Accelerated Low Dose Thrombolytic Catheter Directed Sonothrombolysis

加速低剂量溶栓导管定向声溶栓

• 批准号: 10192806
• 负责人: John A Hossack
• 金额: $ 51.77万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10192806
• 关键词: Acoustics; Address; Adjuvant; Admission activity; Alteplase; Animal Model; Animals; Anticoagulant therapy; Anticoagulants; Anticoagulation; Blood coagulation; Caliber; Caring; Catheterization; Catheters; Cessation of life; Clinical; Clinical Trials; Coagulation Process; Data; Deep Vein Thrombosis; Deterioration; Development; Devices; Dose; Edema; Esthesia; Evaluation; Event; Excision; Exposure to; Fibrinolytic Agents; Fibrosis; Functional disorder; Health Expenditures; Healthcare; Hemorrhage; Hour; Human; Hypertension; In Vitro; Inflammation; Investigation; Ischemic Stroke; Laboratories; Letters; Mechanics; Mediating; Methods; Microbubbles; Microscopy; Modeling; Monitor; Morbidity - disease rate; Mus; Outpatients; Pain; Pathway interactions; Patient-Focused Outcomes; Patients; Phase; Pigmentation physiologic function; Postphlebitic Syndrome; Productivity; Pulmonary Embolism; Quality of life; Rattus; Recurrence; Reflux; Research; Resolution; Risk; Safety; Scientist; Skin; Speed; Swelling; System; Technology; Therapeutic; Thrombolytic Therapy; Thrombosis; Thrombus; Time; Transducers; Ultrasonic Therapy; Ultrasonography; Validation; Varicose Ulcer; Veins; Venous; Vision; Work; clinical practice; clinical translation; cost; design; disability; efficacy evaluation; efficacy testing; experience; first-in-human; improved; improved outcome; in vitro Model; in vivo; in vivo evaluation; innovation; man; mortality; mouse model; pre-clinical; premature; prevent; programs; prototype; response; sensor; societal costs; success; technological innovation; thrombolysis; venous thromboembolism

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

抽象的 静脉血栓栓塞症（VTE）包括深静脉血栓形成（DVT）和肺栓塞（PE）， 造成重大死亡率、发病率和社会成本的重大医疗保健挑战。每年，有 约 900,000 起复发性、致命性和非致命性 VTE 事件导致 300,000 人死亡。总计，每年 VTE 造成的直接医疗保健支出为 $7 – 10 B/年，另外还有 $10 – 15B 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 通过门诊管理使用常规抗凝剂进行治疗，防止血栓扩展，肺部 栓塞和复发，但不溶解或清除血栓。大约一半的患者接受 传统抗凝剂治疗会导致静脉功能障碍，导致血栓后综合征。 PTS 经常涉及：疼痛、肿胀、沉重感、水肿、色素沉着和皮肤退化 皮肤，严重时包括静脉溃疡。提出的关键技术进步涉及一种新的 血管内方法可加速溶栓，同时需要显着减少 溶栓药物的剂量。所提出的导管结合了低剂量溶栓剂的局部给药， 紧邻血凝块，具有辅助超声能量和大直径（~20μm）、低静态 能力微泡（MB），当暴露于超声波时，加速血栓溶解。使用这个应用程序 proach，我们已经证明，相对于传统 tPA，体积血栓丢失率增加了 4.5 倍 在体外模型中给药，使缺血性中风模型中的 tPA 剂量减少了 3.33 倍。 经过临床转化（超出了当前提案的范围），在大型动物试验之后，“首先在人类 man”和一项分阶段的临床试验，我们的愿景是从提议的导管衍生而来，用作直接 替代目前的导管定向治疗，后者通常需要连续几天的导管治疗 化解血栓。 拟议的研究计划围绕以下具体目标进行组织： 具体目标 1：开发带有机载 micro-Coulter 微泡监测系统的声溶栓导管 tem、高功率超声“传输”换能器和用于实时表征的高分辨率换能器 溶栓进展 具体目标 2：对超声、溶栓药物和微泡相互作用进行研究 良好控制的实验室台式体外溶栓模型 具体目标 3：使用小鼠 DVT 模型测试体内方法的功效