Therapeutic Ultrasound Applications Research Articles

Overview of Therapeutic Ultrasound Applications and Safety Considerations: 2024 Update.

A 2012 review of therapeutic ultrasound was published to educate researchers and physicians on potential applications and concerns for unintended bioeffects (doi: 10.7863/jum.2012.31.4.623). This review serves as an update to the parent article, highlighting advances in therapeutic ultrasound over the past 12 years. In addition to general mechanisms for bioeffects produced by therapeutic ultrasound, current applications, and the pre-clinical and clinical stages are outlined. An overview is provided for image guidance methods to monitor and assess treatment progress. Finally, other topics relevant for the translation of therapeutic ultrasound are discussed, including computational modeling, tissue-mimicking phantoms, and quality assurance protocols.

Rational design of CMUTs with annular electrodes for high ultrasonic emission via ESSE enabled stiffness adjustment

Capacitive micromechanical ultrasonic transducers (CMUTs) with high transmitting acoustic pressure are in urgent demand in the rapidly growing field of air-coupled and therapeutic ultras ound. However, most current CMUTs can rarely balance the performance improvement and batch fabrication capacity, which severely impedes their practical applications. This paper proposes novel CMUTs with annular electrodes that can implement significant improvement in multiple performances while featuring a simple structure and batch fabrication feasibility. The annular electrode configurated between the membrane edge and center areas can effectively soften the corresponding-area membrane stiffness through electrostatic spring softening effects, and leave the stiffness of the membrane central area unchanged, finally enabling the membrane to produce a piston-like deformation, thus improving average displacement and output acoustic pressure. A finite element method was employed to analyze the effect of annular electrodes on the CMUT main performance. The results demonstrated that the novel structure could achieve prominent enhancement in multiple performances, such as an average to maximum displacement rate of 0.46 (about 0.32 for conventional CMUTs), maximum improvements of 300%, 255%, and 11% in average displacement, acoustic pressure, and electromechanical coupling coefficients compared to those of conventional ones. Deep analyses of the variation of the main performances including acoustic pressure, receiving sensitivity, and collapse voltage suggested that an optimal electrode coverage range of 36% ∼ 55% can be used to achieve relatively high comprehensive performances. Meanwhile, the proposed CMUTs feature a simpler structure and fabrication process in comparison with previous ones, showing great promise in air-coupled and therapeutic ultrasound applications.

Effects of unilateral superimposed high-frequency jet ventilation on porcine hemodynamics and gas exchange during one-lung flooding.

Superimposed high-frequency jet ventilation (SHFJV) is suitable for respiratory motion reduction and essential for effective lung tumor ablation. Fluid filling of the target lung wing one-lung flooding (OLF) is necessary for therapeutic ultrasound applications. However, whether unilateral SHFJV allows adequate hemodynamics and gas exchange is unclear. To compared SHFJV with pressure-controlled ventilation (PCV) during OLF by assessing hemodynamics and gas exchange in different animal positions. SHFJV or PCV was used alternatingly to ventilate the non-flooded lungs of the 12 anesthetized pigs during OLF. The animal positions were changed from left lateral position to supine position (SP) to right lateral position (RLP) every 30 min. In each position, ventilation was maintained for 15 min in both modalities. Hemodynamic variables and arterial blood gas levels were repeatedly measured. Unilateral SHFJV led to lower carbon dioxide removal than PCV without abnormally elevated carbon dioxide levels. SHFJV slightly decreased oxygenation in SP and RLP compared with PCV; the lowest values of PaO2 and PaO2/FiO2 ratio were found in SP [13.0; interquartile range (IQR): 12.6-5.6 and 32.5 (IQR: 31.5-38.9) kPa]. Conversely, during SHFJV, the shunt fraction was higher in all animal positions (highest in the RLP: 0.30). In porcine model, unilateral SHFJV may provide adequate ventilation in different animal positions during OLF. Lower oxygenation and CO2 removal rates compared to PCV did not lead to hypoxia or hypercapnia. SHFJV can be safely used for lung tumor ablation to minimize ventilation-induced lung motion.

