Search

High‐intensity focused ultrasound (HIFU) is a viable treatment option for small tumors. This study investigates the feasibility of employing a photoacoustic (PA) sensor to monitor the in situ temperature rise during HIFU exposures. The present method also provides means to simultaneously monitor inertial cavitation using the same sensor. Polyacrylamide phantoms with a cylindrical inclusion (3×20 mm) of graphite (0.01 g/ml) were heated using 30 s exposures from a 2 MHz HIFU transducer. The transducer focus was aligned to the tip of a wire thermocouple embedded in the inclusion. A 532 nm pulsed laser was used to illuminate the inclusion. A 15 MHz broadband transducer was employed as a passive receiver (PR) to detect the PA response, which was an ultrasonic pulse emanating from the inclusion due to thermoelastic expansion induced by optical absorption. The native temperature and PR signals were recorded before, during, and after HIFU exposure. Singular‐value decomposition (SVD) was performed on the matrix consisting of the PR signals to extract temperature data. SVD‐deduced, PA‐based temperatures correlated well with the thermocouple measurements (RMS error

Electrohydraulic lithotripter acoustic fields are measured with single-element hydrophones even though the acoustic fields are not highly repeatable. The ability to obtain an instantaneous "snapshot" of the sound field would have broad implications for advancing the understanding of how lithotripters fragment stones and damage kidney tissue. To better characterize the acoustic field of lithotripters, linear hydrophone arrays were fabricated by bonding a 9 μm piezopolymer film to a copper-clad polyimide which had an array pattern etched on the copper layer. After bonding, the devices were backed with an epoxy plug in order to provide structural support. The array elements were each 0.5 by 0.5 mm, spaced 1.25 mm center to center, and there were 20 elements. The relative sensitivity of each hydrophone element was measured at 5.25 MHz for an acoustic pressure of 4.5 kPa and the elements were found to vary by ≈ 6%. The arrays were then placed in the focus of a piezoelectric lithotripter and were found to maintain their sensitivity for roughly 500 shock waves before gradually losing sensitivity. © 2010 American Institute of Physics.

Jacques Souquet a cree, dans le domaine de l’imagerie medicale, deux societes aux Etats-Unis, puis une troisieme a Aix-en-Provence. C’est la qu’est ne un echographe revolutionnaire, capable d’acquerir et de traiter les images pratiquement en temps reel.

This paper summarizes the state of the art in ultrasound imaging. It emphasizes the importance of capturing and preserving broadband information received from tissues. A description of new generation transducers is provided, with a short discussion on future materials to achieve even wider bandwidth. The flexibility and broadband characteristics of the digital beamforming technique is described in detail. An example of the strength of such a technique is given in demonstrating how compounding (in space and/or frequency) the information received from tissue will contribute in enhancing the imaging performance of the ultrasound system by reducing and/or removing artifacts like clutter and speckle.

Interstitial and transurethral catheter‐based ultrasound devices are under development for treatment of prostate cancer and BPH, uterine fibroids, liver tumors and other soft tissue disease. Accurate 3D thermal modeling is essential for designing site‐specific applicators, exploring treatment delivery strategies, and integration of patient‐specific treatment planning of thermal ablations. We are developing a comprehensive 3D modeling and treatment planning platform for ultrasound ablation of tissue using catheter‐based applicators. We explored the applicability of assessing thermal effects in tissue using critical temperature, thermal dose and Arrhenius thermal damage thresholds and performed a comparative analysis of dynamic tissue properties critical to accurate modeling. We used the model to assess the feasibility of automatic feedback control with MR thermometry, and demonstrated the utility of the modeling platform for 3D patient‐specific treatment planning. We have identified critical temperature, thermal dose and thermal damage thresholds for assessing treatment endpoint. Dynamic changes in tissue attenuation/absorption and perfusion must be included for accurate prediction of temperature profiles and extents of the ablation zone. Lastly, we demonstrated use of the modeling platform for patient‐specific treatment planning.

Part of AIP Conference Proceedings, Volume 1215 In this paper the goal was to measure the contrast to noise ratio (CNR) of fast spin echo (FSE) magnetic resonance imaging (MRI) sequences in detecting thermal lesions created by high intensity focused ultrasound (HIFU) in rabbit kidney, liver, heart, and brain and lamb pancreas. A spherically focused transducer was used which is navigated inside MRI by a custom made positioning device. A simple simulation model was developed which predicts the CNR for the two FSE MRI sequences. The maximum contrast measured with T1-W FSE ranges from 10 to 25. For all 5 tissues of interest if one uses TR between 400 and 500 ms the contrast is maximized. The T1, and T2 value of lesion depends strongly on the host tissue and is always lower than the host tissue. The greater the difference in T1 value, the greater the CNR. The simulated model for predicting the CNR was proven successful. The CNR measured with T2-W FSE varies between 12 and 15 for all 5 tissues. With T2-W FSE if one uses TE between 40 and 50 ms, the contrast is maximized. © 2010 American Institute of Physics.

