Asymmetric Waveforms Decrease Lethal Thresholds in High Frequency Irreversible Electroporation Therapies

Abstract

Irreversible electroporation (IRE) is a promising non-thermal treatment for inoperable tumors which uses short (50–100 μs) high voltage monopolar pulses to disrupt the membranes of cells within a well-defined volume. Challenges with IRE include complex treatment planning and the induction of intense muscle contractions. High frequency IRE (H-FIRE) uses bursts of ultrashort (0.25–5 μs) alternating polarity pulses to produce more predictable ablations and alleviate muscle contractions associated with IRE. However, H-FIRE generally ablates smaller volumes of tissue than IRE. This study shows that asymmetric H-FIRE waveforms can be used to create ablation volumes equivalent to standard IRE treatments. Lethal thresholds (LT) of 505 V/cm and 1316 V/cm were found for brain cancer cells when 100 μs IRE and 2 μs symmetric H-FIRE waveforms were used. In contrast, LT as low as 536 V/cm were found for 2 μs asymmetric H-FIRE waveforms. Reversible electroporation thresholds were 54% lower than LTs for symmetric waveforms and 33% lower for asymmetric waveforms indicating that waveform symmetry can be used to tune the relative sizes of reversible and irreversible ablation zones. Numerical simulations predicted that asymmetric H-FIRE waveforms are capable of producing ablation volumes which were 5.8–6.3x larger than symmetric H-FIRE waveforms indicating that in vivo investigation of asymmetric waveforms is warranted.

Avoiding nerve stimulation in irreversible electroporation: a numerical modeling study

“…For this reason, the delivery of bursts consisting of asymmetric bipolar pulses has been proposed and it has indeed been experimentally shown that they significantly reduce the IRE thresholds compared to bursts of regular bipolar pulses (Sano et al 2017). However, due to the charge imbalance of the asymmetric pulses, the stimulation thresholds are also likely to be significantly reduced.…”

“…This contingency was also tested here. Table 3 shows the modeled stimulation thresholds for a nerve termination in a homogeneous field and the IRE thresholds from (Sano et al 2017) for different waveforms. Although the IRE thresholds with asymmetric pulses are reduced about threefold compared to thresholds with symmetric pulses, the excitation thresholds are reduced in more than an order of magnitude.…”

“…(b and c) The same plot for U87 and MDA-MB-231 BR3 cells (IRE data from (Sano et al 2017)) when bursts of bipolar pulses with an energized time of 100 μs and inter-pulse delay of 1 μs are applied (b) and when bursts of bipolar pulses with an energized time of 50 μs and an inter-pulse delay of 1 μs delay are applied (c).…”

Synergistic combinations of short high-voltage pulses and long low-voltage pulses enhance irreversible electroporation efficacy

“…Moreover, Sano et al . 40 found that asymmetric high frequency IRE produced a larger ablation zone compared to symmetric high frequency IRE. On the other hand, Frandsen et al .…”

“…Sano et al . 48 reported that the delivery of ~1 μs pulses leads to the formation of numerous small pores rather than rapid cell membrane destruction caused by pore expansion. Moreover, as we calculated earlier 41 , short high-voltage also suggested that SHV (2 μs) pulses contribute less to pore development and produce small pores, which can recover easily after the pulses.…”