High-intensity Focused Ultrasound Sonications Research Articles

Enhancement of HIFU thermal therapy in perfused tissue models using micron-sized FTAC-stabilized PFOB-core endovascular sonosensitizers

Background High intensity focused ultrasound (HIFU) is clinically accepted for the treatment of solid tumors but remains challenging in highly perfused tissue due to the heat sink effect. Endovascular liquid-core sonosensitizers have been previously suggested to enhance the thermal energy deposition at the focal area and to lower the near-/far-field heating. We are investigating the therapeutic potential of PFOB-FTAC micro-droplets in a perfused tissue-mimicking model and postmortem excised organs. Method A custom-made in vitro perfused tissue-mimicking model, freshly excised pig kidneys (n = 3) and liver (n = 1) were perfused and subjected to focused ultrasound generated by an MR-compatible HIFU transducer. PFOB-FTAC sonosensitizers were injected in the perfusion fluid up to 0.235% v/v ratio. Targeting and on-line PRFS thermometry were performed on a 3 T MR scanner. Assessment of the fluid perfusion was performed with pulsed color Doppler in vitro and with dynamic contrast-enhanced (DCE)-MRI in excised organs. Results Our in vitro model of perfused tissue demonstrated re-usability. Sonosensitizer concentration and perfusion rate were tunable in situ. Differential heating under equivalent HIFU sonications demonstrated a dramatic improvement in the thermal deposition due to the sonosensitizers activity. Typically, the energy deposition was multiplied by a factor between 2.5 and 3 in perfused organs after the administration of micro-droplets, while DCE-MRI indicated an effective perfusion. Conclusion The current PFOB-FTAC micro-droplet sonosensitizers provided a large and sustained enhancement of the HIFU thermal deposition at the focal area, suggesting solutions for less technological constraints, lower risk for the near-/far- field heating. We also report a suitable experimental model for other MRgHIFU studies

3D-specific absorption rate estimation from high-intensity focused ultrasound sonications using the Green's function heat kernel.

To evaluate a numerical inverse Green's function method for deriving specific absorption rates (SARs) from high-intensity focused ultrasound (HIFU) sonications using tissue parameters (thermal conductivity, specific heat capacity, and mass density) and three-dimensional (3D) magnetic resonance imaging (MRI) temperature measurements. SAR estimates were evaluated using simulations and MR temperature measurements from HIFU sonications. For simulations, a "true" SAR was calculated using the hybrid angular spectrum method for ultrasound simulations. This "true" SAR was plugged into a Pennes bioheat transfer equation(PBTE) solver to provide simulated temperature maps, which were then used to calculate the SAR estimate using the presented method. Zero mean Gaussian noise, corresponding to temperature precisions between 0.1 and 2.0°C, was added to the temperature maps to simulate a variety of invivo situations. Experimental MR temperature maps from HIFU sonications in a gelatin phantom monitored with a 3D segmented echo planar imaging MRI pulse sequence were also used. To determine the accuracy of the simulated and phantom data, we reconstructed temperature maps by plugging in the estimated SAR to the PBTE solver. In both simulations and phantom experiments, the presented method was compared to two previously published methods of determining SAR, a linear and an analytical method. The presented numerical method utilized the full 3D data simultaneously, while the two previously published methods work on a slice-by-slice basis. In the absence of noise, SAR distribution estimates obtained from the simulated heating profiles match closely (within 10%) to the initial true SAR distribution. The resulting temperature distributions also match closely to the corresponding initial temperature distributions (<0.2°C RMSE). In the presence of temperature measurement noise, the SAR distributions have noise amplified by the inverse convolution process, while the resulting temperature distributions still match closely to the initial "true" temperature distributions. In general, temperature RMSE was observed to be approximately 20-30% higher than the level of the added noise. By contrast, the previously published linear method is less sensitive to noise, but significantly underpredicts the SAR. The analytic method is also less sensitive to noise and matches SAR in the central plane, but greatly underpredicts in the longitudinal direction. Similar observations are made from the phantom studies. The described numerical inverse Green's function method is very fast - at least two orders of magnitude faster than the compared methods. The presented numerical inverse Green's function method is computationally fast and generates temperature maps with high accuracy. This is true despite generally overestimating the true SAR and amplifying the input noise.

Atlas-based simulations of high-intensity focused ultrasound

In silico investigations of high-intensity focused ultrasound (HIFU) have many applications, including patient selection (determining whether a patient is a good candidate for therapy), treatment verification (determining the cause of adverse events or therapy failures), and treatment planning (determining the optimum sonication parameters before therapy). Here, we use a patient atlas to study the effects of tissue heterogeneities on HIFU sonications in the kidney and liver. The patient atlas is derived from a segmentation of digital cryosection images from the Visible Human Project run by the U.S. National Library of Medicine. For each organ, simulations were repeated under both linear and nonlinear conditions, for different driving frequencies, and for several artificial configurations. These included using a constant sound speed, constant impedance, no absorption, and without particular anatomical features (e.g., the muscle, skin, and ribs). The relative importance of absorption, reflection, refraction, nonlinearity, and frequency is described. The parallel computing requirements needed to perform these large-scale full-wave ultrasound simulations in heterogeneous and absorbing media are also discussed.