As part of the development of a noninvasive treatment for BPH using histotripsy, this study aimed to measure acoustic access for extracorporeal ablation of the prostate. Both transabdominal and transperineal approaches were considered. The objective was to measure the size and shape of a transducer aperture that could target the prostate without obstruction. CT images obtained from 17 subjects >56 years of age were used to create 3D reconstructions of the lower abdomen and pelvis. Target locations on the urethra at the base, mid, and apex in the prostate were marked along with a transrectal imaging probe. Evenly space rays spanning were traced from each target location towards the perineum and separately towards the abdomen with the maximum x‐ray density encountered along each path recorded. The overall free aperture through the perineum was found to be a triangular shaped region bounded by the lower bones of the pelvis and the transrectal probe varying significantly in size between subjects. The free aperture through the abdomen was wedge shaped limited by the pubis also with great subject to subject variability. Average unblocked fractions of an f/1 transducer to target base, veru, and apex through the perineum were 77.0%, 94.4%, and 99.6%, respectively. Averages targeting through the abdomen were 86.1%, 52.3%, and 11.0%. Acoustic access to the prostate for through the perineum was judged to be feasible.

Accurate monitoring of high intensity focused ultrasound (HIFU) surgery is critical to ensuring proper treatment. Pulse‐echo diagnostic ultrasound (DU) is a recognized modality for identifying temperature differentials using speckle tracking between two DU radio frequency (RF) frames [2], [4]. This observation has motivated non‐parametric temperature estimation, which associates temperature changes directly with the displacement estimates. We present an estimation paradigm termed displacement mode analysis (DMA), which uses physical modeling to associate particular patterns of observed displacement, called displacement modes, with corresponding modes of variation in the administered therapy. This correspondence allows DMA to estimate therapy directly using a linear combination of displacement modes, imbuing these displacement estimates into the reference using interpolation, and by aligning with the treatment frame, providing a therapy estimate with the heating modes. Since DMA is maximum likelihood estim...

Current development of HIFU strategies for the treatment of localized abdominal tumors are limited by organ motion during respiration. In preliminary studies, a numerical model simulated the effects of in‐vivo movements on HIFU treatments in the liver. It was shown that a HIFU treatment performed during respiration with juxtaposition of millimetrics lesions is modified in shape and homogeneity. Here, we report recent results from a comparative study which evaluated in simulation and in in‐vivo experiments, the interest of using, during respiratory, a toroidal‐shaped HIFU device developed for the treatment of Liver Metastases from Colorectal Cancer. These experiments were performed during an open procedure, on 9 pigs divided into 3 groups. On the first group, a spherical HIFU transducer was used to juxtapose 49 millimetrics lesions in the liver during respiration. The second group was treated during respiration with a 3 MHz toroidal‐shaped HIFU transducer. The last group (control) was treated during apnea....

Using Focused Ultrasound (FUS) and microbubbles to open the blood‐brain barrier (BBB) has been shown promising for brain drug delivery. However, the exact mechanism behind the opening remains unknown. Here, the effects of the murine skull on the threshold of inertial cavitation were investigated. In order to investigate the pressure threshold for inertial cavitation of preformed microbubbles during sonication, passive cavitation detection in conjunction with B‐mode imaging was used. A cylindrical vessel with a 610‐μm diameter inside a polyacrylamide gel was generated within a polyacrylamide gel to simulate large blood vessels. Definity® (Lantheus Medical Imaging, MA, USA) microbubbles with a 1.1–3.3 μm in diameter at 2.5×107 bubbles/mL were injected into the channel before sonication (frequency: 1.525 MHz; pulse length: 100 cycles; PRF: 10 Hz; sonication duration: 2 s) through an excised mouse skull. A cylindrically focused hydrophone, confocal with the FUS transducer, acted as a passive cavitation detect...

Ultrasound based transurethral and interstitial catheters have been developed and tested in vivo to thermally ablate prostate cancers. Treatment validation and accurate control of therapy is currently done using MR thermal imaging (±1° C, update: 5–15 s). MRTI is effective for real‐time monitoring and guidance, but, cost, setup time, and accessibility can be limiting. Ultrasound imaging methods could be a practicable approach to monitoring. We investigated Ultrasound Strain Imaging (USI) as a tool towards verifying and controlling prostate treatments by developing a novel methodology for tissue compression using ultrasound phantoms and ex vivo tissue models. We estimate strain using quasi real‐time estimation algorithms and added automatic segmentation features. The methodology involved inserting an ultrasound applicator into ex vivo liver or porcine muscle tissue, ablating it for 10 min at 15 W to create a well defined thermal lesion. After treatment, the tissue was compressed either externally (3–5%) us...

The development of the HIFU therapy for the deeply placed cancer has been desired. On problem is the displacement of the focal point due to the inhomogeneity of human body. The objectives are to realize the appropriate phase control of an array transducer and to support the preoperative planning of HIFU therapy by the computational prediction of treatment regions. Our approach is to solve the mass and momentum equations for mixture with the equation of state of media. The heat equation with a heat source of a viscous dissipation is solved to estimate the ablation region of tissue. The ablation, i.e., the heat denaturation of protein, is modeled as a phase transition by the phase field model. The HIFU therapy with a bowl‐shape array transducer for a liver cancer is simulated. As the result with a phase control, we obtain a clear focus which is closer to a target point than the focus without a phase control, when the ultrasound propagates through lib bones. In addition, the development of the ablation region is reproduced numerically.

The goal of the work was to demonstrate feasibility of HIFU tissue ablation through the rib cage using a high power 2D random phased array. A method to minimize heating ribs while maintaining high intensities at the focus of the array was proposed and tested theoretically and experimentally. A 2D 1‐MHz phased array with 254 randomly distributed elements and a phantom of porcine rib cage were used in experiments. Intensity distributions were measured in the plane of the rib phantom and in the focal plane of the array using an infra‐red camera. Theoretical and experimental results show that if the position and the shape of ribs are known it is possible to provide adequate focusing through the ribs without overheating them for a single focus, including steering at ±10–15 mm off and ±20 mm along the array axis. The results suggest that the method is potentially useful for clinical applications of HIFU for which the rib cage lies between the transducer and the targeted tissue.

