Volumetric Hyperthermia Research Articles

Holographic Focused Ultrasound Hyperthermia System for Uniform Simultaneous Thermal Exposure of Multiple Tumor Spheroids.

Hyperthermia is currently used to treat cancer due to its ability to radio- and chemo-sensitize and to stimulate the immune response. While ultrasound is non-ionizing and can induce hyperthermia deep within the body non-invasively, achieving uniform and volumetric hyperthermia is challenging. This work presents a novel focused ultrasound hyperthermia system based on 3D-printed acoustic holograms combined with a high-intensity focused ultrasound (HIFU) transducer to produce a uniform iso-thermal dose in multiple targets. The system is designed with the aim of treating several 3D cell aggregates contained in an International Electrotechnical Commission (IEC) tissue-mimicking phantom with multiple wells, each holding a single tumor spheroid, with real-time temperature and thermal dose monitoring. System performance was validated using acoustic and thermal methods, ultimately yielding thermal doses in three wells that differed by less than 4%. The system was tested in vitro for delivery of thermal doses of 0-120 cumulative equivalent minutes at 43 °C (CEM43) to spheroids of U87-MG glioma cells. The effects of ultrasound-induced heating on the growth of these spheroids were compared with heating using a polymerase chain reaction (PCR) thermocycler. Results showed that exposing U87-MG spheroids to an ultrasound-induced thermal dose of 120 CEM43 shrank them by 15% and decreased their growth and metabolic activity more than seen in those exposed to a thermocycler-induced heating. This low-cost approach of modifying a HIFU transducer to deliver ultrasound hyperthermia opens new avenues for accurately controlling thermal dose delivery to complex therapeutic targets using tailored acoustic holograms. Spheroid data show that thermal and non-thermal mechanisms are implicated in the response of cancer cells to non-ablative ultrasound heating.

Deployable ultrasound applicators for endoluminal delivery of volumetric hyperthermia

Purpose To investigate the design of an endoluminal deployable ultrasound applicator for delivering volumetric hyperthermia to deep tissue sites as a possible adjunct to radiation and chemotherapy. Method This study considers an ultrasound applicator consisting of two tubular transducers situated at the end of a catheter assembly, encased within a distensible conical shaped balloon-based reflector that redirects acoustic energy distally into the tissue. The applicator assembly can be inserted endoluminally or laparoscopically in a compact form and expanded after delivery to the target site. Comprehensive acoustic and biothermal simulations and parametric studies were employed in generalized 3D and patient-specific pancreatic head and body tumor models to characterize the acoustic performance and evaluate heating capabilities of the applicator by investigating the device at a range of operating frequencies, tissue acoustic and thermal properties, transducer configurations, power modulation, applicator positioning, and by analyzing the resultant 40, 41, and 43 °C isothermal volumes and penetration depth of the heating volume. Intensity distributions and volumetric temperature contours were calculated to define moderate hyperthermia boundaries. Results Parametric studies demonstrated the frequency selection to control volume and depth of therapeutic heating from 62 to 22 cm3 and 4 to 2.6 cm as frequency ranges from 1 MHz to 4.7 MHz, respectively. Width of the heating profile tracks closely with the aperture. Water cooling within the reflector balloon was effective in controlling temperature to 37 °C maximum within the luminal wall. Patient-specific studies indicated that applicators with extended OD in the range of 3.6–6.2 cm with 0.5–1 cm long and 1 cm OD transducers can heat volumes of 1.1–7 cm3, 3–26 cm3, and 3.3–37.4 cm3 of pancreatic body and head tumors above 43, 41, and 40 °C, respectively. Conclusion In silico studies demonstrated the feasibility of combining endoluminal ultrasound with an integrated expandable balloon reflector for delivering volumetric hyperthermia in regions adjacent to body lumens and cavities.

Large-Volume Hyperthermia for Safe and Cost-Effective Targeted Drug Delivery Using a Clinical Ultrasound-Guided Focused Ultrasound Device

Lyso-thermosensitive liposomes (LTSLs) are specifically designed to release chemotherapy agents under conditions of mild hyperthermia. Preclinical studies have indicated that magnetic resonance (MR)-guided focused ultrasound (FUS) systems can generate well-controlled volumetric hyperthermia using real-time thermometry. However, high-throughput clinical translation of these approaches for drug delivery is challenging, not least because of the significant cost overhead of MR guidance and the much larger volumes that need to be heated clinically. Using an ultrasound-guided extracorporeal clinical FUS device (Chongqing HAIFU, JC200) with thermistors in a non-perfused ex vivo bovine liver tissue model with ribs, we present an optimised strategy for rapidly inducing (5–15 min) and sustaining (>30 min) mild hyperthermia (ΔT <+4°C) in large tissue volumes (≤92 cm3). We describe successful clinical translation in a first-in-human clinical trial of targeted drug delivery of LTSLs (TARDOX: a phase I study to investigate drug release from thermosensitive liposomes in liver tumours), in which targeted tumour hyperthermia resulted in localised chemo-ablation. The heating strategy is potentially applicable to other indications and ultrasound-guided FUS devices.

