Catheter-based ultrasound technology for image-guided thermal therapy: Current technology and applications

Catheter-based ultrasound (CBUS) is applied to deliver minimally invasive thermal therapy to solid cancer tumours, benign tissue growth, vascular disease, and tissue remodelling. Compared to other energy modalities used in catheter-based surgical interventions, unique features of ultrasound result in conformable and precise energy delivery with high selectivity, fast treatment times, and larger treatment volumes. We present a concise review of CBUS technology being currently utilized in animal and clinical studies or being developed for future applications. CBUS devices have been categorised into interstitial, endoluminal and endovascular/cardiac applications. Basic applicator designs, site-specific evaluations and possible treatment applications have been discussed in brief. Particular emphasis has been given to ablation studies that incorporate image guidance for applicator placement, therapy monitoring, feedback control, and post-procedure assessment. Examples of devices included here span the entire spectrum of the development cycle from preliminary simulation-based design studies to implementation in clinical investigations. The use of CBUS under image guidance has the potential for significantly improving precision and applicability of thermal therapy delivery

MR thermometry-guided ultrasound hyperthermia of user-defined regions using the ExAblate prostate ablation array.

BackgroundHyperthermia therapy (HT) has shown to be an effective adjuvant to radiation, chemotherapy, and immunotherapy. In order to be safe and effective, delivery of HT requires maintenance of target tissue temperature within a narrow range (40-44 °C) for 30-60 min, which necessitates conformal heat delivery and accurate temperature monitoring. The goal of this project was to develop an MR thermometry-guided hyperthermia delivery platform based upon the ExAblate prostate array that would achieve uniform stable heating over large volumes within the prostate, while allowing the user to precisely control the power deposition patterns and shape of the region of treatment (ROT).MethodsThe HT platform incorporates an accelerated multi-slice real time MR thermometry pulse sequence and reconstruction pipeline. Temperature uniformity over a large contiguous area was achieved by multi-point temperature sampling with multi-focal feedback power control. The hyperthermia delivery system was based on an InSightec ExAblate 2100 prostate focused ultrasound ablation system, and HeartVista's RTHawk real-time MRI system integrated with a 3 T MRI scanner. The integrated system was evaluated in experiments with a tissue-mimicking phantom for prolonged exposures with a target temperature increase of 7 °C from baseline.ResultsFive various shapes of the region of treatment, defined on a 5 × 5 grid (35 × 35 mm, 11-25 focal spots per shape), were implemented to evaluate the performance of the system. MR temperature images, acquired after steady state was reached, showed different patterns of heating that closely matched the prescribed regions. Temperature uncertainty of the thermometry acquisition was 0.5 °C. The time to reach the target temperature (2:58-7:44 min) depended on the chosen ROT shape and on the distance from transducer to focal plane. Pre-cooling with circulating water helped to reduce near-field heating.ConclusionsWe have implemented a real-time MR thermometry-guided system for hyperthermia delivery within user-defined regions with the ExAblate prostate array and evaluated it in phantom experiments for different shapes and focal depths. Our results demonstrate the feasibility of using a commercially available endorectal FUS transducer to perform spatially-conformal hyperthermia therapy and could lead to a new set of exciting applications for these devices

Multiple applicator hepatic ablation with interstitial ultrasound devices: Theoretical and experimental investigation