Low-Cost Desktop Printed Sensors for Therapeutic Ultrasound Applications

Low-Cost Desktop Printed Sensors for Therapeutic Ultrasound Applications

Nonlinear Acoustic Holography with Adaptive Sampling.

Accurate and efficient numerical simulation of highly nonlinear ultrasound propagation is essential for a wide range of therapeutic and physical ultrasound applications. However, due to large domain sizes and the generation of higher harmonics, such simulations are computationally challenging, particularly in three-dimensional problems with shock waves. Current numerical methods are based on computationally inefficient uniform meshes that require the highest harmonic to be resolved across the entire domain. To address this challenge, we present an adaptive numerical algorithm for computationally efficient nonlinear acoustic holography. At each propagation step, the algorithm monitors the harmonic content of the acoustic signal and adjusts its discretization parameters accordingly. This enables efficient local resolution of higher harmonics in areas of high nonlinearity while avoiding unnecessary resolution elsewhere. Furthermore, the algorithm actively adapts to the signal's nonlinearity level, eliminating the need for prior reference simulations or information about the spatial distribution of the harmonic content of the acoustic field. The proposed algorithm incorporates an upsampling process in the frequency domain to accommodate the generation of higher harmonics in forward propagation and a downsampling process when higher harmonics are decimated in backward propagation. The efficiency of the algorithm was evaluated for highly nonlinear three-dimensional problems, demonstrating a significant reduction in computational cost with a nearly 50-fold speedup over a uniform mesh implementation. Our findings enable a more rapid and efficient approach to modeling nonlinear high-intensity focused ultrasound wave propagation.

Global sonication of the human intracranial space via a jumbo planar transducer

Contrary to conditioning a Focused Ultrasound (FUS) beam to sonicate a localized region of the human brain, the goal of this investigation was to explore the prospect of distributing homogeneous ultrasound energy over the entire brain space with a large cranium-wide ultrasound beam. Recent ultrasound preclincal studies utilizing large or whole brain stimulation regions create a demand for expanding the treatment envelope of transcranial pulsed-low intensity ultrasound towards Global Brain Sonication (GBS) for potential human investigation. Here, we conduct ultrasound field characterizations when transmitting pulsed ultrasound through human skull specimens using a 1–3 piezocomposite planar transducer operating at 464 kHz with an active single-element surface of 30 × 30 cm. Through computational simulation and hydrophone scanning methodology, ultrasound wave behavior and dose homogeneity in the brain space were evaluated under various trajectories of sonication using the planar transducer. Clinically relevant pulse parameters used for transcranial therapeutic ultrasound applications were used in the experiments. Simulations and empirical testing revealed that dose homogeneity and acoustic intensity over the brain space are influenced by sonication trajectory, skull lens effects, and acoustic wave reflections. The transducer can emit a spatial peak pulse average intensity of 4.03 W/cm2 (0.24 MPa) measured in the free-field at 464 kHz with electrical power of 1 kW. The simulation showed that approximately 99 % of the cranial volume was exposed with <30 % of the maximum external acoustic intensity being transmitted into the skull. The transmission loss across all sonication trajectories is similar to previously reported FUS studies. A marker for GBS dose homogeneity is introduced to score the ultrasound pressure field uniformity in the intracranial space. Results of this study identify the initial challenges of exposing the entire human brain space with ultrasound using a large cranium-wide sonication beam intended for global brain therapeutic modulation.

The effects of cream-based Triticum vulgare with and without therapeutic ultrasound on excisional wound healing in diabetic rats

