Purpose In magnetic resonance-guided focused ultrasound (MRgFUS) breast therapies, the focal location must be characterized to guide successful treatment. Focal characterization is difficult because heterogeneous breast tissues introduce phase aberrations that blur and shift the focus and traditional guidance methods do not work in adipose tissues. The purpose of this work is to evaluate numerical simulations of MRgFUS that predict the focal location. Those simulations are compared to clinical magnetic resonance acoustic radiation force imaging (MR-ARFI) data collected during in vivo treatment of breast tumors.Methods The focal location was evaluated before MRgFUS treatment with MR-ARFI in five patients. The hybrid angular spectrum method (HAS) was applied to simulate pressure fields which were converted to forces, then convolved with a 3D Green’s function (with time-of-arrival weighting) to produce a simulation of the MR-ARFI tissue displacement.Results The focal locations found by the simulations and the MR-ARFI measurements were on average separated by 3.7 mm (SD: 0.9 mm). Characterization of the focal zone spatial distributions had a normalized root mean squared difference of 8.1% (SD: 2.5%). The displacement magnitudes of the simulations underestimated the MR-ARFI measurements by 82% (SD: 5.6%).Conclusions The agreement between MR-ARFI measurements and simulations demonstrates that HAS can predict the in vivo focal location in heterogeneous tissues, though accurate patient-specific properties are needed to improve predictions of tissue displacement magnitude. Tools developed in this study could be used to streamline MRgFUS treatment planning and optimization, for biomechanical property estimation, and in developing phase aberration correction techniques.

Nitinol, a shape memory alloy, has shown immense promise and utility in biomedical engineering with its remarkable biocompatibility and corrosion resistance. Most biomedical applications rely on Nitinol's superelasticity rather than its hysteretic properties, otherwise known as its shape memory. The aim of this research is to determine if local heating from focused ultrasound could be used to induce the shape memory effect of Nitinol safely and non-invasively for biomedical applications deep within the body. Specifically, Nitinol's shape memory properties and focused ultrasound's precise and localized heating in deep tissues could be utilized for non-invasive actuation and slow deployment of stents in the treatment of peripheral artery disease, which affects approximately 21 million Americans today. This approach could reduce the risk of in-stent restenosis, a consequence of injury to arterial walls caused by the traditionally rapid deployment of stents. The current study investigates whether focused ultrasound can actuate a tight coil of Nitinol (representing a simple stent) under experimental conditions that mimic in vivo conditions. Results demonstrate that focused ultrasound-induced actuation of Nitinol stents in deep vessels under physiological conditions is a possibility. Precise positioning and control of the stent and ultrasound transducer will be necessary to achieve stent actuation at power levels that prevent thermal damage to surrounding healthy tissues.

High-intensity focused ultrasound (HIFU) thermal therapies utilize concentrated sound waves to ablate diseased tissue at precise locations within the body. Computational simulations of HIFU can assist clinicians by predicting the death of target tissues, identifying sensitive healthy tissues that risk thermal damage, and optimizing acoustic power delivery to minimize treatment times and maximize treatment efficacy. Accurate simulations require accurate inputs, and many computational solvers neglect property changes induced by tissue heating during treatment. Additionally, temperature-dependent tissue property data in the literature are relatively scarce. This study presents methodology for characterizing temperature-dependent acoustic and thermal properties in ex vivo porcine muscle tissue. From 20 – 50 °C, speed of sound is found to increase from approximately 1580 – 1620 m/s. The acoustic attenuation coefficient increases for 20 – 50 °C from 0.09 – 0.24 Np/cm at 0.5 MHz and 0.16 – 0.37 Np/cm at 1.6 MHz. Thermal conductivity and thermal diffusivity increase from 0.52 – 0.55 W/m °C and 0.147 – 0.158 mm2/s, respectively, over 20 – 60 °C. Specific heat capacity increases from approximately 3500 – 3800 J/kg °C, over 20 – 80 °C. Each property is consistent with data found in the literature, extends the literature to a larger temperature range, and, for acoustic properties, extends to unique frequencies. Temperature-dependent predictive models are also developed for each of the five properties. This study’s property measurement methodologies can be used to characterize other biological tissues, and the predictive models developed herein will facilitate future efforts in temperature-dependent modeling and uncertainty quantification of HIFU thermal therapies.