PurposeTo evaluate multiple applicator implant configurations of interstitial ultrasound devices for large volume ablation of liver tumors.MethodsA 3D bioacoustic-thermal model using the finite element method was implemented to assess multiple applicator implant configurations for thermal ablation with interstitial ultrasound energy. Interstitial applicators consist of linear arrays of up to four 10 mm-long tubular ultrasound transducers, each under separate and dynamic power control, enclosed within a water-cooled delivery catheter (2.4 mm OD). The authors considered parallel implants with two and three applicators (clustered configuration), spaced 2-3 cm apart, to simulate open surgical placement. In addition, the authors considered two applicator implants with applicators converging and diverging at angles of ∼20°, 30°, and 45° to simulate percutaneous placement. Heating experiments (10-15 min) were performed and compared against simulations employing the same experimental parameters. To estimate the performance of parallel, multiple applicator configurations in an in vivo setting, simulations were performed taking into account a range of blood perfusion levels (0, 5, 12, and 15 kg m(-3) s(-1)) that may occur in tumors of varying vascularity. The impact of tailoring the power supplied to individual transducer elements along the length of applicators is explored for applicators inserted in non-parallel (converging and diverging) configurations. Thermal dose (t(43) > 240 min) and temperature thresholds (T > 52 °C) were used to define the ablation zones, with dynamic changes to tissue acoustic and thermal properties incorporated within the model.ResultsExperiments in ex vivo bovine liver yielded ablation zones ranging between 4.0-5.6 cm × 3.2-4.9 cm, in cross section. Ablation zone dimensions predicted by simulations with similar parameters to the experiments were in close agreement (within 5 mm). Simulations of in vivo heating showed that 15 min heating and interapplicator spacing less than 3 cm are required to obtain contiguous, complete ablation zones. The ability to create complete ablation zone profiles for nonparallel implants was illustrated by tailoring applied power levels along the length of applicators.ConclusionsParallel implants consisting of three interstitial ultrasound applicators in a triangular configuration yield complete ablation zones measuring up to 6.2 cm × 5.7 cm after 15 min heating. At larger interapplicator spacing, the level of blood perfusion in the tumor may yield indentations along the periphery of the ablation zone. Tailoring applied power along the length of the applicator can accommodate for nonparallel implants, without compromising safety

Thermal therapy of pancreatic tumours using endoluminal ultrasound: Parametric and patient-specific modelling

PurposeThe aim of this study is to investigate endoluminal ultrasound applicator configurations for volumetric thermal ablation and hyperthermia of pancreatic tumours using 3D acoustic and biothermal finite element models.Materials and methodsParametric studies compared endoluminal heating performance for varying applicator transducer configurations (planar, curvilinear-focused, or radial-diverging), frequencies (1-5 MHz), and anatomical conditions. Patient-specific pancreatic head and body tumour models were used to evaluate feasibility of generating hyperthermia and thermal ablation using an applicator positioned in the duodenal or stomach lumen. Temperature and thermal dose were calculated to define ablation (> 240 EM(43 °C)) and moderate hyperthermia (40-45 °C) boundaries, and to assess sparing of sensitive tissues. Proportional-integral control was incorporated to regulate maximum temperature to 70-80 °C for ablation and 45 °C for hyperthermia in target regions.ResultsParametric studies indicated that 1-3 MHz planar transducers are the most suitable for volumetric ablation, producing 5-8 cm(3) lesion volumes for a stationary 5-min sonication. Curvilinear-focused geometries produce more localised ablation to 20-45 mm depth from the GI tract and enhance thermal sparing (T(max) < 42 °C) of the luminal wall. Patient anatomy simulations show feasibility in ablating 60.1-92.9% of head/body tumour volumes (4.3-37.2 cm(3)) with dose < 15 EM(43 °C) in the luminal wall for 18-48 min treatment durations, using 1-3 applicator placements in GI lumen. For hyperthermia, planar and radial-diverging transducers could maintain up to 8 cm(3) and 15 cm(3) of tissue, respectively, between 40-45 °C for a single applicator placement.ConclusionsModelling studies indicate the feasibility of endoluminal ultrasound for volumetric thermal ablation or hyperthermia treatment of pancreatic tumour tissue

Integration of deployable fluid lenses and reflectors with endoluminal therapeutic ultrasound applicators: Preliminary investigations of enhanced penetration depth and focal gain