Sonication strategies toward volumetric ultrasound hyperthermia treatment using the ExAblate body MRgFUS system

Purpose The ExAblate body MRgFUS system requires advanced beamforming strategies for volumetric hyperthermia. This study aims to develop and evaluate electronic beam steering, multi-focal patterns, and sector vortex beamforming approaches in conjunction with partial array activation using an acoustic and biothermal simulation framework along with phantom experiments. Methods The simulation framework was developed to calculate the 3D acoustic intensity and temperature distribution resulting from various beamforming and scanning strategies. A treatment cell electronically sweeping a single focus was implemented and evaluated in phantom experiments. The acoustic and thermal focal size of vortex beam propagation was quantified according to the vortex modes, number of active array elements, and focal depth. Results Turning off a percentage of the outer array to increase the f-number increased the focal size with a decrease in focal gain. 60% active elements allowed generating a sonication cell with an off-axis of 10 mm. The vortex mode number 4 with 60% active elements resulted in a larger heating volume than using the full array. Volumetric hyperthermia in the phantom was evaluated with the vortex mode 4 and respectively performed with 100% and 80% active elements. MR thermometry demonstrated that the volumes were found to be 18.8 and 29.7 cm3, respectively, with 80% array activation producing 1.58 times larger volume than the full array. Conclusions This study demonstrated that both electronic beam steering and sector vortex beamforming approaches in conjunction with partial array activation could generate large volume heating for HT delivery using the ExAblate body array.

Attenuation estimation using passive acoustic mapping

Passive acoustic mapping (PAM) techniques have been developed in order to reduce risk and improve treatment efficacy by localizing and quantifying cavitation emissions during therapeutic ultrasound procedures. The performance of these techniques may be significantly degraded by attenuation between the internal therapeutic target and the external monitoring system. Attenuation itself is an essential parameter in the determination of therapeutic outcomes and safety of treatments such as HIFU ablation or volumetric hyperthermia. However, the spatial and temporal distributions of this parameter are not typically known in clinical scenarios. To address these challenges, we present a method for estimating attenuation using broadband cavitation emissions, potentially allowing for restoration of PAM performance, improved treatment monitoring and guidance, and mapping of tissue attenuation over the course of a treatment. Results from simulations and flow phantom experiments illustrate: (1) the impact of soft tissue-like attenuation on PAM images, (2) the ability to estimate attenuation from cavitation data, and (3) the enhancement of cavitation source imaging and energy estimation following PAM input data attenuation compensation. In the future, the technique could be expanded as a general broadband method of attenuation correction for conventional diagnostic ultrasound images and improved therapeutic ultrasound treatment planning.

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

Feasibility 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. The 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). Acoustic 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. The ExAblate 2100, designed specifically for thermal ablation, can be controlled for delivering continuous hyperthermia in prostate while working within operational constraints.

Continuous monitoring of cerebral perfusion by thermal clearance

Currently, no commercially available system exists to continuously monitor the effective tissue perfusion within the parenchyma of the brain. While several methods exist for accurately measuring cerebral perfusion; among them: 133xeonon clearance, hydrogen clearance and radiolabeled microsphere injection; none of these methods provides continuous monitoring. The Cook Incorporated VH8500 Volumetric Hyperthermia Treatment System (Bloomington, IN, USA) was initially developed to treat brain tumours by maintaining constant, moderate hyperthermia within a defined tissue volume over an extended duration. The system continuously adjusts the power applied to heating elements in order to maintain a constant temperature within the treatment volume. Because tissue perfusion is a primary factor responsible for removing heat from tissue, monitoring the amount of power applied to the heating elements allows one to continuously estimate tissue perfusion in the vicinity of the heating elements. In the current study, regional blood flow in the vicinity of heater/sensor catheters implanted in the brain parenchyma of three dogs was estimated by the VH8500 tissue perfusion algorithm and directly measured with radioactive labeled microspheres. The accuracy of the perfusion estimate (Thermal Perfusion Index) was evaluated by comparing these values. A range of blood flow was achieved in each animal by infusing nitroprusside. It was found that with the perfusion estimation algorithm of the Cook Incorporated VH8500 Volumetric Hyperthermia Treatment System as it is currently implemented, the Thermal Perfusion Index tended to underestimate regional perfusion as measured with radioactive microspheres, but the relationship was nearly linear. Thus, the system currently tracks changes in regional blood flow.(ABSTRACT TRUNCATED AT 250 WORDS)