Nitinol (NiTi) shape memory alloy exhibits excellent characteristics for use in biomedical engineering. The material has excellent biocompatibility, corrosion resistance, and wear characteristics, which has increased its use in biomedical applications, including stents and guidewires. While NiTi is becoming more common in medical procedures, most of the use has relied on the superelasticity of the wire, rather than its hysteretic qualities. One reason for this is the difficulty in heating NiTi wire in situ, without damaging adjacent tissue. This research explores the use of focused ultrasound to noninvasively heat NiTi wire above its transition temperature. To demonstrate the memory effect, the wire is strained at low temperature, then placed between porcine muscle samples to mimic an in situ biological environment. Using focused ultrasound, the wire is heated until the NiTi actuates and its shape memory is recovered. Embedded thermocouples located close to the wire measure the local temperature. The study found that higher ultrasonic power resulted in (1) faster actuation of the Nitinol, (2) more complete Nitinol actuation, and (3) lower temperatures in the surrounding tissue with less thermal damage.

Purpose Magnetic resonance guided focused ultrasound (MRgFUS) treatment of tumors uses inter-sonication delays to allow heat to dissipate from the skin and other near-field tissues. Despite inter-sonication delays, treatment of tumors close to the skin risks skin burns. This work has designed and evaluated an open-source, conformable, skin-cooling system for body MRgFUS treatments to reduce skin burns and enable ablation closer to the skin. Methods A MR-compatible skin cooling system is described that features a conformable skin-cooling pad assembly with feedback control allowing continuous flow and pressure maintenance during the procedure. System performance was evaluated with hydrophone, phantom and in vivo porcine studies. Sonications were performed 10 and 5 mm from the skin surface under both control and forced convective skin-cooling conditions. 3D MR temperature imaging was acquired in real time and the accumulated thermal dose volume was measured. Gross analysis of the skin post-sonication was further performed. Device conformability was demonstrated at several body locations. Results Hydrophone studies demonstrated no beam aberration, but a 5–12% reduction of the peak pressure due to the presence of the skin-cooling pad assembly in the acoustic near field. Phantom evaluation demonstrated there is no MR temperature imaging precision reduction or any other artifacts present due to the coolant flow during MRgFUS sonication. The porcine studies demonstrated skin burns were reduced in size or eliminated when compared to the control condition. Conclusion An open-source design of an MRgFUS active skin cooling system demonstrates device conformability with a reduction of skin burns while ablating superficial tissues.

The adverse event of skin burns and the restrictions caused by multi-hour treatment times continue to limit the clinical efficacy and cost effectiveness of MRgFUS thermal therapies. This proposal directly addresses these unmet needs with two primary aims. Aim 1 includes design and fabrication of a prototype cooling device, testing of clinically identified design specifications, and initial experimental validation ex vivo tissue experiments. This conformable skin-cooling device will reduce the potential for skin burns in desmoid tumor and other MRgFUS treatments. Aim 2 will assess the skin cooling device on a pre-clinical MRgFUS system with rabbit and pig studies and will integrate the device with the clinical ExAblate 2100 system. The ultimate goal of the device design is to be MRgFUS system independent. This may require a modular design that allows for both clinical and veterinarian applications. The completion of this proposal will deliver the engineering schematic, parts list and use manual of the completed device, validation data and install a single device at the Focused Ultrasound Center of Excellence at Stanford University.Presented here are the open-source parts list and assembly files to reproduce the skin cooling device, along with the device user manual. An open-access publication on the design methods and preclinical results will be published soon.