Defining the Optimal Age for Focal Lesioning in a Rat Model of Transcranial HIFU

This study aimed at determining the optimal age group for high-intensity focused ultrasound (HIFU) experiments for producing lesions in rats. Younger rats have thinner skulls, allowing for the acoustic waves to propagate easily through the skull without causing burns of the skin and brain surface. Younger rats however, have a smaller brain that can make HIFU focusing in the brain parenchyma challenging because of the focus size. In this study, we conducted transcranial HIFU sonications in rat pups of different ages (from 9 to 43 d) with a 1.5MHz MR compatible transducer. The electric power was selected to always reach a target temperature of at least 50°C in the parenchyma. The thickness of the skull and of the brain parenchyma was measured using T2-weighted MR imaging. Results showed that the thickness of the brain parenchyma increased quickly from P9 to P12, reaching 8.5 mm at P16, and then increasing gradually along with age. The skull thickness increased gradually from P9 to P26, and then more quickly after P30. The ratio between brain parenchyma thickness and skull thickness decreased gradually with age. For the pups at 30 d, the temperature in the brain tissue adjacent to the skull increased to 48.9°C, and those from the rodents older than 33 d reached 60°C or higher, which can produce undesired irreversible damage in this location. We conclude that young rats aged 16–26 d are optimal for experiments producing transcranial HIFU lesions in rats with an intact skull.

Suitability of a tumour-mimicking material for the evaluation of high-intensity focused ultrasound ablation under magnetic resonance guidance

This study tests the suitability of a tumour-mimic for targeting magnetic resonance (MR)-guided high-intensity focused ultrasound (HIFU). An agarose-based tumour-mimic was injected as a warm solution that polymerized in tissue. Thermal characteristics and acoustic absorption of the mimic were observed within the values reported for tissues. The relaxation times at 3T were 1679 ± 15 ms for T1 and 41 ± 1 ms for T2. The mimic was clearly visible on T1-weighted images. With lower contrast the tumour-mimic was visible on T2-weighted images, where it was possible to detect the ablated tissue surrounding the mimic after sonications. HIFU sonications were performed to induce thermal ablation on and around the mimic using a Sonalleve system (Philips). MR thermometry maps were performed during HIFU. The average temperature when the sonication was done at the tumour-mimic was 67.6 ± 8.0 °C in vitro and 67.6 ± 5.0 °C in vivo. The average temperature for sonications at tissues was 68.4 ± 8.7 °C in vitro (liver) and 66.0 ± 2.6 °C in vivo (muscle), with no significant difference between tissue and tumour-mimic (p > 0.05). The tumour-mimic behaviour when using MR-guided HIFU was similar to tissues, showing that this mimic can be used as an alternative to tumour models for validating MR-guided HIFU devices targeting.

Monitoring of thermal therapy based on shear modulus changes: II. Shear wave imaging of thermal lesions

The clinical applicability of high-intensity focused ultrasound (HIFU) for noninvasive therapy is currently hampered by the lack of robust and real-time monitoring of tissue damage during treatment. The goal of this study is to show that the estimation of local tissue elasticity from shear wave imaging (SWI) can lead to a precise mapping of the lesion. HIFU treatment and monitoring were respectively performed using a confocal setup consisting of a 2.5-MHz single element transducer focused at 34 mm on ex vivo samples and an 8-MHz ultrasound diagnostic probe. Ultrasound-based strain imaging was combined with shear wave imaging on the same device. The SWI sequences consisted of 2 successive shear waves induced at different lateral positions. Each wave was created with pushing beams of 100 μs at 3 depths. The shear wave propagation was acquired at 17,000 frames/s, from which the elasticity map was recovered. HIFU sonications were interleaved with fast imaging acquisitions, allowing a duty cycle of more than 90%. Thus, elasticity and strain mapping was achieved every 3 s, leading to real-time monitoring of the treatment. When thermal damage occurs, tissue stiffness was found to increase up to 4-fold and strain imaging showed strong shrinkages that blur the temperature information. We show that strain imaging elastograms are not easy to interpret for accurate lesion characterization, but SWI provides a quantitative mapping of the thermal lesion. Moreover, the concept of shear wave thermometry (SWT) developed in the companion paper allows mapping temperature with the same method. Combined SWT and shear wave imaging can map the lesion stiffening and temperature outside the lesion, which could be used to predict the eventual lesion growth by thermal dose calculation. Finally, SWI is shown to be robust to motion and reliable in vivo on sheep muscle.

