High-temperature Thermal Therapy Research Articles

A numerical study on heat transfer in tissues during hyperthermia

A mathematical model describing the process of heat transfer in tissues during high temperature thermal therapy by electromagnetic radiation of organs in human body for different coordinate systems and under different boundary conditions is proposed. The heat transfer in tissues is examined using the modified Pennes’ bioheat transfer equation. The boundary value problem governing this process has been solved by Galerkin’s method using the Bernstein polynomial as a basis function. The system of ordinary differential equations in an unknown time variable, thus obtained, is solved by the variational iteration method. The whole analysis is presented in a dimensionless form. The dimensionless time to achieve the hyperthermia position is calculated. The effects of variability of Pf, Pm, Pr, Ki and Bi on dimensionless tissue temperature during steady state are shown graphically. It has been observed that during thermal therapy, probe shape, boundary conditions and internal heat source should not be the same and must be changed from organ to organ in the human body.

MRI-controlled transurethral ultrasound therapy for localised prostate cancer

Minimally invasive treatments for localised prostate cancer are being developed with the aim of achieving effective disease control with low morbidity. High-temperature thermal therapy aimed at producing irreversible thermal coagulation of the prostate gland is attractive because of the rapid onset of thermal injury, and the immediate visualisation of tissue response using medical imaging. High-intensity ultrasound therapy has been shown to be an effective means of achieving thermal coagulation of prostate tissue using minimally invasive devices inserted into the rectum, urethra, or directly into the gland itself. The focus of this review is to describe the work done in our group on the development of MRI-controlled transurethral ultrasound therapy. This technology utilises high intensity ultrasound energy delivered from a transurethral device to achieve thermal coagulation of prostate tissue. Control over the spatial pattern of thermal damage is achieved through closed-loop temperature feedback using quantitative MR thermometry during treatment. The technology, temperature feedback algorithms, and results from numerical modelling, along with experimental results obtained in animal and human studies are described. Our experience suggests that this form of treatment is technically feasible, and compatible with existing MR imaging systems. Temperature feedback control algorithms using MR thermometry can achieve spatial treatment accuracy of a few millimetres in vivo. Patient-specific simulations predict that surrounding tissues can be spared from thermal damage if appropriate measures are taken into account during treatment planning. Recent human experience has been encouraging and motivates further evaluation of this technology as a potential treatment for localised prostate cancer.

Mathematical spatio-temporal model of drug delivery from low temperature sensitive liposomes during radiofrequency tumour ablation

Purpose: Studies have demonstrated a synergistic effect between hyperthermia and chemotherapy, and clinical trials in image-guided drug delivery combine high-temperature thermal therapy (ablation) with chemotherapy agents released in the heating zone via low temperature sensitive liposomes (LTSL). The complex interplay between heat-based cancer treatments such as thermal ablation and chemotherapy may require computational models to identify the relationship between heat exposure and pharmacokinetics in order to optimise drug delivery.Materials and methods: Spatio-temporal data on tissue temperature and perfusion from heat-transfer models of radiofrequency ablation were used as input data. A spatio-temporal multi-compartmental pharmacokinetic model was built to describe the release of doxorubicin (DOX) from LTSL into the tumour plasma space, and subsequent transport into the extracellular space, and the cells. Systemic plasma and tissue compartments were also included. We compared standard chemotherapy (free-DOX) to LTSL-DOX administered as bolus at a dose of 0.7 mg/kg body weight.Results: Modelling LTSL-DOX treatment resulted in tumour tissue drug concentration of ∼9.3 µg/g with highest values within 1 cm outside the ablation zone boundary. Free-DOX treatment produced comparably uniform tissue drug concentrations of ∼3.0 µg/g. Administration of free-DOX resulted in a considerably higher peak level of drug concentration in the systemic plasma compartment (16.1 µg/g) compared to LTSL-DOX (4.4 µg/g). These results correlate well with a prior in vivo study.Conclusions: Combination of LTSL-DOX with thermal ablation allows localised drug delivery with higher tumour tissue concentrations than conventional chemotherapy. Our model may facilitate drug delivery optimisation via investigation of the interplays among liposome properties, tumour perfusion, and heating regimen.

