Statement on Biological Effects of Therapeutic Ultrasound

Introduction

Ultrasound is most commonly known as a diagnostic imaging modality. Although the mechanical energy of the ultrasound wave is nonionizing, it can still induce biological effects if exposure levels are sufficient.¹ Most ultrasound imaging systems provide indexes to help the sonographer understand the likelihood of bioeffects to avoid unnecessary exposure.^2,3 It is possible to harness ultrasound to intentionally cause bioeffects for therapeutic purposes.⁴ At the time this statement was written (2023), multiple therapeutic ultrasound devices were approved or cleared by the US Food and Drug Administration (FDA), including applications in thermal ablation of pathologic tissue or enhancing the delivery of therapeutic drugs. Further, the U.S. Centers for Medicare and Medicaid Services (CMS) provided reimbursement of ultrasound treatments for certain thrombotic embolisms,⁵ pain due to bone metastases,⁶ essential tremor,⁷ tremor-dominant Parkinson disease,^8,9 and prostate conditions.¹⁰ Additional devices were FDA-approved or cleared for uterine fibroids and pain due to osteoid osteoma. The European Medicines Agency (EMA) had devices approved in these categories and others, including hypertension, varicose veins, thyroid nodules, primary and metastatic tumors (liver, pancreas, bone, soft tissue, kidney, and breast), along with other musculoskeletal and neurological applications. Beyond these approved uses, more than 1,900 active investigations with therapeutic ultrasound were listed on clinicaltrials.gov, ranging from Phase I safety-focused investigations to Phase III efficacy-focused studies (search terms: “therapeutic ultrasound”, “focused ultrasound”, “HIFU” for high-intensity focused ultrasound, “HITU” for high-intensity therapeutic ultrasound). It is anticipated that new applications and devices will be approved or cleared over time.

Ultrasound therapeutic bioeffects are induced through two known mechanisms: thermal and mechanical.¹¹ Thermal effects occur as the result of absorption of ultrasound waves within tissue, resulting in heating.¹² Mechanical effects, such as fluid streaming and radiation force,¹³ are initiated by the transfer of energy/momentum from the incident pulse to tissue or nearby biofluids. Indirect mechanical effects can also occur through interaction of the ultrasound pulse with microbubbles such as ultrasound contrast agents.¹⁴ Importantly, thermal and mechanical mechanisms can trigger biological responses that result in desired therapeutic endpoints. Different bioeffects will require different amounts of ultrasound, and thermal and mechanical mechanisms can occur simultaneously for some exposure conditions. The bioeffects that are generated in situ depend on multiple factors, including the tissue properties (eg, density, sound speed, attenuation, backscatter, acoustic impedance, thermal conductivity, perfusion, stiffness), specifications of the therapeutic device (eg, geometry, frequency, pulse duration, pulsing rate, acoustic intensity, and pressure amplitude), and the potential presence of exogenous agents (eg, microbubbles) that promote cavitation bioeffects. Acoustic cavitation is the formation and ultrasound-induced oscillation of gaseous bodies.¹⁵ There is a spectrum of cavitation behaviors, which are categorized by two primary descriptors: inertial and stable.¹⁶ Inertial cavitation is characterized by a sudden and violent bubble collapse that can potentially damage biological structures. In contrast, stable cavitation is a gentler and repeated bubble oscillation that is less likely to injure tissue.

This statement discusses therapeutic mechanisms with and without exogenous agents. Typical applications are discussed, though not all forms of therapeutic ultrasound are included. Applications can include therapeutic ultrasound as a standalone treatment or as an adjuvant to existing therapies.

