Periodic shock-emission from acoustically driven cavitation clouds:a source of the subharmonic signal

Single clouds of cavitation bubbles, driven by 254 kHz focused ultrasound at pressure amplitudes in the range of 0.48–1.22 MPa, have been observed via high-speed shadowgraphic imaging at 1 × 10⁶ frames per second. Clouds underwent repetitive growth, oscillation and collapse (GOC) cycles, with shock-waves emitted periodically at the instant of collapse during each cycle. The frequency of cloud collapse, and coincident shock-emission, was primarily dependent on the intensity of the focused ultrasound driving the activity. The lowest peak-to-peak pressure amplitude of 0.48 MPa generated shock-waves with an average period of 7.9 ± 0.5 μs, corresponding to a frequency of f₀/2, half-harmonic to the fundamental driving. Increasing the intensity gave rise to GOC cycles and shock-emission periods of 11.8 ± 0.3, 15.8 ± 0.3, 19.8 ± 0.2 μs, at pressure amplitudes of 0.64, 0.92 and 1.22 MPa, corresponding to the higher-order subharmonics of f₀/3, f₀/4 and f₀/5, respectively. Parallel passive acoustic detection, filtered for the fundamental driving, revealed features that correlated temporally to the shock-emissions observed via high-speed imaging, p(two-tailed) 200 μm diameter, at maximum inflation), that developed under insonations of peak-to-peak pressure amplitudes >1.0 MPa, emitted shock-waves with two or more fronts suggesting non-uniform collapse of the cloud. The observations indicate that periodic shock-emissions from acoustically driven cavitation clouds provide a source for the cavitation subharmonic signal, and that shock structure may be used to study intra-cloud dynamics at sub-microsecond timescales

Focused ultrasound radiosensitizes human cancer cells by enhancement of DNA damage

PURPOSE: High-intensity focused ultrasound (HIFU/FUS) has expanded as a noninvasive quantifiable option for hyperthermia (HT). HT in a temperature range of 40–47 °C (thermal dose CEM43 ≥ 25) could work as a sensitizer to radiation therapy (RT). Here, we attempted to understand the tumor radiosensitization effect at the cellular level after a combination treatment of FUS+RT. METHODS: An in vitro FUS system was developed to induce HT at frequencies of 1.147 and 1.467 MHz. Human head and neck cancer (FaDU), glioblastoma (T98G), and prostate cancer (PC-3) cells were exposed to FUS in ultrasound-penetrable 96-well plates followed by single-dose X‑ray irradiation (10 Gy). Radiosensitizing effects of FUS were investigated by cell metabolic activity (WST‑1 assay), apoptosis (annexin V assay, sub-G1 assay), cell cycle phases (propidium iodide staining), and DNA double-strand breaks (γH2A.X assay). RESULTS: The FUS intensities of 213 (1.147 MHz) and 225 W/cm(2) (1.467 MHz) induced HT for 30 min at mean temperatures of 45.20 ± 2.29 °C (CEM43 = 436 ± 88) and 45.59 ± 1.65 °C (CEM43 = 447 ± 79), respectively. FUS improves the effect of RT significantly by reducing metabolic activity in T98G cells 48 h (RT: 96.47 ± 8.29%; FUS+RT: 79.38 ± 14.93%; p = 0.012) and in PC-3 cells 72 h (54.20 ± 10.85%; 41.01 ± 11.17%; p = 0.016) after therapy, but not in FaDu cells. Mechanistically, FUS+RT leads to increased apoptosis and enhancement of DNA double-strand breaks compared to RT alone in T98G and PC-3 cells. CONCLUSION: Our in vitro findings demonstrate that FUS has good potential to sensitize glioblastoma and prostate cancer cells to RT by mainly enhancing DNA damage. SUPPLEMENTARY INFORMATION: The online version of this article (10.1007/s00066-021-01774-5) contains supplementary material, which is available to authorized users

Cavitation Cloud Translation in Focused Ultrasound

Cavitation mediated effects in liquids exposed to ultrasound, play pivotal roles in a number of industrial arenas, including precision acoustic cleaning (megasonics) and sonochemistry. The spontaneous occurrence of cavitation, and the subsequent interaction with the liquid and the acoustic field, is however poorly understood, which prevents optimization for any given application. In this paper we report on observations made of single isolated cavitation-bubble clouds, exposed to a well characterized burst of propagating focused ultrasound, and the resulting translational motion of the clouds under the action of the primary acoustic radiation force. As may be expected, larger clouds develop under higher intensity insonations, which translate away from the ultrasound source more rapidly, although a larger associated drag force somewhat tempers the effect. Critically, however, a resonant condition is identified whereby small clouds at lower intensities translate much more rapidly than might otherwise be expected. A model is derived from first principles, adapted to the experimental conditions and demonstrates good agreement with the observations, including the frequency resonance. We anticipate the results will have significance for any application in which understanding and predicting a dynamic cavitating liquid is important, particularly under non-standing wave conditions

