The Sage Journals
Research Article, First published online June 10, 2025
🚨 No drugs. No wires. No incisions. Just sound waves.
For the first time, we’ve used focused ultrasound to completely liquefy stroke clots in under 2 minutes—without the need for thrombolytics or catheters.
Our latest study on histotripsy marks a major step toward a non-invasive, drug-free and device-free future for stroke care. This could radically expand access to treatment for patients worldwide, democratizing stroke care and even for those ineligible for tPA or mechanical thrombectomy.
🔗 Read the full paper here: https://journals.sagepub.com/doi/10.1177/15910199251347838
Histotripsy: A novel non-invasive ultrasound technology for precision thrombolysis in acute ischemic stroke management
Abstract
Background
Stroke remains a major cause of morbidity and mortality worldwide. Traditional treatments for ischemic stroke such as mechanical thrombectomy and pharmacological thrombolysis are often less effective or inaccessible for certain patient populations, particularly those with delayed hospital arrival, contraindications to thrombolytics, or in regions with limited access to endovascular care. This study investigates the feasibility of using histotripsy, a non-invasive ultrasound technology, to precisely liquefy thrombi in an artificial experimental setup.
Methods
Clot analogs were introduced into sample tubes, and focused ultrasound was applied using optimized parameters, including pulses per burst, repetition rates, and output amplitudes. These parameters were systematically adjusted to determine the most effective settings for clot ablation, with a focus on maximizing clot liquefaction while minimizing residual fragments.
Results
Histotripsy achieved complete clot liquefaction within 60–120 s at a repetition rate of 100 Hz, with 1000 pulses per burst and an output amplitude of 100%. The procedure effectively disintegrated soft (red blood cell-rich) clots, leaving minimal residual fragments (<250 microns). However, dense fibrin-rich clots and anatomical barriers like bone presented challenges, suggesting the need for further optimization.
Conclusions
This proof-of-concept study demonstrates the potential of histotripsy as a non-invasive, rapid, and targeted approach for clot removal in stroke management.
References
1. James SL, Abate D, Abate KH, et al. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: A systematic analysis for the global burden of disease study 2017. Lancet 2018; 392: 1789–1858.
2. Godoi BB, Diniz Vianna BF, Snatos DF. Stroke managementand quality of care in low and middle-income countries: An integrative literature review. Brazilian Journal of Development 2020; 6: 14500–14528.
3. Katzan IL, Hammer MD, Hixson ED, et al. Utilization of intravenous tissue plasminogen activator for acute ischemic stroke. Arch Neurol 2004; 61: 346–350.
4. Reed SD, Cramer SC, Blough DK, et al. Treatment with tissue plasminogen activator and inpatient mortality rates for patients with ischemic stroke treated in community hospitals. Stroke 2001; 32: 1832–1840.
5. Aroor SR, Asif KS, Potter-Vig J, et al. Mechanical thrombectomy access for all? Challenges in increasing endovascular treatment for acute ischemic stroke in the United States. J Stroke 2022; 24: 41–48.
6. Kamel H, Parikh NS, Chatterjee A, et al. Access to mechanical thrombectomy for ischemic stroke in the United States. Stroke 2021; 52: 2554–2561.
7. Frenkel V, Oberoi J, Stone MJ, et al. Pulsed high-intensity focused ultrasound enhances thrombolysis in an in vitro model. Radiology 2006; 239: 86–93.
8. Tsivgoulis G, Alexandrov AV. Ultrasound-enhanced thrombolysis in acute ischemic stroke: Potential, failures, and safety. Neurotherapeutics 2007; 4: 420–427.
9. Hendley SA, Bhargava A, Holland CK, et al. (More than) doubling down: Effective fibrinolysis at a reduced rt-PA dose for catheter-directed thrombolysis combined with histotripsy. PLoS One 2022; 17: e0261567.
10. Laing ST, Moody M, Smulevitz B, et al. Ultrasound-enhanced thrombolytic effect of tissue plasminogen activator-loaded echogenic liposomes in an in vivo rabbit aorta thrombus model–brief report. Arterioscler Thromb Vasc Biol 2011; 31: 1357–1359.
11. Siegel RJ, Atar S, Fishbein MC, et al. Noninvasive, transthoracic, low-frequency ultrasound augments thrombolysis in a canine model of acute myocardial infarction. Circulation 2000; 101: 2026–2029.
12. Braaten JV, Goss R, Francis CW. Ultrasound reversibly disaggregates fibrin fibers. Thromb Haemostasis 1997; 78: 1063–1068.
13. Burgess A, Huang Y, Waspe AC, et al. High-intensity focused ultrasound (HIFU) for dissolution of clots in a rabbit model of embolic stroke. PLoS One 2012; 7: e42311.
