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To compare the quality of life (QOL), cosmesis and cost-utility of open surgery (OS), vacuum-assisted breast biopsy (VABB) and high intensity focused ultrasound (HIFU) for fibroadenoma (FA). A total of 162 patients with 267 FAs were enrolled. Baseline characteristics and treatment information were recorded. Patients were followed up at 3-, 6- and 12-month post-treatment. QOL was evaluated by health survey. Breast cosmesis was evaluated by self-rating survey and Harvard Scale. A decision-analytic model was established and incremental cost was calculated for cost-utility analysis. For QOL evaluation, there was no difference of physical component summary (PCS) score in three groups (P > 0.05), while the mental component summary (MCS) score was significantly higher in HIFU group than the other two groups at 3- and 6-month post-treatment (P < 0.05). The proportion of patients satisfied with breast cosmesis was significantly higher in HIFU group (96.49%) than in VABB group (54.90%) and OS group (49.99%) (P < 0.05). By Harvard Scale, 27.78%, 78.42% and 100.00% of patients were rated as excellent and good in OS group, VABB group and HIFU group, respectively (P < 0.05). To acquire a quality-adjusted life year (QALY), cost of OS, VABB and HIFU was 1034.31 USD, 1776.96 USD and 1277.67 USD, respectively. When compared to OS, incremental cost analysis showed HIFU was cost-effective, while VABB was not. OS, VABB and HIFU were all effective and safe for FA, but among these three treatments, HIFU had the best QOL improvement, breast cosmesis and cost-effectiveness. [ABSTRACT FROM AUTHOR]

To evaluate the impact of high-intensity focused ultrasound (HIFU) ablation on the histopathological features of locally recurrent fibroids tissue. Patients who underwent transabdominal hysterectomy or myomectomy for uterine fibroids from January 1, 2021 to July 1, 2023 at a teaching hospital in China were enrolled in this prospective study. The patients who underwent surgery for local recurrence of uterine fibroids after HIFU ablation were categorized as the HIFU group, and patients who had not undergone HIFU ablation for uterine fibroids were the control group. Hematoxylin-eosin (HE) staining, Masson staining, and immunohistochemical staining were performed to analyze the counts of smooth muscle cells (SMCs), collagen content, microvascular count, and the expression levels of estrogen receptor (ER) and progesterone receptor (PR) in the fibroid tissue specimens. The mean SMC counts in the HIFU and control groups were 337.68/field and 328.52/field respectively. The mean collagen content in the HIFU group and control group were 46.06% and 41.69% respectively. The mean microvessel counts in the HIFU group and control group were 13.66/field and 14.08/field respectively. The mean ER scores in the HIFU and control groups were 6.9 and 7.47 respectively, and the mean PR scores were 7.3 and 7.56 respectively. Overall, there were no significant differences in the SMC counts, collagen content, microvascular counts, and the ER and PR expression levels between the HIFU group and control group (p > 0.05). HIFU ablation has no effect on the pathological characteristics of local recurrent fibroid tissue, and is an ideal non-invasive treatment option. [ABSTRACT FROM AUTHOR]

To investigate whether the quantitative index of signal intensity (SI) heterogeneity on T2-weighted (T2W) magnetic resonance images can predict the difficulty and efficacy of high-intensity focused ultrasound (HIFU) ablation for uterine fibroids. The standard deviation (SD) of T2W image (T2WI) SI was used to quantify SI heterogeneity. The correlation between SD and the non-perfused volume ratio (NPVR) in 575 patients undergoing HIFU treatment was retrospectively analyzed, and the efficacy of SD in predicting NPVR was discussed. Three classifications were made based on the SD, and the ablation difficulty and ablation effect of different grades were compared. A total of 65 cases from another center were used as an external validation set to verify the classification performance of SD. The SD of SI was negatively correlated with NPVR (r = −0.460, p < 0.001). The predictive efficiency of SD for the ablation effect was higher than that of the scaled signal intensity (0.767 vs. 0.701, p = 0.006). Univariate and multivariate logistic regression analyses showed that SD was an independent predictor of ablation effect. Based on SD, the three classifications were divided into SD I: SD < 101.0, SD II: 101.0 ≤ SD < 138.7, and SD III: SD ≥ 138.7. The treatment time, sonication time, treatment intensity, and total energy of SD I were lower than those of SD II and III (p < 0.05). The heterogeneity of T2WI SI of uterine fibroids is negatively correlated with NPVR. The SD of SI can be used to predict the ablation difficulty and ablation effect of HIFU. [ABSTRACT FROM AUTHOR]

• High intensity focused ultrasound (HIFU) is an effective and safe treatment option for abdominal wall endometriosis. • Pain score and lesion size reduction is accomplished without major complications and with a pooled recurrence rate of 12.8%. • There were no significant differences in pain scores, complications and recurrences after surgical excision and USgHIFU. • High-quality randomized controlled trials comparing HIFU to standard care are needed to provide more conclusive evidence. In this review, a systematic literature search on the effectiveness and complication rates of ultrasound-guided and magnetic resonance-guided high-intensity focused ultrasound (USg-/MRgHIFU) for abdominal wall endometriosis (AWE) was conducted in six databases in May/June 2023. Original articles of (non)randomized trials, cohort studies, case-control studies and case series published in peer-reviewed journals were included. Of the included studies the level of evidence (LoE) and methodological quality using the ROBINS-I and IHE-QAT was assessed. Primary outcomes were non-perfused volume ratio (NPV%), lesion size, pain scores, side effects and complication rates according to Society of Interventional Radiology (SIR) guidelines. Secondary outcomes were recurrence and re-intervention rates. Seven cohort studies (one of good methodological quality) (LoE 3) on USgHIFU were included (n = 212, AWE lesions = 240–245). Six months after USgHIFU treatment, pain scores were reduced with 3.3–5.2 points (baseline: 5.1–6.8, n = 135). Self-limiting side effects were pain (85.7 % (114/133)) and swelling (34.6 % (46/133)) in the treatment area. Complications occurred in 17.7 % (32/181), all of which were minor. Recurrence occurred in 12.8 % (11/86). Three of these seven cohort studies compared USgHIFU (n = 61) with surgical excision (n = 74). Pooled results showed no significant differences in pain scores, complications (resp. 26.3 % (10/38) vs. 32.6 % (15/46) (p = 0.53)) and recurrences (resp. 4.9 % (3/61) vs. 5.4 % (4/74) (p = 0.90)). This systematic review suggests that HIFU is an effective and safe treatment option for AWE. USgHIFU treatment led to reduced pain scores and lesion size, was free of major complications and had a pooled recurrence rate of 12.8 %. Compared to surgical excision pooled results showed no significant differences in pain scores, complications and recurrences after USgHIFU. However, many of the included studies had limitations in their methodological quality and therefore the results should be interpreted with caution. Well-structured high-quality randomized controlled trials comparing HIFU to standard care should be conducted to provide more conclusive evidence. [ABSTRACT FROM AUTHOR]

• A novel passive cavitation imaging (PCI) scheme was proposed to tackle two practical problems in monitoring high intensity focused ultrasound (HIFU) treatment. • Firstly, a cavitation detection network (CD-NET) model was introduced for the first time to detect the occurrence of cavitation to avoid false positive visualizations in the PCI procedure. • Secondly, cavitation intensity baseline was derived from experiment data, which can help display the dynamic cavitation activities in a more reliable manner. • The enhanced PCI scheme offer an effective method for monitoring HIFU therapies involving cavitation. Passive cavitation imaging (PCI) is an effective technique for monitoring high intensity focused ultrasound (HIFU) procedure due to the correlation between cavitation activities and the therapeutic effects. Nevertheless, current PCI techniques are unable to recognize noise signals from non-cavitation situations, and they fail to accurately visualize the highly dynamic cavitation activities due to the lack of a stable baseline reference. In this study, a deep learning-based cavitation detection network (CD-NET) was proposed to determine whether passively received channel signals originated from cavitation activities or were merely noises. Additionally, a cavitation intensity baseline was derived to better display the drastically time-varying cavitation activities. The CD-NET model was trained and validated with data collected from in-vitro and ex-vivo HIFU sonication experiments, and then tested by in-vivo rabbit experiments. Both CD-NET models, trained with data from the in-vitro agar phantoms and ex-vivo bovine liver tissues, successfully distinguished between cavitation and non-cavitation activities from the same study object, achieving accuracies as high as 99.7% and 99.5%, respectively. In addition, the models trained on in-vitro and ex-vivo datasets achieved accuracies of 88.1% and 91.4%, respectively, when detecting cavitation events from unseen in-vivo data. The results demonstrate that the improved PCI scheme, utilizing the CD-NET model and a data-derived cavitation baseline, is resistant to noise from non-cavitation situations and can depict the dynamic characteristics of cavitation more reliably. In conclusion, this study addressed two practical challenges in PCI techniques, allowing for better monitoring of cavitation-related HIFU sonication in clinical applications. [ABSTRACT FROM AUTHOR]

