Nanoparticle-mediated radiofrequency capacitive hyperthermia: A phantom study with magnetic resonance thermometry

Abstract

In hyperthermia, focusing heat generation on tumour tissues and precisely monitoring the temperature around the tumour region is important. To focus heat generation in radiofrequency (RF) capacitive heating, magnetic nanoparticles suspended in sodium carboxymethyl cellulose (CMC) solution were used, based on the hypothesis that the nanoparticle suspension would elevate electrical conductivity and RF current density at the nanoparticle-populated region. A tissue-mimicking phantom with compartments with and without nanoparticles was made for RF capacitive heating experiments. An FDTD model of the phantom was developed to simulate temperature increases at the phantom. To monitor temperature inside the phantom, MR thermometry was performed intermittently during RF heating inside a 3Tesla MRI magnet bore. FDTD simulation on the phantom model was performed in two steps: electromagnetic simulation to compute specific absorption rate and thermal simulation to compute temperature changes. Experimental temperature maps were similar to simulated temperature maps, demonstrating that nanoparticle-populated regions drew more heat than background regions. Nanoparticle-mediated RF heating could mitigate concerns about normal tissue death during RF capacitive hyperthermia.     

Thermometry studies of radio-frequency induced hyperthermia on hydrogel based neck phantoms

A cylindrical phantom, resembling average human neck, was prepared by using hydrogel sheets containing vinyl and polysaccharide. The phantom was used to obtain temperature distributions for 6 values of input power of radio frequency (RF) at 8MHz,by invasive thermometry technique, using thermistor probes. The inclusion of cervical vertebrae and calcium carbonate pieces (human bone representative) with a hollow tube (windpipe equivalent) in the phantom simulates the change in thermal distributions. This is similar to the alterations in heat disposition obtained in the real human neck, during RF induced heating, without extensive distortion of the uniform temperature distribution provided by the RF heating instrument. This paper compares the hydrogel neck phantom with other phantoms, that have been developed for studying thermal distributions and optimization of novel non invasive thermometry techniques in hyperthermic oncology.     

Sequential activation of multiple grounding pads reduces skin heating during radiofrequency tumor ablation.

PURPOSE: Radiofrequency (RF) tumor ablation has become an accepted treatment modality for tumors not amenable to surgery. Skin burns due to ground pad heating may become a limiting factor for further increase in ablation zone dimensions and generator power. We investigated a method were groups of ground pads are sequentially activated to reduce skin heating. METHODS: We compared conventional operation (i.e. simultaneous connection of all pads) to sequentially switched activation of the pads where different pad combinations are active for periods of approximately 0.3 - 8 s. The timing during sequential activation was adjusted to keep the leading edge temperature equal between the pads. We created Finite Element Method computer models of three pads (5 x 5 cm, 1 cm apart) placed in line with the RF electrode on a human thigh to determine differences in tissue heating during simultaneous and sequential ground pad activation. We performed experiments with three ground pads (5 x 10 cm, 4 cm apart) placed on a tissue phantom (1.5 A, 12 min) and measured pad surface and leading edge temperatures. RESULTS: Temperature rise below the leading edge for proximal, middle and distal ground pad in relation to active electrode location was 5.9 degrees C +/- 0.1 degrees C, 0.8 degrees C +/- 0.1 degrees C and 0.3 degrees C +/- 0.1 degrees C for conventional operation, and 3.3 degrees C +/- 0.1 degrees C, 3.4 degrees C +/- 0.2 degrees C and 3.4 degrees C +/- 0.2 degrees C for sequentially activated operation in the experiments (p < 0.001). CONCLUSION: Sequential activation of multiple ground pads resulted in reduced maximum tissue temperature. This may reduce the incidence of ground pad burns and may allow higher power RF generators.     

