Accelerated Low Dose Thrombolytic Catheter Directed Sonothrombolysis

加速低剂量溶栓导管定向声溶栓

基本信息

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
项目类别：
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

项目摘要

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（VTE），包括深静脉血栓形成（DVT）和肺栓塞（PE），为一项重大的医疗挑战，导致死亡率，病态和社会成本。每年约有900,000例复发性，致命和非致命的VTE事件可归因于VTE的直接医疗保健支出为$ 7-10 b/yr，额外的$ 10-15B可归因于过早死亡和由于短期和长期残疾而导致的生产力失去。使用常规抗凝剂通过门诊管理治疗可预防血栓延伸，肺部栓塞和复发，但不要溶解或去除凝块。治疗辅助剂会出现静脉功能障碍，导致术后综合征。 PT经常涉及：疼痛，肿胀，天气的感觉，水肿，色素沉着和恶化皮肤，在严重的情况下，包括静脉溃疡。血管内的血管分析加速，同时需要大幅降低溶栓药的剂量。血凝块的Imediate附近，辅助超声能量和大直径（〜20M），低sta-- 可使用微泡（MB），当暴露于超声时，会加速血栓溶解。 proach，我们已经证明了体积凝块损失的速率4.5倍在体外模型中给药，并在缺血性中风模型中降低了3.33倍TPA剂量。在大规模动物试验之后，临床翻译后（超出当前建议的范围），首先 MAN”和一个分阶段的临床试验，我们的视野是，该导管的衍生物是延伸的，可以用作直接代替当前导管的定向治疗 zation解决血栓。围绕以下特定目的组织了支撑的研究计划：特定目的1：开发带有机载微孔微孔监测系统的Sonothrombolsy Searter-sys- TEM，高功率超声“交付”传感器和高分辨率传感器用于实时表征溶栓进展特定目标2：对A中的超声，溶栓药和微生物相互作用进行研究控制良好的实验室台面体外溶栓模型特定目的3：使用鼠DVT模型在体内的测试功效