System for delivering microwave ablation to subcutaneous tumors in small-animals under high-field MRI thermometry guidance.

PURPOSE: Bio-effects following thermal treatments are a function of the achieved temperature profile in tissue, which can be estimated across tumor volumes with real-time MRI thermometry (MRIT). Here, we report on expansion of a previously developed small-animal microwave hyperthermia system integrated with MRIT for delivering thermal ablation to subcutaneously implanted tumors in mice. METHODS: Computational models were employed to assess suitability of the 2.45 GHz microwave applicators for delivering ablation to subcutaneous tumor targets in mice. Phantoms and ex-vivo tissues were heated to temperatures in the range 47-67 °C with custom-made microwave applicators for validating MRIT with the proton resonance frequency shift method against fiberoptic thermometry. HAC15 tumors implanted in nude mice (n = 6) were ablated in vivo and monitored with MRIT in multiple planes. One day post ablation, animals were euthanized, and excised tumors were processed for viability assessment. RESULTS: Average absolute error between temperatures from fiberoptic sensors and MRIT was 0.6 °C across all ex-vivo ablations. During in-vivo experiments, tumors with volumes ranging between 5.4-35.9 mm3 (mean 14.2 mm3) were ablated (duration: 103-150 s) to achieve 55 °C at the tumor boundary. Thermal doses ≥240 CEM43 were achieved across 90.7-98.0% of tumor volumes for four cases. Ablations were incomplete for remaining cases, attributed to motion-affected thermometry. Thermal dose-based ablative tumor coverage agreed with viability assessment of excised tumors. CONCLUSIONS: We have developed a system for delivering microwave ablation to subcutaneous tumors in small animals under MRIT guidance and demonstrated its performance in-vivo.

How large is the periablational zone after radiofrequency and microwave ablation? Computer-based comparative study of two currently used clinical devices.

PURPOSE: To compare the size of the coagulation (CZ) and periablational (PZ) zones created with two commercially available devices in clinical use for radiofrequency (RFA) and microwave ablation (MWA), respectively. METHODS: Computer models were used to simulate RFA with a 3-cm Cool-tip applicator and MWA with an Amica-Gen applicator. The Arrhenius model was used to compute the damage index (Ω). CZ was considered when Ω > 4.6 (>99% of damaged cells). Regions with 0.6<Ω < 2.1 were considered as the PZ (tissue that has undergone moderate sub-ablative hyperthermia). The ratio of PZ volume to CZ volume (PZ/CZ) was regarded as a measure of performance, since a low value implies achieving a large CZ while keeping the PZ small. RESULTS: Ten-min RFA (51 W) created smaller periablational zones than 10-min MWA (11.3 cm3 vs. 17.2-22.9 cm3, for 60-100 W MWA, respectively). Prolonging duration from 5 to 10 min increased the PZ in MWA more than in RFA (2.7 cm3 for RFA vs. 8.3-11.9 cm3 for 60-100 W MWA, respectively). PZ/CZ for RFA were relatively high (65-69%), regardless of ablation time, while those for MWA were highly dependent on the duration (increase of up to 25% between 5 and 10 min) and on the applied power (smaller values as power was raised, 102% for 60 W vs. 81% for 100 W, both for 10 min). The lowest PZ/CZ across all settings was 56%, obtained with 100 W-5 min MWA. CONCLUSIONS: Although RFA creates smaller periablational zones than MWA, 100 W-5 min MWA provides the lowest PZ/CZ.

An integrated platform for small-animal hyperthermia investigations under ultra-high-field MRI guidance.

PURPOSE: Integrating small-animal experimental hyperthermia instrumentation with magnetic resonance imaging (MRI) affords real-time monitoring of spatial temperature profiles. This study reports on the development and preliminary in vivo characterisation of a 2.45 GHz microwave hyperthermia system for pre-clinical small animal investigations, integrated within a 14 T ultra-high-field MRI scanner. MATERIALS AND METHODS: The presented system incorporates a 3.5 mm (OD) directional microwave hyperthermia antenna, positioned adjacent to the small-animal target, radiating microwave energy for localised heating of subcutaneous tumours. The applicator is integrated within the 30 mm bore of the MRI system. 3D electromagnetic and biothermal simulations were implemented to characterise hyperthermia profiles from the directional microwave antenna. Experiments in tissue mimicking phantoms were performed to assess hyperthermia profiles and validate MR thermometry against fibre-optic temperature measurements. The feasibility of delivering in vivo hyperthermia exposures to subcutaneous 4T1 tumours in experimental mice under simultaneous MR thermometry guidance was assessed. RESULTS: Simulations and experiments in tissue mimicking phantoms demonstrated the feasibility of heating 21-982 mm3 targets with 8-12 W input power. Minimal susceptibility and electrical artefacts introduced by the hyperthermia applicator were observed on MR imaging. MR thermometry was in excellent agreement with fibre-optic temperatures measurements (max. discrepancy ≤0.6 °C). Heating experiments with the reported system demonstrated the feasibility of heating subcutaneous tumours in vivo with simultaneous MR thermometry. CONCLUSIONS: A platform for small-animal hyperthermia investigations under ultra-high-field MR thermometry was developed and applied to heating subcutaneous tumours in vivo.