Changes in heating patterns due to perturbations by thermometer probes at 915 and 434 MHz

The changes in heating patterns due to perturbations by thermometer probes in microwave fields were investigated in static phantoms at 915 and 434 MHz. Thermograms taken parallel to the plane of E and H fields, at depths of up to 2 cm, indicated heating changes of +25 to –45 per cent at 915 MHz and ± 15 per cent at 434 MHz. The amount of perturbation is dependent on the length, size and location of the probes in the RF fields and their orientations to the electric field. If proper probe placement techniques are not observed when metallic probes are involved, hot and cool spots can be generated and shifted to sites that are not measured. Therefore misleading temperatures can result when changes in heating patterns are not detected. Perturbation also varies with applicator designs and phantom geometry. If thermistors and thermocouples are used, the effects of perturbation should be investigated with individual applicators under applicable clinical conditions.     

Exploration of MR-guided head and neck hyperthermia by phantom testing of a modified prototype applicator for use with proton resonance frequency shift thermometry

Magnetic resonance thermometry (MRT) offers non-invasive temperature imaging and can greatly contribute to the effectiveness of head and neck hyperthermia. We therefore wish to redesign the HYPERcollar head and neck hyperthermia applicator for simultaneous radio frequency (RF) heating and magnetic resonance thermometry. In this work we tested the feasibility of this goal through an exploratory experiment, in which we used a minimally modified applicator prototype to heat a neck model phantom and used an MR scanner to measure its temperature distribution. We identified several distorting factors of our current applicator design and experimental methods to be addressed during development of a fully MR compatible applicator. To allow MR imaging of the electromagnetically shielded inside of the applicator, only the lower half of the HYPERcollar prototype was used. Two of its antennas radiated a microwave signal (150?W, 434?MHz) for 11?min into the phantom, creating a high gradient temperature profile (ΔT_max?=?5.35?°C). Thermal distributions were measured sequentially, using drift corrected proton resonance frequency shift-based MRT. Measurement accuracy was assessed using optical probe thermometry and found to be about 0.4?°C (0.1–0.7?°C). Thermal distribution size and shape were verified by thermal simulations and found to have a good correlation (r^2?=?0.76).     

Effect of Functional Magnetic Particles on Radiofrequency Capacitive Heating

Magnetic particles (magnetite) were used to make radio frequency (RF) capacitive hyperthermia effective to a specific site. In an agar phantom experiment, a magnetite-containing agar piece was buried in a large agar phantom and heated by an 8 MHz-RF capacitive heating device. The magnetite-containing agar piece was heated more than the magnetite-free agar phantom, and the specific adsorption rate in the phantom was increased 1.5 times by the magnetite particles. The temperature distribution in the large agar phantom showed that the highest temperature was obtained at the center of the magnetite-containing piece. The rate of temperature increase was approximately proportional to the magnetite concentration to the power 0.8. This method was applied to an in vivo experiment using a pig. Magnetite was prepared as a colloidal material dispersed in a carboxymethylcellulose solution (CMC-Mag) and intramuscularly injected in the pig femur. As a result of 8 MHz-RF heating, the temperature at the CMC-Mag-injected point increased to over 43°C after 7 min, while the temperature at a point without magnetite was under 40°C at the same time. The specific adsorption rate in the magnetite-containing tissue was twice that of the magnetite- free tissue. In addition, the time required to reach a temperature of over 43°C was only 7 min, while it was over 15 min in the case without the CMC-Mag.     

Changes in heating patterns due to perturbations by thermometer probes at 915 and 434 MHz

The changes in heating patterns due to perturbations by thermometer probes in microwave fields were investigated in static phantoms at 915 and 434 MHz. Thermograms taken parallel to the plane of E and H fields, at depths of up to 2 cm, indicated heating changes of +25 to -45 per cent at 915 MHz and +/- 15 per cent at 434 MHz. The amount of perturbation is dependent on the length, size and location of the probes in the RF fields and their orientations to the electric field. If proper probe placement techniques are not observed when metallic probes are involved, hot and cool spots can be generated and shifted to sites that are not measured. Therefore misleading temperatures can result when changes in heating patterns are not detected. Perturbation also varies with applicator designs and phantom geometry. If thermistors and thermocouples are used, the effects of perturbation should be investigated with individual applicators under applicable clinical conditions.     