A recurrent neural network solution was proposed to map changes in multiple acoustic parameters, such as apparent displacement, echo backscattered intensity change, echo signal correlation coefficient and tissue elasticity, to temperature rise during High Intensity Focused Ultrasound (HIFU) dosing. The training and testing of the neural network was based on data from experiments on HIFU treated ex‐vivo porcine and bovine liver. The experiments included acquiring 3D echo signals along with directly measuring temperature with thermocouples in the region of the HIFU focal zone (treatment target) before and during the HIFU dosing event. The results demonstrate that the proposed method may provide temperature rise estimation (thermometry) over practical temperature ranges for the therapy, and may reveal the individual acoustic parameters’ correlations with temperature rise.

Nonlinear propagation effects result in the formation of weak shocks in high intensity focused ultrasound (HIFU) fields. When shocks are present, the wave spectrum consists of hundreds of harmonics. In practice, shock waves are modeled using a finite number of harmonics and measured with hydrophones that have limited bandwidths. The goal of this work was to determine how many harmonics are necessary to model or measure peak pressures, intensity, and heat deposition rates of the HIFU fields. Numerical solutions of the Khokhlov‐Zabolotskaya‐Kuznetzov‐type (KZK) nonlinear parabolic equation were obtained using two independent algorithms, compared, and analyzed for nonlinear propagation in water, in gel phantom, and in tissue. Measurements were performed in the focus of the HIFU field in the same media using fiber optic probe hydrophones of various bandwidths. Experimental data were compared to the simulation results.

It has been shown that high‐intensity focused ultrasound can be an efficient method to induce thrombolysis, but the choice of the pulsed‐wave parameters is critical and the risk of thermal lesions in neighbouring tissues is still an important issue. The present work aims at using a bifrequency excitation combining two neighbouring frequencies to reduce the intensity needed to achieve thombolysis without any pharmacological agent. In vitro clots of human blood are inserted in small tubes filled with physiological saline, and placed at the focus of a piezoelectric transducer. The typical clot weight before sonication is 700 mg. Ultrasound excitation consists in monofrequency (resp. bifrequency) pulsed wave at 550 kHz (resp. 535 kHz and 565 kHz), with a pulse length of 27 ms and a duty cycle of 1:10, emitted during 5 min. Efficiency of the thrombolysis is obtained weighting each clot after filtration on a 25 μm filter before and after sonication. The efficiencies of mono‐ and bi‐frequency excitations are com...

This study presents results, obtained from both simulation and experimental techniques that show the effect of mechanically and electronically steering a phased‐array transducer on proximal tissue heating between the transducer and focal zone. The thermal response of a nine‐position, single‐plane, scanning trajectory executed through both electronic and mechanical scanning was evaluated in a homogeneous tissue‐mimicking phantom. Simulations were performed by applying a finite‐difference approximation of the Pennes’ bioheat transfer equation. The power deposition was modeled using the Hybrid Angular Spectrum (HAS) method. Experiments were conducted in a 3T Siemens MRI with a 256‐randomized element phased‐array transducer HIFU system that has both electronic and mechanical steering capabilities. Temperatures were obtained using the proton resonance frequency method. Both simulation and experimental results show that electronically steering the ultrasound beam using a 256‐element randomized phased‐array significantly increases the grating lobe magnitude in the near‐field tissues, depositing more energy in the proximal tissues when directly comparing the same treatment executed through mechanical steering only. Optimization of the scanning path through a treatment volume, utilizing both mechanical and electronic movements would reduce proximal tissue heating, offering significant reductions of treatment times.

The development of new cauterization techniques for hepatic resection is critical for improving the safety of the procedure. Previous studies showed the feasibility of using HIFU or radiofrequency precoagulation to limit blood loss during dissection of the organ. Here we report a new therapeutic modality using high intensity focused ultrasound (HIFU) to perform a bloodless hepatic resection that could represent a promising alternative. A comparative study was performed to evaluate the interest of using this complementary tool to improve surgical resection in the liver. This study used a 3 MHz HIFU toroidal‐shaped phased array transducer which allows the generation of a single conical lesion of 7 cm3 in 40 seconds. In order to minimize blood loss and dissection time, a barrier of coagulative necrosis was generated with the HIFU device before hepatectomy, by juxtaposing single conical lesions on the line of dissection. Resection assisted by HIFU (RA‐HIFU) was compared with classical dissections with clampin...

The results of measurements of longitudinal speed of sound are presented for seven specimens of human calvaria. The study was done for frequencies between 0.27 and 2.525 MHz. Specimens were obtained from fresh cadavers through a protocol with the Division of Anatomy of the University of Toronto. The specimens were mounted in polycarbonate frames that were marked for stereoscopic positioning. CT scans of the skulls mounted on their frames were performed and a three‐dimensional reconstruction of the skull surface was done. A positioning system ensured normal sound incidence of an acoustic signal produced by a focused device with a diameter of 5 cm and a focal length of 10 cm. Speed of sound estimation was done with measurements of time‐of‐flight using a needle hydrophone (diameter of 0.5 mm) and a sound propagation model through layers that takes into account change of speed of sound in function of density. For six of seven specimens, measurements were done on five locations on the calvaria and for the othe...

