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 tumors46–48 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.
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.
- 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.
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- 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.
- 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.
- 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.
- EKOSTM 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.
- 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.
- 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.
- 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.
- 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.
- 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.
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