVT）和肺栓塞（PE）， 这是一项重大的卫生保健挑战，导致显著的死亡率、发病率和社会成本。每年， 约900，000例复发性、致死性和非致死性VTE事件，导致300，000例死亡。每年共计 归因于VTE的直接医疗保健支出为7 - 10 B美元/年，另外10 - 15 B美元归因于 短期和长期残疾造成的过早死亡和生产力损失。目前，VTE通常是 通过使用常规抗凝剂的门诊管理进行治疗，防止血栓扩展，肺 栓塞和复发，但不溶解或去除凝块。大约一半的患者接受 用常规抗凝剂的治疗发展静脉功能障碍，导致血栓形成后综合征。 PTS通常涉及：疼痛、肿胀、沉重感、水肿、色素沉着和皮肤退化。 皮肤，包括严重病例中的静脉溃疡。提出的关键技术进步涉及一种新的 血管内方法加速血栓溶解，同时需要显著降低 溶栓药物剂量。所提出的导管结合了低剂量溶栓的局部给药， 血凝块附近，辅助超声能量和大直径（~20 μ m），低稳态， 当暴露于超声波时，可加速血栓溶解。使用这个AP- 我们已经证实，与传统tPA相比， 在体外模型中，tPA的剂量降低了3.33倍，并且在缺血性中风模型中能够降低tPA的剂量。 经过临床翻译（超出当前提案的范围），在大型动物试验之后，“首先在胡- 人”和分阶段的临床试验，我们的愿景是，导管，从提出的衍生，被用作直接 替代目前的导管导向治疗，其经常需要连续几天的导管， 清除血栓。 拟议的研究计划围绕以下具体目标组织： 具体目标1：开发带有机载micro-Coulter微泡监测系统的超声溶栓导管- 用于实时表征TEM、高功率超声“输送”换能器和高分辨率换能器 溶栓进展 具体目标2：研究超声、溶血栓药物和微泡之间的相互作用， 受控良好的实验室台式体外溶栓模型 具体目标3：使用鼠DVT模型测试体内方法的功效

Abstract Venous thromboembolism (VTE), comprising Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE), is a major health care challenge resulting in significant mortality, morbidity, and societal cost. Annually, there are approximately 900,000 recurrent, fatal and nonfatal VTE events resulting in 300,000 deaths. In total, annual direct healthcare expenditures attributable to VTE are $7 – 10 B/yr with an additional $10 – 15B attributable to premature death and lost productivity caused by both short and long-term disability. Currently, VTE is usually treated via outpatient management using conventional anticoagulants prevent thrombus extension, pulmonary embolism and recurrence, but do not dissolve or remove the clot. Approximately half of all patients undergoing therapy with conventional anticoagulants develop venous dysfunction resulting in post-thrombotic syndrome. PTS frequently involves: pain, swelling, sensation of heaviness, edema, pigmentation, and deterioration of the skin, including venous ulcers in severe cases. The key technological advancement proposed involves a new endovascular approach that accelerates thrombolysis while simultaneously requiring a significantly reduced dose of thrombolytic drug. The proposed catheter combines local administration of low-dose thrombolytic, in the immediate vicinity of the blood clot, with adjuvant ultrasound energy and large diameter (~20 m), low sta- bility microbubbles (MB) that, when exposed to ultrasound, accelerate thrombus dissolution. Using this ap- proach, we have demonstrated a 4.5x increase in the rate of volumetric clot loss relative to conventional tPA administration in an in vitro model and enabled a 3.33x tPA dose reduction in a model of ischemic stroke. After clinical translation (beyond the scope of the current proposal), following large animal trials, “first in hu- man” and a phased clinical trial, our vision is that a catheter, derivative from that proposed, be used as a direct substitute for current catheter directed therapy, which frequently requires several days of continuous catheteri- zation to resolve the thrombus. The proposed program of research is organized around the following specific aims: Specific Aim 1: Develop sonothrombolysis catheter with on-board micro-Coulter microbubble monitoring sys- tem, high power ultrasound “delivery” transducer and high-resolution transducer for real-time characterization of thrombolysis progress Specific Aim 2: Perform an Investigation of ultrasound, thrombolytic drug and microbubbble interactions in a well-controlled laboratory benchtop in vitro thrombolysis model Specific Aim 3: Test efficacy of approach in vivo using a murine DVT model