Treatment of tissues without exogenous agents

For relatively low intensity but sustained (>0.1 s duration) exposures, the ultrasound wave can cause tissue displacement or fluid streaming due to acoustic radiation force. Devices that generate fluid streaming are designed to improve the penetration of drugs into a target, such as catheter systems with integrated ultrasound sources to treat pulmonary embolism.¹⁷ Low-intensity pulses can also be used for neuromodulation¹⁸ by targeting areas within the brain or peripheral nervous system to stimulate or suppress neural activity.¹⁹ Low-intensity pulsed ultrasound has also been shown to send regulatory signals to bone, causing physical remodeling of the tissue, providing a means to promote healing for nonunion fractures.²⁰

As the acoustic intensity and exposure time increase, heating effects become more important. The relationship between temperature increase, duration of ultrasound exposure, and type of bioeffect are described by the “thermal dose.”²¹ If the tissue temperature is raised to 42°C over the course of several minutes,²² the target tissue will experience mild hyperthermia. Preclinical and clinical studies have investigated mild hyperthermia as an adjuvant for other oncologic interventions (eg, chemotherapy or radiation).^23,24 The ultrasound intensity and exposure duration can reach a point where irreversible coagulative necrosis from heating occurs. For example, thermal necrosis in soft tissue is initiated within 5 seconds if the temperature is increased to 55°C or greater.²⁵ One CMS-reimbursement-approved application of thermal ablation is thalamotomy for essential tremor or tremor-dominant Parkinson disease.^26,27 Partial thalamotomy is achieved via a thermal lesion within the ventral intermediate nucleus, ablating misfiring neurons responsible for symptoms.²⁸ Ablative heating can also be administered indirectly for treatment. Applying high-intensity therapeutic ultrasound to heat bone tissue ablates nearby nerves, thereby relieving pain due to bone metastases.²⁹ For patients with hypertension, ultrasound can heat the tissue surrounding an artery supplying a kidney to decrease the over-activity of nerves and reduce blood pressure.³⁰

Mechanical effects can also be used to ablate tissue. Histotripsy (histo: cells; tripsy: breaking) applies short-duration pulses (usually 1 µs to 10 ms) with much higher pulse-average intensities than used in thermal ablation to generate inertial cavitation.³¹ The bubble oscillations cause fractionation of the cellular structure without heating the target.³²

Ablation can also produce other desired outcomes. Preclinical studies indicate thermal and mechanical ablation can induce an immunomodulatory effect, with increased infiltration and activation of immune cells.³³ Current results are promising but preliminary, and the precise role of ablative ultrasound and other forms of therapeutic ultrasound in immunomodulation remains to be determined.

Lithotripsy (litho: stone; tripsy: breaking) relies on intense shock waves to break down unwanted mineralizations, like kidney stones, gallstones, and calcified vessels or heart valves.^34–36 In addition to inertial cavitation, other mechanical effects play a prominent role in lithotripsy due to a direct interaction between the incident pulse and the target, including spallation (interference between a reverberating ultrasound wave within the mineralization), shear stresses, super focusing, squeezing, and fatigue.³⁷ The primary goal of lithotripsy is to break down the structure to return the patient to homeostasis. For instance, kidney stones and gallstones are reduced to a manageable size that can be passed naturally. For vessels or valves, lithotripsy is used to generate fractures that reduce the nominal stiffness of the calcification to increase their flexibility and function.

Treatment with exogenous agents

The administration of exogenous agents substantially reduces the ultrasound intensity required to induce cavitation bioeffects.³⁸ There are multiple types of agents that may be used for the generation of stable or inertial cavitation in vivo. Stabilized microbubbles have been the most widely investigated agents, in part because several ultrasound contrast agents have been FDA-approved for diagnostic imaging and are therefore commercially available.³⁹ Other agents under testing include nanobubbles,⁴⁰ nano/micro-droplets,⁴¹ and gas-stabilizing solid cavitation agents.⁴² 