Ultrasound interstitial thermal therapy (USITT) for the treatment of uterine myomas.

Uterine myomas (fibroids) are the most common pelvic tumors occurring in women, and are the leading cause of hysterectomy. Symptoms can be severe, and traditional treatments involve either surgical removal of the uterus (hysterectomy), or the fibroids (myomectomy). Interstitial ultrasound technologies have demonstrated potential for hyperthermia and high temperature thermal therapy in the treatment of benign and malignant tumors. These ultrasound devices offer favorable energy penetration allowing large volumes of tissue to be treated in short periods of time, as well as axial and angular control of heating to conform thermal treatment to a targeted tissue, while protecting surrounding tissues from thermal damage. The goal of this project is to evaluate interstitial ultrasound for controlled thermal coagulation of fibroids. Multi-element applicators were fabricated using tubular transducers, some of which were sectored to produce 180° directional heating patterns, and integrated with water cooling. Human uterine fibroids were obtained after routine myomectomies, and instrumented with thermocouples spaced at 0.5, 1.0, 1.5, 2.0, 2.5 and 3.0 cm from the applicator. Power levels ranging from 8-15 W per element were applied for up to 15 minute heating periods. Results demonstrated that therapeutic temperatures >50° C and cytotoxic thermal doses (t43) extended beyond 2 cm radially from the applicator (>4 cm diameter). It is anticipated that this system will make a significant contribution toward the treatment of uterine fibroids.

Thermal ablation and high-temperature thermal therapy: Overview of technology and clinical implementation

High-temperature hyperthermia or thermal therapy is being applied for destruction of canceroustissue, eradication or reduction of benign tumours and targeted tissue modification and remodelling.Many of these high-temperature technologies provide a minimally-invasive alternative with lowermorbidities compared to the traditional surgical procedures. The effects of high-temperature thermalexposure on tissues, examples of heating technology and procedures of clinical practice related tohigh-temperature thermal therapy are reviewed. This brief review encompasses interstitial, endocavity,intraluminal and external applications of RF, microwave, ultrasound, laser and thermal conductionenergy sources. The technology is prevalent and in various levels of advancement, with themove toward more spatially-accurate and controllable heating systems combined with image-guidanceand treatment verification warranted, especially for the treatment of cancer.

Readdressing the Issue of Thermally Significant Blood Vessels Using a Countercurrent Vessel Network

A physiologically realistic arterio-venous countercurrent vessel network model consisting of ten branching vessel generations, where the diameter of each generation of vessels is smaller than the previous ones, has been created and used to determine the thermal significance of different vessel generations by investigating their ability to exchange thermal energy with the tissue. The temperature distribution in the 3D network (8178 vessels; diameters from 10 to 1000 microm) is obtained by solving the conduction equation in the tissue and the convective energy equation with a specified Nusselt number in the vessels. The sensitivity of the exchange of energy between the vessels and the tissue to changes in the network parameters is studied for two cases; a high temperature thermal therapy case when tissue is heated by a uniformly distributed source term and the network cools the tissue, and a hypothermia related case, when tissue is cooled from the surface and the blood heats the tissue. Results show that first, the relative roles of vessels of different diameters are strongly determined by the inlet temperatures to those vessels (e.g., as affected by changing mass flow rates), and the surrounding tissue temperature, but not by their diameter. Second, changes in the following do not significantly affect the heat transfer rates between tissue and vessels; (a) the ratio of arterial to venous vessel diameter, (b) the diameter reduction coefficient (the ratio of diameters of successive vessel generations), and (c) the Nusselt number. Third, both arteries and veins play significant roles in the exchange of energy between tissue and vessels, with arteries playing a more significant role. These results suggest that the determination of which diameter vessels are thermally important should be performed on a case-by-case, problem dependent basis. And, that in the development of site-specific vessel network models, reasonable predictions of the relative roles of different vessel diameters can be obtained by using any physiologically realistic values of Nusselt number and the diameter reduction coefficient.