PURPOSE:Treating uterine fibroids with less invasive therapies such as magnetic resonance-guided focused ultrasound (MRgFUS) is an attractive alternative to surgery. Treatment planning can improve MRgFUS procedures and reduce treatment times, but the tissue properties that currently inform treatment planning tools are not adequate. This study aims to develop an ex vivo uterine fibroid model that can emulate the in vivo environment allowing for characterization of the uterus and fibroid MR, acoustic, and thermal tissue properties while maintaining viability for the necessary postsurgical histopathological assessments. METHODS:Women undergoing a hysterectomy due to fibroid-related symptoms were invited to undergo a preoperative pelvic MRI and to permit postoperative testing of their uterine specimen. Patients that declined or could not be scheduled for a pre-operative MRI were still able to allow post-operative testing of their excised tissue. Following surgical removal of the uterus, nonmorcellated tissues were reperfused with a Krebs-Henseleit buffer solution. An MR-compatible perfusion system was designed to maintain tissue viability inside the MR suite during scanning. MR imaging protocols utilized preoperatively were repeated on whole sample, reperfused ex vivo uterus specimens. Thermal properties including thermal diffusivity and thermal conductivity of the uterus and fibroids were determined using an invasive needle sensor device in 50% of the specimens. Acoustic property measurements (density, speed of sound and attenuation) were obtained for approximately 20% of the tissue samples using both through-transmission and radiation force balance techniques. Differences between fibroid and uterus and in vivo and ex vivo measurements were evaluated with a two-tailed Student t test. RESULTS:Fourteen patients participated in the study and measurements were obtained from 22 unique fibroids. Of the 16 fibroids available for preoperative MRI testing, 69% demonstrated classic hypo-intensity relative to the myometrium, with the remainder presenting with iso- (25%) or hyper-intensity (6%). While thermal diffusivity was not significantly different between fibroid and myometrium tissues (0.217 ± 0.047 and 0.204 ± 0.039 mm2 /s, respectively), the acoustic attenuation in fibroid tissue was significantly higher than myometrium (0.092 ± 0.021 and 0.052 ± 0.023 Np/cm/MHz, respectively). When comparing in vivo with ex vivo MRI T1 and T2 measurements in fibroids and myometrium tissue, the only difference was found in the fibroid T2 property (P < 0.05). Finally, the developed perfusion protocol successfully maintained tissue viability in ex vivo tissues as evaluated through histological analysis. CONCLUSIONS:This study developed an MR-compatible extracorporeal perfusion technique that effectively maintains tissue viability, allowing for the direct measurement of patient-specific MR, thermal, and acoustic property values for both fibroid and myometrium tissues. These measured tissue property values will enable further development and validation of treatment planning models that can be utilized during MRgFUS uterine fibroid treatments.

Purpose: This study validates that phase aberrations in breast magnetic resonance-guided focussed ultrasound (MRgFUS) therapies can be corrected in a clinically relevant time frame to generate more intense, smaller and more spatially accurate foci.Materials and methods: Hybrid angular spectrum (HAS) ultrasound calculations in an magnetic resonance imaging (MRI)-based tissue model, were used to compute phase aberration corrections for improved experimental MRgFUS heating in four heterogeneous breast-mimicking phantoms (n=18 total locations). Magnetic resonance(MR) temperature imaging was used to evaluate the maximum temperature rise, focus volume and focus accuracy for uncorrected and phase aberration-corrected sonications. Thermal simulations assessed the effectiveness of the phase aberration correction implementation.Results: In 13 of 18 locations, the maximum temperature rise increased by an average of 30%, focus volume was reduced by 40% and focus accuracy improved from 4.6 to 3.6mm. Mixed results were observed in five of the 18 locations, with focus accuracy improving from 6.1 to 2.5mm and the maximum temperature rise decreasing by 8% and focus volume increasing by 10%. Overall, the study demonstrated significant improvements (p<0.005) in maximum temperature rise, focus volume and focus accuracy. Simulations predicted greater improvements than observed experimentally, suggesting potential for improvement in implementing the technique. The complete phase aberration correction procedure, including model generation, segmentation and phase aberration computations, required less than 45min per sonication location.Conclusion: The significant improvements demonstrated in this study i.e., focus intensity, size and accuracy from phase aberration correction have the potential to improve the efficacy, time-efficiency and safety of breast MRgFUS therapies.

