The Impact of Biomaterial Charge on Cells' Bioelectrical Signaling.

backgroundBioelectrical signaling, a collection of electrical currents driven mainly by ionic fluxes and transmembrane potential gradients, is recognized as a central regulator of cell behavior, tissue patterning, and regeneration, extending far beyond classical roles in excitable tissues. While electrically conductive materials are widely used to deliver exogenous stimulation, the specific contribution of intrinsic biomaterial charge (fixed charges, counterions, piezoelectric polarization, electric field) to bioelectrical signaling remains comparatively underexplored. SUMMARY: This review focuses on how charged biomaterials influence bioelectrical signaling and downstream human cell responses. We first outline the fundamentals of bioelectricity, including electrochemical gradients, Nernst potentials, and resting membrane potential as key regulators of ion flux, metabolism, and cell fate. We then discuss major classes of charged biomaterials (charged polymers, ionically conductive hydrogels, piezoelectric systems, and charged nanoparticles) and how their charge density, polarity, and dynamic behavior shape protein adsorption, integrin-mediated signaling, or membrane potential. Mechanistic links between material charge and some signaling pathways are highlighted in the context of cell adhesion, viability, migration, proliferation, and differentiation. Finally, we examine tissue-specific applications in cardiac tissue engineering, bone regeneration, neural interfaces, and skin wound healing and immunomodulation. KEY MESSAGES: Charged biomaterials have the potential to modulate bioelectrical signaling not only through electronic conductivity but also via electrostatic fields, Donnan effects, and piezoelectric or ionic charge transport. The charge density of the biomaterials often plays a more dominant role than charge polarity in regulating protein adsorption and cell proliferation, whereas polarity can bias lineage-specific differentiation and immunomodulation. In many regenerative systems, the effects of charge are confounded with mechanical and biochemical cues; mechanistic studies that isolate charge-driven bioelectric phenomena remain limited. Although it is known that surface charge affects the adaptive and innate immune systems, such as through macrophage polarization, the broader consequences of charge-mediated immune modulation remain inadequately explored. Therefore, a more comprehensive discussion and studies on the cell-biomaterial charge interactions are warranted to advance the field and guide future biomaterial design.