Catheter-based ultrasound applicators for selective thermal ablation: progress towards MRI-guided applications in prostate

High-temperature thermal therapy is emerging as a feasible treatment option for prostate cancer and benign prostatic hyperplasia. Previous investigations have demonstrated distinct advantages of catheter-based ultrasound technology over other heating modalities for thermal ablation therapies, with significant potential for better spatial control and faster heating times. The purpose of this study was to develop ultrasound devices and techniques specifically for treating prostate cancer in conjunction with magnetic resonance thermal imaging (MRTI) to monitor and control treatment progression. Directional transurethral applicators have been designed with arrays of sectored tubular (90° active acoustic sector) or with narrow planar transducer segments and integrated with a flexible delivery catheter with a cooling balloon. This applicator can be rotated within the prostatic urethra to target specific regions during treatment. MRI compatible catheter-cooled interstitial ultrasound applicators with 180° active acoustic sectors were developed specifically to treat the prostate. These applicators may be implanted through the perineum into the posterior portion of the prostate, with their heating energy directed away from the rectum. Both heating strategies were evaluated via biothermal simulations and in vivo experiments within canine prostate (n = 3). During the in vivo studies, MRTI was used to monitor treatment temperatures, cytotoxic thermal doses (t43>240 min) and corresponding maximum temperature thresholds (Tmax>52°C) within three imaging planes simultaneously. Urethral and endorectal cooling was employed with both treatment strategies to provide further protection of the urethral mucosa and rectum from thermal damage. Results using the transurethral applicators demonstrated that narrow zones of coagulation (∼30° sector for planar, ∼90° for tubular), extending up to 20 mm from the urethra to the periphery of the prostate gland, could be produced within 10–15 min. Further, rotation of the applicator during treatment could be used to destroy larger regions in the prostate. Experiments using multiple interstitial directional applicators (∼180° active sectors), implanted within the posterior margin of the prostate with the energy directed away from the rectum, produced contiguous zones of thermal coagulation which extended from the posterior prostate toward the anterior-lateral periphery of the gland. Both transurethral and interstitial treatment strategies demonstrated significant potential for thermal ablation of localized prostate cancer, particularly when MRTI is used to guide and assess treatment.

Current limitations of radiofrequency ablation in renal cell carcinoma.

Current limitations of radiofrequency ablation in renal cell carcinoma.

MRI-guided thermal therapy of transplanted tumors in the canine prostate using a directional transurethral ultrasound applicator.

To evaluate MRI-based techniques for visual guidance, thermal monitoring, and assessment during transurethral ultrasound thermal therapy of implanted tumors in an in vivo canine prostate model. Transmissible venereal tumors (TVT) were grown in the right lobe of the prostate in four dogs. High-temperature thermal therapy was selectively applied to the tumor-bearing lobe using a transurethral ultrasound applicator with a 180 degrees directional heating pattern. Temperature-sensitive MRI (MRTI) using a fast interleaved gradient-echo echo-planar (iGE-EPI) imaging sequence was used for cumulative thermal dose calculations in multiple image planes during the treatment. The results from MRTI-based dose maps and post-treatment MRI were compared to those from histologic analysis. MRTI monitoring in multiple planes across the prostate guided the use and control of a directive ultrasound applicator for the selective ablation of the sections of the prostate that contained implanted tumors. Findings in gadolinium enhanced MRI obtained immediately after thermal therapy slightly underestimated the size of tissue necrosis after treatment, as verified by histopathologic analysis. The use of multiplanar MRTI with a transurethral ultrasound applicator shows significant potential for selective thermal ablation of prostate tumor and tissue.

Theoretical model of internally cooled interstitial ultrasound applicators for thermal therapy

