Burst and continuous high frequency irreversible electroporation protocols evaluated in a 3D tumor model

Abstract

High frequency irreversible electroporation (H-FIRE) is an emerging cancer therapy which uses bursts of alternating polarity pulses to target and destroy the membranes of cells within a predictable volume. Typically, 2 µs pulses are rapidly repeated 24–50 times to create a 48–100 µs long energy burst. Bursts are repeated 100× at 1 Hz, resulting in an integrated energized time of 0.01 s per treatment. A 3D in vitro tumor model was used to investigate H-FIRE parameters in search of optimal energy timing protocols. Monopolar IRE treatments (100 × 100 µs positive polarity pulses) resulted in a lethal electric field threshold of 423 V cm−1. Baseline H-FIRE treatments (100 × 100 µs bursts of 2 µs pulses) resulted in a lethal threshold of 818 V cm−1. Increasing the number of H-FIRE bursts from 100× to 1000× reduced the lethal threshold to 535 V cm−1. An alternative diffuse H-FIRE protocol, which delivers 4 µs pulse cycles (one positive and one negative 2 µs pulse) continuously at 100 Hz, resulted in the lowest H-FIRE lethal threshold of 476 V cm−1. Finite element simulations using 5 kV pulses predict an IRE ablation volume of 3.9 cm3 (1.7 cm diameter) and a maximum H-FIRE ablation volume of 5.3 cm3 (2.4 cm diameter) when a clinical electrode and grounding pad configuration is used. Ablations as large as 15.7 cm3 (3.3 cm diameter) are predicted for H-FIRE treatments with 10 kV pulses. These results combine to demonstrate the importance of electrode geometry, pulse timing, and clinical delivery protocols for the creation of large clinically meaningful ablations.