Because of their gas core, microbubbles are substantially more compressible than the surrounding tissue and undergo stable cavitation oscillations that can cause larger fluid streaming effects than would occur in tissue without microbubbles.⁴³ The increased shear stresses and convection from streaming can be exploited to increase the penetration of a drug into a target. Microbubble oscillations can also cause direct mechanical forces on cells leading to paracellular or transcellular penetration of therapeutics into or beyond the vascular tissue.⁴⁴ These mechanisms may be exploited for transient opening of the blood brain barrier,⁴⁵ which ordinarily prohibits most therapeutics bigger than a few hundred Daltons from passing beyond the vasculature and into brain tissue. First-in-human and phase I clinical trials have been published for applications in brain tumors^46–48 and Alzheimer’s disease.^49,50 Drug delivery can be achieved in other organs, such as the liver using both microbubbles⁵¹ and thermally sensitive agents that respond to ultrasound hyperthermia.⁵² It is also possible to reversibly permeabilize cell membranes and enhance endocytosis (ie, sonoporation) for the delivery of therapeutics directly into cells.^53–55 To achieve sonoporation, microbubbles are administered intravascularly and the target is exposed to therapeutic ultrasound. Microbubble oscillations have also been shown to induce biological effects without a therapeutic drug. A phase I randomized controlled trial demonstrated improved recanalization of the microvasculature following percutaneous coronary intervention of ST-segment elevation myocardial infarction.⁵⁶ At increased ultrasound pressure, microbubbles can generate ablation-like cavitation activity for mechanical ablation similar to what was described without exogenous agents.

Monitoring Bioeffects

Therapeutic ultrasound is a non- or minimally invasive procedure. Imaging is used to monitor the generation of ultrasound mechanisms (eg, heating or cavitation) within the target, and achievement of the intended bioeffect. To monitor heating, magnetic resonance imaging (MRI) thermometry maps the tissue temperature spatially and temporally.⁵⁷ Cavitation can be detected as hyperintense regions on B-mode ultrasound imaging and other contrast-specific sequences.³¹ For example, histotripsy can be monitored by initial hyperechoic regions due to cavitation followed by hypoechoic regions due to liquified tissue with weak backscatter.⁵⁸ Some thermal ablation systems also have integrated sensors to detect strong acoustic emissions generated by cavitation to avoid unwanted mechanical effects.⁵⁹ Elastography may be used to detect an increase in tissue stiffness following thermal ablation. Follow-up imaging after the procedure is used to ensure the intended bioeffect was achieved. In the case of ablation, nonperfusion regions on contrast computerized tomography (CT) or MRI are the most common surrogate for the extent of the lesion.⁶⁰ Contrast-enhanced ultrasound imaging can also be used to assess nonperfusing regions.⁶¹ For vascular applications, digital subtraction angiography can be used to confirm the restoration of flow within the targeted vessel. 

Conclusions

• Although safe when used properly for diagnostic imaging and image-guided intervention, ultrasound can cause bioeffects associated with therapeutic benefits when administered at sufficient exposure levels.
• The type of bioeffects generated by ultrasound depends on many factors, including the ultrasound source, exposure conditions, presence of cavitation nuclei, and tissue type.
• Appropriate monitoring techniques based on the mechanism of action and intended bioeffect should be implemented.