• In this study, we proposed a novel diffusion-based deep learning (DL) model (HIFU-Diff) for suppressing the HIFU interference in the ultrasound guiding images. • The HIFU-Diff network can achieve superior performance in preserving fine details of the original ultrasound image even under strong acoustic interference from the HIFU sonication, especially in the complex in-vivo situations. • The proposed HIFU-Diff network has high potential to realize truly real-time monitoring of HIFU treatment in ultrasound guided HIFU systems. In ultrasound guided high-intensity focused ultrasound (HIFU) surgery, it is necessary to transmit sound waves at different frequencies simultaneously using two transducers: one for the HIFU therapy and another for the ultrasound imaging guidance. In this specific setting, real-time monitoring of non-invasive surgery is challenging due to severe contamination of the ultrasound guiding images by strong acoustic interference from the HIFU sonication. This paper proposed the use of a deep learning (DL) solution, specifically a diffusion implicit model, to suppress the HIFU interference. We considered the images contaminated with HIFU interference as low-resolution images, and those free from interference as high-resolution. While suppressing HIFU interference using the diffusion implicit (HIFU-Diff) model, the task was transformed into generating a high-resolution image through a series of forward diffusion steps and reverse sampling. A series of ex-vivo and in-vivo experiments, conducted under various parameters, were designed to validate the performance of the proposed network. Quantitative evaluation and statistical analysis demonstrated that the HIFU-Diff network achieved superior performance in reconstructing interference-free images under a variety of ex-vivo and in-vivo conditions, compared to the most commonly used notch filtering and the recent 1D FUS-Net deep learning network. The HIFU-Diff maintains high performance with 'unseen' datasets from separate experiments, and its superiority is more pronounced under strong HIFU interferences and in complex in-vivo situations. Furthermore, the reconstructed interference-free images can also be used for quantitative attenuation imaging, indicating that the network preserves acoustic characteristics of the ultrasound images. With the proposed technique, HIFU therapy and the ultrasound imaging can be conducted simultaneously, allowing for real-time monitoring of the treatment process. This capability could significantly enhance the safety and efficacy of the non-invasive treatment across various clinical applications. To the best of our knowledge, this is the first diffusion-based model developed for HIFU interference suppression. [ABSTRACT FROM AUTHOR]

Encapsulation of cytotoxic drugs for a localized release is an effective way to increase the therapeutic window of such agents. In this article we present the localized release of doxorubicin (DOX) from phosphatidyldiglycerol (DPPG 2) based thermosensitive liposomes using MR-HIFU mediated hyperthermia in a swine model. German landrace pigs of weights between 37.5 and 53.5 kg received a 30-min infusion of DOX containing thermosensitive liposomes (50 mg DOX/m2). The pigs' biceps femoris was treated locally in two separate target areas with mild hyperthermia using magnetic resonance guided high intensity focused ultrasound, starting 10 min and 60 min after initiation of the infusion, respectively. The pharmacokinetics and biodistribution of DOX were determined and an analysis of the treatment parameters' influence was performed. Compared to untreated tissue, we found a 15-fold and a 7-fold increase in DOX concentration in the muscle volumes that had undergone hyperthermia starting 10 min and 60 min after the beginning of the infusion, respectively. The pharmacokinetic analysis showed a prolonged circulation time of DOX and a correlation between the AUC of extra-liposomal DOX in the bloodstream and the amount of DOX accumulated in the target tissue. We have demonstrated a workflow for MR-HIFU hyperthermia drug delivery that can be adapted to a clinical setting, showing that HIFU-hyperthermia is a suitable method for local drug release of DOX using DPPG 2 based thermosensitive liposomes in stationary targets. Using the developed pharmacokinetic model, an optimization of the drug quantity deposited in the target via the timing of infusion and hyperthermia should be possible. [Display omitted] • MR-HIFU Hyperthermia-mediated release of doxorubicin from thermosensitive liposomes • A human-like large animal model was used to facilitate clinical translation. • Local enhancement of drug concentration by factor 15 compared to control tissue. • The leakage half-life of DPPG 2 -TSL-DOX was calculated via pharmacokinetic modelling. • Local drug delivery is maximized by maximized blood doxorubicin during hyperthermia. [ABSTRACT FROM AUTHOR]

• BH ablation rate in liver tissue was insensitive to the changes in pulsing protocol. • BH ablation rate in bovine myocardium increased with pulse length and number. • A universal BH dose sufficient for any tissue type is unlikely to be established. • Product of pulse duration and their number per point is a more relevant dose metric for planning BH of collagenous tissues. • Number of pulses per point is a more suitable dose metric for treatment planning of primarily cellular targets. This work was focused on the newly developed ultrasonic approach for non-invasive surgery – boiling histotripsy (BH) – recently proposed for mechanical ablation of tissues using pulsed high intensity focused ultrasound (HIFU). The BH lesion is known to depend in size and shape on exposure parameters and mechanical properties, structure and composition of tissue being treated. The aim of this work was to advance the concept of BH dose by investigating quantitative relationships between the parameters of the lesion, pulsing protocols, and targeted tissue properties. A HIFU focus of a 1.5 MHz 256-element array driven by power-enhanced Verasonics system was electronically steered along the grid within 12 × 4 × 12 mm volume to produce volumetric lesions in porcine liver (soft, with abundant collagenous structures) and bovine myocardium (stiff, homogenous cellular) ex vivo tissues with various pulsing protocols (1–10 ms pulses, 1–15 pulses per point). Quantification of the lesion size and completeness was performed through serial histological sectioning, and a computer vision approach using a combination of manual and automated detection of fully fractionated and residual tissue based on neural network ResNet-18 was developed. Histological sample fixation led to underestimation of BH ablation rate compared to the ultrasound-based estimations, and provided similar qualitative feedback as did gross inspection. This suggests that gross observation may be sufficient for qualitatively evaluating the BH treatment completeness. BH efficiency in liver tissue was shown to be insensitive to the changes in pulsing protocol within the tested parameter range, whereas in bovine myocardium the efficiency increased with either increasing pulse length or number of pulses per point or both. The results imply that one universal mechanical dose metric applicable to an arbitrary tissue type is unlikely to be established. The dose metric as a product of the BH pulse duration and the number of pulses per sonication point (BHD1) was shown to be more relevant for initial planning of fractionation of collagenous tissues. The dose metric as a number of pulses per point (BHD2) is more suitable for the treatment planning of softer targets primarily containing cellular tissue, allowing for significant acceleration of treatment using shorter pulses. [ABSTRACT FROM AUTHOR]

• The first demonstration of the generation of cavitation clouds within an intravascular scale hollow cylindrical transducer. • Peak internal pressures are dependant on element length and resonant mode. • Highest pressures are achieved in thickness mode and are impacted by internal reflections and the eventual development of a standing wave pattern. • Cavitation investigated as a function of pulsing scheme using a combination of hydrophone and imaging based methods. • This approach has potential use for enhancing aspiration based mechanical thrombectomy. Thrombotic occlusions of large blood vessels are increasingly treated with catheter based mechanical approaches, one of the most prominent being to employ aspiration to extract clots through a hollow catheter lumen. A central technical challenge for aspiration catheters is to achieve sufficient suction force to overcome the resistance of clot material entering into the distal tip. In this study, we examine the feasibility of inducing cavitation within hollow cylindrical transducers with a view to ultimately using them to degrade the mechanical integrity of thrombus within the tip of an aspiration catheter. Hollow cylindrical radially polarized PZT transducers with 3.3/2.5 mm outer/inner diameters were assessed. Finite element simulations and hydrophone experiments were used to investigate the pressure field distribution as a function of element length and resonant mode (thickness, length). Operating in thickness mode (∼5 MHz) was found to be associated with the highest internal pressures, estimated to exceed 23 MPa. Cavitation was demonstrated to be achievable within the transducer under degassed water (10 %) conditions using hydrophone detection and high-frequency ultrasound imaging (40 MHz). Cavitation clouds occupied a substantial portion of the transducer lumen, in a manner that was dependent on the pulsing scheme employed (10 and 100 μs pulse lengths; 1.1, 11, and 110 ms pulse intervals). Collectively the results support the feasibility of achieving cavitation within a transducer compatible with mounting in the tip of an aspiration format catheter. [ABSTRACT FROM AUTHOR]

A new reconstruction approach that combines Reverse Time Migration (RTM) and Genetic Algorithms (GAs) is proposed for solving the inverse problem associated with transluminal shear wave elastography. The transurethral identification of the first thermal lesion generated by transrectal High Intensity Focused Ultrasound (HIFU) for the treatment of prostate cancer, was used to preliminarily test in silico the combined reconstruction method. The RTM method was optimised by comparing reconstruction images from several cross-correlation techniques, including a new proposed one, and different device configurations in terms of the number and arrangement of emitters and receivers of the conceptual transurethral probe. The best results were obtained for the new proposed cross-correlation method and a device configuration with 3 emitters and 32 receivers. The RTM reconstructions did not completely contour the shape of the HIFU lesion, however, as planned for the combined approach, the areas in the RTM images with high level of correlation were used to narrow down the search space in the GA-based technique. The GA-based technique was set to find the location of the HIFU lesion and the increment in stiffness and viscosity due to thermal damage. Overall, the combined approach achieves lower level of error in the reconstructed values, and in a shorter computational time, compared to the GA-based technique alone. The lowest errors were accomplished for the location of HIFU lesion, followed by the contrast ratio of stiffness between thermally treated tissue and non-treated normal tissue. The homologous ratio of viscosity obtained higher level of error. Further investigation considering diverse scenarios to be reconstructed and with experimental data is required to fully evaluate the feasibility of the combined approach. • Reverse Time Migration and Genetic Algorithm are combined for elastography. • Monitoring a HIFU lesion is used to in silico test the combined inversion approach. • The change in viscoelastic properties serves to identify the HIFU lesion location. • A new correlation method yields improved results for the Reverse Time Migration. • The combined approach speeds up the inversion and yields lower reconstruction errors. [ABSTRACT FROM AUTHOR]

