Deep vein thrombosis (DVT) is a condition characterized by the formation a blood clot in the deep veins of the legs and affects nearly two million Americans per year. Clinical treatments for DVT include thrombolytic drugs and catheter-based surgical procedures, both of which have significant drawbacks, such as invasiveness and risks of bleeding and infection. Guided by ultrasound imaging, histotripsy is a cavitation-based ultrasound therapy that fractionates tissue. Using our laboratory prototype, histotripsy fractionated in vitro clots into debris smaller than red blood cells at a speed fifty-fold faster tan current clinical thrombolysis methods. Using an in vivo porcine DVT model, histotripsy non-invasively eradicated the thrombus in 10 of 12 cases. By eliminating thrombolytic drugs and catheters, shortening the treatment time, and maintaining or possibly increasing the efficacy for clot removal, histotripsy has the potential to truly change the landscape of thrombosis therapy. The goal of this proposal is to advance the clinical translation of histotripsy thrombolysis. To achieve this goal, we propose the following three specific aims. 1) Design and build an integrated image-guided histotripsy thrombolysis system for DVT patients. 2) Develop two technical innovations (microtripsy and bubble-induced color Doppler feedback) to further improve the safety and efficacy of histotripsy thrombolysis. 3) Determine the in vivo safety and efficacy of the clinically designed histotripsy thrombolysis system through a comprehensive pre-clinical study in the porcine DVT model.
These aims are designed to obtain results that are crucial towards achieving approval from the United States Food and Drug Administration (FDA) to inaugurate the first clinical trial of histotripsy thrombolysis. In addition, our proposed comprehensive preclinical in vivo safety study will quantitatively measure all the possible adverse effects of cavitation, which will be essential for clinical translation of all cavitation-bsed thrombolysis techniques including histotripsy. While we are currently studying DVT, there are many other diseases which could benefit from this revolutionary new thrombolysis technique, including stroke, myocardial infarction, superficial vein thrombosis, and peripheral arterial and graft thrombosis. Each poses a significant clinical problem where histotripsy thrombolysis may improve upon current treatment methods.

Public Health Relevance

Deep vein thrombosis (DVT) is a condition characterized by the formation a blood clot in the deep veins of the legs and affects nearly two million Americans per year. We propose to advance the clinical translation of histotripsy thrombolysis, a new non-invasive thrombolysis technique that has the potential to significantly improve the standard of care for DVT patients. There are many other diseases which could also benefit from this revolutionary thrombolysis technique, including stroke, myocardial infarction, superficial vein thrombosis, and peripheral arterial and graft thrombosis.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
2R01EB008998-06
Application #
8755293
Study Section
Biomedical Imaging Technology Study Section (BMIT)
Program Officer
Liu, Christina
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Biomedical Engineering
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Vlaisavljevich, Eli; Maxwell, Adam; Warnez, Matthew et al. (2014) Histotripsy-induced cavitation cloud initiation thresholds in tissues of different mechanical properties. IEEE Trans Ultrason Ferroelectr Freq Control 61:341-52
Lin, Kuang-Wei; Duryea, Alexander P; Kim, Yohan et al. (2014) Dual-beam histotripsy: a low-frequency pump enabling a high-frequency probe for precise lesion formation. IEEE Trans Ultrason Ferroelectr Freq Control 61:325-40
Kim, Yohan; Maxwell, Adam D; Hall, Timothy L et al. (2014) Rapid prototyping fabrication of focused ultrasound transducers. IEEE Trans Ultrason Ferroelectr Freq Control 61:1559-74
Kim, Y; Vlaisavljevich, E; Owens, G E et al. (2014) In vivo transcostal histotripsy therapy without aberration correction. Phys Med Biol 59:2553-68
Lin, Kuang-Wei; Kim, Yohan; Maxwell, Adam D et al. (2014) Histotripsy beyond the intrinsic cavitation threshold using very short ultrasound pulses: microtripsy. IEEE Trans Ultrason Ferroelectr Freq Control 61:251-65
Lin, Kuang-Wei; Hall, Timothy L; McGough, Robert J et al. (2014) Synthesis of monopolar ultrasound pulses for therapy: the frequency-compounding transducer. IEEE Trans Ultrason Ferroelectr Freq Control 61:1123-36
Maxwell, Adam D; Park, Simone; Vaughan, Benjamin L et al. (2014) Trapping of embolic particles in a vessel phantom by cavitation-enhanced acoustic streaming. Phys Med Biol 59:4927-43
Vlaisavljevich, Eli; Kim, Yohan; Owens, Gabe et al. (2014) Effects of tissue mechanical properties on susceptibility to histotripsy-induced tissue damage. Phys Med Biol 59:253-70
Wang, Tzu-Yin; Hall, Timothy L; Xu, Zhen et al. (2014) Imaging feedback for histotripsy by characterizing dynamics of acoustic radiation force impulse (ARFI)-induced shear waves excited in a treated volume. IEEE Trans Ultrason Ferroelectr Freq Control 61:1137-51
Miller, Ryan M; Kim, Yohan; Lin, Kuang-Wei et al. (2013) Histotripsy cardiac therapy system integrated with real-time motion correction. Ultrasound Med Biol 39:2362-73

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