Purpose The purpose of the current study was to evaluate the effect of Triticum vulgare (TVE) alone or combined with therapeutic ultrasound (TUS) on wound healing in a diabetic rat model. Materials and Methods A total of 72 male Wistar rats were randomly divided into four groups: Group Control, wounded rats without treatment; Group TUS, wounded rats with TUS application; Group TVE, wounded rats treated with TVE; and Group TVE + TUS, wounded rats treated with TVE + TUS. Wound healing was assessed using wound area calculation and thermographic, biochemical, histopathologic, immunohistochemical, and immunofluorescence analyses on post-wounding days 7, 14, and 21. Results On day 21, the wound surface area was significantly decreased in Group TVE + TUS (0.18 ± 0.07 cm2) compared to the other groups (p < 0.001). A significant increase in wound area temperature was recorded on days 7, 14, and 21 in all groups compared to day 0 (p < 0.001). On day 21, Group TVE + TUS (35.4 ± 0.2 °C) had the most significantly highest wound area temperature compared to the other groups (p < 0.001). The highest histopathological scores were recorded in Group TVE + TUS on days 7, 14, and 21 (p = 0.04). The highest vascular endothelial growth factor expression was observed in Group TVE + TUS (82.53 ± 1.98) on day 7 (p = 0.03). Conclusion In conclusion, treatment with a combination of TVE and TUS effectively enhanced wound healing in diabetic rats compared with other treatment groups.

Sound advice—Sound design

Ultrasound energy offers unique capabilities to treat a wide range of medical conditions, through numerous distinct physical interactions with tissue. Unlike diagnostic ultrasound, where safety and efficacy are easily demonstrated and the underlying technology has been available for decades, therapeutic ultrasound applications have explored new regimes and therefore required novel technologies and approaches. This presentation will describe the journey from discovery to clinic, based on examples from the author’s personal experience as a consultant and entrepreneur. Developing therapeutic ultrasound products involves several specific and sometimes unique steps. It generally starts with the observation of a therapeutic effect, or a realization that an existing approach could be applied to a different clinical situation. Moving from “N = 1” to a repeatable treatment paradigm can be both exciting and discouraging. The next key steps, which are the hardest, involve translating the initial idea/data/concept into a commercial design, or at least a plan for one. The regulatory, financial, commercial, and clinical environments can be as challenging as the purely technical hurdles, and all factor into the development process. While creating new clinical ultrasound treatments and devices can be difficult and time consuming, it can also be immensely rewarding and satisfying.

Holography-based measurement of sound speed and attenuation coefficient values for small samples of tissue phantoms

For therapeutic ultrasound applications, design and planning of treatments often involve simulations to predict the in situ acoustic field, and these simulations rely on estimates of the acoustic properties of soft tissues. As defined in simulation models, these properties describe how a plane wave propagates in a homogeneous medium. However, because soft tissues inherently contain inhomogeneities, measurements are most appropriately performed on small, relatively homogeneous samples. In addition, mostly small samples of human tissue, either autopsy or post-surgical, are typically available for characterization. As published in a recent paper [J. Acoust. Soc. Am. 2021, 149(1): 386–404], we have proposed a holography-based technique to extract plane-wave measurements from ultrasound beams passing through small (cm-sized) material samples. Here, we seek to adapt this technique for measuring small samples of deformable materials using an apparatus that holds such samples with two plane, parallel surfaces that can be interrogated by an incident ultrasound beam having a diameter smaller than that of the sample. Initial testing over a range of frequencies from 0.5 to 10MHz is performed utilizing well characterized materials, such as hydrogels and silicone rubber. [Work supported by NIH grant R01EB025187.]

The Best Arm Position for Therapeutic Ultrasound Application in Lateral Elbow Tendinopathy Patients

Objectives: To determine which is the best arm position for Therapeutic Ultrasound (TUS) application in Lateral Elbow Tendinopathy (LET) patients. Patients and Methods: A randomized clinical trial was carried out with 33 patients who had Let in a research center. They were randomly allocated to three groups. Group A (n=11) was treated with were treated with an exercise program and application of TUS with the wrist in full flexion. An exercise program and application of TUS with the wrist in mid position between flexion and extension was given to group B (n=11). Group C (n=11) received an exercise program and application of TUS with the wrist in full extension. All patients received three treatments per week for six weeks. The pain was evaluated using a visual analogue scale and function using a visual analogue scale and pain-free grip strength at the end of the four-week course of treatment (week 4) and one month (week 8) after the end of treatment. Results: The application of TUS with the wrist in full extension produced the largest effect in the reduction of pain and in the improvement of function at the end of the treatment (P&lt;0.05) and at any of the follow-up time points (P&lt;0.05). Conclusion: The application of TUS with the wrist in full extension was the most effective treatment. Future well-designed studies are needed to confirm the results of the present trial.