Capacitive heating of phantom and human tumors with an 8 MHz radiofrequency applicator (Thermotron RF-8)

The thermal profile was investigated in agar phantoms and in human tumors heated capacitively with 8 MHz RF. Deep and homogeneous heating could be achieved in a large homogeneous phantom of 25 cm diameter and 24 cm thick when heated with a pair of 25 cm diameter electrodes, coupled to both bases of the phantom. When the size of the two electrodes was not the same, the region near the smaller electrode was preferentially heated. It was, therefore, possible to control the depth of heating by choosing properly sized electrodes. Therapeutic temperature (greater than 42 degrees C) could be obtained in 7 out of 9 small, as well as, bulky superficial human tumors as large as 8 X 8 X 10 cm. Indications are that heating of some deep-seated human tumors might be achieved by the capacitive method, provided that subcutaneous fat layer is cooled by temperature controlled bolus and large electrodes are used. The effect of the anatomical structure on the power deposition in the human body during capacitive heating should be further investigated.     

Sequential activation of multiple grounding pads reduces skin heating during radiofrequency tumor ablation

Purpose: Radiofrequency (RF) tumor ablation has become an accepted treatment modality for tumors not amenable to surgery. Skin burns due to ground pad heating may become a limiting factor for further increase in ablation zone dimensions and generator power. We investigated a method were groups of ground pads are sequentially activated to reduce skin heating.

Methods: We compared conventional operation (i.e. simultaneous connection of all pads) to sequentially switched activation of the pads where different pad combinations are active for periods of ～0.3 - 8 s. The timing during sequential activation was adjusted to keep the leading edge temperature equal between the pads. We created Finite Element Method computer models of three pads (5 × 5 cm, 1 cm apart) placed in line with the RF electrode on a human thigh to determine differences in tissue heating during simultaneous and sequential ground pad activation. We performed experiments with three ground pads (5 × 10 cm, 4 cm apart) placed on a tissue phantom (1.5 A, 12 min) and measured pad surface and leading edge temperatures.

Results: Temperature rise below the leading edge for proximal, middle and distal ground pad in relation to active electrode location was 5.9°C ± 0.1°C, 0.8°C ± 0.1°C and 0.3°C ± 0.1°C for conventional operation, and 3.3°C ± 0.1°C, 3.4°C ± 0.2°C and 3.4°C ± 0.2°C for sequentially activated operation in the experiments (p < 0.001).

Conclusion: Sequential activation of multiple ground pads resulted in reduced maximum tissue temperature. This may reduce the incidence of ground pad burns and may allow higher power RF generators.     

Potential applicability of clinical hyperthermia using a Thermotron-RF8 as assessed from thermal distribution in an agar phantom containing hydroxyapatite

We have already reported the antitumour effect of hydroxyapatite (HAP) containing anticancer drugs. In this study, we found an increased temperature effect around HAP particle(s) in an agar phantom in comparison with other areas when a Thermotron-RF8 (RF generator) was used for heating. Furthermore, it was revealed that the quantity of doxorubicin hydrochloride (DOX) released from HAP containing the drug (DOX-HAP complex) was increased by raising the temperature. These results indicated that the antitumor effect of the DOX-HAP complex + hyperthermia system was greater than that of either the DOX-HAP complex or hyperthermia system alone.     

A method of MRI-based thermal modelling for a RF phased array

Magnetic Resonance Imaging (MRI) is an attractive method of temperature monitoring in vivo due to its non-invasive nature. The natural extension of this temperature monitoring is to implement temperature control. This work outlines a method of MRI-based thermal modelling for multi-source phased array heating systems that can potentially be employed, in the future, for real time temperature prediction and control. This method is based on Pennes bioheat equation. It employs the superposition of an empirically acquired basis set of temperature distributions that define the heating system's temperature response. MR thermal images based on the proton resonance frequency shift (PRFS) technique are used to acquire this basis set. The feasibility of this approach is tested in phantom using a radiofrequency (RF) heating system. The results show that this method can accurately reproduce measured temperature distributions outside of the basis set.     