Interstitial ultrasound applicators for high-temperature thermal therapy are currently being developed for treating cancerous and benign disease. Internally cooled, direct-coupled (ICDC) applicators, composed of a segmented array of cylindrical ultrasound transducers, have demonstrated capabilities of producing controllable and conformal heating distributions along the applicator length and angular orientation. In this study, 2D transient acoustic and biothermal models of ICDC applicators were developed using a mixed implicit and explicit finite difference solution with variable node spacing in cylindrical coordinates for enhanced speed, stability and accuracy. The model incorporates dynamic behaviour of acoustic parameters and blood perfusion as a function of temperature and thermal dose. Acoustic intensity distributions were modelled as a composite of measured and theoretical intensity distributions. The shape and time evolution of temperature contours and thermal lesions for 90°, 200° and 360° angularly directional applicators and multi-transducer applicators were modelled for heating durations between 1 and 5 min. Model parameters were selected to match previously reported ex vivo and in vivo studies of 2.2 mm diameter ICDC devices in thigh muscle and liver (15–30 W cm−2 applied power density, 0.5–5 min treatment times, 2.8–3.6 cm diameter thermal lesions). The temperatures and lethal thermal dose (600 EM43 °C) contours calculated using the models were in excellent agreement with temperatures and thermal lesion dimensions (visible coagulation) determined experimentally. The differences between maximum radial depths of coagulation calculated using the r–z and r–θ models were small, less than ∼2 mm for 10–15 mm lesions. There was a strong correlation between the calculated 50 °C contour and the radial, angular and axial lesion dimensions obtained for 3–5 min heating protocols. The models developed in this study have significant application in design studies and potential future use in treatment planning of ICDC interstitial ultrasound thermal therapy.

Evaluation of multielement catheter-cooled interstitial ultrasound applicators for high-temperature thermal therapy.

Catheter-cooled (CC) interstitial ultrasound applicators were evaluated for their use in high-temperature coagulative thermal therapy of tissue. Studies in ex vivo beef muscle were conducted to determine the influences of applied electrical power levels (5-20 W per element), catheter flow rate (20-60 ml min(-1)), circulating water temperature (7-40 degrees C), and frequency (7-9 MHz) on temperature distribution and thermal lesion geometry. The feasibility of using multiple interstitial applicators to thermally coagulate a predetermined volume of tissue was also investigated. Results of these studies revealed that the directional shape of the thermal lesions is maintained with increasing time and power. Radial depths of the thermal lesions ranged from 10.7 +/- 0.7 mm after heating for 4 min with an applied power level of 5 W, to 16.2 +/- 1.4 mm with 20 W. The axial length of the thermal lesions is controlled tightly by the number of active transducers. A catheter flow rate of 20 to 40 ml min(-1) (52.2 +/- 5.5 kPa at 40 ml min(-1)) with 22 degrees C water was determined to provide sufficient cooling of the transducers for power levels used in this study. In vivo temperatures measured in the center of a 3-cm-diam peripheral implant of four applicators in pig thigh muscle reached 89.3 degrees C after 4 min of heating, with boundaries of coagulation clearly defined by applicator position and directivity. Conformability of heating in a clinically relevant model was demonstrated by inserting two directional CC applicators with a 2 cm separation within an in vivo canine prostate, and generating a thermal lesion measuring 3.8 cm x 2.2 cm in cross section while directing energy away from, and protecting the rectum. Maximum measured temperatures at midgland exceeded 90 degrees C within 20 min of heating. The results of this study demonstrate the utility of single or multiple CC applicators for conformal thermal coagulation and high temperature thermal therapy, with potential for clinical applications in sites such as prostate, liver, breast, or uterus.

Comparison of thermal damage calculated using magnetic resonancethermometry, with magnetic resonance imaging post-treatment and histology,after interstitial microwave thermal therapy of rabbit brain

Clinical application of high-temperature thermal therapy as a treatment forsolid tumours requires an accurate and close to real-time method forassessing tissue damage. Imaging methods that detect structural changesduring heating may underestimate the extent of thermal damage. This is dueto the occurrence of delayed damage manifested at tissue locations exposedto temperatures lower than those required to cause immediate structuralchanges. An alternative approach is to measure temperature and thencalculate the expected damage based on the temperature history at eachtissue location. Magnetic resonance (MR) imaging methods now allowtemperature maps of the target and surrounding tissues to be generated inalmost real-time. The aim of this work was to evaluate whether thermaldamage zones calculated on the basis of MR thermometry maps measured duringheating correspond to actual tissue damage as measured after treatment byhistological methods and MR imaging.Four male rabbits were treated with high-temperature thermal therapydelivered in the brain by a single microwave antenna operating at 915 MHz.MR scanning was performed before, during and after treatment in a 1.5 Twhole-body scanner. Temperature maps were produced using the protonresonance frequency (PRF) shift method of MR thermometry. In addition,conventional T1-weighted and T2-weighted spin-echo images wereacquired after treatment. Thermal damage zones corresponding to cell death,microvascular blood flow stasis and protein coagulation were calculatedusing an Arrhenius analysis of the MR temperature/time course data. Thecalculated zones were compared with the lesions seen on histopathologicalexamination of the brains which were removed within 6-8 h of treatment.The results showed that calculated damage zones based on MR thermometryagreed well with areas of damage as assessed using histology after heatingwas completed. The data suggest that real-time calculations of finalexpected thermal damage based on an Arrhenius analysis of MR temperaturedata may provide a useful method of real-time monitoring of thermal therapywhen combined with conventional T2-weighted images taken aftertreatment.