Electroencephalographic Response of Brain Stimulation by Shock Waves from Laser Generated Carbon Nanotube Transducer.

Neuromodulation is used to treat neurological disorders. Focused ultrasound can deliver acoustic energy to local regions of the brain, including deep brain structures. In addition, it is possible to induce the activation or inhibition of nerves through parameter adjustments of focused ultrasound. Laser-generated focused ultrasound (LGFUS) has demonstrated a potential use in precise therapeutic ultrasound applications owing to the ability to produce high-pressure, broadband frequency of shock waves with a tight focal spot, resulting in confined acoustic exposure of a small area. However, there have been few studies of neurostimulation using shock waves with pulse durations of several nanoseconds. The purpose of this study is to investigate the possibility of neurostimulation by shock waves generated from a focused Carbon Nanotube (fCNT) transducer. We measured electroencephalographic (EEG) signals in three rat brains before and after shock wave stimulation and compared them in the time and frequency domains. In the time domain, the number of peaks of EEG signals was measured significantly higher after shock wave stimulation than before stimulation in all three rats. The three rats showed differences in three frequency bands: theta(4-7 Hz), alpha(8-12), and 1-30 Hz, before and after shock wave stimulation (p < 0.001). These differences in EEG signals after shock wave stimulation of three rats were confirmed mainly because of shock waves. The stimulation of a rat brain was feasible using shock waves generated by the fCNT transducer. This study provides a basis for the applications of shock waves to brain stimulation for precise targeting.

A mechanistic journey in shock wave lithotripsy research

As a remarkable engineering innovation, shock wave lithotripsy (SWL) has revolutionized the treatment of kidney stone disease since 1980s with worldwide clinical acceptance. Over the past three decades, the long journey to understand the transient interaction of focused shock waves with kidney stones and soft tissues has propelled fundamental research at multiple fronts, including (1) the generation, propagation, and interaction of various stress waves inside the bulk stone materials, and surface acoustic waves associated with Mach stem formation at the stone boundary; (2) dynamic fracture and comminution processes in relation to lithotripter field characteristics; and (3) cavitation-induced stone surface erosion and vascular injury. In this talk, I will present illustrative examples to highlight chronologically the progressive understanding regarding the mechanisms of stone comminution and tissue injury, and how the acquired knowledge has influenced the technology evolution and clinical practice in SWL. I will also discuss how the fundamental concepts and techniques of SWL have been widely utilized in other therapeutic ultrasound and lithotripsy applications; and future perspectives, especially related to 3D cavitation detection and monitoring, as well as multi-spark shock wave generator development.

Detection and quantification of bubble activity in therapeutic ultrasound: Magnetic resonance imaging for cavitation detection and quantification

For some applications of therapeutic ultrasound, magnetic resonance imaging (MRI) may serve as a useful tool for detecting, measuring, and quantifying cavitation activity—especially in cases where direct sampling of acoustic emissions are difficult. Doing so can be challenging because the physical phenomena that drive ultrasonic cavitation (e.g., pressure, surface tension, micro-second time scales) have little overlap with the phenomena that drive MRI (e.g., quantum spin, Faraday induction, milli-second time scales). However, this same principle also protects MRI-based cavitation detection from common confounds that plague traditional direct acoustic detection. The proposed paper will first review known methods for encoding cavitation behavior into MR images. These methods generally employ one of two strategies: (1) Encode transient cavitation activities into otherwise approximately static MR signal sources.; and (2) Leverage the time-average effects of many, many cycles of cavitation activity to alter MR signal sources. This paper will then discuss how these methods may be useful to therapeutic ultrasound applications. Finally, this paper will pose opportunities for future development.

Characterization of Acoustic, Cavitation, and Thermal Properties of Poly(vinyl alcohol) Hydrogels for Use as Therapeutic Ultrasound Tissue Mimics.

