| Summary: | Abstract Irreversible electroporation (IRE) has emerged as an appealing non‐ionizing, non‐thermal ablation therapy, independent of antineoplastic drugs. Limited but successful outcomes in IRE conducted in vivo, in small focal hepatocellular carcinomas (HCC), have been reported. Nonetheless, the electric parameters of IRE are usually delivered in an unplanned manner. This work investigates the integration of computational modeling to hydrogels mimicking the HCC microenvironment, as a powerful framework to: circumvent ethical concerns of in vivo experimentation; safely tune the electric parameters reaching the IRE electric field threshold; and propel the translation of IRE as a routine clinical alternative to the treatment of HCC. Therefore, a parametric study served to evaluate the effects of the pulse amplitude, the number of pulses and electrodes, the treatment time, the hydrogel–tumor size, and the cell type. The ablation extent was surveyed by confocal microscopy and magnetic resonance imaging (MRI) in cylindrical and realistic tumor‐shaped hydrogels, respectively. A large ablation (70%–100%) was verified in all constructs.
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