Heating patterns induced by a 13.56 MHz radiofrequency generator in large phantoms and pig abdomen and thorax

Heating patterns generated by a commercially available 13.5 MHz radiofrequency generator and induction coil hyperthermia system in human size phantoms and a 230 pound pig were studied using a multichannel computermonitored thermometry system that is noninteractive in electromagnetic fields. The phantom studies were composed of synthetic muscle equivalent material and fresh tissue. The pig was heated in the regions of the upper abdomen and the midthorax, both under anesthesia and dead. The temperature was measured along fine penetrating catheters at 1 cm intervals in all experiments. In a homogeneous cylindrical phantom, under our measurement conditions, the temperature profile across the diameter is parabolic with marked superficial heating and essentially no central heating. In nonhomogeneous phantoms and in the pig, the symmetry of this profile was distorted but the basic pattern of marked superficial heating and nearly absent deep central heating remained. Blood flow in the living animal produced some thermal smoothing. It is considered probable that substantial radial temperature gradients will exist within eccentrically located human tumors heated with this device and that certain deep central tumors will be difficult or impossible to heat. Determination of its ultimate value for investigational clinical hyperthermia studies will require accurate temperature mapping of tumors and normal tissues in various anatomic sites in comparison with other approaches to deep heating.     

CDRH RF phantom for hyperthermia systems evaluations

The National Cancer Institute (NCI) sponsored clinical evaluations of investigational 'regional' hyperthermia systems at four clinical institutions. To support this project, the Center for Devices and Radiological Health (CDRH) developed a series of test instruments to evaluate the magnitude and repeatability of the induced heating by radiofrequency (RF) systems. Data from three institutions using the same model hyperthermia system have been analyzed. After heating, the average temperature from measurements taken at several points in the test phantom at each institution agree within +/- 0.002 degrees C. These differences are about equal to the measurement uncertainty. Thus, this technique can be used for preclinical evaluation and quality control of the total system operation. After one of the institutions relocated its hyperthermia system, a subsequent set of data showed inconsistencies compared to their earlier data. Investigation traced this to cable loss and power meter interference. From the analysis of the data from the three institutions, the utility of the CDRH RF phantom for hyperthermia systems evaluation is demonstrated.     

Computer modeling of the effect of perfusion on heating patterns in radiofrequency tumor ablation.

PURPOSE: To use an established computer simulation model of radiofrequency (RF) ablation to further characterize the effect of varied perfusion on RF heating for commonly used RF durations and electrode types, and different tumor sizes. METHODS: Computer simulation of RF heating using 2-D and 3-D finite element analysis (Etherm) was performed. Simulated RF application was systematically modeled on clinically relevant application parameters for a range of inner tumor perfusion (0-5 kg/m3-s) and outer normal surrounding tissue perfusion (0-5 kg/m3-s) for internally cooled 3-cm single and 2.5-cm cluster electrodes over a range of tumor diameters (2-5 cm), and RF application times (5-60 min; n = 4618 simulations). Tissue heating patterns and the time required to heat the entire tumor +/- a 5-mm margin to > 50 degrees C were assessed. Three-dimensional surface response contours were generated, and linear and higher order curve-fitting was performed. RESULTS: For both electrodes, increasing overall tissue perfusion exponentially decreased the overall distance of the 50 degrees C isotherm (R2 = 0.94). Simultaneously, increasing overall perfusion exponentially decreased the time required to achieve thermal equilibrium (R2 = 0.94). Furthermore, the relative effect of inner and outer perfusion varied with increasing tumor size. For smaller tumors (2 cm diameter, 3-cm single; 2-3 cm diameter, cluster), the ability and time to achieve tumor ablation was largely determined by the outer tissue perfusion value. However, for larger tumors (4-5 cm diameter single; 5 cm diameter cluster), inner tumor perfusion had the predominant effect. CONCLUSION: Computer modeling demonstrates that perfusion reduces both RF coagulation and the time to achieve thermal equilibrium. These results further show the importance of considering not only tumor perfusion, but also size (in addition to background tissue perfusion) when attempting to predict the effect of perfusion on RF heating and ablation times.     