Early exploration of MRI-compatible diagnostic ultrasound transducers

Ultrasonic echography and magnetic resonance imaging (MRI) are widely used medical diagnostic tools. The interest of combining them is based on the fact that the images are created in different ways and show different features of human tissue. Ultrasound creates images based on mechanical properties whereas MRI creates images based ultimately on chemical composition. MRI-guided focused ultrasound surgery (MRgFUS) requires operation of ultrasound transducers within the MRI system. In this case, the ultrasound intensities and corresponding electrical excitation signals are large and careful engineering can realize MRI-compatible hardware. Ultrasound imaging within MRI is more complicated, since the electrical signals in ultrasound receive mode are very much smaller. The preliminary work reported here aimed to show that it is possible to combine ultrasound and MRI technologies for imaging, with little or no degradation in signal and image quality, even though the MRI environment is hostile to other passive and electrically-active devices. The particular innovation that is reported is the use of 0–3 connectivity Cu — epoxy composites providing both electromagnetic shielding and ultrasonic matching

Laser-nucleated acoustic cavitation in focused ultrasound

Acoustic cavitation can occur in therapeutic applications of high-amplitude focused ultrasound. Studying acoustic cavitation has been challenging, because the onset of nucleation is unpredictable. We hypothesized that acoustic cavitation can be forced to occur at a specific location using a laser to nucleate a microcavity in a pre-established ultrasound field. In this paper we describe a scientific instrument that is dedicated to this outcome, combining a focused ultrasound transducer with a pulsed laser. We present high-speed photographic observations of laser-induced cavitation and laser-nucleated acoustic cavitation, at frame rates of 0.5×106 frames per second, from laser pulses of energy above and below the optical breakdown threshold, respectively. Acoustic recordings demonstrated inertial cavitation can be controllably introduced to the ultrasound focus. This technique will contribute to the understanding of cavitation evolution in focused ultrasound including for potential therapeutic applications

Vein wall shrinkage induced by thermal coagulation with high-intensity-focused ultrasound: numerical modeling and in vivo experiments in sheep

Background Varicose veins are a common disease that may significantly affect quality of life. Different approaches are currently used in clinical practice to treat this pathology. Materials and methods In thermal therapy (radiofrequency or laser therapy), the vein is directly heated to a high temperature to induce vein wall coagulation, and the heat induces denaturation of the intramural collagen, which results macroscopically in vein shrinkage. Thermal vein shrinkage is a physical indicator of the efficiency of endovenous treatment. High-intensity focused ultrasound (HIFU) is a noninvasive technique that can thermally coagulate vein walls and induce vein shrinkage. In this study, we evaluated the vein shrinkage induced in vivo by extracorporeal HIFU ablation of sheep veins: six lateral saphenous veins (3.4mm mean diameter) were sonicated for 8 s with 3MHz continuous waves. Ultrasound imaging was performed before and immediately post-HIFU to quantify the HIFU-induced shrinkage. Results Luminal constriction was observed in 100% (6/6) of the treated veins. The immediate findings showed a mean diameter constriction of 53%. The experimental HIFU-induced shrinkage data were used to validate a numerical model developed to predict the thermally induced vein contraction during HIFU treatment. Conclusions This model is based on the use of the k-wave library and published contraction rates of vessels immersed in hot water baths. The simulation results agreed well with those of in vivo experiments, showing a mean percent difference of 5%. The numerical model could thus be a valuable tool for optimizing ultrasound parameters as functions of the vein diameter, and future clinical trials are anticipated

Efficacy and safety assessment of an ultrasound-based thermal treatment of varicose veins in a sheep model

