Objectives: in recent biomedical applications for regenerative and tissue engineering, the use of electric and magnetic fields is increasingly exploited. Among the wide application range, an innovative treatment for Spinal Cord Injury (SCI) is urgent. The European project RISEUP proposes a novel device development, that will provide highly intense microsecond pulsed electric fields (µsPEFs) to stimulate stem cells differentiation towards neuronal phenotypes, through an electroporation-driven process, and regenerate the lesioned tissue. Within RISEUP the use of advanced computational models is crucial to predict the cellular functional response through microdosimetry studies. Technology or Method: a multiphysic neuro-functionalized computational model has been built, using a realistic induced Neuronal Stem Cell (iNSC) model (a iNSC digital twin), to predict the effect of µsPEFs stimulation on both neuronal response and pore formation dynamics. Results: considering a 100-µsPEF and an intensity of 30 kV/m, the pore density can reach up to 10¹⁴ m⁻² over the plasma membrane, with a consequent hyperpolarization and a phase shift of the neuronal firing. Whereas, where the pore density remains at its default value 10⁹ m⁻², the neuronal response is slightly affected in spikes frequency and shape, but still maintaining its firing functions. Conclusions: this study provides an innovative multiphysics implementation on a realist 2D iNSC model, that has demonstrated the 100-µsPEF influence on the neurodynamic response. Clinical or Biological Impact: the results obtained give powerful insights for further in vitro and in vivo experiments, that will validate the use of the device proposed within RISEUP for SCI regeneration. © 2025 Elsevier B.V., All rights reserved.

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