Introduction
Glioblastoma multiforme (GBM) is a highly aggressive and invasive brain
tumor. The World Health Organization (WHO) classifies grade IV glioma as
the most severe form of central nervous system disease. The median
survival rate ranges from 14.6 to 16.7 months, with a five-year survival
rate of merely 5%, even with treatments such as surgery, radiation
therapy, and chemotherapy [1]. Consequently, developing effective
therapies for GBM remains a significant challenge.
Recent studies have demonstrated the potential of electric fields in
cancer treatment. Tumor Treating Fields (TTFields), utilizing
high-frequency alternating current (AC) fields (100-300 kHz), have shown
efficacy in tumor treatment [2-3]. In vitro studies indicate
that TTFields can inhibit cell proliferation at intensities of 1-3 V/cm.
TTFields are hypothesized to disrupt or delay cell division during early
mitotic phases. During cytokinesis, TTFields may induce
dielectrophoretic forces that displace polarizable macromolecules and
ions toward the furrow, causing membrane blebbing and subsequent cell
death [4-5]. TTFields have been clinically validated as an adjuvant
therapy to chemotherapy in GBM treatment and have received FDA approval
as a monotherapy for recurrent GBM.
The Optune system, developed by Novocure Ltd., generates TTFields for
clinical administration. Clinical trials demonstrated a median overall
survival of 20.5 months (16.7-25.0 months) for TTFields combined with
temozolomide, significantly longer than the 15.6 months (13.3-19.1
months) observed with temozolomide alone [6]. TTFields shows a
promising adjuvant therapy for GBM treatment.
Effective TTFields treatment requires high-frequency AC fields (100-300
kHz) with intensities of 1-3 V/cm. However, few studies have addressed
the design of TTFields delivery devices. For research experiment, the
protocol that oscillator or an AC generator, connected to a high voltage
amplifier is usually used to produce AC field with high frequency in the
range from 100 kHz to 300 kHz. In general, Novocure Ltd. also used this
protocol to generate AC field for TTFields experiment by lab researchers
[7-9]. Due to the conflict of interest, they did not open the
structure of clinical apparatus. Optune apparatus consists of the
transducer arrays with insulated electrodes, electric field generator
(set at a frequency of 200 kHz) and battery. Patients receive TTFields
via four transducer arrays delivering 200 kHz electric fields to the
brain. Each transducer array delivers currents ranging from 400 to 1000
mA, typically 900 mA, with head impedance values between 58.6 and 91.2
Ω. The system generates voltages exceeding 50 V and power outputs around
50 W [10-12]. The use of insulated electrodes creates predominantly
capacitive impedance, resulting in displacement currents through the
head. However, the output power is constrained by the limitations of
high-voltage amplifiers. For instance, generating 50 V AC fields
requires matching DC power supplies, with average power consumption
reaching at least 36 W when delivering 1000 mA currents. These technical
constraints pose challenges for developing portable clinical devices
with stable high-power outputs.
With advancements in power electronics, DC/AC inverters have become
widely adopted in industrial applications including induction heating
systems, communication networks, and uninterruptible power supplies
[13-21]. A typical DC/AC inverter comprises a full-bridge inverter
and a resonant tank utilizing PWM control. The full-bridge inverter
generates rectangular pulses, while resonant step-up topologies
(LLC/LCC/LCLC) serve dual functions: filtering to produce AC waveforms
and voltage boosting through high-ratio line-frequency transformers
[22-26]. For instance, Blinov et al. developed a 50 kHz DC/AC
inverter converting 40 V DC to 230 V AC for telecommunications [27],
while Kummari et al. demonstrated a DC/AC inverter achieving 325 V AC
output [28]. High-power DC/AC inverters for UPS and battery systems
typically combine low-voltage SPWM circuits with line-frequency
transformers for voltage amplification [29-30].
High-frequency AC fields (100-300 kHz) constitute the operational
foundation of TTFields devices. Although DC/AC inverters represent a
viable topology for therapeutic high-frequency AC field generation, PWM
control becomes impractical at therapeutic frequencies (>2
MHz) due to excessive switching losses. Resonant step-up converters
(LLC/LCC/LCLC) offer dual advantages: extracting fundamental frequency
components from rectangular pulses while providing voltage gain.
Standard 3.7 V lithium batteries provide portable high-current DC
sources suitable for outdoor TTFields operation, addressing the Optune
system’s requirement for supplemental batteries during mobile use
exceeding one hour [31]. Developing 3.7 V-powered inverters with
optimized high-gain/high-frequency characteristics remains critical for
portable TTFields implementation.
Notably, no prior studies have reported TTFields generation using
capacitive-impedance DC/AC inverters. At therapeutic frequencies,
capacitive impedance may interact with resonant converters, potentially
compromising voltage output. This work implements a 3.7 V-powered
full-bridge inverter with resonant tank to generate 200 kHz therapeutic
fields. An LCLLC topology was developed by integrating a 1:1 line
transformer into the LCLC converter, achieving 17.8× voltage gain (66.0
V). Theoretical analysis guided parameter selection for the modified
circuit, where transformer excitation inductance was optimized to align
the operating frequency with the primary resonance. A prototype
employing four parallel 3.7 V/3200 mAh batteries successfully generated
200 kHz waveforms, maintaining stable AC output for 8.7 hours suitable
for extended outdoor use. This study showed an easy-implemented topology
with a voltage regulation to design the TTFields apparatus.