Axial control of thermal coagulation using a multi-element interstitial ultrasound applicator with internal cooling

A multi-element, direct-coupled ultrasound (US) applicator with internal water cooling was investigated for axial control of interstitial thermal coagulation. A prototype implantable applicator was constructed with a linear array of three tubular PZT ultrasound transducers (each 2.5 mm OD, 10 mm length, 360 degrees emittance). Acoustic beam distributions from each element were measured and found to be collimated within the transducer length. The internally cooled applicator could sustain high levels of applied power to each transducer (0 to 40 W) and maintain acceptable applicator surface temperatures (<100 degrees C). Thermal performance of the applicator was investigated through heating trials in vivo (porcine thigh muscle and liver) and in vitro (bovine liver). The radial depth of thermal lesions produced was dependent on the applied power and sonication time and was controlled independently with power levels to each transducer element. With 18 W per element (applied electrical power) for 3 min, cylindrical thermal lesions were produced with a diameter of ~3 cm and a length ranging from 1.2 cm (with one element) to 3.5 cm (three elements). Higher powers (24 to 30 W) for 3 to 5 min provided increased depths of coagulation (~4 cm diameter lesions). Analysis of axial lesion shapes demonstrated that individual variation of power to each transducer element provided control of axial heating and depth of coagulation (for custom lesion shapes); lesion lengths corresponded to the number of active transducers. This ability to control the heating distribution dynamically along the length of the applicator has potential for improved target localization of thermal coagulation and necrosis in high temperature thermal therapy.

Combination of transurethral and interstitial ultrasound applicators for high-temperature prostate thermal therapy

The purpose of this study was to determine the feasibility of using a transurethral ultrasound applicator in combination with implantable ultrasound applicators for inducing thermal coagulation and necrosis of localized cancer lesions or benign disease within the prostate gland. The potential to treat target zones in the anterior and lateral portions of the prostate with the angularly directive transurethral applicator, while simultaneously treating regions of extracapsular extension and zones in the posterior prostate with the directive implantable applicators in combination with a rectal cooling bolus, is evaluated. Biothermal computer simulations, acoustic characterizations, and in vivo thermal dosimetry experiments with canine prostates were used to evaluate the performance of each applicator type and combinations thereof. Simulations have demonstrated that transurethral applicators with 180-270° acoustic active zones can direct therapeutic heating patterns to the anterior and lateral prostate, implantable needles can isolate heating to the posterior gland while avoiding rectal tissue, and that the combination of applicators can be used to produce conformal heating to the whole gland. Single implantable applicators (1.8mm ODx10mm long, ∼180° active sector, ∼7MHz, direct-coupled type) produced directional thermal lesions within in vivo prostate, with temperatures >50°C extending more than 10mm radially after 10-15min. Combination of interstitial applicators (1-2) and a transurethral applicator (3-2.5mm ODx6 mm long, 180° active sector, 6.8MHz, 6 mm OD delivery catheter) produced conforming temperature distributions (48-85°C) and zones of acute thermal damage within 15min. The preliminary results of this investigation demonstrate that implantable directional ultrasound applicators, in combination with a transurethral ultrasound applicator, have the potential to provide thermal coagulation and necrosis of small or large regions within the prostate gland, while sparing thermally sensitive rectal tissue.