In dendritic cells (DCs)‐based cancer immunotherapy, it is important to present the epitope peptide derived from tumor associated antigens (TAAs) on MHC class I in order to induce tumor specific cytotoxic T lymphocytes (CTLs). However, MHC class I molecules generally present the epitope peptides derived from endogenous antigens for DCs but not exogenous ones such as TAAs. Recently, we developed the novel liposomal bubbles (Bubble liposomes) encapsulating perfluoropropane nanobubbles. In this study, we attempted to establish the novel antigen delivery system to induce MHC class I presentation using the combination of ultrasound and Bubble liposomes. Using ovalbumin (OVA) as model antigen, the combination of Bubble liposomes and ultrasound exposure for the DC could induce MHC class I presentation. In addition, the viability of DCs was more than 80%. These results suggest that Bubble liposomes might be a novel ultrasound enhanced antigen delivery tool in DC‐based cancer immunotherapy.

A wide variety of treatment protocols have been employed in high intensity focused ultrasound (HIFU) treatments, and the resulting bioeffects observed include both mechanical as well as thermal effects. In recent studies, there has been significant interest in generating purely mechanical damage using protocols with short, microsecond pulses. Tissue erosion effects have been attained by operating HIFU sources using short pulses of 10–20 cycles, low duty cycles (

In this work a more time efficient approach for tissue assessment with MR‐ARFI is proposed. During HIFU treatments gadolinium‐free assessment of treated tissue is highly desirable. MR‐ARFI allows measuring tissue displacement in the focal spot. Therefore raster‐scanning the ultrasound focal spot through the tissue of interest can give information about tissue stiffness in the “probed” area. To enhance efficiency of such ultrasound “probing,” we replaced a conventional point focus with a line focus that allows greater area coverage during MR‐ARFI acquisitions. This approach was tested in a phantom and in ex vivo bovine muscle. The results of the study showed that the line focus produces a fairly uniform line shape focal spot in both temperature and displacement maps. Using one line focus position, the displacement maps obtained in the muscle tissue well depicted the difference in displacement in the area where lesion was created. This shows great potential for line focus geometry combined with MR‐ARFI as a...

A novel MR‐guided brain therapy device operating at 1 MHz has been designed and constructed. The system has been installed and tested in a clinical 1.5 T Philips Achieva MRI. Three dimensional time domain finite differences simulations were used to compute the propagation of the wave field through three human skulls. The simulated phase distortions were used as inputs for transcranial correction and the corresponding pressure fields were scanned in the focal plane. At half of the maximum power (10 W/cm2 on the surface of the transducers), necroses were induced 2 cm deep in turkey breasts placed behind a human skull. In vitro experiments on human skulls show that simulations restore more than 85% of the pressure level through the skull bone when compared to a control correction performed with an implanted hydrophone. Finally, high power experiments are performed though the skull bone and a MR‐Thermometry sequence is used to map the temperature rise in a brain phantom every 3 s in two orthogonal planes (foc...

Ultrasound (US) exposures are widely used with in vitro cell systems e.g. in stem cell and tissue engineering research. However, without the knowledge of factors affecting the level of US exposure, the outcome of the biological result may vary from test to test or even be misinterpreted. Thereby, some of the factors affecting in vitro US exposures were studied.The level of US exposure was characterized in standard commercial cell culturing plates. The temperature distributions were measured inside the wells using infrared camera and fine wire thermocouples, and pressure and intensity distributions using a laser vibrometer and a schlieren system. The measurements were made at operating frequency of around 1 MHz with varying temporal parameters and powers (up to 2 W of acoustic power).Heat accumulation between the wells varied up to 40–50% depending on the location of the well on the plate. This well‐to‐well variation was be linked to the activity of reporter plasmid on osteoblastic cells. Similar temperatu...

Ultrasound phased arrays can be used for noninvasive surgical applications, and are ideal for intracavitary applications, where their properties of dynamic focusing and beam steering compensate for the spatial constraints. Phase shifting without grating lobes requires small elements, which results in low width‐thickness ratios and thus high electrical impedance. This study demonstrates, for the first time, a method of lateral coupling for the purposes of reduction of electrical impedance of linear phased arrays. Fabrication procedure for a lateral coupled array for therapeutic purposes is demonstrated. Impedance analysis of a thickness mode driven phased array is compared to a lateral coupling mode array. For a 1.5 MHz resonant frequency, impedance drop of 33 times is seen at antiresonance, and 6 times at resonance. Thickness mode phase peak is never higher than −41.3°, whereas it reaches to 42.3° in the lateral coupling mode. This allows for a phase crossing of 0° for lateral mode transducer, where the i...

In this study we present results demonstrating how information from thermal and acoustic modeling can be used to improve the monitoring of MR guided high intensity focused ultrasound (MRgHIFU) treatments. A model predictive filtering (MPF) algorithm has been developed to combine thermal model predictions of how the temperature distribution evolves with undersampled k‐space data to create temperature maps with good spatial resolution, fast scan times and large volume coverage. The tissue thermal and acoustic properties are determined using both MR temperature data, acquired during a pre‐treatment step, and ultrasound beam simulation software. A 4‐point, electronically steered HIFU heating experiment was performed with a 256‐element phased array transducer on an agar phantom to validate the method. At a data reduction factor of 9, the MPF algorithm was able to reconstruct temperature maps that correlated very well with fully sampled PRF temperature maps for heating at on‐axis and off‐axis locations.

