Therapeutic ultrasound transducer technology and monitoring techniques: a review with clinical examples.

The exponential growth of therapeutic ultrasound applications demonstrates the power of the technology to leverage the combinations of transducer technology and treatment monitoring techniques to effectively control the preferred bioeffect to elicit the desired clinical effect.Objective: This review provides an overview of the most commonly used bioeffects in therapeutic ultrasound and describes existing transducer technologies and monitoring techniques to ensure treatment safety and efficacy.Methods and materials: Literature reviews were conducted to identify key choices that essential in terms of transducer design, treatment parameters and procedure monitoring for therapeutic ultrasound applications. Effective combinations of these options are illustrated through descriptions of several clinical indications, including uterine fibroids, prostate disease, liver cancer, and brain cancer, that have been successful in leveraging therapeutic ultrasound to provide effective patient treatments.Results: Despite technological constraints, there are multiple ways to achieve a desired bioeffect with therapeutic ultrasound in a target tissue. Visualizations of the interplay of monitoring modality, bioeffect, and applied acoustic parameters are presented that demonstrate the interconnectedness of the field of therapeutic ultrasound. While the clinical indications explored in this review are at different points in the clinical evaluation path, based on the ever expanding research being conducted in preclinical realms, it is clear that additional clinical applications of therapeutic ultrasound that utilize a myriad of bioeffects will continue to grow and improve in the coming years.Conclusions: Therapeutic ultrasound will continue to improve in the next decades as the combination of transducer technology and treatment monitoring techniques will continue to evolve and be translated in clinical settings, leading to more personalized and efficient therapeutic ultrasound mediated therapies.

Evidence of cerebral hypoperfusion consecutive to ultrasound-mediated blood-brain barrier opening in rats.

PURPOSE: This work aims to explore the effect of Blood Brain Barrier (BBB) opening using ultrasound combined with microbubbles injection on cerebral blood flow in rats. METHODS: Two groups of n = 5 rats were included in this study. The first group was used to investigate the impact of BBB opening on the Arterial Spin Labeling (ASL) signal, in particular on the arterial transit time (ATT). The second group was used to analyze the spatiotemporal evolution of the change in cerebral blood flow (CBF) over time following BBB opening and validate these results using DSC-MRI. RESULTS: Using pCASL, a decrease in CBF of up to 29 . 6 ± 15 . 1 % $$ 29.6\pm 15.1\% $$ was observed in the target hemisphere, associated with an increase in arterial transit time. The latter was estimated to be 533 ± 121ms $$ 533\pm 12\mathrm{1ms} $$ in the BBB opening impacted regions against 409 ± 93ms $$ 409\pm 93\mathrm{ms} $$ in the contralateral hemisphere. The spatio-temporal analysis of CBF maps indicated a nonlocal hypoperfusion. DSC-MRI measurements were consistent with the obtained results. CONCLUSION: This study provided strong evidence that BBB opening using microbubble intravenous injection induces a transient hypoperfusion. A spatiotemporal analysis of the hypoperfusion changes allows to establish some points of similarity with the cortical spreading depression phenomenon.

Combination of Focused Ultrasound, Immunotherapy, and Chemotherapy: New Perspectives in Breast Cancer Therapy.

Focused ultrasound is a treatment modality increasingly used for diverse therapeutic applications, and currently approved for several indications, including prostate cancers and uterine fibroids. But what about breast cancer? Breast cancer is the most common and deadliest cancer in women worldwide. While there are different treatment strategies available, there is a need for development of more effective and personalized modalities, with fewer side effects. Therapeutic ultrasound is such an option, and this review summarizes the state of the art in their use for the treatment of breast cancer and evaluate potentials of novel treatment approaches combining therapeutic ultrasound, immuno- and chemo-therapies.

A simulation study on the sensitivity of transcranial ray-tracing ultrasound modeling to skull properties.

In transcranial focused ultrasound therapies, such as treating essential tremor via thermal ablation in the thalamus, acoustic energy is focused through the skull using a phased-array transducer. Ray tracing is a computationally efficient method that can correct skull-induced phase aberrations via per-element phase delay calculations using patient-specific computed tomography (CT) data. However, recent studies show that variations in CT-derived Hounsfield unit may account for only 50% of the speed of sound variability in human skull specimens, potentially limiting clinical transcranial ultrasound applications. Therefore, understanding the sensitivity of treatment planning methods to material parameter variations is essential. The present work uses a ray-tracing simulation model to explore how imprecision in model inputs, arising from clinically significant uncertainties in skull properties or considerations of acoustic phenomena, affects acoustic focusing quality through the skull. We propose and validate new methods to optimize ray-tracing skull simulations for clinical treatment planning, relevant for predicting intracranial target's thermal rise, using experimental data from ex-vivo human skulls.