Monitoring of thermal therapy based on shear modulus changes: I. shear wave thermometry

The clinical applicability of high-intensity focused ultrasound (HIFU) for noninvasive therapy is today hampered by the lack of robust and real-time monitoring of tissue damage during treatment. The goal of this study is to show that the estimation of local tissue elasticity from shear wave imaging (SWI) can lead to the 2-D mapping of temperature changes during HIFU treatments. This new concept of shear wave thermometry is experimentally implemented here using conventional ultrasonic imaging probes. HIFU treatment and monitoring were, respectively, performed using a confocal setup consisting of a 2.5-MHz single-element transducer focused at 30 mm on ex vivo samples and an 8-MHz ultrasound diagnostic probe. Thermocouple measurements and ultrasound-based thermometry were used as a gold standard technique and were combined with SWI on the same device. The SWI sequences consisted of 2 successive shear waves induced at different lateral positions. Each wave was created using 100-μs pushing beams at 3 depths. The shear wave propagation was acquired at 17,000 frames/s, from which the elasticity map was recovered. HIFU sonications were interleaved with fast imaging acquisitions, allowing a duty cycle of more than 90%. Elasticity and temperature mapping was achieved every 3 s, leading to realtime monitoring of the treatment. Tissue stiffness was found to decrease in the focal zone for temperatures up to 43°C. Ultrasound-based temperature estimation was highly correlated to stiffness variation maps (r² = 0.91 to 0.97). A reversible calibration phase of the changes of elasticity with temperature can be made locally using sighting shots. This calibration process allows for the derivation of temperature maps from shear wave imaging. Compared with conventional ultrasound-based approaches, shear wave thermometry is found to be much more robust to motion artifacts.

Real‐time volumetric MRI thermometry of focused ultrasound ablation in vivo: a feasibility study in pig liver and kidney

MR thermometry offers the possibility to precisely guide high-intensity focused ultrasound (HIFU) for the noninvasive treatment of kidney and liver tumours. The objectives of this study were to demonstrate therapy guidance by motion-compensated, rapid and volumetric MR temperature monitoring and to evaluate the feasibility of MR-guided HIFU ablation in these organs. Fourteen HIFU sonications were performed in the kidney and liver of five pigs under general anaesthesia using an MR-compatible Philips HIFU platform prototype. HIFU sonication power and duration were varied. Volumetric MR thermometry was performed continuously at 1.5 T using the proton resonance frequency shift method employing a multi-slice, single-shot, echo-planar imaging sequence with an update frequency of 2.5 Hz. Motion-related suceptibility artefacts were compensated for using multi-baseline reference images acquired prior to sonication. At the end of the experiment, the animals were sacrificed for macroscopic and microscopic examinations of the kidney, liver and skin. The standard deviation of the temperature measured prior to heating in the sonicated area was approximately 1 °C in kidney and liver, and 2.5 °C near the skin. The maximum temperature rise was 30 °C for a sonication of 1.2 MHz in the liver over 15 s at 300 W. The thermal dose reached the lethal threshold (240 CEM(43) ) in two of six cases in the kidney and four of eight cases in the liver, but remained below this value in skin regions in the beam path. These findings were in agreement with histological analysis. Volumetric thermometry allows real-time monitoring of the temperature at the target location in liver and kidney, as well as in surrounding tissues. Thermal ablation was more difficult to achieve in renal than in hepatic tissue even using higher acoustic energy, probably because of a more efficient heat evacuation in the kidney by perfusion.

A method for MRI guidance of intercostal high intensity focused ultrasound ablation in the liver

High intensity focused ultrasound (HIFU) is a promising method for the noninvasive treatment of liver tumors. However, the presence of ribs in the HIFU beam path remains problematic since it may lead to adverse effects (skin burns) by absorption and reflection of the incident beam at or near the bone surface. This article presents a method based on magnetic resonance (MR) imaging for identification of the ribs in the HIFU beam, and for selection of the transducer elements to deactivate. The ribs are visualized on anatomical images acquired prior to heating and manually segmented. The resulting regions of interest surrounding the ribs are projected onto the transducer surface by ray tracing from the focal point. The transducer elements in the "shadow" of the ribs are then deactivated. The method was validated ex vivo and in vivo in pig liver during breathing under multislice real-time MR thermometry, using the proton resonance frequency shift method. Ex vivo and in vivo temperature data showed that the temperature increase near the ribs was substantial when HIFU sonications were performed with all elements active, whereas the temperature was reduced with deactivation of the transducer elements located in front of the ribs. The temperature at the focal point was similar with and without deactivation of the transducer elements, indicative of no loss of heat efficiency with the proposed technique. This method is simple, rapid, and reliable, and enables intercostal HIFU ablation while sparing ribs and their surrounding tissues.

The Correlation Between Bubble-Enhanced HIFU Heating and Cavitation Power

It has been established that while the inherent presence of bubbles increases heat generation due to scattering and absorption, inertial cavitation is responsible for elevated heating during high-intensity focused ultrasound (HIFU) application. The contribution of bubble-induced heating can be an important factor to consider, as it can be several times greater than the expected heat deposition from absorption of energy from the primary ultrasound field. The temperature and cavitation signal near the focus were measured for 5.5-s continuous-wave 1.1-MHz HIFU sonications in tissue mimicking phantoms. The measured temperature was corrected for heating predicted from the primary ultrasound absorption to isolate the temperature rise from the bubble activity. The temperature rise induced from cavitation correlates well with a measurement of the instantaneous "cavitation power" as indicated by the mean square voltage output of a 15-MHz passive cavitation detector. The results suggest that careful processing of the cavitation signals can serve as a proxy for measuring the heating contribution from inertial cavitation.