High intensity focused ultrasound (HIFU) has been widely used in clinical treatment of cervical cancer for its non-invasiveness and sharp treatment margins with very low complication rates. However, how to intensify the therapeutic efficacy of HIFU by specifically focusing the ultrasound energy on targeting pathological tissues is still a bottleneck for it to realize successful cancer ablation. Herein, a multifunctional organic-inorganic hybrid nanovesicles, by coating ultrathin silica shell on the surface of poly (lactic- co -glycolic acid) (PLGA) loaded with perfluorocarbon (PFOB), hydrophobic antitumor ruthenium complex (RuPOP) and superparamagnetic Fe 3 O 4 , has been designed to achieve synchronous ultrasound (US)/magnetic resonance imaging (MR) dual mode imaging-guided HIFU-triggered chemotherapy. The introduction of PFOB in this nanosystem could cause phase transition and make it gasification to cause collapse of the outer ultrathin silicon shell under HIFU irradiation, which results in enhanced intensive mechanical stress during blasting and enhanced therapeutic effect. The blasting behavior of this nanosystem triggered by HIFU also induced the on-demand RuPOP burst release in tumor site, thus maximizing the inhibition on residual tumor induced by inhomogeneous HIFU ablation. Taken together, this treatment strategy could overcome the inevitable tumor recurrence and significantly reduces systemic side effects of HIFU, thus could be further developed for noninvasive cancer therapy. Herein an intelligent nano-bomb has been designed to achieve synchronous ultrasound/magnetic resonance dual-modality imaging-guided HIFU-triggered on-demand site-specific drug release and successful cancer ablation. Unlabelled Image • An intelligent nano-bomb with on-demand drug burst release property is designed. • The nano-bomb synergizes with HIFU to realize successful cancer ablation. • The nano-bomb achieves synchronous ultrasound/MRI dual mode imaging-guided therapy. [ABSTRACT FROM AUTHOR]

Theranostic nanocarriers of antivascular drug encapsulated in thermosensitive ultramagnetic liposomes can be advantageously designed to provide a locally high concentration and an active delivery, with image-guided Magnetic Resonance Imaging (MRI) so as to reliably cure tumor. We propose a novel therapeutic strategy consisting of the magnetic accumulation of Ultra Magnetic Liposomes (UML) followed by High-Intensity Focused Ultrasound (HIFU) to trigger the release of an antivascular agent monitored by MRI. For this purpose, we co-encapsulated Combretastatin A4 phosphate (CA4P), a vascular disrupting agent, in the core of UML to obtain CA4P-loaded thermosensitive Ultra Magnetic Liposomes (CA4P-UML). To assess the HIFU parameters, the CA4P release has been triggered in vitro by local heating HIFU at the lipids transition temperature. Morphology of endothelial cells was assessed to evaluate the effect of encapsulated versus non-encapsulated CA4P. The efficiency of a treatment combining the magnetic targeting of CA4P-UML with the CA4P release triggered by HIFU was studied in CT26 murine tumors. Tumor perfusion and volume regression parameters were monitored by multiparametric quantitative anatomical and dynamic in vivo MRI at 7 T. Additionally, vascularization and cellularity were evaluated ex-vivo by histology. This thorough investigation showed that the combined treatment exhibited a full benefit. A 150-fold improvement compared with the chemotherapy alone was obtained using a magnetic targeting of CA4P-UML triggered by HIFU, and was consistent with an expected effect on vascularization 24 h after treatment. Unlabelled Image • First magnetic thermosensitive liposomes encapsulating CA4P and magnetic nanoparticles. • Proof of concept of combined magnetic targeting + HIFU-drug release with CA4P-magnetic liposomes. • Similar efficacy of targeted liposomes encapsulating CA4P as the free drug at a 150 lower dose. • MRI Engineering to evidence the efficiency of a novel theranostic liposome. [ABSTRACT FROM AUTHOR]

The aim is to investigate the potential significance of combining minimally invasive high-intensity focused ultrasound (HIFU) with hydroxyapatite (HA) nanorods treatment for the remineralization of demineralized coronal dentine-matrix. HA having nanorods structure were synthetized using ultrasonication with precipitation method. HA nanorods were characterized by TEM for average-size/shape. Following phosphoric acid demineralization, dentine specimens were treated with HA-nanorods with/without subsequent HIFU exposure for 5 s, 10 s and 20 s then stored in artificial saliva for 1-month. Dentine specimens were characterized using different SEM and Raman spectroscopic techniques. In addition, the biochemical stability and HA-nanorods were examined using ATR-FTIR to observe attachment of nanoparticles. Also, surface nanoindentation properties were evaluated using AFM in tapping-mode. HA-nanorods displayed well-defined, homogenous plate-like nanostructure. TEM revealed intact collagen-fibrils network structure with high density due to obliteration of interfibrillar spaces with clear evidence of remineralization in combined HA/HIFU treatment. With HA-nanorods treatment collagen-network structure was visible, consisting of fibrils interlaced into a compact pattern with evidence of minerals deposition. AFM investigation revealed clear mineral formation with the increase of HIFU exposure time. Bands associated with inorganic phase dominate well in HIFU exposed specimens with PO stretching within dentine mineral identified at 960 cm−1. Characteristic dentine structure for control and HIFU 20 s specimens is reflected as oscillatory mean Amide-I intensity with measurement giving a precise sinusoidal response of polarization angle β within dentinal tissue. Nanoindentation testing showed a gradual significant increase in elastic-modulus with the increase in HIFU exposure time after 1-month storage. FTIR spectrum of the HIFU exposed dentine displayed bands at 1650 cm−1, 1580 cm−1 and 1510 cm−1 that can be attributed to Amide-I, II and III. The synergetic effect of HIFU exposure on remineralization potential of demineralized dentine-matrix following nano-hydroxyapatite treatment was revealed. This synergetic effect is dependent on HIFU exposure time. [ABSTRACT FROM AUTHOR]

Placenta accreta is an abnormal invasion of the placenta within the myometrium, which has increasing rate and could result in maternal mortality or morbidity. The objective of this study was to evaluate the feasibility of treating placenta accreta with high-intensity focused ultrasound (HIFU) using an ex vivo model. A toroidal HIFU transducer working at 2.5 MHz with an integrated ultrasound-imaging probe was used. Ex vivo experiments were performed in eight human placentae (from 39 to 40 weeks) within a configuration that mimicked clinical conditions as closely as possible. The fetal side of the placenta was placed in contact with the sterile envelope that covered the HIFU device to simulate the uterine serosa. HIFU lesions were studied on sonograms and macroscopically. In total, 19 single HIFU lesions were created with the same exposure parameters for all of the lesions. The exposure time was 75 s. The acoustic power was 90 W. HIFU lesions were created at different distances (2, 6, 7 and 8 mm) from the uterine serosa by adjusting the thickness of the coupling water and thus, the distance between the HIFU emitters and placental tissues. All of the lesions were homogeneous and approximately spherical in shape. The two diameters of the HIFU lesions were on average 14.6 ± 2.1 mm and 14.1 ± 2.3 mm. Lesions were immediately visible on sonograms after each HIFU exposure as a hyperechoic region. The distance between the surface of the placenta and HIFU lesion as measured on ultrasound images was closely correlated with the same distance that was measured on gross pathology (r = 0.89 , p < 0.05). This study demonstrates that HIFU may be an interesting option for adjuvant treatment during a cesarean of placenta accreta. These results must be validated under real clinical conditions. • A toroidal HIFU transducer can create large lesions in the placenta in short time. • All of the lesions were homogeneous and approximately spherical in shape. • HIFU may be an interesting option for adjuvant treatment of placenta accreta. [ABSTRACT FROM AUTHOR]