MR‐guided high intensity focused ultrasound (HIFU) has evolved into a promising non‐invasive technique for the ablation of pathological tissue in abdominal organs. However, since the high perfusion rates of these organs lead to effective cooling, sustained sonications of 30–90 s are required to achieve a sufficiently high temperature elevation to induce necrosis. This is complicated by the constant displacement of the target due to the respiratory cycle. This study proposes sub‐second 3D HIFU‐beam steering under MR‐guidance for the near real‐time compensation of respiratory motion as a possible solution. The target position is observed in 3D space by coupling rapid 2D MR‐imaging with prospective slice tracking (PST) based on pencil‐beam navigator echoes. Continuous real‐time image processing provides temperature maps, thermal dose estimates and the target position at a frequency of 10 Hz and an update latency of less than 120 ms. The suggested method is evaluated with phantom experiments and its feasibility is verified in‐vivo with an ablation experiment on a porcine kidney where it allows to achieve a thermal energy deposition which is comparable to static control experiments.

While the development of transcranial MR‐guided High Intensity Focused Ultrasound has been driven mainly by applications for tumor ablation this new intervention method is also very attractive for functional neurosurgery due to its non‐invasiveness, the absence of ionizing radiation and the closed‐loop intervention control by MRI. Here we provide preliminary data to demonstrate the clinical feasibility, safety and precision of non‐invasive functional neurosurgery by transcranial MR‐guided High Intensity Focused Ultrasound.

Previous numerical simulations have shown that MRI‐guided transurethral ultrasound therapy can generate highly accurate volumes of thermal coagulation conforming to 3‐D human prostate geometries. The goal of this work is to simulate, quantify and evaluate the thermal impact of these treatments on the rectum, pelvic bone, neurovascular bundles (NVB) and urinary sphincters. This study used twenty 3‐D anatomical models of prostate cancer patients and detailed bio‐acoustic simulations incorporating an active feedback algorithm which controlled a rotating, planar ultrasound transducer (17–4×3 mm elements, 4.7/9.7 MHz, 10 Wac/cm2). Heating of the adjacent surrounding anatomy was evaluated using thermal tolerances reported in the literature. Heating of the rectum poses the most important safety concern and is influenced largely by the water temperature flowing through an endorectal cooling device; temperatures of 7–37° C are required to limit potential damage to less than 10 mm3 on the outer 1 mm layer of rectum...

A gene transfer system that uses ultrasound, known as sonoporation, has recently been developed, and it is known that micro‐bubbles can help gene transfection in this technique. However, the mechanism and optimal induction conditions have not yet been fully clarified. We examined the factors that affect the gene induction rate, and attempted to devise a method for high‐efficiency gene induction. In vitro, we inducted a GFP‐containing plasmid into fibroblast cells (NIH3T3) using an ultrasound contrast agent (Sonazoid®, or micro‐bubbles) and piezoelectric transducer. Cells were cultured on 24‐well plates. The GFP‐containing plasmid (concentration: 15 mg/ml) and Sonazoid® were mixed with the cell suspension. Ultrasound frequency was 2.0 MHz (burst wave, duty cycle: 10%), ultrasound intensity was varied from 0 W/cm2 to 11.0 W/cm2, exposure time ranged from 0 s to 120 s, and burst repetition frequency was varied from 50 Hz to 50000 Hz. Gene induction ratio was higher with stronger or longer ultrasound exposure...

Thermal dose is the most generally accepted concept for estimating temperature‐related tissue damage thresholds. However, another approach based on the intensity‐time product of the form D = Itm has been used, where D is a tissue‐dependent damage threshold, I is the spatial‐peak, temporal‐average intensity, t is time, and m is an exponent not greater than one. In this study these two relationships were compared analytically by substituting a well‐known soft tissue solution for temperature vs. time into the thermal dose equation. The commonly accepted value for t43 of 240 minutes was used as a thermal dose threshold for necrosis. Then power law fits were found for I vs. t for various frequencies and beam diameters. Using published values for soft tissue acoustic and thermal properties, typical high intensity focused ultrasound (HIFU) frequencies and beam diameters, and exposure times from 1–20 s, the exponent m was found to fall between about 0.3 and 0.8. The value for m increased with increasing diameter ...

This study investigated the in vivo feasibility of using histotripsy to non‐invasively create a flow channel between the ventricles by generating a perforation of the ventricular septum, clinically referred to as a ventricular septum defect (VSD). The overall goal is to develop a non‐invasive procedure to aid in the treatment of neonatal patients with complex congenital heart diseases such as Hypoplastic Left Heart Syndrome (HLHS). Histotripsy is a therapeutic ultrasound technique that produces mechanical fractionation of soft tissue through controlled cavitation. The study was conducted in a live and intact neonatal pig model. The ventricular septum in the neonatal pig heart was treated with histotripsy delivered by a spherically focused 1 MHz transducer positioned outside the chest wall. Histotripsy treatment was applied using 5‐cycle ultrasound pulses at 1 kHz pulse repetition frequency with 12–18 MPa peak negative pressure. The treatment was guided and monitored with ultrasound imaging. In all nine subjects treated, a bubble cloud was generated on the ventricular septum using histotripsy, and visualized with ultrasound imaging. Within 20 seconds to 4 minutes following the initiation of a bubble cloud, a VSD was created in all nine pigs and confirmed by the detection of blood flow through the ventricular septum with color Doppler ultrasound. Gross morphology and histology on all hearts showed a demarcated perforation in the ventricular septum. This study shows that a VSD can be created in an intact neonatal animal using extracorporeal histotripsy under real‐time ultrasound guidance.