Proof of Concept: Protein Delivery into Human Erythrocytes Using Stable Cavitation.

Human erythrocytes represent candidates of choice as carriers for a wide range of drugs due to their unique biophysical and physiological properties. In this study, we used a sonoporation device generating and monitoring acoustic stable cavitation without any addition of contrast or nucleation agents. The device was evaluated for bovine serum albumin (BSA) delivery into human erythrocytes. After determining the adequate hematocrit percentage compatible with the generation of stable cavitation, we determined the optimal sonoporation conditions allowing BSA delivery while preserving erythrocyte integrity. Our results demonstrate that stable cavitation allows efficient delivery of proteins into human erythrocytes with limited lysis of these cells. In conclusion, our study allowed for the development of a stable and regulated cavitation program and the establishment of sonoporation conditions suitable for intracellular protein delivery while maintaining erythrocyte integrity. Additional investigations are needed to move from the proof of concept to a larger-scale application.

Salvage High-Intensity Focused Ultrasound for Local Recurrence in the Prostatic Bed after Prostatectomy and Adjuvant or Salvage Radiotherapy: Preliminary Results.

PURPOSE: We sought to report the preliminary results of salvage high-intensity focused ultrasound for locally recurrent prostate cancer in the prostatic bed after radical prostatectomy and adjuvant or salvage radiotherapy. MATERIALS AND METHODS: We retrospectively analyzed a single-center cohort of men treated with salvage high-intensity focused ultrasound for locally recurrent prostate cancer after radical prostatectomy and adjuvant or salvage radiotherapy. All patients had a combination of choline positron emission tomography, multiparametric magnetic resonance imaging, and transrectal biopsies to confirm the local recurrence. Treatment failure was defined as persistent or recurrent prostate cancer in the prostatic bed and/or metastasis and/or introduction of systemic treatment. Progression was defined as metastasis and/or introduction of systemic treatment. Complications (Clavien-Dindo classification) and continence (Ingelman-Sundberg score) were evaluated. Kaplan-Meier analysis estimated oncological outcomes. RESULTS: Between July 2009 and November 2018, 22 patients were included; the median followup was 2.32 years. At 3 years, treatment failure-free survival rate was estimated to be 49.7% and progression-free survival rate 60.4%. Prostate specific antigen nadir ≤0.2 ng/ml was reached in 50% of the patients. A nadir of ≤0.2 ng/ml was significantly associated with better treatment failure-free and progression-free survival probabilities (p=0.003 and p=0.037, respectively). Grade III complications occurred in 6 patients (27.3%). Onset of grade II-III incontinence was significantly more frequent in cases of perianastomotic (36.4%) compared to retrovesical recurrence (0%; p=0.027). CONCLUSIONS: Salvage high-intensity focused ultrasound for locally recurrent prostate cancer after radical prostatectomy and salvage radiotherapy showed encouraging oncological results despite significant morbidity. The perianastomotic recurrence was linked to a higher risk of incontinence.

Salvage high-intensity focused ultrasound for locally recurrent prostate cancer after low-dose-rate brachytherapy: oncological and functional outcomes.

OBJECTIVES: To evaluate the oncological and functional outcomes of salvage high-intensity focused ultrasound (S-HIFU) for locally recurrent prostate cancer after low-dose-rate (LDR) brachytherapy. PATIENTS AND METHODS: Clinical phase II studies (2003-2015) included 50 consecutive patients with post-brachytherapy local recurrence treated by S-HIFU. S-HIFU was performed with post-external beam radiotherapy (EBRT) parameters and, since 2008, with specific post-brachytherapy parameters. Treatments were whole-gland ablation and, since 2009, hemi-ablation in cases of unilateral prostate cancer. The primary objective was to assess oncological outcomes: treatment failure-free survival, progression-free survival (PFS), overall survival (OS), cancer-specific survival (CSS), and metastasis-free survival (MFS) rates. The secondary objective was to evaluate adverse events, continence, and erectile function. Kaplan-Meier analysis estimated oncological outcomes. RESULTS: In all, 13 patients were treated with post-EBRT parameters, 37 with post-brachytherapy parameters, 35 with whole-gland treatment, and 15 with hemi-ablation. The median follow-up was 4.6 years. After S-HIFU, the median prostate-specific antigen level was 0.3 ng/mL. At 6 years, treatment failure-free survival, PFS, OS, CSS, and MFS rates were 41%, 45%, 93%, 98%, and 80%, respectively. Post-brachytherapy compared with post-EBRT parameters reduced Grade 2-3 incontinence (34% vs 62%, P = 0.015). Incontinence, bladder outlet obstruction and Grade ≥III complications were significantly reduced with hemi-ablation compared with whole-gland treatment (14% vs 54%, P < 0.001; 13% vs 46%, P = 0.03; 13% vs 63%, P = 0.001; respectively). Before S-HIFU, 25 patients had a five-item version of the International Index of Erectile Function score of ≥17, which was maintained in 48% at 12 months. CONCLUSION: S-HIFU for locally recurrent prostate cancer after LDR brachytherapy is associated with favourable survival rates at a price of significant morbidity. Dedicated post-brachytherapy parameters and hemi-ablation improve the safety of the treatment.

