Gamma-distributed energy heterogeneity modulates pulsed electric field ablation efficacy in millimeter-scale multicellular monolayers

Abstract

Numerical models evaluating macroscopic pulsed electric field (PEF) efficacy typically neglect multicellular heterogeneity and assume homogeneous absorbed energy to reduce computational costs. In this Letter, through theoretical analyses from maximum information entropy methods and finite-element simulations of a realistic millimeter-scale monolayer (1393 cells in a 1 mm2 square target), we demonstrate that cellular absorbed energy universally follows a gamma distribution in response to a single pulse, remaining invariant across pulsed types, cell types, and observation scales. We propose a dimensionless heterogeneity metric h (0–1) derived from gamma distribution, to quantify local fluctuations of absorbed energy. Results show h exhibits a hyperbolic tangent dependence on the pulsed width, independent of the field strength. In vitro experiments confirm that the dimensionless h also critically governs PEF efficacy: Reduced h exponentially enhances the response rate of high-dose phase in the survival curves. Real-time fluorescence damage kinetics (169 cells) further validate the gamma-distributed energy pattern. This work uncovers spatial heterogeneity as an essential predictor for PEF efficacy, which advances the resolution setting of theoretical models for PEF efficacy prediction.