References 

1. Fowlkes JB, Bioeffects Committee of the American Institute of Ultrasound in Medicine. American Institute of Ultrasound in Medicine consensus report on potential bioeffects of diagnostic ultrasound. J Ultrasound Med 2008; 27:503–515. doi:10.7863/jum.2008.27.4.503.
2. International Electrotechnical Commission. “Particular requirements for the basic safety and essential performance of ultrasonic medical diagnostic and monitoring equipment. Edition 2.1.,” Geneva, Switzerland, 2015.
3. Recommended Maximum Scanning Times for Displayed Thermal Index (TI) Values. Laurel, MD: American Institute of Ultrasound in Medicine. Available at: https://www.aium.org/officialStatements/65. Accessed April 18, 2022.
4. Miller DL, Smith NB, Bailey MR, Czarnota GJ, Hynynen K, Makin IRS. Overview of therapeutic ultrasound applications and safety considerations. J Ultrasound Med 2012; 31:623–634. doi: 10.7863/jum.2012.31.4.623.
5. EKOS^TM Endovascular System 2022 Coding & Payment Guide. Maple Grove, MN: Boston Scientific. Available at: https://www.bostonscientific.com/content/dam/bostonscientific/pi/portfolio-group/Vascular%20Surgery/ekos/recent-updates/EKOS-Reimbursement-Coding-Guide-vF-PI-874704-AA.pdf. Accessed April 18, 2022.
6. Summary of Data Changes Integrated OCE v 16.0. Baltimore, MD: Centers for Medicare & Medicaid Services. Available at: https://www.cms.gov/files/document/finalsumofdatachngsspeccms-report508pdf-0. Accessed April 18, 2022.
7. Magnetic Resonance Guided Focused Ultrasound Surgery System (MRgFUS) for the treatment of neurologic conditions. Baltimore, MD: Centers for Medicare & Medicaid Services. Available at: https://www.cms.gov/medicare-coverage-database/view/lcd.aspx?lcdid=37790&ver=15&ContrId=238&ContrVer=2&CntrctrSelected=238*2&Cntrctr=238&name=&DocType=4&bc=AAAAAACAAAAA&=. Accessed April 10, 2022.
8. Billing and Coding: Magnetic Resonance Guided Focused Ultrasound Surgery System (MRgFUS) for the treatment of neurologic conditions. Baltimore, MD: Centers for Medicare & Medicaid Services. Available at: https://www.cms.gov/medicare-coverage-database/view/article.aspx?articleid=58323&ver=4&keyword=ultrasound surgery&keywordType=starts&areaId=all&docType=NCA,CAL,NCD,MEDCAC,TA,MCD,6,3,5,1,F,P&contractOption=all&sortBy=relevance&bc=1. Accessed April 18, 2022.
9. Magnetic Resonance Guided Focused ULTRASOUND SURGERY System (MRgFUS) for the treatment of neurologic conditions. Baltimore, MD: Centers for Medicare & Medicaid Services. Available at: https://www.cms.gov/medicare-coverage-database/view/lcd.aspx?lcdid=37790&ver=15&. Accessed April 18, 2022.
10. Salvage High-intensity Focused Ultrasound (HIFU) Treatment in Prostate Cancer (PCa). Baltimore, MD: Centers for Medicare & Medicaid Services. Available at: https://www.cms.gov/medicare-coverage-database/view/lcd.aspx?lcdId=38262&ver=3. Accessed April 18, 2022.
11. Nyborg WL, Carson PL, Carstensen, et al. Exposure Criteria for Medical Diagnostic Ultrasound: II. Criteria Based on All Known Mechanisms; NCRP Report No. 140. 1st ed. Bethesda, MD: National Council on Radiation Protection and Measurements; 2002.
12. Dalecki D, Carstensen EL, Parker KJ, Bacon DR. Absorption of finite amplitude focused ultrasound. J Acoust.Soc Am 1991; 89:2435.
13. Nyborg WL. Acoustic streaming due to attenuated plane waves. J Acoust Soc Am 1953; 25:68.