Doxorubicin Delivery into Tumor Cells by Stable Cavitation without Contrast Agents.

Doxorubicin, alone or in combination with other anticancer agents, is one of the most widely used chemotherapeutic agents and is administered in a wide range of cancers. However, the use of doxorubicin is limited due to its potential serious adverse reactions. Previous studies have established the ability of high intensity focused ultrasound (HIFU) in combination with various contrast agents to increase intracellular doxorubicin delivery in a targeted and noninvasive manner. In this study, we developed a new sonoporation device generating and monitoring acoustic cavitation bubbles without any addition of contrast agents. The device was used to potentiate the delivery of active doxorubicin into both adherent and suspended cell lines. Combining doxorubicin with ultrasound resulted in a significant enhancement of doxorubicin intracellular delivery and a decrease in cell viability at 48 and 72 h, in comparison to doxorubicin alone. More importantly and unlike previous investigations, our procedure does not require the addition of contrast agents to generate acoustic cavitation and to achieve high levels of doxorubicin delivery. The successful translation of this approach for an in vivo application may allow a significant reduction in the dosage and the adverse effects of doxorubicin therapy in patients.

Numerical study of a confocal ultrasonic setup for cavitation creation.

Acoustic cavitation has found a wide range of applications in the last few decades. For potential applications involving cavitation, the acoustic characteristics of a confocal ultrasonic setup are studied: two high-intensity focused ultrasound transducers are mounted so that their focal points overlap. A mathematical simulator is developed that takes into account nonlinear propagation, absorption, and diffraction. Each one of these physical effects is solved in the frequency domain for successive planes. Comparing the confocal setup with equivalent single transducer setups, it is shown that, with the confocal configuration, nonlinear distortion of the waveform is reduced, resulting in a greater peak rarefactional pressure and a lower peak positive pressure. Furthermore, additional features are investigated for confocal configurations such as a greater spatial stability for the focal point, which can be maintained while increasing the pressure level, and a focal region consisting of interference acting as an acoustic trap.

New isolated bovine colon model dedicated to colonic ESD hands-on training: development and first evaluation.

INTRODUCTION: ESD is the reference method to achieve en bloc resections for large digestive lesions. Nevertheless, it is a difficult and risky technique. Animal models exist to teach the initial skills, particularly in Japan, where pigs' stomachs are dedicated models to gastric ESD. In Europe, we have to develop different strategies of teaching with dedicated colon models. A pig colon is a good model but thinner and narrower than a human's. In this present work, we evaluated a bovine colon model to perform rectal ESD in retroflexion. METHODS: First, we prepared six bowels to precise the preparation protocol. Then, two endoscopists unexperienced in ESD performed 64 procedures on eight models. Learning curves and factors of variation were studied. RESULTS: A precise protocol to prepare the colon was defined. The two students achieved en bloc resection in 89.1 % of cases with a rate of 6.2 % of perforations. A large heterogeneity appeared between the speed and the success rate depending mainly on the age of the animal bowel. Using calf colons, the failure rates were higher (p = 0.002) and the speed was lower (p < 0.001) than for adult bovine ones. A learning curve appeared with, respectively, 0.49 and 0.59 cm(2)/min throughout the study. No significant difference appeared between measured and calculated specimen areas. DISCUSSION: Bovine colon is a new model to teach ESD in colorectal conditions. The bovine age is important to homogenize the model. A learning curve existed with a time procedure decreasing throughout the study. Further studies are needed to evaluate the precise learning curve with more students. CONCLUSION: A bovine colon model is a suitable model to teach colorectal ESD. Nevertheless, an adult bovine colon model is more homogeneous than a calf one.

Treatment of glaucoma with high intensity focused ultrasound.