HIFU has been recognized as a minimally invasive treatment option for localized prostate cancer. The purpose of the study was to assess with a long‐term outcome of HIFU for prostate cancer. From January 1999, a total of 657 patients who had HIFU with at least 2 year follow‐up were treated with four different types of Sonablate® (Focus Surgery, Indianapolis, USA) devices. Thirty‐three patients were treated with Sonablate® 200 (S200) from 1999 to 2001, 406 patients with Sonablate® 500 (S500) from 2001 to 2005, 200 patients with Sonablate® 500 version 4 (V4) from 2005–2008 and 19 patients with Sonablate® 500 TCM (TCM) from 2007. Biochemical disease‐free survival rate (bDFS) in all patients was 59% in 8 years. bDFS in 8 years in patients with S200 and S500 groups were 55% and 56%, and bDFS in 4 and 2 years in patients with V4 and TCM group were 72% and 84%, respectively. bDFS in low, intermediate, and high risk groups were 75%, 54%, and 43% in S200/S500 and 93%, 72%, and 58% in V4/TCM group. Negative prostate...

Sonoporation would be linked to cavitation, which generally appears to be a non reproducible and unstationary phenomenon. In order to obtain an acceptable trade‐off between cell mortality and transfection, a regulated cavitation generator based on an acoustical cavitation measurement was developed and tested.The medium to be sonicated is placed in a sample tray. This tray is immersed in in degassed water and positioned above the face of a flat ultrasonic transducer (frequency: 445 kHz; intensity range: 0.08–1.09 W/cm2). This technical configuration was admitted to be conducive to standing‐wave generation through reflection at the air/medium interface in the well thus enhancing the cavitation phenomenon. Laterally to the transducer, a homemade hydrophone was oriented to receive the acoustical signal from the bubbles. From this spectral signal recorded at intervals of 5 ms, a cavitation index was calculated as the mean of the cavitation spectrum integration in a logarithmic scale, and the excitation power i...

Accurate monitoring of ultrasonically induced thermal lesions in biological tissue has been one of the challenges behind bringing focused ultrasound surgery to mainstream clinical use. Recent research has shown the potential of using radiation force impulses to monitor displacement changes that may be related to the formation of the lesion. It has been suggested that as the lesion forms a reduction in displacement should occur due to a stiffening of the tissue in the focal region, indicating the onset of ablation. More recent literature has reported initial increases in the displacements prior to stiffening which were explained by a softening in the tissue before denaturation took place. In this paper we present results supporting that initial increase, however here we propose that these changes are dominated by an increase in sound absorption in the tissue, rather than a tissue softening. The results show that a lesion may have already formed before decreases in displacement are observed. The measurement of displacement change using this method could provide valuable information not only about the onset of ablation but also the size of the induced lesion.

Focused ultrasound (FUS) in combination with the administration of gas‐filled microbubbles, can induce a localized and reversible opening of the blood brain barrier (BBB). Contrast enhanced magnetic resonance imaging (MRI) has been demonstrated as a precise tool to monitor such a local BBB disruption. However, the opening/closing mechanisms of the BBB with FUS are still largely unknown. In this ongoing project, we study the BBB opening dynamics in mouse brain comparing an interstitial and an intravascular MR contrast agent (CA).FUS in mouse brain was performed with an MRI compatible treatment setup (1.7 MHz fix‐focus US transducer, f′ = 68 mm, NA = 0.44; focus: 8.1 mm length; O/ = 1.1 mm) in a 1.5 T whole body MRI system. For BBB opening, forty 10 ms‐long FUS‐pulses were applied at a repetition rate of 1 Hz at 1 MPa. The i.v. administration of the micro bubbles (50 μl SonoVue®) was started simultaneously with FUS exposure. To analyze the BBB opening process, short‐term and long‐term MRI signal dynamics of...

The lack of accurate and low‐cost techniques for real‐time monitoring and feedback during ablative therapies such as HIFU has limited its widespread clinical adoption. A good ultrasound solution would enable a much more widespread usage of HIFU therapy. An acoustic radiation force (ARF) based technique for controlling the lesion size and its placement during HIFU therapy has been developed. A series of experiments were performed in excised bovine liver tissue to evaluate the proposed technique. The change in the ARF induced displacements during therapy at each spatial location was quantified by a unitless parameter, normalized displacement difference (NDD), defined as the difference between normalized displacement at the therapy endpoint and a reference determined from the data. The 2‐D displacement map (normalized to the value before therapy commenced) illustrated that displacements initially increased due to the temperature rise, reached a maximum, and then decreased with continuing therapy. Strong corr...

Repetitive MR thermometry was performed on the brain of nine volunteers using GRE, seg EPI, and ss EPI sequences on whole‐body 1.5 T and 3 T clinical systems using comparable acquisition parameters. Phase stability and temperature data precision in the human head were determined over 12 minutes for the three sequences at both field strengths. The ss EPI sequence was the fastest and the most precise sequence for MR thermometry, with significantly higher accuracy compared to GRE. An ex‐vivo swine skeletal muscle model was used to evaluate temperature accuracy of the ss EPI sequence during heating by high intensity focused ultrasound (HIFU).