PurposeCatheter-based ultrasound applicators can generate thermal ablation of tissues adjacent to body lumens, but have limited focusing and penetration capabilities due to the small profile of integrated transducers required for the applicator to traverse anatomical passages. This study investigates a design for an endoluminal or laparoscopic ultrasound applicator with deployable acoustic reflector and fluid lens components, which can be expanded after device delivery to increase the effective acoustic aperture and allow for deeper and dynamically adjustable target depths. Acoustic and biothermal theoretical studies, along with benchtop proof-of-concept measurements, were performed to investigate the proposed design.MethodsThe design schema consists of an array of tubular transducer(s) situated at the end of a catheter assembly, surrounded by an expandable water-filled conical balloon with a secondary reflective compartment that redirects acoustic energy distally through a plano-convex fluid lens. By controlling the lens fluid volume, the convex surface can be altered to adjust the focal length or collapsed for device insertion or removal. Acoustic output of the expanded applicator assembly was modeled using the rectangular radiator method and secondary sources, accounting for reflection and refraction at interfaces. Parametric studies of transducer radius (1-5 mm), height (3-25 mm), frequency (1.5-3 MHz), expanded balloon diameter (10-50 mm), lens focal length (10-100 mm), lens fluid (silicone oil, perfluorocarbon), and tissue attenuation (0-10 Np/m/MHz) on beam distributions and focal gain were performed. A proof-of-concept applicator assembly was fabricated and characterized using hydrophone-based intensity profile measurements. Biothermal simulations of endoluminal ablation in liver and pancreatic tissue were performed for target depths between 2 and 10 cm.ResultsSimulations indicate that focal gain and penetration depth scale with the expanded reflector-lens balloon diameter, with greater achievable performance using perfluorocarbon lens fluid. Simulations of a 50 mm balloon OD, 10 mm transducer outer diameter (OD), 1.5 MHz assembly in water resulted in maximum intensity gain of ~170 (focal dimensions: ~12 mm length × 1.4 mm width) at ~5 cm focal depth and focal gains above 100 between 24 and 84 mm depths. A smaller (10 mm balloon OD, 4 mm transducer OD, 1.5 MHz) configuration produced a maximum gain of 6 at 9 mm depth. Compared to a conventional applicator with a fixed spherically focused transducer of 12 mm diameter, focal gain was enhanced at depths beyond 20 mm for assembly configurations with balloon diameters ≥ 20 mm. Hydrophone characterizations of the experimental assembly (31 mm reflector/lens diameter, 4.75 mm transducer radius, 1.7 MHz) illustrated focusing at variable depths between 10-70 mm with a maximum gain of ~60 and demonstrated agreement with theoretical simulations. Biothermal simulations (30 s sonication, 75 °C maximum) indicate that investigated applicator assembly configurations, at 30 mm and 50 mm balloon diameters, could create localized ellipsoidal thermal lesions increasing in size from 10 to 55 mm length × 3-6 mm width in liver tissue as target depth increased from 2 to 10 cm.ConclusionsPreliminary theoretical and experimental analysis demonstrates that combining endoluminal ultrasound with an expandable acoustic reflector and fluid lens assembly can significantly enhance acoustic focal gain and penetration from inherently smaller diameter catheter-based applicators

880 kHz ultrasound treatment for drug delivery to the vitreous humor.

Clinical management of many chronic ophthalmological disorders requires direct delivery of drugs into the vitreous. There is an important need to investigate novel needle-less alternatives to deliver drugs to the vitreous. The purpose of this study is to assess the effects of a needle-less system using ultrasound to enhance vitreal delivery of small molecules through the sclera in an ex vivo model and to evaluate whether changes in permeability are mainly due to the heat generated by sonication. An eye cup containing 1 mL of sodium fluorescein 0.1% was placed on top of the sclera of cadaveric rabbit eyes. Treated eyes were sonicated for 10 minutes, and left in contact with the fluorescein solution for an additional 50 minutes. Control eyes received the same exposure to fluorescein solution (60 minutes) in the eye cup without ultrasound treatment. Vitreous humor was collected and analyzed using a fluorescence spectrophotometer to calculate the concentration of fluorescein that diffused into the vitreous humor. An additional set of eyes was treated using a heating probe to evaluate whether changes in permeability were mainly due to heat. Vitreous samples from ultrasound-treated eyes showed a 44.6% higher concentration of fluorescein compared to control eyes. The concentration of fluorescein in the vitreous of heat-treated eyes did not show a significant difference when compared to control eyes. Thus, phonophoresis is a promising needle-less method for vitreal drug delivery, and local heating conducted to the surface of the sclera should be mitigated because it does not enhance the efficacy of the method

