Time-multiplexed two-channel capacitive radiofrequency hyperthermia with nanoparticle mediation
© Kim et al. 2015
Received: 29 July 2015
Accepted: 12 October 2015
Published: 24 October 2015
Capacitive radiofrequency (RF) hyperthermia suffers from excessive temperature rise near the electrodes and poorly localized heat transfer to the deep-seated tumor region even though it is known to have potential to cure ill-conditioned tumors. To better localize heat transfer to the deep-seated target region in which electrical conductivity is elevated by nanoparticle mediation, two-channel capacitive RF heating has been tried on a phantom.
We made a tissue-mimicking phantom consisting of two compartments, a tumor-tissue-mimicking insert against uniform background agarose. The tumor-tissue-mimicking insert was made to have higher electrical conductivity than the normal-tissue-mimicking background by applying magnetic nanoparticle suspension to the insert. Two electrode pairs were attached on the phantom surface by equal-angle separation to apply RF electric field to the phantom. To better localize heat transfer to the tumor-tissue-mimicking insert, RF power with a frequency of 26 MHz was delivered to the two channels in a time-multiplexed way. To monitor the temperature rise inside the phantom, MR thermometry was performed at a 3T MRI intermittently during the RF heating. Finite-difference-time-domain (FDTD) electromagnetic and thermal simulations on the phantom model were also performed to verify the experimental results.
As compared to the one-channel RF heating, the two-channel RF heating with time-multiplexed driving improved the spatial localization of heat transfer to the tumor-tissue-mimicking region in both the simulation and experiment. The two-channel RF heating also reduced the temperature rise near the electrodes significantly.
Time-multiplexed two-channel capacitive RF heating has the capability to better localize heat transfer to the nanoparticle-mediated tumor region which has higher electrical conductivity than the background normal tissues.
Capacitive radiofrequency (RF) hyperthermia is one of the hyperthermia methods that aim to selectively induce cancer cell death by delivering heat to the cancer tissues [1, 2]. It is well recognized that cancer cells are more prone to death by heat than normal cells due to limited blood supply to the cancer tissues during heating . Capacitive RF hyperthermia systems, mostly operated at the frequency of 13.56 MHz because of its public availability for general application, have simple configurations. A typical capacitive RF hyperthermia system consists of a surface electrode pair placed at opposite sides of the tumor region and a RF power system to apply RF potential to the electrodes . RF potential difference produces electric field between the electrode and the electric field induces Joule heating in the tissues. Higher Joule heating in the tumor tissues than in the background tissues are highly desired, and higher electric conductivity of the tumor tissues contributes to higher heat transfer to them to some extent. However, since the electrodes are directly contacted to the patient’s skin, higher current density and hence higher heat transfer inevitably appear at the contact region. Even though the electrode has a cooling layer, skin burning may happen nearby the electrode, which may complicate the RF hyperthermia treatment.
In addition to skin burning, there is another big problem in capacitive RF hyperthermia, that is, poorly localized heat transfer. Unlike ultrasound or microwave hyperthermia in which an array of transducers or antennae are employed to focus the energy delivery to the tumor region, capacitive RF hyperthermia only relies on higher electric conductivity of tumor tissues to draw more electric currents to the tumor tissues than to the surrounding normal tissues . However, the conductivity difference between the normal and tumor tissues are not so big as to draw substantially higher electric currents to the tumor region. To increase electric current density at the tumor region, nanoparticles coupled with salts may be employed [5–9]. There have been a few reports that nanoparticles coupled with salts can increase the electric conductivity at the nanoparticle-populated region [10, 11].
In this paper, a new method is introduced to better localize heat transfer to the tumor region with reducing temperature rise near the electrodes in capacitive RF hyperthermia. By employing a cooling layer at the electrode, the skin temperature may be maintained at a desired level during the RF hyperthermia, but, fatty tissues below the skin may not be sufficiently cooled down due to the low thermal conductivity of fatty tissues. To overcome these problems, two electrode pairs, which are placed perpendicularly to one another, are employed in this study. The RF power is then delivered to the electrode pairs in a time-multiplexed way so that only one electrode pair is operating at a time. To monitor the temperature rise all over the interested region, magnetic resonance (MR) thermometry is employed in this study. MR thermometry is based on the linear response of the proton resonance frequency (PRF) of water molecules to the temperature [12–15]. Finite-difference-time-domain (FDTD) simulations on a phantom model, consisting of tumor-tissue-mimicking and normal-tissue-mimicking compartments, has been performed to verify the RF heating experiment inside a 3T MRI magnet with monitoring the temperature inside the phantom. The experimental temperature rise in the phantom is compared with the temperature rise in the FDTD simulation model.