Temperature rise during HIFU procedures and the possibility of cavitation activity during heating are important to quantify in planning a safe and effective treatment. Therefore, in pre‐clinical testing it is essential to characterize clinical HIFU devices using tissue‐mimicking materials (TMMs) with well known characteristics, including cavitation properties. The purpose of this study was to monitor cavitation behavior and determine its effect on temperature rise in a HIFU TMM containing an embedded thermocouple. A 50 μm fine wire thermocouple was embedded in a hydrogel‐based TMM previously developed for HIFU. HIFU at 1.1 MHz was focused at the thermocouple junction. HIFU focal pressures from 1–5 MPa were applied and the temperature rise and decay were recorded. Three hydrophones were used to monitor cavitation activity during sonication. A hydrophone confocal with the HIFU transducer and a cylindrical hydrophone lateral to the HIFU beam were used as passive cavitation detectors for spectral analysis of cavitation signals, and a needle hydrophone placed beyond the HIFU focus was used to record changes in the pressure amplitude due to blockage by bubbles at or near the focus. B‐mode imaging scans were employed to visualize bubble presence during sonication. Forward and reverse electrical powers also were measured. Temperature traces obtained at various pressure levels demonstrated a wide range of heating profiles in the TMM due to the occurrence of cavitation. Hydrophone and reflected power signals varied with focal pressure, and the signals could be correlated with suspected cavitation‐induced anomalies of the temperature profile as well as B‐mode images. Of the several methods studied for detecting cavitation, both the needle hydrophone and electrical power measurements were convenient adjuncts to spectral analysis for evaluating cavitation activity in the TMM.

The targets of therapeutic ultrasound are often located behind strongly scattering objects and layered tissue. These inhomogeneities can degrade the intended foci and misdirect acoustic energy causing unwanted hot spots or failure to meet the therapeutic endpoint at the target. We have previously shown the capabilities of dual‐mode ultrasound arrays (DMUAs) in imaging strongly scattering objects in the path of the HIFU beam and, consequently, refocusing the beam to optimize the power deposition at the target while minimizing direct exposure to the obstacles. This capability may be a key to successful transthoracic targeting of abdominal tumors. We have experimentally verified the efficacy of this approach in improving the quality of the therapeutic focus and minimizing collateral damage to critical tissue structures in the path of the HIFU beam. In order to study the phenomena associated with transthoracic focusing more thoroughly, we have developed a finite‐difference time‐domain simulation capable of characterizing the transient propagation of the therapeutic beam through inhomogeneous, attenuating media. This simulation is shown to provide the necessary information for aberration correction of deep seated foci as well as control over the acoustic field at select points. In addition, the FDTD simulation allows for computation of the temperature rise throughout the therapeutic region as governed by the transient bioheat transfer equation. We have validated the predictive abilities of our simulation with hydrophone measurements as well as thermocouple readings from within tissue mimicking phantoms. The experimental validation of the simulation model allows for its use as a key component in treatment planning of thermal therapy using HIFU. Experimental and simulation results demonstrating the role of the advantages of incorporation of the computational model in optimizing the quality of HIFU beams will be presented and discussed.

This work presents the first clinical results of the treatment of uterine fibroids using a new volumetric high‐intensity focused ultrasound (HIFU) ablation strategy. This treatment technique combines volumetric ablations using concentric circle trajectories with a binary feedback control algorithm. 13 patients have been treated so far with the proposed method with good results. The use of volumetric ablation increased the efficiency and speed of the treatment, while the binary feedback control ensured a reproducible thermal lesions size without prior knowledge of tissue specific parameters. The algorithm uses a simple and robust feedback control method that relies on rapid MR thermometry to control the HIFU exposure during the heating. The algorithm automatically modified the durations of the ablations to compensate for differences in the local ultrasound absorption and heat diffusion. This approach successfully produced consistent treated volumes with small deviations in the resulting lesion diameters. Four different trajectory sizes were used with diameters of 4 mm, 8 mm, 12 mm and 16 mm.

Previous work from our group has shown that transurethral ultrasound therapy, with a single ultrasound transducer guided by temperature feedback from a single MRI plane (slice), can be used to treat a targeted region accurately in the prostate gland. We have extended this approach to a larger, 3D, targeted volume within the prostate, using a multi‐element transducer controlled concurrently by temperature feedback from multiple imaging planes. Animals were placed supine in a 1.5 T clinical MRI, and the transurethral heating device was positioned with image guidance. A four‐element transducer (each element was 5 mm long, operating at ∼8 MHz) was rotated to treat a targeted volume around the device. Temperature maps transverse to each element were acquired during heating and used to control the acoustic power of each element and the rate of rotation of the device. T2‐weighted and contrast‐enhanced (CE) MR images were obtained pre‐ and post‐heating. Following the treatment, prostates were removed and fixed, axially sliced, stained with H&E, and digitally imaged at high‐resolution to outline boundaries of cell death. Slice alignment and image registration techniques were developed to enable quantitative comparison of the axial MRI images and matching histological sections. Prostate sections showed clear regions of coagulative necrosis, extending ∼20 mm along the urethra, which correlated well with CE MRI data and transducer length. After registration, the outer border of coagulative necrosis on H&E conformed well to the target isotherm, similar to results from our previous (single element) acute studies. These results confirm that our previous analysis techniques for a single transducer can be extended to multiple elements, and that a large volumetric ablation of the prostate gland is feasible with a high degree of accuracy.

HIFU treatment with microbubbles is investigated in the present study. It is well known that microbubbles have the potential to enhance the heating effect in an ultrasound field. In the present study, the heat produced by microbubble oscillation was used to occlude varicose veins. The heated area by HIFU irradiation was initially investigated with white‐egg gel, which denatures at over 70° C. The heated area mainly depends on the frequency of the ultrasound, the intensity at focus, and the irradiation time. The attenuation coefficient was also measured in order to confirm that attenuation at the skin is such that HIFU energy can reach the vein. Then, we conducted an animal experiment. We completely dehaired a rabbit and washed the exposed skin with soap and degassed water in order to eliminate bubbles (which interfere with the passage of ultrasound) from the boundary face. The frequency of the ultrasound was 1.7 MHz. The intensity at focus was 1,800 W/cm2, and the irradiation time was 20 s. We chose the c...