14. Miller DL, Brayman AA, Holland CK, Wu J. Bioeffects considerations for diagnostic ultrasound contrast agents. J Ultrasound Med 2008; 27:611–632.
15. Apfel RE. Acoustic Cavitation. In Edmonds PD (ed). Methods in Experimental Physics: Ultrasonics. 1st ed. New York: Academic Press, Inc, 1981:355–411.
16. Flynn HG. Physics of Acoustic Cavitation in Liquids. In Mason WP (ed). Physical Acoustics. 1st ed. New York: Academic Press, Inc. 1964:58–172.
17. Lin PH, Annambhotla S, Bechara CF, et al. Comparison of percutaneous ultrasound-accelerated thrombolysis versus catheter-directed thrombolysis in patients with acute massive pulmonary embolism. Vascular 2009; 17(3 suppl):137–147. doi:10.2310/6670.2009.00063.
18. Deffieux T, Younan Y, Wattiez N, Tanter M, Pouget P, Aubry JF. Low-intensity focused ultrasound modulates monkey visuomotor behavior. Curr Biol 2013; 23(23):2430–2433. doi:10.1016/j.cub.2013.10.029.
19. King RL, Brown JR, Newsome WT, Pauly KB. Effective parameters for ultrasound-induced in vivo neurostimulation. Ultrasound Med Biol 2013; 39:312–331. doi:10.1016/j.ultrasmedbio.2012.09.009.
20. Ultrasound Stimulation for Nonunion Fracture Healing. Baltimore, MD: Centers for Medicare & Medicaid Services. Available at: https://www.cms.gov/medicare-coverage-database/view/ncacal-decision-memo.aspx?proposed=N&ncaid=135. Accessed April 18, 2022.
21. Sapareto SA, Dewey WC. Thermal dose determination in cancer therapy. Int J Radiat Oncol 1984; 10:787–800.
22. Statement on Biological Effects of Ultrasound in Vivo. Laurel, MD: American Institute of Ultrasound in Medicine. Available at: https://www.aium.org/resources/official-statements/view/statement-on-biological-effects-in-tissues-with-ultrasound-contrast-agents-2. Accessed April 18, 2022.
23. Hurwitz MD, Kaplan ID, Hansen JL. Hyperthermia combined with radiation in treatment of locally advanced prostate cancer is associated with a favourable toxicity profile. Int J Hyperth 2005; 21:649–656. doi:10.1080/02656730500331967.
24. Wang S, Zderic V, Frenkel V. Extracorporeal, low-energy focused ultrasound for noninvasive and nondestructive targeted hyperthermia. Futur Oncol 2010; 6:1497–1511. doi:10.2217/fon.10.101.
25. Chopra R, Tang K, Burtnyk M, et al. Analysis of the spatial and temporal accuracy of heating in the prostate gland using transurethral ultrasound therapy and active MR temperature feedback. Phys Med Biol 2009; 54(9):2615–2633.
26. Agrawal M, Garg K, Samala R, Rajan R, Naik V, Singh M. Outcome and complications of MR guided focused ultrasound for essential tremor: A systematic review and meta-analysis. Front Neurol 2021; 12(article number 654711). doi:10.3389/fneur.2021.654711.
27. Fishman PS, Fischell JM. Focused ultrasound mediated opening of the blood-brain barrier for neurodegenerative diseases. Front Neurol 2021; 12(article number 749047). doi:10.3389/fneur.2021.749047.
28. Bruno F, Catalucci A, Arrigoni F, et al. An experience-based review of HIFU in functional interventional neuroradiology: transcranial MRgFUS thalamotomy for treatment of tremor. Radiol Med 2020; 125:877–886. doi:10.1007/s11547-020-01186-y.
29. Huisman M, ter Haar G, Napoli A, et al. International consensus on use of focused ultrasound for painful bone metastases: Current status and future directions. Int J Hyperth 2015; 31(3):251–259. doi:10.3109/02656736.2014.995237.