Purpose Varicose veins are a common pathology that can be treated by endovenous thermal procedures like radiofrequency ablation (RFA). Such catheter-based techniques consist in raising the temperature of the vein wall to 70 to 120 °C to induce vein wall coagulation. Although effective, this treatment option is not suited for all types of veins and can be technically challenging. Materials and methods In this study, we used High-Intensity Focused Ultrasound (HIFU) as a non-invasive thermal ablation procedure to treat varicose veins and we assessed the long-term efficacy and safety of the procedure in a sheep model. In vivo experiments were first conducted on two saphenous veins to measure the temperature rise induced at the vein wall during HIFU ablation and were compared with reported RFA-induced thermal rise. Thermocouples were inserted in situ to perform 20 measurements during 8-s ultrasound pulses at 3 MHz. Eighteen saphenous veins of nine anesthetized sheep (2–2.5 % Isoflurane) were then exposed to similar pulses (85 W acoustic, 8 s). After treatments, animals recovered from anesthesia and were followed up 30, 60 and 90 days post-treatment (n = 3 animals per group). At the end of the follow-up, vein segments and perivenous tissues were harvested and histologically examined. Results Temperatures induced by HIFU pulses were found to be comparable to reported RFA treatments. Likewise, histological findings were similar to the ones reported after RFA and laser-based coagulation necrosis of the vein wall, thrombotic occlusions and vein wall fibrosis. Conclusion These results support strongly the effectiveness and safety of HIFU for ablating non-invasively veins

Periodic shock-emission from acoustically driven cavitation clouds: A source of the subharmonic signal-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/)

a b s t r a c t Single clouds of cavitation bubbles, driven by 254 kHz focused ultrasound at pressure amplitudes in the range of 0.48-1.22 MPa, have been observed via high-speed shadowgraphic imaging at 1 Â 10 6 frames per second. Clouds underwent repetitive growth, oscillation and collapse (GOC) cycles, with shock-waves emitted periodically at the instant of collapse during each cycle. The frequency of cloud collapse, and coincident shock-emission, was primarily dependent on the intensity of the focused ultrasound driving the activity. The lowest peak-to-peak pressure amplitude of 0.48 MPa generated shock-waves with an average period of 7.9 ± 0.5 ls, corresponding to a frequency of f 0 /2, half-harmonic to the fundamental driving. Increasing the intensity gave rise to GOC cycles and shock-emission periods of 11.8 ± 0.3, 15.8 ± 0.3, 19.8 ± 0.2 ls, at pressure amplitudes of 0.64, 0.92 and 1.22 MPa, corresponding to the higher-order subharmonics of f 0 /3, f 0 /4 and f 0 /5, respectively. Parallel passive acoustic detection, filtered for the fundamental driving, revealed features that correlated temporally to the shock-emissions observed via high-speed imaging, p(two-tailed) < 0.01 (r = 0.996, taken over all data). Subtracting the isolated acoustic shock profiles from the raw signal collected from the detector, demonstrated the removal of subharmonic spectral peaks, in the frequency domain. The larger cavitation clouds (>200 lm diameter, at maximum inflation), that developed under insonations of peak-to-peak pressure amplitudes >1.0 MPa, emitted shock-waves with two or more fronts suggesting non-uniform collapse of the cloud. The observations indicate that periodic shock-emissions from acoustically driven cavitation clouds provide a source for the cavitation subharmonic signal, and that shock structure may be used to study intra-cloud dynamics at sub-microsecond timescales

Laser-nucleated Acoustic Cavitation: Size Matters

We report on the development of an instrument for hybrid ‘sonoptic’ cavitation studies. A focused ultrasound transducer is housed in a custom built chamber, which permits optical access to the focal volume, without perturbing the propagating acoustic field. This configuration allows pulsed-laser irradiation of the fluid at the focus, and simultaneous high speed observation of cavitation activity in this region. In this paper we provide a brief description of the apparatus and present preliminary data on distinct cavitation regimes we have observed. Specifically, laser-induced cavitation in an established field, and a new phenomenon that we refer to as laser-nucleated acoustic cavitation. The former involves a laser pulse of energy above the threshold value for optical breakdown for the medium, in a pre-established ultrasound field. Here, a cavity rapidly expands to a maximum diameter of a few 100µms, from the plasma generated on absorption of the optical energy, and collapses to form debris that is subsequently driven by the ultrasound radiation. By contrast, laser-nucleated acoustic cavitation is initiated by a pulse of energy below the ambient breakdown threshold, in a pre-established field. For this regime, either form of radiation does not result in cavitation activity without the other. In combination, the role of the laser pulse is to initiate activity which is dominated by the ultrasound exposure from the outset. Crucially, the spatial and temporal precision afforded to the occurrence of cavitation by laser-nucleation, allows the use of high speed micro-photography to resolve cavitation cloud evolution and behavior. This allows us to consolidate our assertion of acoustic cavitation, with close-up ultra-high speed images of the clouds, and observation of constituent cavity sizes. It is expected that such observations will contribute to a greater understanding of cavitation in focused ultrasound, including for potential future therapeutic applications