A unique aspect of electrostimulation (ES) with nanosecond electric pulses (nsEP) is the inhibition of effects when the polarity is reversed. This bipolar cancellation feature makes bipolar nsEP less efficient at biostimulation than unipolar nsEP. We propose to minimize stimulation near pulse-delivering electrodes by applying bipolar nsEP, whereas the superposition of two phase-shifted bipolar nsEP from two independent sources yields a biologically-effective unipolar pulse remotely. This is accomplished by electrical compensation of all nsEP phases except the first one, resulting in the restoration of stimulation efficiency due to cancellation of bipolar cancellation (CANCAN-ES). We experimentally proved the CANCAN-ES paradigm by measuring YO-PRO-1 dye uptake in CHO-K1 cells which were permeabilized by multiphasic nsEP (600 ns per phase) from two generators; these nsEP were synchronized either to overlap into a unipolar pulse remotely from electrodes (CANCAN), or not to overlap (control). Enhancement of YO-PRO-1 entry due to CANCAN was observed in all sets of experiments and reached ~3-fold in the center of the gap between electrodes, exactly where the unipolar pulse was formed, and equaled the degree of bipolar cancellation. CANCAN-ES is promising for non-invasive deep tissue stimulation, either alone or combined with other remote stimulation techniques to improve targeting.

Introduction: A method that utilizes nanosecond bipolar cancellation (BPC) near a quadrupole electrodes to suppress a biological response but cancels the distal BPC at the quadrupole center, i.e., cancellation of cancellation (CANCAN), may allow for a remote focused stimulation at the quadrupole center. Objectives: The primary object of this study was to outline the requirement of the CANCAN implementation and select an effective quadrupole configuration. Results: We have studied three quadrupole electrode configurations, a rod quadrupole, a plate quadrupole (Plate-Q), and a resistor quadrupole. The pulse shapes of electric fields include monophasic pulses, cancellation pulses, and additive pulses. The Plate-Q appears the best for CANCAN as it shows the highest percentage of cancellation pulses among all pulse shapes, allowing for the best spatial focus. Conclusion: For the region of interest characterized in the Plate-Q configuration, the maximum magnitude of bipolar field is twice as that of the unipolar field, which allows for the CANCAN demonstration that involves membrane electropermeabilization.

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