It is still not known which mode of ultrasound action - thermal or mechanical - plays the predominant role in ultrasound mediated drug delivery. This project will combine results from two powerful imaging modalities, MRI and RFP imaging, to better understand and quantify the major effects. Several experimental variables will be tested in vivo using RFP-transfected pancreatic cancer MiaPaCa2 subcutaneous tumors grown in nude mice, providing information to better understand the mechanisms involved in ultrasound-mediated drug delivery.

In focused ultrasound (FUS) thermal ablation of diseased tissue, acoustic beam and thermal simulations enable treatment planning and optimization. In this study, a treatment-planning methodology that uses the hybrid angular spectrum (HAS) method and the Pennes' bioheat equation (PBHE) is experimentally validated in homogeneous tissue-mimicking phantoms. Simulated three-dimensional temperature profiles are compared to volumetric MR thermometry imaging (MRTI) of FUS sonications in the phantoms, whose acoustic and thermal properties are independently measured. Additionally, Monte Carlo (MC) uncertainty analysis is performed to quantify the effect of tissue property uncertainties on simulation results. The mean error between simulated and experimental spatiotemporal peak temperature rise was +0.33°C (+6.9%). Despite this error, the experimental temperature rise fell within the expected uncertainty of the simulation, as determined by the MC analysis. The average errors of the simulated transverse and longitudinal full width half maximum (FWHM) of the profiles were -1.9% and 7.5%, respectively. A linear regression and local sensitivity analysis revealed that simulated temperature amplitude is more sensitive to uncertainties in simulation inputs than in the profile width and shape. Acoustic power, acoustic attenuation and thermal conductivity had the greatest impact on peak temperature rise uncertainty; thermal conductivity and volumetric heat capacity had the greatest impact on FWHM uncertainty. This study validates that using the HAS and PBHE method can adequately predict temperature profiles from single sonications in homogeneous media. Further, it informs the need to accurately measure or predict patient-specific properties for improved treatment planning of ablative FUS surgeries.

Purpose: To construct a predictive model that describes how the duration and symmetry of a k-space-weighted image contrast (KWIC) window affects the temporal resolution of differently sized ultrasound foci when using a pseudo-golden angle stack-of-stars acquisition. Methods: We performed a modulation analysis of proton resonance frequency temperature measurements to create the temporal modulation transfer function for KWIC windows of different symmetry and temporal duration. We reconstructed simulated ultrasound heating trajectories and stack-of-stars k-space data as well as experimental phantom data using the same trajectories. Images were reconstructed using symmetric and asymmetric KWIC windows of 3 different temporal durations. Simulated results were compared against temporal modulation transfer function predictions, experimental results, and the original simulated temperatures. Results: The temporal modulation transfer function shows that temporal resolution with KWIC reconstructions depend on the object size. The KWIC window duration affected SNR and severity of undersampling artifacts. Accuracy and response delay improved as the KWIC window duration decreased or the size of the heated region within the KWIC plane increased. Precision worsened as the window duration decreased. Using a symmetric window eliminated the response delay to heated region size but introduced a large reconstruction delay. Conclusion: The accuracy and precision of proton resonance frequency temperature measurements from a stack-of-stars acquisition using a sliding KWIC window reconstruction are dependent on the size of the KWIC window and the size and shape of the heated region. The temporal modulation transfer function of KWIC reconstructions for any object size can predict the temporal response to changes in signal being acquired, such as temperature and contrast enhancement.

Overcoming the resistant to change - is there a strategy that could bring all the different stakeholders to combine and align efforts?

