A Sustainable Alternative to PVDF for Neural Tissue Engineering via Piezoelectric PHBV and Cellulose Acetate Fibers

Poly(vinylidene fluoride) (PVDF) is widely used in neural tissue engineering for its strong piezoelectric response, yet its nonbiodegradability and environmental persistence limit its clinical translation. Neural regeneration demands scaffolds that not only replicate the extracellular matrix but also deliver bioelectrical cues to guide neuronal growth. Here, we introduce aligned electrospun fibers of poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) and cellulose acetate (CA) as biodegradable, sustainable alternatives to PVDF for studying how piezoelectricity, surface charge, and nanotopography influence neuronal function. Compared to polycaprolactone (PCL) as a nonpiezoelectric control, the PVDF, PHBV, and CA scaffolds exhibited distinct morphologies and progressively decreasing piezoelectric coefficients. All supported robust adhesion and proliferation of B35 neuronal cells; however, piezoelectric fibers significantly enhanced intracellular Ca²⁺ influx, neurite elongation, and β3-tubulin expression. Both PVDF and PHBV activated the WNT/GSK3β signaling pathway and downregulated the pro-apoptotic BAX/BCL-2 ratio, suggesting enhanced neuroprotective capacity. Notably, while PVDF induced strong Ca²⁺-mediated neuronal maturation through piezoelectric stimulation, PHBV elicited additional antiapoptotic effects, likely linked to 3-hydroxybutyrate metabolism. Together, these findings demonstrate that combining nanoscale alignment, surface charge, and intrinsic piezoelectricity generates a bioelectrically active microenvironment conducive to neuronal regeneration. Importantly, PHBV emerges as a sustainable, biodegradable alternative to PVDF, bridging environmental responsibility with functional performance in neural tissue engineering.