A method of MRI-based thermal modelling for a RF phased array.

Magnetic Resonance Imaging (MRI) is an attractive method of temperature monitoring in vivo due to its non-invasive nature. The natural extension of this temperature monitoring is to implement temperature control. This work outlines a method of MRI-based thermal modelling for multi-source phased array heating systems that can potentially be employed, in the future, for real time temperature prediction and control. This method is based on Pennes bioheat equation. It employs the superposition of an empirically acquired basis set of temperature distributions that define the heating system's temperature response. MR thermal images based on the proton resonance frequency shift (PRFS) technique are used to acquire this basis set. The feasibility of this approach is tested in phantom using a radiofrequency (RF) heating system. The results show that this method can accurately reproduce measured temperature distributions outside of the basis set.     

Performance and use of current sheet antennae for RF-hyperthermia of a phantom monitored by 3 tesla MR-thermography

Several MR-compatible current sheet antennae (CSA) of different height ( h ) (16cm ( l ) &#50 8cm ( w ) &#50 1-5cm ( h )) were built for simulated RF (96MHz) hyperthermia of a medium-sized (12 l ) tissue-equivalent phantom inside a 3 tesla whole body tomograph. Prior to use, efficiencies of the CSA were determined by network analysis and by calorimetry. Depending on the height h of the CSA and on the thickness d bolus of the water bolus used for RF-coupling of the CSA to the lossy medium, their efficiency varied between 20-70% and the CSA with h = 3cm was selected for simulated RF hyperthermia. During heating, spatial temperature distributions (20-42°C) of five slices (voxel size 2 &#50 2 &#50 10mm 3 ) were recorded intermittently within 4 s/slice by measuring the temperature dependent shift of the 1 H resonance frequency (125.32MHz). A phased array consisting of two identical CSA produced distinctly different spatial temperature distributions at 0 and 180° phase difference between both RF channels feeding the antennae. Within a one-dimensional heat diffusion model, the specific absorption rate (SAR) of the electromagnetic wave generated by a single antenna was deduced from the experimental data resulting in a penetration depth (1/e 2 ) of ~4cm.     

Effect of functional magnetic particles on radiofrequency capacitive heating.

Magnetic particles (magnetite) were used to make radiofrequency (RF) capacitive hyperthermia effective to a specific site. In an agar phantom experiment, a magnetite-containing agar piece was buried in a large agar phantom and heated by an 8 MHz-RF capacitive heating device. The magnetite-containing agar piece was heated more than the magnetite-free agar phantom, and the specific adsorption rate in the phantom was increased 1.5 times by the magnetite particles. The temperature distribution in the large agar phantom showed that the highest temperature was obtained at the center of the magnetite-containing piece. The rate of temperature increase was approximately proportional to the magnetite concentration to the power 0.8. This method was applied to an in vivo experiment using a pig. Magnetite was prepared as a colloidal material dispersed in a carboxymethylcellulose solution (CMC-Mag) and intramuscularly injected in the pig femur. As a result of 8 MHz-RF heating, the temperature at the CMC-Mag-injected point increased to over 43 degrees C after 7 min, while the temperature at a point without magnetite was under 40 degrees C at the same time. The specific adsorption rate in the magnetite-containing tissue was twice that of the magnetite-free tissue. In addition, the time required to reach a temperature of over 43 degrees C was only 7 min, while it was over 15 min in the case without the CMC-Mag.     

