Investigating Direct Current Stimulation of Wounded Cell Collectives via Bioelectronic Microfluidic Wound Healing: A Review

Upon cutaneous injury, the human body naturally heals the injured area by developing an endogenous electric field (EF) that guides cellular and tissue repair complexes towards the wound site. The resulting Direct Current (DC) ionic flow, generated by disruption of the transepithelial potential, influences a variety of biological processes relevant to wound repair. This DC stimulation can impact both diabetic and healthy in vitro keratinocyte tissues to clarify the effects of EF/DC stimulation on wound healing dynamics. Keratinocytes constitute the predominant cell type in the human epidermis, forming densely packed lateral layers that migrate collectively during wound closure. A bioelectronic microfluidic platform was developed to study the effects of different EF spatial configurations on wound gap closure using non-metal, pseudocapacitive PEDOT:PSS hydrogel-coated laser-induced graphene electrodes combined with prudent microfluidic channel architecture. Two spatial stimulation strategies were rigorously examined: unidirectional EF (electrotactically closing a wound from one edge) versus pseudo- converging EF (alternately polarizing both wound edges). Unidirectional electrical guidance cues proved superior in driving collective keratinocyte healing dynamics, accelerating wound closure rates by approximately three-fold for both healthy and diabetic-like keratinocyte collectives compared to pseudo- converging EF and non-stimulated controls. Under unidirectional electrical stimulation, motility- inhibited diabetic-like keratinocytes recovered wound closure rates (increasing from 1.0 to 2.8% h−1) comparable to healthy, non-stimulated counterparts (3.5% h−1). The results support the hypothesis that regulated electrical stimulation represents a practical therapeutic strategy for accelerating wound healing, particularly in chronic wound contexts. These findings also establish a translational baseline for optimizing electrode design for in vivo DC stimulation applications in regenerative medicine.