In the framework of HIFU transcranial brain therapy, it is mandatory to develop techniques capable of assessing the focusing quality and location before the treatment. Monitoring heat deposition in real time and verifying the extension of the treated area are also important steps. In this study, an imaging protocol is proposed to:1/ locate the US radiation force induced displacement in tissues and quantify the acoustic pressure at focus prior to HIFU; 2/ monitor the temperature rise during HIFU; and 3/ assess the changes in elasticity in the treated area. A 7T MRI scanner was equipped with a home‐made stereotactic frame for rats and a US focused transducer working at 1.5 MHz. Such a tool is key for the evaluation of the biological effects of HIFU on brain tissue and tumors. The proposed protocol was successfully tested on 12 rats with and without injected tumors. The accurate localization of the focal point prior to HIFU was demonstrated in vivo. Furthermore, the pressure estimation in situ allowed to acc...

New method for direct synthesis of dynamically focused acoustic field suitable for HIFU therapeutic applications is proposed. The method is based on the continuous cyclic generation of different focal patterns at optimal repetition frequency by simultaneous applying of “M” different frequency signals to “N” sectors of spherically shaped sectored transducer. The HIFU transducers comprising a spherical piezoceramic caps with back electrodes divided circumferentially into 4 regular shaped sectors were designed and tested. The sectors were simultaneously powered by 4 sinuses or burst drive signals with different frequencies from 6 dB bandwidth of the transducer. Calculation and modeling of acoustic field patterns for different transducer configurations and frequencies sets were performed. In vitro experiments on different tissues confirming the advantages of dynamical focusing method were performed.

Proton resonance frequency shift (PRFS)‐based MR thermometry is hampered by temporal field changes. Temporal changes in the susceptibility distribution lead to field changes and are therefore a possible source of errors. The susceptibility of fat, χfat, is temperature dependent, in the same order of magnitude as the temperature dependence of the chemical shift of water (0.01 ppm/° C). PRFS‐based temperature measurements may therefore be corrupted by non‐local field effects due to temperature induced susceptibility changes in fatty tissue. We performed simulations to quantify the influence of dχfat/dT on PRFS‐based MR temperature maps during thermal interventions in the breast. Susceptibility distributions were calculated for a 3D breast model without and with a stationary Gaussian temperature distribution and a maximum temperature of 57° C. Subsequently, the magnetic field was calculated in Fourier‐domain from these susceptibility distributions. Changes in the magnetic field distribution were quantified b...

Recent research has shown that beneficial therapeutic effects in soft tissues can be induced by the low power ultrasound (LPUS). For example, increasing of cells immunity to stress (among others thermal stress) can be obtained through the enhanced heat shock proteins (Hsp) expression induced by the low intensity ultrasound. The possibility to control the Hsp expression enhancement in soft tissues in vivo stimulated by ultrasound can be the potential new therapeutic approach to the neurodegenerative diseases which utilizes the known feature of cells to increase their immunity to stresses through the Hsp expression enhancement. The controlling of the Hsp expression enhancement by adjusting of exposure level to ultrasound energy would allow to evaluate and optimize the ultrasound‐mediated treatment efficiency. Ultrasonic regimes are controlled by adjusting the pulsed ultrasound waves intensity, frequency, duration, duty cycle and exposure time. Our objective was to develop the numerical model capable of pred...

Thermal ablation induced by high intensity focused ultrasound has produced promising clinical results to treat hepatocarcinoma and other liver tumors. However skin burns have been reported due to the high absorption of ultrasonic energy by the ribs. This study proposes a method to produce an acoustic field focusing on a chosen target while sparing the ribs, using the decomposition of the time‐reversal operator (DORT method). The idea is to apply an excitation weight vector to the transducers array which is orthogonal to the subspace of emissions focusing on the ribs. The ratio of the energies absorbed at the focal point and on the ribs has been enhanced up to 100‐fold as demonstrated by the measured specific absorption rates.

To prevent complications in diabetes, the proper management of blood glucose levels is essential. Previously, ultrasonic transdermal methods using a light‐weight cymbal transducer array has been studied for noninvasive methods of insulin delivery for Type‐1 diabetes and glucose level monitoring. In this study, the ultrasound systems of insulin delivery and glucose sensing have been combined by a feedback controller. This study was designed to show the feasibility of the feedback controlled ultrasound system for the noninvasive glucose control. For perspective human application, in vivo experiments were performed on large animals that have a similar size to humans. Four in vivo experiments were performed using about 200 lbs pigs. The cymbal array of 3×3 pattern has been used for insulin delivery at 30 kHz with the spatial‐peak temporal‐peak intensity (Isptp) of 100 mW/cm2. For glucose sensing, a 2×2 array was operated at 20 kHz with Isptp = 100 mW/cm2. Based on the glucose level determined by biosensors after the ultrasound exposure, the ultrasound system for the insulin delivery was automatically operated. The glucose level of 115 mg/dl was set as a reference value for operating the insulin delivery system. For comparison, the glucose levels of blood samples collected from the ear vein were measured by a commercial glucose meter. Using the ultrasound system operated by the close‐loop, feed‐back controller, the glucose levels of four pigs were determined every 20 minutes and continuously controlled for 120 minutes. In comparison to the commercial glucose meter, the glucose levels determined by the biosensor were slightly higher. The results of in vivo experiments indicate the feasibility of the feedback controlled ultrasound system using the cymbal array for noninvasive glucose sensing and insulin delivery. Further studies on the extension of the glucose control will be continued for the effective method of glucose control.