This study introduced the potential and proof-of-concept of high intensity focused ultrasound (HIFU) technology for dentin-surface treatment for resin-dentin bonding without acid-aided demineralization. This new strategy could provide a way to enhance interface-integrity and bond-durability by changing the nature of dentin-substrate; bonded-interface structure and properties; and minimizing denuded-collagen exposure. The interaction between HIFU waves and dentin-surface in terms of structural, mechanical and chemical variations were investigated by SEM, TEM, AFM, nano-indentation and Raman-analysis. The bonding between HIFU-treated dentin and two-step, etch-and-rinse, adhesive was preliminary explored by characterizing dentin-bound proteases activities, resin-dentin interfacial morphology and bond-durability with HIFU exposure at different time-points of 60, 90 and 120 s compared to conventional acid-etching technique. With the increase in HIFU exposure-time from 60-to-120 s, HIFU waves were able to remove the smear-layer, expose dentinal-tubules and creating textured/rough dentin surface. In addition, dentin surfaces showed a pattern of interlocking ribbon-like minerals-coated collagen-fibrils protruding from the underlaying amorphous dentin-background with HIFU exposure for 90 s and 120 s. This characteristic pattern of dentin-surface showing inorganic-minerals associated/aligned with collagen-fibrils, with 90-to-120 s HIFU-treatment, was confirmed by the Raman-analysis. HIFU-treated specimens showed higher nano-indentation properties and lower concentrations of active MMP-2 and Cathepsin-K compared to the acid-etched specimens. The resin-dentin bonded interface revealed the partial/complete absence of the characteristic hybrid-layer formed with conventional etch-and-rinse bonding strategy. Additionally, resin-infiltration and resin-tags formation were enhanced with the increase in HIFU exposure-time to 120 s. Although, all groups showed significant decrease in bond-strength after 12 months compared to 24 h storage in artificial saliva, groups exposed to HIFU for 90 s and 120 s showed significantly higher μTBS compared to the control acid-etched group. The implementation of HIFU-technology for dental hard-tissues treatment could be of potential significance in adhesive/restorative dentistry owing to its ability of controlled, selective and localised combined tissue alteration/ablation effects. [ABSTRACT FROM AUTHOR]

Highlights • Thermal response of biological samples subjected to focused ultrasound waves. • Hyperbolic heat conduction models. • Non-Fourier effects. • Temperature distributions and thermal dosage. Abstract The present study is concerned with the numerical analysis of the non-Fourier heat transfer phenomena in biological tissue samples subjected to high intensity focused ultrasound (HIFU). Due to the inherent non-homogeneous nature of biological samples, the well-known Pennes bioheat equation (PBHTE) is not strictly suitable for correctly predicting the temperature distribution in the tissue medium subjected to HIFU. In this respect, thermal wave model of bioheat transfer (TWMBT), which takes into account the finite propagation speed of thermal front, plays an important role in describing the observed wave-like behavior of heat transfer in biological tissue medium. The temperature profiles obtained from TWMBT show the presence of oscillations during the process of diffusion of thermal wave after reaching its maximum peak, depending upon the corresponding relaxation time. Results show that the thermal dosage with finite value of relaxation time gives lesser heat-affected area compared to the dosage calculated by considering the infinite propagation of thermal front as in the case of the conventional Fourier model. These observations make the present study important as otherwise, the target area is prone to remain under insufficiently heated conditions. [ABSTRACT FROM AUTHOR]

Highlights • The appearance of rectified bubble growth during boiling histotripsy is shown. • Accounting for tissue elasticity adds a mechanical constraint on bubble growth. • The asymmetry in a shockwave and water vapour transport result in rectified growth. • Rectified bubble growth could be responsible for HIFU tissue decellularisation. • Strain induced by rectified growth can damage tissue while preserving blood vessels. Abstract In boiling histotripsy, the presence of a boiling vapour bubble and understanding of its dynamic behaviour are crucially important for the initiation of the tissue fractionation process and for the control of the size of a lesion produced. Whilst many in vivo studies have shown the feasibility of using boiling histotripsy in mechanical fractionation of solid tumours, not much is known about the evolution of a boiling vapour bubble in soft tissue induced by boiling histotripsy. The main objective of this present study is therefore to investigate the formation and dynamic behaviour of a boiling vapour bubble which occurs under boiling histotripsy insonation. Numerical and experimental studies on the bubble dynamics induced in optically transparent tissue-mimicking gel phantoms exposed to the field of a 2.0 MHz High Intensity Focused Ultrasound (HIFU) transducer were performed with a high speed camera. The Gilmore-Zener bubble model coupled with the Khokhlov-Zabolotskaya-Kuznetsov and the Bio-heat Transfer equations was used to simulate bubble dynamics driven by boiling histotripsy waveforms (nonlinear-shocked wave excitation) in a viscoelastic medium as functions of surrounding temperature and of tissue elasticity variations. In vivo animal experiments were also conducted to examine cellular structures around a freshly created lesion in the liver resulting from boiling histotripsy. To the best of our knowledge, this is the first study reporting the numerical and experimental evidence of the appearance of rectified bubble growth in a viscoelastic medium. Accounting for tissue phantom elasticity adds a mechanical constraint on vapour bubble growth, which improves the agreement between the simulation and the experimental results. In addition the numerical calculations showed that the asymmetry in a shockwave and water vapour transport can result in rectified bubble growth which could be responsible for HIFU-induced tissue decellularisation. Strain on liver tissue induced by this radial motion can damage liver tissue while preserving blood vessels. [ABSTRACT FROM AUTHOR]

Abstract Conventional tissue engineering approaches rely on scaffold-based delivery of exogenous proteins, genes, and/or cells to stimulate regeneration via growth factor signaling. However, scaffold-based approaches do not allow active control of dose, timing, or spatial localization of a delivered growth factor once the scaffold is implanted, yet these are all crucial parameters in promoting tissue regeneration. To address this limitation, we developed a stable cell line containing a heat-activated and rapamycin-dependent gene expression system. In this study, we investigate how high intensity focused ultrasound (HIFU) can spatiotemporally control firefly luciferase (fLuc) transgene activity both in vitro and in vivo by the tightly controlled generation of hyperthermia. Cells were incorporated into composite scaffolds containing fibrin and hydroxyapatite particles, which yielded significant increases in acoustic attenuation and heating in response to HIFU compared to fibrin alone. Using 2.5 MHz HIFU, transgene activation was observed at acoustic intensities of 201 W/cm2 and higher. Transgene activation was spatially patterned in the scaffolds by rastering HIFU at speeds up to 0.15 mm/s. In an in vivo study, a 67-fold increase in fLuc activity was observed in scaffolds exposed to HIFU and rapamycin versus rapamycin only at 2 days post implantation. Repeated activation of transgene expression was also demonstrated 8 days after implantation. No differences in in vivo scaffold degradation or compaction were observed between +HIFU and -HIFU groups. These results highlight the potential utility of using this heat-activated and rapamycin-dependent gene expression system in combination with HIFU for the controlled stimulation of tissue regeneration. Graphical abstract Image 1 [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Nanoemulsions as synergists of high intensity focused ultrasound (HIFU) have been widely investigated, since they possess huge potential for improving the efficiency to ablate tumor. However, their clinical applications are limited due to the unsatisfactory phase-transition effect of nanoemulsions during the process of generating nanobubbles. Herein, a novel synergist for HIFU therapy was designed by encapsulating 1,1,2-trichlorotrifluoroethane (CFC) into pH-sensitive pullulan-doxorubicin (Pu-DOX/CFC) nanoparticles. These Pu-DOX/CFC nanoemulsions, with moderate vaporization temperature threshold of 47 °C, could provide favorable phase-transition effect, thus facilitating HIFU energy deposition. Meanwhile, Pu-DOX/CFC nanoemulsions could effectively deliver DOX/CFC to the tumor site and carry out combined therapy. The in vitro and in vivo results confirmed that Pu-DOX/CFC nanoemulsions notably enhanced both ablation and therapeutic efficiency comparing with other synergists. In conclusion, Pu-DOX/CFC nanoemulsions might serve as a novel synergist for HIFU therapy, and possess great potential in clinical implication. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • The experimental design investigates the effects of macrophage phenotype on HIFU in addition to the surface micro-topography and Nano-scale surface mechanical properties of dental cementum. • The experimental analysis is completely novel as this has never been tried in dentistry. • The HIFU effect has been shown to induce a smoothening effect on the cemental surface. • HIFU technique provides an alternative to current methods used in periodontal therapy to achieve smooth root surfaces. Abstract Objective To investigate effects of HIFU on macrophage phenotype, surface micro-topography and nano-scale surface mechanical properties of dental cementum. Materials and methods Root discs (2 mm thickness) were cut apical to CEJ and sectioned into quadrants. HIFU setup with bowl-shaped piezo ceramic transducer submerged in a water tank was used for exposure on each specimen for 15 s, 30 s or 60 s. The specimens of the control group were left without any HIFU exposure. HIFU was generated with a continuous sinusoidal wave of 120Vpp amplitude, 250 KHZ resonance-frequency and highest ultrasonic pressure of ∼10 bar at the focus. Specimens for SEM were viewed, and micro-topography characterization performed, using AFM and Ra parameter and surface area (SA) calculated by specialized SPM surface analysis software. For nano-indentation testing, experiments were carried out using AFM. Macrophage cell isolation and culturing was performed on cementum to receive the HIFU treatment at different time periods. Raman spectroscopy were scanned to create spectra perpendicular to the cementum substrate to analyze generation of standard spectra for Raman intensity ratio of hydroxyapatite normalized to the peaks ν 1 960 cm−1. Data was expressed as means ± standard deviations and analyzed by one-way ANOVA in term of Ra, SA, H and E r. Different points for fluorescence intensity ratio were analyzed by Raman using Wilcoxon rank sum test. Results HIFU exposure at 60 s removed the smear layer and most of cementum appeared smoothened. AFM characterisation, showed a slight decrease in the irregularity of the surface as exposure time increased. Intact macrophages can be identified in control and all experimental HIFU groups. The level of fluorescence for the control and HIFU 15 and 30 s were low as compared to HIFU 60 s. Conclusion If HIFU can be successfully implemented, it may be a possible alternative to current methods used in periodontal therapy to achieve smooth root surfaces. [ABSTRACT FROM AUTHOR]