Extracorporeal Removal of Thermosensitive Liposomal Doxorubicin from Systemic Circulation after Tumor Delivery to Reduce Toxicities.

Thermosensitive liposomal doxorubicin (TSL-Dox) combined with localized hyperthermia enables targeted drug delivery. Tumor drug uptake occurs only during hyperthermia. We developed a novel method for removal of systemic TSL-Dox remaining after hyperthermia-triggered delivery to reduce toxicities. The carotid artery and jugular vein of Norway brown rats carrying two subcutaneous BN-175 tumors were catheterized. After allowing the animals to recover, TSL-Dox was infused at 7 mg/kg dose. Drug delivery to one of the tumors was performed by inducing 15 min microwave hyperthermia (43 °C). At the end of hyperthermia, an extracorporeal circuit (ECC) comprising a heating module to release drug from TSL-Dox followed by an activated carbon filter to remove free drug was established for 1 h (n = 3). A computational model simulated TSL-Dox pharmacokinetics, including ECC filtration, and predicted cardiac Dox uptake. In animals receiving ECC, we were able to remove 576 ± 65 mg of Dox (29.7 ± 3.7% of the infused dose) within 1 h, with a 2.9-fold reduction of plasma AUC. Fluorescent monitoring enabled real-time quantification of blood concentration and removed drug. Computational modeling predicted that up to 59% of drug could be removed with an ideal filter, and that cardiac uptake can be reduced up to 7×. We demonstrated removal of drug remaining after tumor delivery, reduced plasma AUC, and reduced cardiac uptake, suggesting reduced toxicity.

Preclinical Studies in Small Animals for Advanced Drug Delivery Using Hyperthermia and Intravital Microscopy.

This paper presents three devices suitable for the preclinical application of hyperthermia via the simultaneous high-resolution imaging of intratumoral events. (Pre)clinical studies have confirmed that the tumor micro-environment is sensitive to the application of local mild hyperthermia. Therefore, heating is a promising adjuvant to aid the efficacy of radiotherapy or chemotherapy. More so, the application of mild hyperthermia is a useful stimulus for triggered drug release from heat-sensitive nanocarriers. The response of thermosensitive nanoparticles to hyperthermia and ensuing intratumoral kinetics are considerably complex in both space and time. To obtain better insight into intratumoral processes, longitudinal imaging (preferable in high spatial and temporal resolution) is highly informative. Our devices are based on (i) an external electric heating adaptor for the dorsal skinfold model, (ii) targeted radiofrequency application, and (iii) a microwave antenna for heating of internal tumors. These models, while of some technical complexity, significantly add to the understanding of effects of mild hyperthermia warranting implementation in research on hyperthermia.

Simulation-based design and characterization of a microwave applicator for MR-guided hyperthermia experimental studies in small animals.

Purpose: The objective of this study was to design and characterize a 2.45 GHz microwave hyperthermia applicator for delivering hyperthermia in experimental small animals to 2 - 4 mm diameter targets located 1 - 3 mm from the skin surface, with minimal heating of the surrounding tissue, under 14.1 T MRI real-time monitoring and feedback control. Materials and methods: An experimentally validated 3D computational model was employed to design and characterize a non-invasive directional water-cooled microwave hyperthermia applicator. We assessed the effects of: reflector geometry, monopole shape, cooling water temperature, and flow rate on spatial-temperature profiles. The system was integrated with real-time MR thermometry and feedback control to monitor and maintain temperature elevations in the range of 4 - 5 °C at 1 - 3 mm from the applicator surface. The quality of heating was quantified by determining the fraction of the target volume heated to the desired temperature, and the extent of heating in non-targeted regions. Results: Model-predicted hyperthermic profiles were in good agreement with experimental measurements (Dice Similarity Coefficient of 0.95 - 0.99). Among the four considered criteria, a reflector aperture angle of 120 °, S-shaped monopole antenna with 0.6 mm displacement, and coolant flow rate of 150 ml/min were selected as the end result of the applicator design. The temperature of circulating water and input power were identified as free variables, allowing considerable flexibility in heating target sizes within varying distances from the applicator surface. 2 - 4 mm diameter targets positioned 1 - 3 mm from the applicator surface were heated to hyperthermic temperatures, with target coverage ratio ranging between 76 - 93 % and 11 - 26 % of non-targeted tissue heated. Conclusion: We have designed an experimental platform for MR-guided hyperthermia, incorporating a microwave applicator integrated with temperature-based feedback control to heat deep-seated targets for experimental studies in small animals.