Model‐based feasibility assessment and evaluation of prostate hyperthermia with a commercial MR‐guided endorectal HIFU ablation array

PurposeFeasibility of targeted and volumetric hyperthermia (40-45 °C) delivery to the prostate with a commercial MR-guided endorectal ultrasound phased array system, designed specifically for thermal ablation and approved for ablation trials (ExAblate 2100, Insightec Ltd.), was assessed through computer simulations and tissue-equivalent phantom experiments with the intention of fast clinical translation for targeted hyperthermia in conjunction with radiotherapy and chemotherapy.MethodsThe simulations included a 3D finite element method based biothermal model, and acoustic field calculations for the ExAblate ERUS phased array (2.3 MHz, 2.3 × 4.0 cm(2), ∼1000 channels) using the rectangular radiator method. Array beamforming strategies were investigated to deliver protracted, continuous-wave hyperthermia to focal prostate cancer targets identified from representative patient cases. Constraints on power densities, sonication durations and switching speeds imposed by ExAblate hardware and software were incorporated in the models. Preliminary experiments included beamformed sonications in tissue mimicking phantoms under MR temperature monitoring at 3 T (GE Discovery MR750W).ResultsAcoustic intensities considered during simulation were limited to ensure mild hyperthermia (Tmax < 45 °C) and fail-safe operation of the ExAblate array (spatial and time averaged acoustic intensity ISATA < 3.4 W/cm(2)). Tissue volumes with therapeutic temperature levels (T > 41 °C) were estimated. Numerical simulations indicated that T > 41 °C was calculated in 13-23 cm(3) volumes for sonications with planar or diverging beam patterns at 0.9-1.2 W/cm(2), in 4.5-5.8 cm(3) volumes for simultaneous multipoint focus beam patterns at ∼0.7 W/cm(2), and in ∼6.0 cm(3) for curvilinear (cylindrical) beam patterns at 0.75 W/cm(2). Focused heating patterns may be practical for treating focal disease in a single posterior quadrant of the prostate and diffused heating patterns may be useful for heating quadrants, hemigland volumes or even bilateral targets. Treatable volumes may be limited by pubic bone heating. Therapeutic temperatures were estimated for a range of physiological parameters, sonication duty cycles and rectal cooling. Hyperthermia specific phasing patterns were implemented on the ExAblate prostate array and continuous-wave sonications (∼0.88 W/cm(2), 15 min) were performed in tissue-mimicking material with real-time MR-based temperature imaging (PRFS imaging at 3.0 T). Shapes of heating patterns observed during experiments were consistent with simulations.ConclusionsThe ExAblate 2100, designed specifically for thermal ablation, can be controlled for delivering continuous hyperthermia in prostate while working within operational constraints

Passive cavitation imaging with ultrasound arrays

A method is presented for passive imaging of cavitational acoustic emissions using an ultrasound array, with potential application in real-time monitoring of ultrasound ablation. To create such images, microbubble emissions were passively sensed by an imaging array and dynamically focused at multiple depths. In this paper, an analytic expression for a passive image is obtained by solving the Rayleigh–Sommerfield integral, under the Fresnel approximation, and passive images were simulated. A 192-element array was used to create passive images, in real time, from 520-kHz ultrasound scattered by a 1-mm steel wire. Azimuthal positions of this target were accurately estimated from the passive images. Next, stable and inertial cavitation was passively imaged in saline solution sonicated at 520 kHz. Bubble clusters formed in the saline samples were consistently located on both passive images and B-scans. Passive images were also created using broadband emissions from bovine liver sonicated at 2.2 MHz. Agreement was found between the images and source beam shape, indicating an ability to map therapeutic ultrasound beams in situ. The relation between these broadband emissions, sonication amplitude, and exposure conditions are discussed