Highlights • Experimental characterization of acoustic streaming flow generated by focused ultrasound. • According to a scaling analysis, the maximum velocity obeys a 4/3 power law with respect to the excitation pressure amplitude. • On the basis of a comparison with a free circular jet flow, a self-similar region is identified downstream of the focus. Abstract This study aims at characterizing acoustic streaming produced by High Intensity Focused Ultrasound (HIFU) propagating in a liquid medium. Particle Image Velocimetry (PIV) technique was used to determine velocity fields in an infinite medium of water subjected to a focused ultrasonic field. The tests were carried out at a transducer resonance frequency of 550 kHz for different applied acoustic pressure at the focus (ranging from 2.6 to 18.4 bar). The experimental results allowed characterizing the mean streaming flow and its evolution with the wave amplitude: In particular, it is shown that a region where viscous effects are negligible, which leads to a linear behavior of the axial velocity with respect to the excitation pressure amplitude, does exist but is limited to the region upstream of the focal area of the transducer. A scaling analysis provides an estimate of the maximum velocity, and shows that it obeys a 4/3 power law with respect to the excitation pressure amplitude, as long as the position of this maximum velocity corresponds to the focal point, which is not the case for highest pressure amplitude, for which it is shifted downstream of the focus. In addition, the streaming flow is compared to a classical free jet flow. Similarities and differences existing between both flows are reviewed and a self-similar zone for the velocity transverse profile is identified in the expansion zone of the flow. [ABSTRACT FROM AUTHOR]

Boiling histotripsy is a non-invasive, cavitation-based ultrasonic technique which uses a number of millisecond pulses to mechanically fractionate tissue. Though a number of studies have demonstrated the efficacy of boiling histotripsy for fractionation of solid tumours, treatment monitoring by cavitation measurement is not well studied because of the limited understanding of the dynamics of bubbles induced by boiling histotripsy. The main objectives of this work are to (a) extract qualitative and quantitative features of bubbles excited by shockwaves and (b) distinguish between the different types of cavitation activity for either a thermally or a mechanically induced lesion in the liver. A numerical bubble model based on the Gilmore equation accounting for heat and mass transfer (gas and water vapour) was developed to investigate the dynamics of a single bubble in tissue exposed to different High Intensity Focused Ultrasound fields as a function of temperature variation in the fluid. Furthermore, ex vivo liver experiments were performed with a passive cavitation detection system to obtain acoustic emissions. The numerical simulations showed that the asymmetry in a shockwave and water vapour transport are the key parameters which lead the bubble to undergo rectified growth at a boiling temperature of 100°C. The onset of rectified radial bubble motion manifested itself as (a) an increase in the radiated pressure and (b) the sudden appearance of higher order multiple harmonics in the corresponding spectrogram. Examining the frequency spectra produced by the thermal ablation and the boiling histotripsy exposures, it was observed that higher order multiple harmonics as well as higher levels of broadband emissions occurred during the boiling histotripsy insonation. These unique features in the emitted acoustic signals were consistent with the experimental measurements. These features can, therefore, be used to monitor (a) the different types of acoustic cavitation activity for either a thermal ablation or a mechanical fractionation process and (b) the onset of the formation of a boiling bubble at the focus in the course of HIFU exposure. [ABSTRACT FROM AUTHOR]

Highlights • Sumatriptan increased mechanical thresholds in the periorbital region for four days. • Pulsed FUS increased mechanical thresholds post therapy in the periorbital region. • Ablative HIFU did not increase mechanical thresholds post therapy. • FUS may provide a therapeutic option for patients suffering from chronic migraines. Abstract Chronic migraines (CM) are the third most common disease and are refractory to medical treatment in 15% of patients. Currently, temporary relief is achieved with steroid blocks or pulsed radiofrequency ablation, which have short-term benefits. Our project aims to develop a non-invasive treatment for medically refractory chronic migraine, which does not require a permanent implant. This project investigates the safety and effectiveness of pulsed focused ultrasound (FUS) in a validated rodent headache model of cutaneous allodynia associated with chronic migraine (CM) as compared to sumatriptan and ablative lesioning. We demonstrate a significant reduction in mechanical thresholds as measured through Von Frey filaments in CM in the forepaw and periorbital region (p < 0.001). Sumatriptan and pulsed FUS both significantly improve thresholds at day 3 after treatment in the periorbital region. Ablative lesioning has no effect. This study provides initial evidence that FUS may provide an important therapeutic option for patients suffering from CM. [ABSTRACT FROM AUTHOR]

• A new sonothrombolysis method is proposed and demonstrated. • Fringe pattern-like acoustic fields can capture the flowing blood clot. • The captured-blood clot is mechanically fractionated by boiling histotripsy. • No mechanical and thermal damage are produced on a blood vessel wall. Whilst sonothrombolysis is a promising and noninvasive ultrasound technique for treating blood clots, bleeding caused by thrombolytic agents used for dissolving clots and potential obstruction of blood flow by detached clots (i.e., embolus) are the major limitations of the current approach. In the present study, a new sonothrombolysis method is proposed for treating embolus without the use of thrombolytic drugs. Our proposed method involves (a) generating a spatially localised acoustic radiation force in a blood vessel against the blood flow to trap moving blood clots (i.e., generation of an acoustic net), (b) producing acoustic cavitation to mechanically destroy the trapped embolus, and (c) acoustically monitoring the trapping and mechanical fractionation processes. Three different ultrasound transducers with different purposes were employed in the proposed method: (1) 1-MHz dual focused ultrasound (dFUS) transducers for capturing moving blood clots, (2) a 2-MHz High Intensity Focused Ultrasound (HIFU) source for fractionating blood clots and (3) a passive acoustic emission detector with broad bandwidth (10 kHz to 20 MHz) for receiving and analysing acoustic waves scattered from a trapped embolus and acoustic cavitation. To demonstrate the feasibility of the proposed method, in vitro experiments with an optically transparent blood vessel-mimicking phantom filled with a blood mimicking fluid and a blood clot (1.2 to 5 mm in diameter) were performed with varying the dFUS and HIFU exposure conditions under various flow conditions (from 1.77 to 6.19 cm/s). A high-speed camera was used to observe the production of acoustic fields, acoustic cavitation formation and blood clot fragmentation within a blood vessel by the proposed method. Numerical simulations of acoustic and temperature fields generated under a given exposure condition were also conducted to further interpret experimental results on the proposed sonothrombolysis. Our results clearly showed that fringe pattern-like acoustic pressure fields (fringe width of 1 mm) produced in a blood vessel by the dFUS captured an embolus (1.2 to 5 mm in diameter) at the flow velocity up to 6.19 cm/s. This was likely to be due to the greater magnitude of the dFUS-induced acoustic radiation force exerted on an embolus in the opposite direction to the flow in a blood vessel than that of the drag force produced by the flow. The acoustically trapped embolus was then mechanically destructed into small pieces of debris (18 to 60 μm sized residual fragments) by the HIFU-induced strong cavitation without damaging the blood vessel walls. We also observed that acoustic emissions emitted from a blood clot captured by the dFUS and cavitation produced by the HIFU were clearly distinguished in the frequency domain. Taken together, these results can suggest that our proposed sonothrombolysis method could be used as a promising tool for treating thrombosis and embolism through capturing and destroying blood clots effectively. [ABSTRACT FROM AUTHOR]

Interest in mechanical high intensity focused ultrasound (HIFU) ablation is rapidly growing. Boiling histotripsy (BH) is applied for mechanical fragmentation of soft tissue into submicron fragments with limited temperature increase using the shock wave and cavitation effects of HIFU. Research on BH has been largely limited to ex vivo experiments. As a consequence, the in vivo pathology after BH treatment and the relation to preexistent tissue characteristics are not well understood. This study reports on in vivo MR guided BH treatment, either with 100 or 200 pulses per focal spot, in three different subcutaneous mouse tumor models: a soft-tissue melanoma (B16OVA), a compact growing thymoma (EL4), and a highly vascularized neuroblastoma (9464D). Extensive treatment evaluation was performed using MR imaging followed by histopathology 2 h after treatment. T2 weighted MRI allowed direct in vivo visualization of the BH lesions in all tumor models. The 100-pulse treated area in the B16OVA tumors was larger than the predicted treatment volume (500 ± 10%). For the more compact growing EL4 and 9464D tumors this was 95 ± 13% and 55 ± 33%, respectively. Histopathology after the 100-pulse treatment revealed completely disintegrated lesions in the treated area with sharp borders in the compact EL4 and 9464D tumors, while for B16OVA tumors the lesion contained a mixture of discohesive (partly viable) clusters of cells, micro-vessel remainings, and tumor cell debris. The treatment of B16OVA with 200 pulses increased the fragmentation of tumor tissue. In all tumor types only micro-hemorrhages were detected after ablation (slightly higher after 200-pulse treatment for the highly vascularized 9464D tumors). Collagen staining revealed that the collagen fibers were to a greater or lesser extent still intact and partly clotted together near the lesion border in all tumor models. In conclusion, this study reveals effective mechanical fragmentation of different tumor types using BH without major hemorrhages. However, treatment settings may need to be adjusted to the tissue characteristics for optimal tissue fragmentation. [ABSTRACT FROM AUTHOR]