14. Wright C, Hynynen K, Goertz D. In vitro and in vivo high-intensity focused ultrasound thrombolysis. Invest Radiol 2012; 47: 217–225.
15. Khokhlova VA, Fowlkes JB, Roberts WW, et al. Histotripsy methods in mechanical disintegration of tissue: Towards clinical applications. Int J Hyperthermia 2015; 31: 145–162.
16. Li Y, Li Y, Chen H. The effect of ultrasound-assisted thrombolysis studied in blood-on-a-chip. Artif Organs 2024; 48: 734–742.
17. Zafar A, Quadri SA, Farooqui M, et al. MRI-Guided High-Intensity focused ultrasound as an emerging therapy for stroke. A Review. J Neuroimaging 2019; 29: 5–13.
18. Venketasubramanian N, Yeo LLL, Tan B, et al. Sonothrombolysis for ischemic stroke. J Cardiovasc Dev Dis 2024; 11: 75.
19. Duffy S, Farrell M, McArdle K, et al. Novel methodology to replicate clot analogs with diverse composition in acute ischemic stroke. J Neurointerv Surg 2017; 9: 486–491.
20. IEC Technical Specification 62556: Ultrasonics – Field characterization – Specification and measurement of field parameters for high intensity therapeutic ultrasound (HITU) transducers and systems. International Electrotechnical Commission; 2014.
21. Zhou Y, Zhai L, Simmons R, et al. Measurement of high intensity focused ultrasound fields by a fiber optic probe hydrophone. J Acoust Soc Am 2006; 120: 676–685.
22. Bollen V, Hendley SA, Paul JD, et al. In vitro thrombolytic efficacy of single- and five-cycle histotripsy pulses and rt-PA. Ultrasound Med Biol 2020; 46: 336–349.
23. Khokhlova T, Rosnitskiy P, Hunter C, et al. Dependence of inertial cavitation induced by high intensity focused ultrasound on transducer F-number and nonlinear waveform distortion. J Acoust Soc Am 2018; 144: 1160.
24. Collis J, Manasseh R, Liovic P, et al. Cavitation microstreaming and stress fields created by microbubbles. Ultrasonics 2010; 50: 273–279.
25. Bader KB, Bouchoux G, Holland CK. Sonothrombolysis. Adv Exp Med Biol 2016; 880: 339–362.
26. Goudot G, Mirault T, Arnal B, et al. Pulsed cavitational therapy using high-frequency ultrasound for the treatment of deep vein thrombosis in an in vitro model of human blood clot. Phys Med Biol 2017; 62: 9282–9294.
27. Yang W, Zhou Y. Effect of pulse repetition frequency of high-intensity focused ultrasound on in vitro thrombolysis. Ultrason Sonochem 2017; 35: 152–160.
28. Pajek D, Hynynen K. The design of a focused ultrasound transducer array for the treatment of stroke: A simulation study. Phys Med Biol 2012; 57: 4951–4968.
29. Sukovich JR, Cain CA, Pandey AS, et al. In vivo histotripsy brain treatment. J Neurosurg 2019; 131: 1331–1338.
30. Gerhardson T, Sukovich JR, Chaudhary N, et al. Histotripsy clot liquefaction in a porcine intracerebral hemorrhage model. Neurosurgery 2020; 86: 429–436.
31. Zhang X, Macoskey JJ, Ives K, et al. Non-Invasive thrombolysis using microtripsy in a porcine deep vein thrombosis model. Ultrasound Med Biol 2017; 43: 1378–1390.
32. Teleb M, Porres-Aguilar M, Rivera-Lebron B, et al. Ultrasound-Assisted catheter-directed thrombolysis: A novel and promising endovascular therapeutic modality for intermediate-risk pulmonary embolism. Angiology 2017; 68: 494–501.
33. Garcia MJ. Endovascular management of acute pulmonary embolism using the ultrasound-enhanced EkoSonic system. Semin Intervent Radiol 2015; 32: 384–387.
34. Dumantepe M, Uyar I, Teymen B, et al. Improvements in pulmonary artery pressure and right ventricular function after ultrasound-accelerated catheter-directed thrombolysis for the treatment of pulmonary embolism. J Card Surg 2014; 29: 455–463.
35. Zhang X, Owens GE, Cain CA, et al. Histotripsy thrombolysis on retracted clots. Ultrasound Med Biol 2016; 42: 1903–1918.
36. Zhang X, Miller RM, Lin KW, et al. Real-time feedback of histotripsy thrombolysis using bubble-induced color Doppler. Ultrasound Med Biol 2015; 41: 1386–1401.
37. Lu N, Yeats EM, Sukovich JR, et al. Treatment envelope of transcranial histotripsy: Challenges and strategies to maximize the treatment location profile. Phys Med Biol 2024; 69: 225006.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.