Modeling a Conventional Electroporation Pulse Train: Decreased Pore Number, Cumulative Calcium Transport and an Example of Electrosensitization

Pulse trains are widely used in electroporation (EP) for both general biomedical research and clinical applications such as nonthermal tumor ablation. Here we use a computational method based on a meshed transport network to investigate a cell system model's response to a train of identical, evenly spaced electric field pulses. We obtain an unexpected result: the number of membrane pores decreases during the application of twenty 1.0 kV/cm, 100 mu s pulses, delivered at 1 Hz. This pulse train initially creates 13,000 membrane pores, but pore number decreases by a factor of 15 to about 830 pores throughout subsequent pulses. We conclude that pore number can greatly diminish during a train of identical pulses, with direct consequences for the transport of solutes across an electroporated membrane. Although application of additional pulses is generally intended to increase the effects of EP, we show that these pulses do not significantly enhance calcium delivery into the cell. Instead, calcium delivery can be significantly increased by varying inter-pulse intervals. We show that inserting a 300-s interruption midway in a widely used eight-pulse train (a protocol for electrosensitization) yields a similar to twofold delivery increase. Overall, our modeling shows support for electrosensitization, in which multiple pulse protocols that maximize pore number over time can yield significant increase of transport of calcium compared to standard pulse trains.