In this study, a concave annular array transducer was designed to generate high intensity focused ultrasound for medical therapeutic applications. First, a detailed theoretical equation was derived to determine the sound pressure distribution from the transducer. To facilitate the design, each annulus in the array was simulated by multiple piston sources. Use of the piston sources can generalize the acoustic field analysis of the concave annular transducer and thus it is applicable to any other types of ultrasound transducers. The validity of the equation was verified by comparing the results calculated by the equation with those calculated from finite element analysis. Using this equation, we developed a new design scheme to optimize the structure of the annular transducer, using OptQuest-Nonlinear Programming algorithm, to meet the constraints that the main lobe should exist at a specific region on the normal axis of the transducer and the level of the maximum sidelobe, including the grating lobe, should be lower than the main lobe by −12.0 dB that is a very strict criterion when compared with that in precedent works. For the annular structure, two different schemes were investigated: (1) an equal area channel structure obtained by setting the area of all the channels equal and (2) an equal angle channel structure obtained by setting the angular width of all the channels equal. The optimized structures of both configurations satisfied all the performance constraints for the sidelobe level as well as the geometric and dynamic focusing. The new design method developed in this work can facilitate the analysis and efficient development of HIFU transducers for medical treatment. [ABSTRACT FROM AUTHOR]

High Intensity Focused Ultrasound (HIFU) is an emerging noninvasive, nonionizing physical energy based modality to ablate solid tumors with high power, or increase local permeability in tissues/tumors in pulsed mode with relatively low power. Compared with traditional ablative HIFU, nondestructive pulsed HIFU (pHIFU) is present in the majority of novel applications recently developed for enhancing the delivery of drugs and genes. Previous studies have demonstrated the capability of pHIFU to change tissue local permeability for enhanced drug delivery in both mouse tumors and mouse muscle. Further study based on bulk tissues in large animals and clinical HIFU system revealed correlation between therapeutic effect and thermal parameters, which was absent in the previous mouse studies. In this study, we further investigated the relation between the therapeutic effect of pHIFU and thermal parameters in bulky normal muscle tissues based on a rabbit model and a preclinical HIFU system. Correlation between therapeutic effect and thermal parameters was confirmed in our study on the same bulk tissues although different HIFU systems were used. Following the study in bulky normal muscle tissues, we further created bulky tumor model with VX2 tumors implanted on both hind limbs of rabbits and investigated the feasibility to enhance tumor permeability in bulky VX2 tumors in a rabbit model using pHIFU technique. A radiolabeled peptidomimetic integrin antagonist, 111 In-DOTA-IA, was used following pHIFU treatment in our study to target VX2 tumor and serve as the radiotracer for follow-up single-photon emission computed tomography (SPECT) scanning. The results have shown significantly elevated uptake of 111 In-DOTA-IA in the area of VX2 tumors pretreated by pHIFU compared with the control VX2 tumors not being pretreated by pHIFU, and statistical analysis revealed averaged 34.5% enhancement 24 h after systematic delivery of 111 In-DOTA-IA in VX2 tumors pretreated by pHIFU compared with the control VX2 tumors. [ABSTRACT FROM AUTHOR]

Combination of polymer therapeutics and hyperthermia has been shown to enhance accumulation in selectively heated tumor tissue. The additional use of heat shock (HS)-targeting towards tumor tissues can further enhance accumulation and retention, and improve therapeutic outcomes. In this work, high intensity focused ultrasound (HIFU) was used to generate hyperthermia in prostate tumor tissue. Upregulation of the cell surface HS receptor glucose regulated protein 78 kDa (GRP78) was observed after treatment with HIFU hyperthermia which was then targeted by specific HS-targeting peptides. We used the peptide sequence WDLAWMFRLPVG attached to the side chains of water-soluble N -(2-hydroxypropyl)methacrylamide (HPMA) copolymers containing docetaxel (DOC) conjugated via a lysosomally degradable linker. It was shown that HIFU-mediated HS-targeted copolymer–DOC conjugates improved treatment efficacy in a murine prostate tumor xenograft model. These results show that the use of HIFU hyperthermia in combination with HS-targeted polymer–drug conjugates has potential to improve therapeutic outcomes in prostate cancer treatment. [ABSTRACT FROM AUTHOR]

High Intensity Focused Ultrasound (HIFU) is an emerging technology of focal destruction in daily clinical practice. Alternative techniques of focal destruction, such as radiofrequency ablation (RFA) or more recently irreversible electroporation, have been used in digestive diseases for many years, mainly in hepatobiliary and pancreatic systems. Likewise, HIFU is currently used in the treatment of tumors located in the liver and in the pancreas. HIFU is quite exclusively applied for the treatment of malignancies, with an extracorporeal approach. Treatment of the liver is difficult because presence of the ribcage may stop propagation of ultrasound waves and respiratory motion may cause targeting problems. Pancreatic cancer is also challenging to treat with HIFU because the pancreas is a deep-seated organ surrounded by major vessels. The interposition of bowel gas may significantly obstruct the acoustic window, potentially leading to incomplete tumor ablation and injury of the interposed bowel and/or other intra-abdominal organs. The two main applications of HIFU are the treatment of hepatocellular carcinoma (HCC) and pancreatic cancer. In the management of HCC, HIFU with transarterial chemoembolization (TACE) seems to provide a survival advantage compared to TACE alone. HIFU showed similar results when compared to RFA for small tumors. HIFU could be interesting for tumors located in difficult location. For pancreatic cancer, HIFU is mostly used in the palliative setting to treat cancer-related pain. Some publications showed encouraging results about downsizing when HIFU is used in combination with chemotherapy and/or radiotherapy, which could be interesting in locally advanced tumors. This review focused on the clinical applications of HIFU in liver and pancreatic tumors. • HIFU ablation seems to be as effective as other ablative techniques for small HCC. • HIFU could improve the prognosis of patients with otherwise unablatable liver tumors. • HIFU could be an interesting option in patients when tumor downsizing is aimed. • HIFU seems to be feasible and safe in patients with unresectable pancreatic cancer. • The level of evidence is low in general. [ABSTRACT FROM AUTHOR]

An important limitation to successful cancer treatment with chemotherapeutics is the inability to achieve therapeutically effective drug concentrations while avoiding healthy tissue damage. In this work, a new tumor-targeting peptide iRGD (CCRGDKGPDC) was used to modify drug-loaded low temperature-sensitive liposomes (iRGD-LTSL-DOX) to explore the anti-tumor effects in combination with high intensity focused ultrasound (HIFU) in vitro and in vivo. iRGD-LTSL-DOX can specifically target to ανβ3-positive cells and locally release the encapsulated doxorubicin (DOX) in a hyperthermia-triggered manner. In vivo results showed that DOX from iRGD-LTSL-DOX was intravascularly released and rapidly penetrated into tumor interstitial space after HIFU-triggered heat treatment, thereby overcoming the limited tumor penetration of anticancer drugs. Significantly stronger anti-tumor efficacy further supported the effective combination of iRGD-LTSL-DOX with HIFU-induced hyperthermia. Our study provided a novel tumor-targeting LTSL-DOX and demonstrated its usefulness in HIFU-induced hyperthermia-triggered drug delivery. [ABSTRACT FROM AUTHOR]

• The novelty of using short HIFU pulses to compensate for the continuous sonication drawbacks. • The novelty of considering different fractions of hypoxic region as real tumor microenvironment. • The novelty of noticing the thermal inertia and microstructural interaction in the TSL-HIFU system. • By the expansion of hypoxic fraction to 70%, the therapeutic efficacy of conventional drug delivery is reduced up to 2 times. • High acoustic powers induce coagulation necrosis in the hypoxic region and mild hyperthermia in richly vascularized regions. Poor half-life, short circulation, systemic toxicity, insufficient accumulation, and ultimately weak therapeutic response are the most important obstacles in the conventional chemotherapy. Thermosensitive liposomes (TSLs) with encapsulated anti-cancer drug doxorubicin combined with high intensity focused ultrasound (HIFU) has the potential to overcome the shortcomings of conventional chemotherapy through targeted drug delivery. In the HIFU-TSL drug delivery system, complex physicochemical and biological processes are involved; however, many works in this field suffer from a comprehensive analysis. Regarding this, the present study has the novelty of developing an advanced multi-physical and multi-compartment model to simulate the complex processes in conventional and TSL-mediated chemotherapy paired with HIFU-induced hyperthermia. Elaborating the determinant role of tumor microenvironment is another novelty, which was underrepresented in earlier investigations and is noticed in our study through the modeling of hypoxic region. Additionally, unlike previous studies that used the classical bio-heat transfer model, this study has innovation in considering the thermal inertia as well as microstructural interactions in the bio-heat transfer equation. Last by not the least, many researchers evaded the harms of continuous irradiation, which in the present work is replaced by pulsed ultrasound as an emerging method for thermal necrosis and mild hyperthermia. The results reveal that the hypoxic region prevents efficient drug delivery due to the disruption of microvascular network and reduces chemotherapy-induced cell death. A comparison between targeted drug delivery and conventional chemotherapy suggests that TSL-mediated drug delivery leads to increased cell death by more than 100% by providing high circulation time and improved bioavailability. Besides this, increasing the acoustic power (from 3 to 8.7 W) leads to a desirable achievement, which is thermal necrosis of central tumor region and high fraction of killed cells (FKCs). The FKCs in the proposed HIFU-TSL system reaches about 58% (3 W), 60% (4.1 W), 70% (7 W), and 78% (8.7 W) at 24 h after TSL-doxorubicin administration, while this value is about 30% in the conventional chemotherapy. In conclusion, this study confirms the benefits of HIFU-TSL drug delivery system. This method has the potential to be used as a targeted drug delivery system to improve anti-cancer drug efficacy, while considerably prevents the normal tissue damage. [Display omitted]. [ABSTRACT FROM AUTHOR]

