Burst and Continuous High Frequency Irreversible Electroporation Protocols Evaluated in a 3D Tumor Model.

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 mu s pulses are rapidly repeated 24-50 times to create a 48-100 mu s long energy burst. Bursts are repeated 100x 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 x 100 mu s positive polarity pulses) resulted in a lethal electric field threshold of 423 V cm(-1). Baseline H-FIRE treatments (100 x 100 mu s bursts of 2 mu s pulses) resulted in a lethal threshold of 818 V cm(-1). Increasing the number of H-FIRE bursts from 100x to 1000x reduced the lethal threshold to 535 V cm(-1). An alternative diffuse H-FIRE protocol, which delivers 4 mu s pulse cycles (one positive and one negative 2 mu s 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 cm(3) (1.7 cm diameter) and a maximum H-FIRE ablation volume of 5.3 cm(3) (2.4 cm diameter) when a clinical electrode and grounding pad configuration is used. Ablations as large as 15.7 cm(3) (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.