Abstract Purpose: This study investigates the feasibility of non-invasively determining thermal diffusivity (α) and the Pennes perfusion parameter (w) from pre-clinical and clinical magnetic resonance-guided focussed ultrasound (MRgFUS) temperature data. Materials and methods: Pre-clinical MRgFUS experiments were performed in rabbit muscle (N = 3, 28 sonications) using three-dimensional MR thermometry. Eight sonications were made in a clinical QA phantom with two-dimensional thermometry. Retrospective property determination was performed on clinical uterine fibroid (N = 8, 9 sonications) and desmoid tumour (N = 4, 7 sonications) data. The property determination method fits an analytical solution to MRgFUS temperatures in the coronal MR plane, including all temperatures acquired during heating and one cooling image. When possible, additional cooling data were acquired for property determination. Results: Rabbit α and w from Heating Data (α = 0.164 mm2s−1, w = 7.9 kg m−3 s−1) and Heating and Cooling Data (α = 0.146 mm2s−1, w = 3.3 kg m−3 s−1) were within the range of gold-standard invasive measurements, with >50% reduction in variability by including cooling data. QA phantom property determination with cooling data yielded properties within 3% of expected values (α = 0.144 mm2s−1, w = 0.0 kg m−3 s−1), a difference that was not statistically significant (p = 0.053). Uterine fibroid (Heating Data: α = 0.212 mm2s−1, w = 11.0 kg m−3 s−1) and desmoid tumour (Heating & Cooling Data: α = 0.245 mm2s−1, w = 4.7 kg m−3 s−1) properties are feasible but lack independent verification. Conclusions: Thermal diffusivity and the Pennes perfusion parameter can be obtained from in vivo data and with clinical MRgFUS protocols. Property values are consistently improved by including cooling data. The utility of this property determination method will increase as clinical protocols implement improved temperature imaging.

This study evaluates the sensitivity of two magnetic resonance-guided focused ultrasound (MRgFUS) thermal property estimation methods to errors in required inputs and different data inclusion criteria. Using ex vivo pork muscle MRgFUS data, sensitivities to required inputs are determined by introducing errors to ultrasound beam locations (rerror = −2 to 2 mm) and time vectors (terror = −2.2 to 2.2 s). In addition, the sensitivity to user-defined data inclusion criteria is evaluated by choosing different spatial (rfit = 1–10 mm) and temporal (tfit = 8.8–61.6 s) regions for fitting. Beam location errors resulted in up to 50% change in property estimates with local minima occurring at rerror = 0 and estimate errors less than 10% when rerror < 0.5 mm. Errors in the time vector led to property estimate errors up to 40% and without local minimum, indicating the need to trigger ultrasound sonications with the MR image acquisition. Regarding the selection of data inclusion criteria, property estimates reached stable values (less than 5% change) when rfit > 2.5 × FWHM, and were most accurate with the least variability for longer tfit. Guidelines provided by this study highlight the importance of identifying required inputs and choosing appropriate data inclusion criteria for robust and accurate thermal property estimation. Applying these guidelines will prevent the introduction of biases and avoidable errors when utilizing these property estimation techniques for MRgFUS thermal modeling applications.

Axial T1 projection showing the relation of VIM target 3 mm medial and anterior to pyramidal tract and medial lemniscus respectively

MR-guided high-intensity focussed ultrasound (MRgHIFU) non-invasive ablative surgeries have advanced into clinical trials for treating many pathologies and cancers. A remaining challenge of these surgeries is accurately planning and monitoring tissue heating in the face of patient-specific and dynamic acoustic properties of tissues. Currently, non-invasive measurements of acoustic properties have not been implemented in MRgHIFU treatment planning and monitoring procedures. This methods-driven study presents a technique using MR temperature imaging (MRTI) during low-temperature HIFU sonications to non-invasively estimate sample-specific acoustic absorption and speed of sound values in tissue-mimicking phantoms. Using measured thermal properties, specific absorption rate (SAR) patterns are calculated from the MRTI data and compared to simulated SAR patterns iteratively generated via the Hybrid Angular Spectrum (HAS) method. Once the error between the simulated and measured patterns is minimised, the estimated acoustic property values are compared to the true phantom values obtained via an independent technique. The estimated values are then used to simulate temperature profiles in the phantoms, and compared to experimental temperature profiles. This study demonstrates that trends in acoustic absorption and speed of sound can be non-invasively estimated with average errors of 21% and 1%, respectively. Additionally, temperature predictions using the estimated properties on average match within 1.2 °C of the experimental peak temperature rises in the phantoms. The positive results achieved in tissue-mimicking phantoms presented in this study indicate that this technique may be extended to in vivo applications, improving HIFU sonication temperature rise predictions and treatment assessment.