Glaucoma is a common disease mainly due to an increase in pressure inside the eye, leading to a progressive destruction of the optic nerve, potentially to blindness. Intraocular pressure (IOP) is the result of a balance between production of liquid that fills the eye--aqueous humour--and its resorption. All treatments for glaucoma aim to reduce IOP and can therefore have two mechanisms of action: reducing aqueous humour production by the partial destruction or medical inhibition of the ciliary body--the anatomical structure responsible for production of aqueous humour--or facilitating the evacuation of aqueous humour from the eye. Several physical methods can be used to destroy the ciliary body, e.g. laser, cryotherapy, microwave. All these methods have two major drawbacks: they are non-selective for the organ to be treated and they have an unpredictable dose­effect relationship. High intensity focused ultrasound (HIFU) can be used to coagulate the ciliary body and avoid these drawbacks. A commercially available device was marketed in the 1980s, but later abandoned, essentially for technical reasons. A smaller circular device using miniaturised transducers was recently developed and proposed for clinical practice. Experimental studies have shown selective coagulation necrosis of the treated ciliary body. The first three clinical trials in humans have shown that this device was well tolerated and allowed a significant, predictable and sustained reduction of IOP. The aim of this contribution is to present a summary of the work concerning the use of HIFU to treat glaucoma.

High-pressure jet injection of viscous solutions for endoscopic submucosal dissection: a study on ex vivo pig stomachs.

BACKGROUND: Long-lasting lifting is a key factor during endoscopic submucosal dissection (ESD) and can be obtained by water-jet injection of saline solution or by injection of viscous macromolecular solutions. Combination of the jet injection and the macromolecular viscous solutions has never been used yet. We assessed the ability of a new water-jet system to inject viscous solutions in direct viewing and in retroflexion. We compared jet injection of saline solution and hyaluronate 0.5 % to perform ESD on ex vivo pig stomachs in order to evaluate the benefits of macromolecular solutions when injected by a jet-injector system. METHODS: This is a prospective comparative study in pig stomachs. Using the jet injector, four viscous solutions were tested: hydroxyethyl starch, glycerol mix, hyaluronate sodic (0.5 %), and poloxamer mix. Ten ESDs larger than 25 mm (five in direct viewing and five in retroflexion) and one larger than 10 cm were performed with each solution. ESD with hyaluronate jet injection was then compared with ESD with saline jet injection by performing 50 ESDs in each group. A single, minimally-experienced operator conducted all the procedures. RESULTS: All 145 resections were complete, including all marking points with two perforations. Eleven jet ESDs per solution were conducted without any injection issue. In the second part of the study, when compared with saline, significant benefit of hyaluronate was observed on dissection speed (0.80 vs. 1.08 cm(2)/min, p < 0.001). CONCLUSION: This is the first report on a jet-injector system allowing injection of macromolecular viscous solutions even with retroflexed endoscope. Jet injection of macromolecular solutions can speed up dissection in comparison with saline, and should now be tested on humans.

Passive Elastography for Clinical HIFU Lesion Detection.

High-intensity Focused Ultrasound (HIFU) is a promising treatment modality for a wide range of pathologies including prostate cancer. However, the lack of a reliable ultrasound-based monitoring technique limits its clinical use. Ultrasound currently provides real-time HIFU planning, but its use for monitoring is usually limited to detecting the backscatter increase resulting from chaotic bubble appearance. HIFU has been shown to generate stiffening in various tissues, so elastography is an interesting lead for ablation monitoring. However, the standard techniques usually require the generation of a controlled push which can be problematic in deeper organs. Passive elastography offers a potential alternative as it uses the physiological wave field to estimate the elasticity in tissues and not an external perturbation. This technique was adapted to process B-mode images acquired with a clinical system. It was first shown to faithfully assess elasticity in calibrated phantoms. The technique was then implemented on the Focal One® clinical system to evaluate its capacity to detect HIFU lesions in vitro (CNR = 9.2 dB) showing its independence regarding the bubbles resulting from HIFU and in vivo where the physiological wave field was successfully used to detect and delineate lesions of different sizes in porcine liver. Finally, the technique was performed for the very first time in four prostate cancer patients showing strong variation in elasticity before and after HIFU treatment (average variation of 33.0 ± 16.0 % ). Passive elastography has shown evidence of its potential to monitor HIFU treatment and thus help spread its use.

In vivo exposure of the bladder using a non-invasive high intensity focused ultrasound toroidal transducer.