30. Azizi M, Sanghvi  K, Saxena M, et al. Ultrasound renal denervation for hypertension resistant to a triple medication pill (RADIANCE-HTN TRIO): a randomised, multicentre, single-blind, sham-controlled trial. Lancet 2021; 397(10293):2476–2486. doi:10.1016/S0140-6736(21)00788-1.
31. Xu Z, Hall TL, Vlaisavljevich E, Lee FT. Histotripsy: the first noninvasive, non-ionizing, non-thermal ablation technique based on ultrasound. Int J Hyperth 2021; 38:561–575. doi:10.1080/02656736.2021.1905189.
32. Bader KB, Vlaisavljevich E, Maxwell AD. For whom the bubble grows: physical principles of bubble nucleation and dynamics in histotripsy ultrasound therapy. Ultrasound Med Biol 2019; 45:1056–1080. doi:10.1016/j.ultrasmedbio.2018.10.035.
33. Bijgaart RJE, Eikelenboom DC, Hoogenboom M, Fütterer JJ, Brok MH, Adema GJ. Thermal and mechanical high-intensity focused ultrasound: perspectives on tumor ablation, immune effects and combination strategies. Cancer Immunol Immunother 2016; 66:247–258.
34. Cleveland RO, McAteer JA. The Physics of Shock Wave Litotripsy. In Smith AD, Badlani GH, Preminger GM, Kavoussi LR (eds) Smith’s Textbook of Endourology. 2nd ed. Hoboken: Wiley-Blackwell; 2006:527–558.
35. Messas E, Ijsselmuiden A, Goudot G, et al. Safety, feasibility and performance of Valvosoft non-invasive ultrasound therapy in patients with severe symptomatic calcific aortic valve stenosis. First-in-Man. Eur Heart J 2020; 41(suppl 2):ehaa946.1932. doi:10.1093/ehjci/ehaa946.1932.
36. Ali ZA, Nef H, Escaned J, et al. Safety and effectiveness of coronary intravascular lithotripsy for treatment of severely calcified coronary stenoses: The disrupt CAD II study. Circ. Cardiovasc. Interv 2019; 12:1–10. doi:10.1161/CIRCINTERVENTIONS.119.008434.
37. Rassweiler JJ, Knoll T, Köhrmann KU, et al. Shock wave technology and application: An update. Eur Urol 2011; 59:784–796. doi:10.1016/j.eururo.2011.02.033.
38. Bader KB, Holland CK. Gauging the likelihood of stable cavitation from ultrasound contrast agents. Phys Med Biol 2013; 58:127–144. doi:10.1088/0031-9155/58/1/127.
39. Kooiman K, Roovers S, Langeveld SAG, et al.Ultrasound-responsive cavitation nuclei for therapy and drug delivery. Ultrasound Med Biol 2020; 46:1296–1325. doi:10.1016/j.ultrasmedbio.2020.01.002.
40. Exner AA, Kolios MC. Bursting microbubbles: How nanobubble contrast agents can enable the future of medical ultrasound molecular imaging and image-guided therapy. Curr Opin Colloid Interface Sci 2021; 54:101463. doi:10.1016/j.cocis.2021.101463.
41. Sheeran PS, Dayton PA. Phase-change contrast agents for imaging and therapy. Curr Pharm Des 2012; 18(15):2152–2165. doi:10.2174/138161212800099883.
42. Thomas RG, Jonnalagadda US, Kwan JJ. Biomedical applications for gas-stabilizing solid cavitation agents. Langmuir 2019; 35(31):10106–10115. doi:10.1021/acs.langmuir.9b00795.
43. Collis J, Manasseh R, Liovic P, et al. Cavitation microstreaming and stress fields created by microbubbles. Ultrasonics 2010; 50:273–279.
44. Sutton JT, Haworth KJ, Pyne-Geithman G, Holland CK. Ultrasound-mediated drug delivery for cardiovascular disease. Expert Opin Drug Deliv 2013; 10:573–592.
45. Hynynen K, McDannold N, Vykhodtseva N, Jolesz FA. Noninvasive MR imaging-guided focal opening of the blood-brain barrier in rabbits. Radiology 2001; 220(3):640–646.
46. Carpentier A, Canney M, Vignot A, et al. Clinical trial of blood-brain barrier disruption by pulsed ultrasound. Sci Transl Med 2016; 8(343):1–9. doi:10.1126/scitranslmed.aaf6086.