Purpose:This simulation study evaluates the effects of phase aberration in breast MR‐guided focused ultrasound (MRgFUS) ablation treatments performed with a phased‐array transducer positioned laterally to the breast. A quantification of these effects in terms of thermal dose delivery and the potential benefits of phase correction is demonstrated in four heterogeneous breast numerical models.Methods:To evaluate the effects of varying breast tissue properties on the quality of the focus, four female volunteers with confirmed benign fibroadenomas were imaged using 3T MRI. These images were segmented into numerical models with six tissue types, with each tissue type assigned standard acoustic properties from the literature. Simulations for a single‐plane 16‐point raster‐scan treatment trajectory centered in a fibroadenoma in each modeled breast were performed for a breast‐specific MRgFUS system. At each of the 16 points, pressure patterns both with and without applying a phase correction technique were determined with the hybrid‐angular spectrum method. Corrected phase patterns were obtained using a simulation‐based phase aberration correction technique to adjust each element's transmit phase to obtain maximized constructive interference at the desired focus. Thermal simulations were performed for both the corrected and uncorrected pressure patterns using a finite‐difference implementation of the Pennes bioheat equation. The effect of phase correction was evaluated through comparison of thermal dose accumulation both within and outside a defined treatment volume. Treatment results using corrected and uncorrected phase aberration simulations were compared by evaluating the power required to achieve a 20 °C temperature rise at the first treatment location. The extent of the volumes that received a minimum thermal dose of 240 CEM at 43 °C inside the intended treatment volume as well as the volume in the remaining breast tissues was also evaluated in the form of a dose volume ratio (DVR), a DVR percent change between corrected and uncorrected phases, and an additional metric that measured phase spread.Results:With phase aberration correction applied, there was an improvement in the focus for all breast anatomies as quantified by a reduction in power required (13%–102%) to reach 20 °C when compared to uncorrected simulations. Also, the DVR percent change increased by 5%–77% in seven out of eight cases, indicating an improvement to the treatment as measured by a reduction in thermal dose deposited to the nontreatment tissues. Breast compositions with a higher degree of heterogeneity along the ultrasound beam path showed greater reductions in thermal dose delivered outside of the treatment volume with correction applied than beam trajectories that propagated through more homogeneous breast compositions. An increasing linear trend was observed between the DVR percent change and the phase‐spread metric (R2 = 0.68).Conclusions:These results indicate that performing phase aberration correction for breast MRgFUS treatments is beneficial for the small‐aperture transducer (14.4 × 9.8 cm) evaluated in this work. While all breast anatomies could benefit from phase aberration correction, greater benefits are observed in more heterogeneous anatomies.

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.

For thermal modeling to play a significant role in treatment planning, monitoring, and control of magnetic resonance-guided focused ultrasound (MRgFUS) thermal therapies, accurate knowledge of ultrasound and thermal properties is essential. This study develops a new analytical solution for the temperature change observed in MRgFUS which can be used with experimental MR temperature data to provide estimates of the ultrasound initial heating rate, Gaussian beam variance, tissue thermal diffusivity, and Pennes perfusion parameter. Simulations demonstrate that this technique provides accurate and robust property estimates that are independent of the beam size, thermal diffusivity, and perfusion levels in the presence of realistic MR noise. The technique is also demonstrated in vivo using MRgFUS heating data in rabbit back muscle. Errors in property estimates are kept less than 5% by applying a third order Taylor series approximation of the perfusion term and ensuring the ratio of the fitting time (the duration of experimental data utilized for optimization) to the perfusion time constant remains less than one.