Mild hyperthermia has been used in combination with polymer therapeutics to further increase delivery to solid tumors and enhance efficacy. An attractive method for generating heat is through non-invasive high intensity focused ultrasound (HIFU). HIFU is often used for ablative therapies and must be adapted to produce uniform mild hyperthermia in a solid tumor. In this work a magnetic resonance imaging guided HIFU (MRgHIFU) controlled feedback system was developed to produce a spatially uniform 43 °C heating pattern in a subcutaneous mouse tumor. MRgHIFU was employed to create hyperthermic conditions that enhance macromolecular delivery. Using a mouse model with two subcutaneous tumors, it was demonstrated that MRgHIFU enhanced delivery of both Evans blue dye (EBD) and Gadolinium-chelated N -(2-hydroxypropyl)methacrylamide (HPMA) copolymers. The EBD accumulation in the heated tumors increased by nearly 2-fold compared to unheated tumors. The Gadolinium-chelated HPMA copolymers also showed significant enhancement in accumulation over control as evaluated through MRI T1-mapping measurements. Results show the potential of HIFU-mediated hyperthermia for enhanced delivery of polymer therapeutics. [ABSTRACT FROM AUTHOR]

Liver transplantation is the mainstay of treatment for end stage liver diseases, including metabolic and congenital liver diseases. The number of suitable donor organs is, however, limited, and a whole-liver transplant requires complex surgery. Cell therapy, such as intra-portal hepatocytes transplantation, has been considered as a bridging therapy to liver transplantation but has shown a mixed clinical outcome with limited success, including low level of engraftment of transplanted hepatocytes. Here, we report a novel cell delivery technique in a rat model by creating a cavity inside the liver parenchyma by non-invasive high intensity focused ultrasound histotripsy. Our in vivo experimental results together with histologic observations show that direct injection of cells inside the cavity can facilitate successful uptake, proliferation and integration of the transplanted hepatocytes in the recipient liver. We were able to restore the plasma albumin level to 50% of the normal level in Nagase analbuminemic rats (serum albumin level of the Nagase rats was initially nil) by cell therapy after high intensity focused ultrasound-mediated histotripsy. We believe that this novel technique would enable the delivery of a large number of cells into the liver to restore liver function, particularly as a treatment for metabolic liver diseases. This novel method of intra-hepatic hepatocyte transplantation might be an invaluable tool for cell therapy in the future. [ABSTRACT FROM AUTHOR]

Using transducer arrays and appropriate emission delays allow to focus acoustic waves at a chosen location in a medium. The focusing spatial accuracy depends on the accurate knowledge of its acoustic properties. When those properties are unknown, methods based on the Time-Reversal principle allow accurate focusing. Still, these methods are either intrusive (an active source has to be introduced at the target location first), either blind (the target cannot be selected in the presence of several objects.) The purpose of the present work is to achieve non-invasive accurate focusing on a selected target using inaccurate acoustic properties for the investigated medium. Potential applications are for instance noninvasive surgery based on High Intensity Focused Ultrasound (HIFU). Numerical experiments are presented and demonstrate accurate focusing on a previously designated target located in an unknown heterogeneous medium. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the performance of multiparametric magnetic resonance imaging (mpMRI) and PSA testing in follow-up after high intensity focused ultrasound (HIFU) focal therapy for localized prostate cancer.Methods: A total of 73 men with localized prostate cancer were prospectively enrolled and underwent focal HIFU followed by per-protocol PSA and mpMRI with systematic plus targeted biopsies at 12 months after treatment. We evaluated the association between post-treatment mpMRI and PSA with disease persistence on the post-ablation biopsy. We also assessed post-treatment functional and oncological outcomes.Results: Median age was 69 years (Interquartile Range (IQR): 66-74) and median PSA was 6.9 ng/dL (IQR: 5.3-9.9). Of 19 men with persistent GG ≥ 2 disease, 58% (11 men) had no visible lesions on MRI. In the 14 men with PIRADS 4 or 5 lesions, 7 (50%) had either no cancer or GG 1 cancer at biopsy. Men with false negative mpMRI findings had higher PSA density (0.16 vs. 0.07 ng/mL2, P = 0.01). No change occurred in the mean Sexual Health Inventory for Men (SHIM) survey scores (17.0 at baseline vs. 17.7 post-treatment, P = 0.75) or International Prostate Symptom Score (IPSS) (8.1 at baseline vs. 7.7 at 24 months, P = 0.81) after treatment.Conclusions: Persistent GG ≥ 2 cancer may occur after focal HIFU. mpMRI alone without confirmatory biopsy may be insufficient to rule out residual cancer, especially in patients with higher PSA density. Our study also validates previously published studies demonstrating preservation of urinary and sexual function after HIFU treatment. [ABSTRACT FROM AUTHOR]

The blood–brain barrier (BBB), comprised of brain endothelial cells with tight junctions (TJ) between them, regulates the extravasation of molecules and cells into and out of the central nervous system (CNS). Overcoming the difficulty of delivering therapeutic agents to specific regions of the brain presents a major challenge to treatment of a broad range of brain disorders. Current strategies for BBB opening are invasive, not specific, and lack precise control over the site and timing of BBB opening, which may limit their clinical translation. In the present report, we describe a novel approach based on a combination of stem cell delivery, heat-inducible gene expression and mild heating with high-intensity focused ultrasound (HIFU) under MRI guidance to remotely permeabilize BBB. The permeabilization of the BBB will be controlled with, and limited to where selected pro-inflammatory factors will be secreted secondary to HIFU activation, which is in the vicinity of the engineered stem cells and consequently both the primary and secondary disease foci. This therapeutic platform thus represents a non-invasive way for BBB opening with unprecedented spatiotemporal precision, and if properly and specifically modified, can be clinically translated to facilitate delivery of different diagnostic and therapeutic agents which can have great impact in treatment of various disease processes in the central nervous system. [ABSTRACT FROM AUTHOR]

This study evaluates the feasibility of using high intensity focused ultrasound (HIFU) for the treatment of hydatid cysts of the liver. HIFU ablation was carried out in 62 patients with echinococcosis of the liver. The mean age of patients was 40.76 ± 14.84 (range: 17–72 years). The effectiveness of the treatment was monitored in real-time by changes in the gray-scale, and by morphological studies, computed tomography, magnetic resonance imaging, and ultrasound. Criteria for evaluating the effectiveness of treatment in real time were outlines. Cytomorphological picture of destructive changes of parasitic elements was presented as well. Loss of embryonic elements of the parasite was observed at the subcellular level after HIFU-ablation and underlines the effectiveness of HIFU. [ABSTRACT FROM AUTHOR]

Diffuse uterine leiomyomatosis (DUL) is a rare and unique type of uterine leiomyoma which affects women of reproductive age. While treatments like medication, uterine artery embolization (UAE) and hysteroscopic myomectomy show some effectiveness, hysterectomy is currently the only known treatment capable of eliminating the symptoms of this disease. This case report demonstrates that high intensity focused ultrasound (HIFU) ablation may offer these patients a new treatment strategy that could control the symptoms of DUL and spare the uterus from hysterectomy. [ABSTRACT FROM AUTHOR]

This study evaluates the feasibility of using high intensity focused ultrasound (HIFU) for the treatment of liver alveococcosis. HIFU ablation was carried out in 36 patients with alveococcosis of the liver. The median age of patients was 39.24 ± 12, 93 years (range: 20–66 years). The efficiency of treatment was monitored in real time with morphological evaluation, computed tomography (CT), magnetic resonance imaging (MRI), ultrasound (US), and with morphological cytological and electron microscopy studies. HIFU ablation has shown effectiveness in destroying the protoscolexes, laminar and cell elements of the cuticular and germinal membrane of the alveococcosis larvocyst, causing the death of the cells of initial metamorphosis of alveococcosis, which is responsible for the dissemination of the parasite in the liver. Therefore HIFU-therapy is a promising and effective treatment for liver alveococcosis. [ABSTRACT FROM AUTHOR]

High-intensity focused ultrasound (HIFU) is a non-invasive technique that allows a small, well-circumscribed thermal lesion to be generated within a tissue target. Tissue destruction occurs due to direct heating within the lesion and the mechanical effects of acoustic cavitation. HIFU has been used in a broad range of clinical applications, including the treatment of malignancies, uterine fibroids and cardiac arrhythmias. Interest in the use of the technique to treat pain has recently increased. A number of painful conditions have been successfully treated, including musculoskeletal degeneration, bone metastases and neuropathic pain. The exact mechanism by which HIFU results in analgesia remains poorly understood, but it is thought to be due to localised denervation of tissue targets and/or neuromodulatory effects. The majority of studies conducted investigating the use of HIFU in pain are still at an early stage, although initial results are encouraging. Further research is indicated to improve our understanding of the mechanisms underlying this treatment and to fully establish its efficacy; however, it is likely that HIFU will play a role in pain management in the future. This narrative review provides a synthesis of the recent, salient clinical and basic science research related to this topic and gives a general introduction to the mechanisms by which HIFU exerts its effects. [ABSTRACT FROM AUTHOR]