The tissue-mimicking phantom
The normal-tissue-mimicking compartment, the diameter of 100 mm and the height of 110 mm, was made of 2.5 % agarose (Yakuri Pure Chemicals Co., Japan) and 0.125 % CuSO4 solution. CuSO4 ionic solution was mixed to control both electrical conductivity and spin–lattice relaxation time (T1) of agar. CuSO4 shortens T1 of water molecules which can facilitate fast magnetic resonance imaging. The concentration of CuSO4 was determined by a trial-and-error approach to make electrical conductivity be around 0.1 S/m which is similar to the electrical conductivity of muscular tissues. The tumor-tissue-mimicking insert, the diameter of 25 mm and the height of 25 mm, was made of 2.5 % agarose, 0.125 % CuSO4, 4 % carboxymethyl cellulose (Sigma Aldrich, USA) and 0.4 mmol/L Fe3O4 nanoparticle suspension (Magnetite, RND Korea, Korea). The carboxymethyl cellulose (CMC) and magnetic nanoparticle suspension were mixed with the agarose gel at 60 °C with slow whirling for 40 min, and then, the mixed agarose was cooled down slowly for solidification. The average diameter of the magnetic nanoparticles was 17.5 nm.
Electric permittivity and conductivity of the agaroses were measured by a coaxial surface probe (DAK-12, SPEAG, Switzerland) at the temperature of 25 °C and at the frequency of 26 MHz. The frequency range of the coaxial surface probe was from 10 MHz to 3 GHz. The electric conductivity σ of the normal-tissue-mimicking and tumor-tissue-mimicking agaroses are 0.1 and 0.6 S/m, respectively, with the electric permittivity εr of 79 and 80, respectively.
Two-channel RF driving system for RF heating
Electromagnetic and thermal simulation
The SAR distribution computed in the electromagnetic simulation was input to the thermal solver as a heat generator to compute temperature rise inside the phantom. The Pennes bioheat equation was solved with applying Dirichlet boundary condition between the phantom body and the distilled water layer with consideration of cooling effect of the distilled water layer . Dirichlet boundary condition was also applied between the outer acryl frame and the free space. The temperature of the free space was set to 18 °C, the actual ambient temperature of the MRI shield room. It was assumed that the effects of inaccurate boundary condition setting in the FDTD computation be not significant considering the distance from the phantom surface to the region of interest.
Physical parameters for the electromagnetic and thermal simulations
Conductivity σ (S/m)
Relative permittivity εr
Physical density ρ (kg/m ) 3
Specific heat capacity cp (J/kg/K)
Thermal conductivity k (W/m/K)
RF heating experiments with MR thermometry
Ten hours before the RF heating experiment, the phantom was placed in the RF coil to make the thermal equilibrium between the phantom and the ambient space in the MRI shield room. The ambient temperature in the MRI shield room was 18 °C. RF heating was repeated three times, so the total heating time was 24 min. MR thermometry was repeated four times with an additional MR thermometry before the RF heating experiment. The first MR thermometry was for making a reference phase map at the initial temperature of 18 °C. RF heating experiments were performed two times, one in the two-channel heating configuration and another in the one-channel heating configuration. In the one-channel heating experiment, the horizontal channel was chosen arbitrarily, and the channel was driven without switching.
For MR thermometry, the gradient echo imaging sequence was used with the repetition time (TR) and echo time (TE) of 110/10 ms, the flip angle of 60o, and the image matrix size of 128 × 128 over the field of view of 220 × 220 mm. The number of averages was two which made the scan time for each round of MR thermometry be about 30 s. To set a temperature reference in MR thermometry, an optic fiber temperature sensor was placed in the middle of the phantom and the temperature read by MR thermometry was compared with the one read by the optic fiber sensor.
