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)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
5R01EB008998-08
Application #
9096075
Study Section
Biomedical Imaging Technology Study Section (BMIT)
Program Officer
Krosnick, Steven
Project Start
2008-09-30
Project End
2018-06-30
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
8
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Biomedical Engineering
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Shi, Aiwei; Lundt, Jonathan; Deng, Zilin et al. (2018) Integrated Histotripsy and Bubble Coalescence Transducer for Thrombolysis. Ultrasound Med Biol 44:2697-2709
Macoskey, Jonathan J; Zhang, Xi; Hall, Timothy L et al. (2018) Bubble-Induced Color Doppler Feedback Correlates with Histotripsy-Induced Destruction of Structural Components in Liver Tissue. Ultrasound Med Biol 44:602-612
Shi, Aiwei; Xu, Zhen; Lundt, Jonathan et al. (2018) Integrated Histotripsy and Bubble Coalescence Transducer for Rapid Tissue Ablation. IEEE Trans Ultrason Ferroelectr Freq Control 65:1822-1831
Macoskey, Jonathan J; Hall, Timothy L; Sukovich, Jonathan R et al. (2018) Soft-Tissue Aberration Correction for Histotripsy. IEEE Trans Ultrason Ferroelectr Freq Control 65:2073-2085
Macoskey, J J; Choi, S W; Hall, T L et al. (2018) Using the cavitation collapse time to indicate the extent of histotripsy-induced tissue fractionation. Phys Med Biol 63:055013
Gerhardson, Tyler; Sukovich, Jonathan R; Pandey, Aditya S et al. (2017) Catheter Hydrophone Aberration Correction for Transcranial Histotripsy Treatment of Intracerebral Hemorrhage: Proof-of-Concept. IEEE Trans Ultrason Ferroelectr Freq Control 64:1684-1697
Gerhardson, Tyler; Sukovich, Jonathan R; Pandey, Aditya S et al. (2017) Effect of Frequency and Focal Spacing on Transcranial Histotripsy Clot Liquefaction, Using Electronic Focal Steering. Ultrasound Med Biol 43:2302-2317
Mancia, Lauren; Vlaisavljevich, Eli; Xu, Zhen et al. (2017) Predicting Tissue Susceptibility to Mechanical Cavitation Damage in Therapeutic Ultrasound. Ultrasound Med Biol 43:1421-1440
Vlaisavljevich, Eli; Gerhardson, Tyler; Hall, Tim et al. (2017) Effects of f-number on the histotripsy intrinsic threshold and cavitation bubble cloud behavior. Phys Med Biol 62:1269-1290
Lundt, Jonathan E; Allen, Steven P; Shi, Jiaqi et al. (2017) Non-invasive, Rapid Ablation of Tissue Volume Using Histotripsy. Ultrasound Med Biol 43:2834-2847

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