The transmitter aperture dependence of the ultrasonic nonlinear field was investigated by using Westervelt equation, Khokhlov-Zabolotskaya-Kuznetsov (KZK) equation and spheroidal beam equation (SBE) models. 1.0-MHz focusing spherical transducers with varied half aperture angles from 10° to 40° was employed as the transmitter, the curvatures of which were fixed as 8 cm. The results show that: (1) KZK equation could simulate the acoustic distribution well for half aperture angle less than 20°; (2) the divergence between KZK equation and Westervelt equation is in proportion to the half aperture angle and surface pressure amplitude; (3) although the focus pressure was different for KZK and Westervelt equation, the shape of focal region of KZK equation was almost the same of Westervelt equation; and (4) the SBE model could simulate the acoustic distribution for a large aperture angle range. [ABSTRACT FROM AUTHOR]

A recipe was created to improve the tissue-mimicking (TM) bovine serum albumin (BSA) polyacrylamide hydrogel (PAG) reported in our previous study (Choi MJ, Guntur SR, Lee KI, Paeng DG, Coleman AJ. Ultrasound Med Biol 2013; 29:439–448). In that work, the concentration of acrylamide in TM BSA PAG was increased to make its attenuation coefficient the same as that of a tissue. However, this increase made the PAG stiffer and less homogeneous. In addition, the increase in acrylamide caused a significant increase in temperature over the denaturation threshold of BSA during polymerization, which required forced cooling so that the PAG did not become opaque at room temperature after polymerization. To eliminate those shortcomings, we substituted the increased acrylamide with a viscous polysaccharide liquid (corn syrup). The concentration of corn syrup was optimized to 20% (w/v, tested in the volume of 50 mL), so that the acoustic properties of the PAG would be close to those of human liver. The improved TM (iTM) BSA PAG constructed in this study had a speed of sound of 1588 ± 9 m/s, an attenuation coefficient of 0.51 ± 0.06 dB cm −1 at 1 MHz and a backscattering coefficient of 0.22 ± 0.09 × 10 −3 sr −1 cm −1 MHz −1 . The density and acoustic impedance were 1057 kg/m 3 and 1.68 MRayl, respectively, and the non-linear parameter ( B / A ) was 5.9 ± 0.3. The thermal, optical and mechanical properties were almost the same as those of the BSA PAG ( Lafon et al.2005 ). Experimental verification indicated that the thermal lesions visualized in the proposed iTM BSA PAG by high-intensity focused ultrasound were highly reproducible. In conclusion, iTM BSA PAG was proven to eliminate TM BSA PAG shortcomings effectively and is expected to be a promising test phantom for clinical high-intensity focused ultrasound device. [ABSTRACT FROM AUTHOR]

Résumé La prise en charge de la récidive du cancer de la prostate après radiothérapie ou curiethérapie est évolutive et non standardisée. La récidive locale est observée en moyenne dans 30 % des cas quelques années après l’irradiation. Un des principaux défis est de déterminer le site de la récidive et les examens d’imagerie (IRM et TEP à la choline) couplés aux biopsies prostatiques sont importants pour confirmer le caractère local. Un traitement de rattrapage réalisé par l’urologue peut alors contrôler la situation. La prostatectomie totale soumise à des conditions techniques strictes est un des traitements locaux les plus efficaces au prix d’une morbidité urinaire non négligeable ; les thérapeutiques mini-invasives (ultrasons focalisés et cryothérapie) ont également leur place dans des indications précises. Chaque situation clinique de récidive après irradiation doit faire l’objet d’une discussion en réunion de concertation pluridisciplinaire en intégrant le statut carcinologique et fonctionnel lors de la récidive, le rapport bénéfice/risque de chaque traitement, les souhaits du patient et sa probabilité de survie. The management of recurrent prostate cancer after radiotherapy or brachytherapy is non-standardized and rapidly evolving. Local recurrence is observed on average in 30% of cases several years following irradiation. A key challenge is to determine the site of recurrence and imaging (MRI and PET choline) coupled to prostate biopsies are important to confirm the local character. Salvage therapy performed by the urologist can then control the situation. Radical prostatectomy subject to strict technical conditions is one of the most efficient local treatments, however it comes at the cost of significant urinary morbidity; minimally invasive therapies (focused ultrasound and cryotherapy) have also their place in specific indications. Each clinical situation should be discussed in pluridisciplinary meetings integrating the oncologic and functional status at recurrence, the risk/benefit ratio of each treatment, the patient's wishes and probability of survival. [ABSTRACT FROM AUTHOR]

Background: To evaluate the clinical and oncological outcomes of partial gland ablation (PGA) using high intensity focused ultrasound (HIFU) technique for the clinically unilateral prostate cancer.Methods: We performed a retrospective analysis for the 163 patients who treated by PGA for clinically unilateral prostate cancer. The PGA was performed using Focal one system with concurrent trans-urethral prostatectomy. The oncological and functional outcomes were evaluated as well as risk factors for remnant disease after PGA. Clinically significant cancer was defined as grade group ≥2.Results: Among the entire subjects, grade group 2 or greater was present at pre-treatment biopsy in 76.7%. Median follow-up time was 17 months and 60.1% of total subjects had follow-up biopsy at postoperative 1 year. There were 25 subjects (24.2%) with any cancer and 13 subjects (12.6%) with CS cancer at the follow-up biopsy. The preoperative age and number of positive cores at preoperative biopsy were significantly associated with positive results at follow-up biopsy. Incontinence which requires 2 or more pads per day was observed at 4 subjects (2.5%) postoperatively. There were no subjects who needed intensive care or experienced rectal complications.Conclusion: The PGA with HIFU was safe and showed good preservation of functional outcomes as well as satisfactory oncological control. The remnant disease was observed in the 24.5% of patients who underwent follow-up biopsy in the present study. Thus, further prospective study is needed to evaluate oncological and functional outcomes of PGA with HIFU more accurately. [ABSTRACT FROM AUTHOR]

Highlights: [•] HIFU triggers both apoptosis pathways.. [•] Coupling of MRI and HIFU is optimal variant for pinpoint induction of apoptosis.. [•] Combining of HIFU and modulators of apoptosis is new method of cure of cancer. [ABSTRACT FROM AUTHOR]

Abstract: Au nanoparticles-coated, perfluorohexane-encapsulated and PEGylated mesoporous silica nanocapsule-based enhancement agents (MSNC@Au-PFH-PEG, abb. as MAPP) have been synthesized, for the ultrasound-induced cytoclasis, contrast-intensified ultrasound (US) imaging and US-guided high intensity focused ultrasound (HIFU) surgical therapy. Both the US-induced thermal effect and US triggered release of loaded model drug with MAPP under US exposure indicated the excellent US sensitivity of MAPP and its applicability for the combined chemo-/thermal therapy and future potential for HIFU ablation; US imaging under different modes verify the attractive US contrast intensification by using MAPP; US-guided HIFU therapy ex vivo and in vivo with MAPP is found to be highly efficient on rabbit VX2 xenograft tumor ablation due to the high thermal energy accumulation and increased mechanical/thermal effects from US-induced PFH bubble cavitations. MAPP can be promisingly used as an inorganic theranostic platform for contrast-intensified US imaging, combined chemotherapy and efficient HIFU tumor ablation under the guidance by the intensified US. [Copyright &y& Elsevier]

Abstract: A design of high-precision angular position control system for calibrating high intensity focused ultrasound (HIFU) is presented with alignment procedures. Two independent angular controls are achieved by combining a worm gear and a belt gear system. The proposed system verifies alignment by comparing simulation data and experimental data with three different transducers and two different types of hydrophones. The performance of the proposed system is compared to that of a commercial system. The results indicate that the proposed system provides high precision angular alignment (e.g., <0.01radians) with robust reproducibility regardless of the hydrophone type. [Copyright &y& Elsevier]

Abstract: Abstract: In this paper, we propose a mechanical system identification method for the Non-Invasive Ultrasound Theragnostic System (NIUTS). NIUTS tracks and follows the movement in an affected area (kidney stones, in the present study) by irradiating the area with high-intensity focused ultrasound (HIFU). Blur noise caused by oscillation of the mechanical systems deteriorates the servoing performance. To enhance the servoing performance, it should be required to identify the mechanical system with mechanical oscillation part. [Copyright &y& Elsevier]

Abstract: We have developed a non-invasive ultrasound theragnostic system (NIUTS) that tracks and follows the movement of an affected area (kidney stone/tumor, in this study) while irradiating it with high-intensity focused ultrasound (HIFU). In this paper, we propose a method to simplify extracting, tracking and following, monitoring the affected area by using a bed-type non-invasive ultrasound theragnostic system. [Copyright &y& Elsevier]