The thermal and mechanical effects induced in tissue by ultrasound can be exploited for therapeutic applications. Tissue-mimicking materials (TMMs), reflecting different soft tissue properties, are required for experimental evaluation of therapeutic potential. In the study described here, poly(vinyl alcohol) (PVA) hydrogels were characterized. Hydrogels prepared using different concentrations (5%-20% w/w) and molecular weights of PVA ± cellulose scatterers (2.5%-10% w/w) were characterized acoustically (sound speed, attenuation) as a function of temperature (25°C-45°C), thermally (thermal conductivity, specific heat capacity) and in terms of their cavitation thresholds. Results were compared with measurements in fresh sheep tissue (kidney, liver, spleen). Sound speed depended most strongly on PVA concentration, and attenuation, on cellulose content. For the range of formulations investigated, the PVA gel acoustic properties (sound speed: 1532 ± 17 to 1590 ± 9 m/s, attenuation coefficient: 0.08 ± 0.01 to 0.37 ± 0.02 dB/cm) fell within those measured in fresh tissue. Cavitation thresholds for 10% PVA hydrogels (50% occurrence: 4.1-5.4 MPa, 75% occurrence: 5.4-8.2 MPa) decreased with increasing cellulose content. In summary, PVA cellulose composite hydrogels may be suitable mimics of acoustic, cavitation and thermal properties of soft tissue for a number of therapeutic ultrasound applications.

Robust and durable aberrative and absorptive phantom for therapeutic ultrasound applications.

Phase aberration induced by soft tissue inhomogeneities often complicates high-intensity focused ultrasound (HIFU) therapies by distorting the field and, previously, we designed and fabricated a bilayer gel phantom to reproducibly mimic that effect. A surface pattern containing size scales relevant to inhomogeneities of a porcine body wall was introduced between gel materials with fat- and muscle-like acoustic properties-ballistic and polyvinyl alcohol gels. Here, the phantom design was refined to achieve relevant values of ultrasound absorption and scattering and make it more robust, facilitating frequent handling and use in various experimental arrangements. The fidelity of the interfacial surface of the fabricated phantom to the design was confirmed by three-dimensional ultrasound imaging. The HIFU field distortions-displacement of the focus, enlargement of the focal region, and reduction of focal pressure-produced by the phantom were characterized using hydrophone measurements with a 1.5 MHz 256-element HIFU array and found to be similar to those induced by an ex vivo porcine body wall. A phase correction approach was used to mitigate the aberration effect on nonlinear focal waveforms and enable boiling histotripsy treatments through the phantom or body wall. The refined phantom represents a practical tool to explore HIFU therapy systems capabilities.

Imaging mechanisms of therapeutic ultrasound in human islets

We have previously shown that therapeutic ultrasound (TUS) has a wide range of effects on rat pancreas cells. We aim to explore additional possible mechanisms of TUS on the pancreas in a more physiologically relevant human islet model with the goal of potential therapies for type-2 diabetes. Fluorescence microscopy was performed on live human islets with dyes that can label for intracellular calcium, sodium, and reactive oxygen species (ROS). During microscopy, TUS was applied at 800 kHz at 0.5 W/cm2 with a pulse repetition frequency of 0.166 Hz and a 16.6% duty cycle. The amount of insulin released from human islets as a result of TUS application was quantified with an enzyme-linked immunoassay (ELISA). Thus far, we have noticed a trend of increased intracellular sodium and ROS generation due to TUS application; however, the percent increase in ROS appears to be less than for intracellular sodium. Our initial ELISA results show that TUS does appear to increase insulin release from human islets (0.55 ± 0.90 μU/ml min) when compared to control (−0.14 ± 0.19 μU/ml min), however, not as much as with the high glucose application at 20 mM (2.47 ± 3.54 μU/ml min). Ongoing studies aim to better characterize TUS effects.

Ultrasound at the pulmonary air-tissue interface: Mechanism of haemorrhage induction and implications for safe use of diagnostic and therapeutic lung ultrasound applications

Despite the high-diagnostic value of sonographic lung imaging, providing substantial patient benefit, clinician should be aware that ultrasound exposure on lung is not absolutely without risk of harm. As shown in animal models, lung ultrasound (LUS) even in the diagnostic regime can induce pulmonary capillary haemorrhage (PCH) at the alveolar epithelium-gas interface. Acoustic peak negative pressure in the range of 1.0–1.5 MPa correlates well with PCH threshold. However, in retrospective human studies, adverse events could not be demonstrated following LUS examination, which is evidence of symptomatic PCH after therapeutic ultrasound ablation in proximity of lung exists. Therefore, this subject remains controversial. This work summarizes the underlying physical causes and consequences of ultrasound induced PCH. The complexity of PCH thresholds depending on imaging modes, pathological lung conditions including ventilation parameters will be presented. In addition, current recommendations for the safe use of LUS based on Safety Indices given by AIUM and EFSUMB guidelines and the impact of LUS specific settings, available on modern scanners, will be discussed.