47. Idbaih A, Canney  M, Belin L, et al. Safety and feasibility of repeated and transient blood-brain barrier disruption by pulsed ultrasound in patients with recurrent glioblastoma. Clin Cancer Res 2019; 25(13):3793–3801. doi:10.1158/1078-0432.CCR-18-3643.
48. Mainprize T, Lipsman N, Huang Y, et al. Blood-brain barrier opening in primary brain tumors with non-invasive MR-guided focused ultrasound: A clinical safety and feasibility study. Sci Rep 2019; 9:1–7. doi:10.1038/s41598-018-36340-0.
49. Lipsman N, Meng Y, Bethune  AJ, et al. Blood–brain barrier opening in Alzheimer’s disease using MR-guided focused ultrasound. Nat Commun 2018; 9:1–8. doi:10.1038/s41467-018-04529-6.
50. Epelbaum S, Burgos N, Canney M, et al. Pilot study of repeated blood-brain barrier disruption in patients with mild Alzheimer’s disease with an implantable ultrasound device. Alzheimers Res Ther 2022; 14:1–13. doi:10.1186/s13195-022-00981-1.
51. Banerji U, Tiu CD, Curcean A, et al. Phase I trial of acoustic cluster therapy (ACT) with chemotherapy in patients with liver metastases of gastrointestinal origin (ACTIVATE study). J Clin Oncol 2021; 39(15 suppl):TPS3145–TPS3145. doi:10.1200/JCO.2021.39.15\_suppl.TPS3145.
52. Lyon PC, Gray MD, Mannaris C, et al. Safety and feasibility of ultrasound-triggered targeted drug delivery of doxorubicin from thermosensitive liposomes in liver tumours (TARDOX): a single-centre, open-label, phase 1 trial. Lancet Oncol 2018; 19:1027–1039. doi:10.1016/S1470-2045(18)30332-2.
53. Deng CX, Sieling F, Pan H, Cui J. Ultrasound-induced cell membrane porosity. Ultrasound Med Biol 2004; 30:519–526. doi:https://doi.org/10.1016/j.ultrasmedbio.2004.01.005.
54. Derieppe M, Rojek K, Escoffre JM, De Senneville BD, Moonen C, Bos C. Recruitment of endocytosis in sonopermeabilization-mediated drug delivery: A real-time study. Phys Biol 2015; 12:article number 046010. doi:10.1088/1478-3975/12/4/046010.
55. Fekri F, Abousawan J, Bautista S, et al. Targeted enhancement of flotillin-dependent endocytosis augments cellular uptake and impact of cytotoxic drugs. Sci Rep 2019; 9:1–15. doi:10.1038/s41598-019-54062-9.
56. Mathias W, Tsutsui  JM, Tavares BG, et al. Sonothrombolysis in ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention. J Am Coll Cardiol 2019; 73(22):2832–2842. doi:10.1016/j.jacc.2019.03.006.
57. Rieke V, Butts Pauly K. MR thermometry. J Magn Reson Imaging 2008; 27:376–390.
58. Hall T, Fowlkes J, Cain C. A real-time measure of cavitation induced tissue disruption by ultrasound imaging backscatter reduction. Ultrason Ferroelectr Freq Control IEEE Trans 2007; 54:569–575.
59. Eranki A, Farr N, Partanen A, et al. Mechanical fractionation of tissues using microsecond-long HIFU pulses on a clinical MR-HIFU system. Int J Hyperth 2018; 34:1213–1224. doi:10.1080/02656736.2018.1438672.
60. Rouvière O, Souchon R, Salomir R, Gelet A, Chapelon JY, Lyonnet D. Transrectal high-intensity focused ultrasound ablation of prostate cancer: Effective treatment requiring accurate imaging. Eur J Radiol 2007; 63(3):317–327.
61. Serres-Creixams X, Vidal-Jove J, Ziemlewicz TJ, et al. 2021 Contrast-enhanced ultrasound: A useful tool to study and monitor hepatic tumors treated with histotripsy. IEEE Trans Ultrason Ferroelectr Freq Control 2021; 68:2853–60.