Experimental assessment of microwave ablation computational modeling with MR thermometry.

PURPOSE: Computational models are widely used during the design and characterization of microwave ablation (MWA) devices, and have been proposed for pretreatment planning. Our objective was to assess three-dimensional (3D) transient temperature and ablation profiles predicted by MWA computational models with temperature profiles measured experimentally using magnetic resonance (MR) thermometry in ex vivo bovine liver. MATERIALS AND METHODS: We performed MWA in ex vivo tissue under MR guidance using a custom, 2.45 GHz water-cooled applicator. MR thermometry data were acquired for 2 min prior to heating, during 5-10 min microwave exposures, and for 3 min following heating. Fiber-optic temperature sensors were used to validate the accuracy of MR temperature measurements. A total of 13 ablation experiments were conducted using 30-50 W applied power at the applicator input. MWA computational models were implemented using the finite element method, and incorporated temperature-dependent changes in tissue physical properties. Model-predicted ablation zone extents were compared against MRI-derived Arrhenius thermal damage maps using the Dice similarity coefficient (DSC). RESULTS: Prior to heating, the observed standard deviation of MR temperature data was in the range of 0.3-0.7°C. Mean absolute error between MR temperature measurements and fiber-optic temperature probes during heating was in the range of 0.5-2.8°C. The mean DSC between model-predicted ablation zones and MRI-derived Arrhenius thermal damage maps for 13 experimental set-ups was 0.95. When comparing simulated and experimentally (i.e. using MRI) measured temperatures, the mean absolute error (MAE %) relative to maximum temperature change was in the range 5%-8.5%. CONCLUSION: We developed a system for characterizing 3D transient temperature and ablation profiles with MR thermometry during MWA in ex vivo liver tissue, and applied the system for experimental validation of MWA computational models.

Temperature estimation for MR-guided microwave hyperthermia using block-based compressed sensing.

Mild hyperthermia has been clinically employed as an adjuvant for radiation/chemotherapy and is under investigation for precise thermally-mediated delivery of cancer therapeutic agents. Magnetic Resonance Imaging (MRI) facilitates non-invasive, real-time spatial thermometry for monitoring and guiding hyperthermia procedures. Long image acquisition time during MR-guided hyperthermia may fail to capture rapid changes in temperature. This may lead to unwanted heating of healthy tissue and/or temperature rise above hyperthermic range. We have developed a block-based compressed sensing approach to reconstruct volumetric MR-derived microwave hyperthermia temperature profiles using a subset of measured data. This algorithm exploits the sparsity of MR images due to the presence of inter- and intra-slice correlation of hyperthermic MR-derived temperature profiles. We have evaluated the performance of our developed algorithm on a phantom and in vivo in mice using previously implemented microwave applicators. This algorithm reconstructs 3D temperature profiles with PSNR of 33 dB - 49 dB in comparison to the original profiles. In summary, this study suggests that microwave hyperthermia induced temperature profiles can be reconstructed using subsamples to reduce MR image acquisition time.

Evaluation of the Effect of Uterine Fibroids on Microwave Endometrial Ablation Profiles.

Thermal ablation of the endometrial lining of the uterus is a minimally-invasive technique for treatment of menorrhagia. We have previously presented a 915 MHz microwave triangular loop antenna for endometrial ablation. Uterine fibroids are benign pelvic tumors, of considerably different water content compared to normal uterus, and may change the shape of the uterus. Collectively, these changes introduced by fibroids may alter the pattern of microwave endometrial ablation. In this study, we have investigated the effect of 1 - 3 cm diameter uterine fibroids in different locations around the uterine cavity on ablation profiles following 60 W, 150 s microwave exposure with a loop antenna. Our computational model predicts ablation zone extents within 1 ± 0.8 of ablation zones observed in experiments in ex vivo tissue. The maximum change in simulated ablation depths due to the presence of fibroids was 1.1 mm. In summary, this simulation study suggests that 1 - 3 cm diameter uterine fibroids can be expected to have minimal impact on the extent of microwave endometrial ablation patterns.