Performance and use of current sheet antennae for RF-hyperthermia of a phantom monitored by 3 tesla MR-thermography.

Several MR-compatible current sheet antennae (CSA) of different height (h) (16 cm (l) x 8 cm (w) x 1-5 cm (h)) were built for simulated RF (96 MHz) hyperthermia of a medium-sized (12l) tissue-equivalent phantom inside a 3 tesla whole body tomograph. Prior to use, efficiencies of the CSA were determined by network analysis and by calorimetry. Depending on the height h of the CSA and on the thickness d(bolus) of the water bolus used for RF-coupling of the CSA to the lossy medium, their efficiency varied between 20-70% and the CSA with h = 3 cm was selected for simulated RF hyperthermia. During heating, spatial temperature distributions (20-42 degrees C) of five slices (voxel size 2 x 2 x 10mm(3)) were recorded intermittently within 4 s/slice by measuring the temperature dependent shift of the (1)H resonance frequency (125.32 MHz). A phased array consisting of two identical CSA produced distinctly different spatial temperature distributions at 0 and 180 degrees phase difference between both RF channels feeding the antennae. Within a one-dimensional heat diffusion model, the specific absorption rate (SAR) of the electromagnetic wave generated by a single antenna was deduced from the experimental data resulting in a penetration depth (1/e(2)) of approximately 4 cm.     

An investigation into the combined effects of X-irradiation and microwave heating on pig skin

An investigation has been made of the effects of microwave heating in enhancing the radiation response of pig skin following exposure to X-rays. Areas on the flanks of pigs were treated with X-rays alone or with X-rays followed by heating for 90 minutes at either 42°C or 44°C. Treatment was given as either a single dose or as three fractions over six days. Microwave heating was produced by two types of direct contact applicator operating at a frequency of 2450 MHz. Skin temperature was monitored with a liquid crystal thermometer and with thermocouples. The early skin reaction was scored quantitatively up to 16 weeks following treatment. The thermal enhancement ratios (TER's) measured were close to unity for all treatments. For single dose treatments and heating at 42°C for 90 minutes, the TERwas 1.05. For the three fraction treatments, the TER was found to be 1.1 when heat treatment was either 42°C/90 minutes or 44°C/90 minutes. Such TER values are in general agreement with those recommended by the Radiation Therapy Oncology Group (RTOG) in North America.     

Non-invasive thermometry using magnetic resonance diffusion imaging: potential for application in hyperthermic oncology.

The proposition to use non-invasive thermometry based on magnetic resonance diffusion imaging for applications in therapeutic hyperthermia is examined. The measurement of proton motion predominantly associated with the self-diffusion of water can be characterized by a Boltzmann temperature dependence (i.e. e-Ea/kT). The activation energy (Ea) is on the order of 0.2 eV and, for a restricted range (approximately 30 degrees) at a base temperature of approximately 300 K, the relationship between the effective diffusion coefficient and temperature is approximately linear. This response has been empirically demonstrated in water-based gel phantoms using magnetic resonance imaging (MRI). Additionally, it is feasible to have compatibility between radiofrequency (RF) heating devices and MRI equipment. An MRI-compatible heating applicator that includes a hexagonal array of coherently phased dipoles was assembled. This heating array easily fits into a standard 1.5 T head imaging coil (diameter 28 cm). The RF fields associated with heating (130 MHz) and imaging (64 MHz) were decoupled using bandpass filters providing isolation in excess of 100 dB. This isolation was sufficient to allow simultaneous imaging and RF heating without deterioration of the image signal-to-noise ratio. In this report temperature, spatial and time resolution achieved in phantom are examined in order to assess the potential for using this non-invasive temperature measurement in applications of hyperthermic oncology. Using this system and conventional multi-slice imaging techniques, 0.5 degrees C resolution in a voxel size of less than 1 cm3 has been achieved using an acquisition time of 4.15 min.