Ultrasound does not activate but can inhibit in vivo mammalian nerves across a wide range of parameters

Ultrasound (US) has been shown to stimulate brain circuits, however, the ability to excite peripheral nerves with US remains controversial. To the best of our knowledge, there is still no in vivo neural recording study that has applied US stimulation to a nerve isolated from surrounding tissue to confirm direct activation effects. Here, we show that US cannot excite an isolated mammalian sciatic nerve in an in vivo preparation, even at high pressures (relative to levels recommended in the FDA guidance for diagnostic ultrasound) and for a wide range of parameters, including different pulse patterns and center frequencies. US can, however, reliably inhibit nerve activity whereby greater suppression is correlated with increases in nerve temperature. By prohibiting the nerve temperature from increasing during US application, we did not observe suppressive effects. Overall, these findings demonstrate that US can reliably inhibit nerve activity through a thermal mechanism that has potential for various health disorders, though future studies are needed to evaluate the long-term safety of therapeutic ultrasound applications.

Non-invasive approach for sterilization in male dogs using therapeutic ultrasound

The objective of this study was to evaluate the efficacy of noninvasive technique of sterilization in male dogs using therapeutic ultrasound. Twelve male dogs were randomly divided into two equal groups subjected to therapeutic ultrasound application with frequenciesl MHz (group B) and 3MHz (group B) performed on days 0, 2, 4, 6 and 8, for 5 minutes in animals of both groups. Sterilization by therapeutic ultrasound application was confirmed by atrophy of testes grossly and by testicular histopathology microscopically. It was concluded that the therapeutic ultrasound sterilization technique is satisfactory in dogs as sufficient testicular degeneration, considerable decline in testosterone levels and azoospermia was evident during post-therapeutic period. Treatment with therapeutic ultrasound with frequency of 1 MHz had better results than 3 MHz.

Feasibility of Therapeutic Ultrasound Application in Topical Scleral Delivery of Avastin.

PurposeMacromolecules have been shown to be effective in vision-saving treatments for various ocular diseases, such as age-related macular degeneration and diabetic retinopathy. The current delivery of macromolecules requires frequent intraocular injections and carries a risk of serious adverse effects.MethodsWe tested the application of therapeutic ultrasound as a minimally invasive approach for the delivery of Avastin into the diseased regions of the eye. Avastin (bevacizumab) is an anti-vascular endothelial growth factor (VEGF) antibody with a molecular weight of 149 kDa. We tested the effectiveness and safety of Avastin delivery through rabbit sclera in vitro using a standard diffusion cell model. Ultrasound at frequencies of 400 kHz or 3 MHz with an intensity of 1 W/cm2 was applied for the first 5 minutes of 1-hour drug exposure. Sham treatments mimicked the ultrasound treatments, but ultrasound was not turned on. Absorbance measurements of the receiver compartment solution were performed at 280 nm using a spectrophotometer.ResultsAbsorbance measurements indicated no statistical difference between the sham (n = 13) and 400 kHz ultrasound group (n = 15) in the delivery of Avastin through the sclera. However, the absorbance values were statistically different (P < 0.01) between the 3 MHz ultrasound group (0.004, n = 8) and the matched sham group (0.002, n = 7). There was 2.3 times increase in drug delivery in the 3 MHz ultrasound when compared to the corresponding sham group. Histological studies indicated no significant damage in the ultrasound-treated sclera due to ultrasound application.ConclusionsOur preliminary results provided support that therapeutic ultrasound may be effective in the delivery of Avastin through the sclera.Translational RelevanceOur study offers clinical potential for a minimally invasive retinopathy treatment.