In this work, complex and advanced multiphysics and multiscale models of a 2D virtual induced neuronal stem cell (iNSC) and a mesenchymal stem cell (MSC) are presented to estimate the biophysical effects induced by microsecond-duration pulsed electric fields (µsPEFs) for neurogenesis purposes. Particularly, this study is part of the RISEUP project, which aims to promote axonal regeneration in spinal cord injuries by manipulating stem cells within an electropulsed bio-hybrid (EPB) device. This device delivers tailored µsPEF protocols to induce electropermeabilization of plasma and intracellular membranes. The two key focuses of this work are the development of a neurofunctionalized iNSC model and, for the first time in the literature, of a calcium oscillations model on the virtual MSC, to assess the impact of µsPEFs on iNSC neuronal dynamics and on changes in ionic fluxes across electroporated MSC membranes, respectively. Numerical simulations are carried out in COMSOL Multiphysics (v. 6.2) using a bipolar µsPEFs with a combination of 30 and 60 kV/m field intensities with 100 and 1000 µs durations. Results demonstrate that the µsPEF application affects iNSC neuronal firing: fully silenced at 60 kV/m, and partially suppressed at 30 kV/m, with activity resuming poststimulation at both pulse durations. Moreover, µsPEF can extend calcium oscillation periods up to 50%, highlighting their potential to modulate calcium dynamics and steer stem cell fate, supporting the core RISEUP mechanisms of proliferation and differentiation. The multiphysics methodologies implemented are crucial to deeply investigate the cellular mechanisms underlying the RISEUP approach, thereby unveiling key processes driving neural regeneration and paving the way for innovative, targeted therapies. © 2025 Mary Ann Liebert (NY), Inc.

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