A toroidal high-intensity focused ultrasound (HIFU) transducer was used to expose normal bladder wall tissues non-invasively in vivo in a porcine model in order to investigate the potential to treat bladder tumors. The transducer was divided into 32 concentric rings with equal surface areas, operating at 2.5 MHz. Eight animals were split into two groups of 4. In the first group, post-mortem evaluation was performed immediately after ultrasound exposure. In the second group, animals survived for up to seven days before post-mortem evaluation. The ultrasound imaging guided HIFU device was hand-held during the procedure using optical tracking to ensure correct targeting. One thermal lesion in each animal was created using a 40 s exposure at 80 acoustic Watts (free-field) in the trigone region of the bladder wall. The average (±Standard Deviation) abdominal wall and bladder wall thicknesses were 10.3 ± 1.4 mm and 1.1 ± 0.4 mm respectively. The longest and shortest axes of the HIFU ablations were 7.7 ± 2.9 mm and 6.0 ± 1.8 mm, respectively, resulting in an ablation of the whole thickness of the bladder wall in most cases. Ablation were performed at an average depth (distance from the skin surface to the centre of the HIFU lesion) of 42.5 ± 3.8 mm and extended throughout the thickness of the bladder. There were two cases of injury to tissues immediately adjacent to the bladder wall but without signs of perforation, as confirmed by histological analysis. Non-invasive HIFU ablation using a hand-held toroidal transducer was successfully performed to destroy regions of the bladder wall in vivo.

A multi-element interstitial ultrasound applicator for the thermal therapy of brain tumors.

Interstitial thermal therapy is a minimally invasive treatment modality that has been used clinically for ablating both primary and secondary brain tumors. Here a multi-element interstitial ultrasound applicator is described that allows for increased spatial control during thermal ablation of tumors as compared to existing clinical devices. The device consists of an array of 56 ultrasound elements operating at 6 MHz, oriented on the seven faces of a 3.2 mm flexible catheter. The device was first characterized using the acoustic holography method to examine the functioning of the array. Then experiments were performed to measure heating in tissue-mimicking gel phantoms and ex vivo tissue samples using magnetic resonance imaging-based thermometry. Experimental measurements were compared with results obtained using numerical simulations. Last, simulations were performed to study the feasibility of using the device for thermal ablation in the brain. Experimental results show that the device can be used to induce a temperature rise of greater than 20 °C in ex vivo tissue samples and numerical simulations further demonstrate that tumors with diameters of greater than 30-mm could potentially be treated.

Therapeutic applications of ultrasound in ophthalmology.

Therapeutic ultrasound, although less well known than ultrasound for diagnostic imaging, has become a topic of growing interest in ophthalmology. High intensity focused ultrasound (HIFU) for the treatment of glaucoma and ultrasonic drug delivery are the two main areas of research and potential clinical applications. For the treatment of glaucoma, the specific advantage of HIFU, particularly when compared to the laser, is that the energy can be focused through optically opaque media, especially through the sclera which is a strongly light-scattering medium. HIFU is therefore a possible method for partial coagulation of the ciliary body (an anatomical structure responsible for the production of the liquid filling the eye) and, hence, reducing intraocular pressure and the risk of glaucoma. Ocular drug bioavailability also remains a challenge, being limited by multiple barriers to drug entry and lacrimal drainage, and making it difficult to achieve a sufficient drug concentration for numerous diseases of the front and back of the eye. As the front wall of the eye (cornea and anterior sclera) is a pathway for topically applied drugs, locally applied ultrasound has been proposed as a way of enhancing the delivery and activity of drugs and genes. Despite the fact that experimental studies seem to confirm the potential benefit of ultrasound ocular drug delivery, there is still a lack of clinical evidence. The aim of this contribution is to provide an update on recent advances in the field of therapeutic ultrasound in ophthalmology.

Locoregional therapies and their effects on the tumoral microenvironment of pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is expected to become the second leading cause of death from cancer by 2030. Despite intensive research in the field of therapeutics, the 5-year overall survival is approximately 8%, with only 20% of patients eligible for surgery at the time of diagnosis. The tumoral microenvironment (TME) of the PDAC is one of the main causes for resistance to antitumoral treatments due to the presence of tumor vasculature, stroma, and a modified immune response. The TME of PDAC is characterized by high stiffness due to fibrosis, with hypo microvascular perfusion, along with an immunosuppressive environment that constitutes a barrier to effective antitumoral treatment. While systemic therapies often produce severe side effects that can alter patients' quality of life, locoregional therapies have gained attention since their action is localized to the pancreas and can thus alleviate some of the barriers to effective antitumoral treatment due to their physical effects. Local hyperthermia using radiofrequency ablation and radiation therapy - most commonly using a local high single dose - are the two main modalities holding promise for clinical efficacy. Recently, irreversible electroporation and focused ultrasound-derived cavitation have gained increasing attention. To date, most of the data are limited to preclinical studies, but ongoing clinical trials may help better define the role of these locoregional therapies in the management of PDAC patients.