There were some mismatches of temperature patterns between the experiments and simulations, particularly around the insert as noticed in Figs. 8 and 11. In the physical phantom, a thin PVC film with thickness of 0.2 mm was placed between the insert and the background to prevent molecular diffusion across the interface, and the film may have prohibited thermal conduction across the interface. In the simulation model, the thin film was not considered since the film thickness was too small as compared to the FDTD element size. It is thought that the heating was less localized in actual experiments than simulations due to the thin film.
Multi-channel RF heating in a time-multiplexed way can improve spatial localization of heat transfer to the region of interest. RF currents induced by the RF potential applied to the two electrode pairs are piled up together at the region of interest, which in turn increases SAR at the region. To better localize the heat transfer, the shape and position of the electrodes should be optimized along with consideration of the tumor size, tumor position, and the electrical properties of the tissues. In this study, a simple and symmetric phantom has been used with arbitrary choice of the electrode size and position. If the region of interest is not at the center of the body, and if the electrical conductivity and permittivity are not uniform, the electrode optimization will not be a simple task. However, recent developments in EM simulation on realistic human body models, usually derived from 3D medical images of a human subject, would make it feasible to find optimal shape and position of electrodes for clinical practice.
Spatial localization of heat transfer to the region of interest and reduction of temperature rise at the skin region would be improved if more number of channels are employed. Since RF power amplifier output is divided in a time-multiplexed way, a single RF power amplifier with inexpensive switching circuits would suffice for the multi-channel RF heating with the number of channels greater than two. Multi-channel RF heating also reduces the heat loads at the electrodes which would need higher cooling capacity otherwise.
It is observed that the magnetic nanoparticle suspension mixed with CMC elevates the conductivity of the nanoparticle-populated agarose and the elevated conductivity is maintained for a for a few days. This implies that the nanoparticles somehow bind the ions derived from the CMC salts thereby limiting diffusion of ions to outside the nanoparticle-populated region [22, 23]. There have been a few reports that nanoparticles and salts elevate the heat transfer in capacitive RF heating possibly due to the elevated conductivity at the nanoparticle-populated region [10, 11]. In this study, the nanoparticle-populated region has six times higher conductivity than the background region. Considering that much denser magnetic nanoparticles are injected to the tumor region in human studies of magnetic fluid hyperthermia , the conductivity difference in this phantom study, between the nanoparticle-populated region and the background region, would not be unrealistic to emulate the clinical situation. However, the mechanism of conductivity elevation by nanoparticles and salts should be investigated further for the clinical application of nanoparticles in hyperthermia.
MR thermometry was intermittently performed during the RF heating experiment. The phantom was positioned inside the head RF coil and the matching circuits were placed near the coil. With this configuration, little interference was observed between the RF heating devices and the RF coil, and high-quality temperature maps could be obtained. However, for human studies in which large-sized electrodes are employed, coupling between the RF heating devices and the MRI RF system could be so big as to compromise the temperature mapping. Decoupling between them, particularly in high field MRI, would be a technical challenge.
Two-channel capacitive RF heating in a time-multiplexed way can make better localized heat transfer to the nanoparticle-populated tumor region than one-channel heating. In addition to the better localized heat transfer, the two-channel RF heating can reduce the temperature rise near the surface electrodes. With intermittent MR thermometry during RF heating, the temperature rise can be monitored at the region of interest. It is expected that time-multiplexed multi-channel RF heating would greatly facilitate capacitive RF hyperthermia which suffers from excessive temperature rise near the electrodes and poorly localized heat transfer to the tumor region.
KS carried out the implementation of the idea, the FDTD simulation, the RF heating and MR thermometry experiments, and data analysis. He also drafted the manuscript. Daniel participated in the design of the RF circuits. SY conceived of this study, participated in its design, analysis and interpretation of the data. He also helped to draft the manuscript and finalized the manuscript. All authors read and approved the final manuscript.
This work was supported by the National Research Foundation (NRF) of Korea funded by the Korean government (No: NRF-2013-R1A2A2A03006812) and Samsung Electronics. Special thanks to ZMT for providing free license of Sim4Life used in this study.
The authors declare that they have no competing interests.
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