Dr. Zhen Xu, PhD, and her group at the University of Michigan recently completed a Foundation-funded study that evaluated the use of histotripsy for thrombolysis—dissolving unwanted blood clots.
This important work may one day create non-invasive treatment options for deep vein thrombosis, stroke, myocardial infarction, and other clotting diseases. Dr. Xu’s study investigated the safety of 1) applying histotripsy to free-flowing blood while measuring hemolytic effects; 2) applying “microtripsy” to the lumen of the blood vessel to avoid epithelial damage on the vessel walls; and 3) evaluating the use of bubble-induced, real-time color Doppler for quantitatively monitoring the thrombolysis.
The results of this highly successful study have garnered much attention, including:
- More than $2M of follow-on R01 funding awarded by the NIH
- Multiple manuscripts published or in progress
- Presentations at several scientific meetings
Because some forms of therapeutic ultrasound cause intravascular hemolysis, this study investigated the extent and consequences of histotripsy-induced hemolysis in vivo on free flowing blood in the porcine femoral vein. Based on collaboration with an interventional cardiologist, the use of systemic heparinization was compared to not using heparin. All animals in the heparin group survived (the non-heparin group mortality was 45%, p<0.05). Histotripsy applied to the circulating blood volume is generally safe, and systemic heparinization should be used. It is currently the standard of care for interventional cardiovascular procedures.
Previous histotripsy studies to treat thrombolysis used multi-cycle pulses that formed cavitation clouds on the vessel walls. Damaging the endothelial layer has been shown to increase the risk of re-thrombosis. So, to avoid potentially damaging the vessel walls with histotripsy, Dr. Xu’s group created a new histotripsy approach, “microtripsy,” that uses single-cycle pulses to generate and confine cavitation in the vessel lumen without contacting the vessel wall. They then used the microtripsy for clot recanalization in an in vitro flow model. After each treatment, a flow channel was successfully generated through and completely confined inside the clot, showing the potential of microtripsy thrombolysis for fast, precise, and effective clot recanalization that minimizes the risks of vessel damage and re-thrombosis.
Real-time quantitative feedback is needed to monitor treatment progress during histotripsy clot fractionation. B-mode ultrasound imaging can be used to visualize and guide cavitation targeting during histotripsy because the bubble cloud is hyperechoic, but it cannot quantitatively measure the therapy. Bubble-induced color Doppler (BCD) has been shown in gel and ex vivo liver tissue to be correlated with histotripsy fractionation, so the group investigated its potential for real-time monitoring, validated the BCD feedback, and created/ed an algorithm to predict complete clot fractionation during histotripsy thrombolysis.
“Now I am a scientist who is looking for investors. There is really a gap in between, and that is why the Focused Ultrasound Foundation is so great – the translational research funding that you provide is really helpful. This type of funding represents a real unmet need in getting the technology to the patients who need it.”—Zhen Xu, PhD
Grant Title: Image-guided Non-invasive Ultrasonic Thrombrolysis Using Histotripsy
Funding Mechanism: R01 renewal
Amount: $2,032,190 (all to U of Michigan)
Funding Period: 7/1/2014 - 6/30/2018
This R01 renewal covers many aspects of the clinical translation of histotripsy for DVT and technical advancements to expand histotripsy thrombolysis for other applications.
Because of the discoveries made from the work in this grant:
- The ultrasound-guided histotripsy thrombolysis system will be redesigned to incorporate microtripsy and bubble-induced color Doppler to increase the safety and efficacy of histotripsy thrombolysis system.
- The in vivo safety and efficacy of this new system will be determined through a comprehensive preclinical study in the porcine DVT model.
- Together with HistoSonics, the University of Michigan team will actively seek industry partners to pursue the commercialization of the histotripsy thrombolysis technique.