Bioelectric Design of Charged Hydrogels for Stem Cell Fate Control: Fixed-Charge Density, the Ionic Microenvironment, and the Path from Donnan Physics to Regenerative Medicine — A Comprehensive Review
Year: 2026
Type: preprint
Abstract: Regenerative medicine has, for two decades, instructed stem cell fate through two dominant biomaterial levers: biochemical signaling and substrate mechanics. A third, comparatively underexploited axis is now re-emerging with renewed mechanistic clarity — bioelectricity, the endogenous transmembrane voltage (Vmem) and associated ion-channel, pump, and gap-junction activity that non-excitable cells, including human mesenchymal stem/stromal cells (hMSCs), use to encode proliferative and lineage-commitment states. This review synthesizes the literature bridging three historically separate fields — cellular bioelectricity, polyelectrolyte/charged-hydrogel physical chemistry, and hMSC mechanobiology — to evaluate a specific, testable hypothesis: that the fixed-charge density of a hydrogel network can passively shape the local ionic microenvironment surrounding encapsulated cells through Donnan-type ion partitioning, and thereby shift membrane potential and lineage-specific differentiation without external electrical hardware. We trace the mechanistic foundations of bioelectric signaling from excitable to non-excitable tissue, detail the classical and recent physics of fixed-charge/Donnan equilibrium in synthetic and native charged gels, and catalogue the expanding landscape of charge-tunable hydrogel platforms — interpenetrating polymer networks, conductive polymer composites, piezoelectric and self-powered systems, and natural polyelectrolyte matrices — that could serve as delivery vehicles for this design principle. We give particular attention to the confounding pathways (electrostatic protein adsorption, growth-factor sequestration, adhesion-mediated cytoskeletal tension, and antifouling behavior) that are physically coupled to hydrogel charge and that any bioelectric hydrogel study must control for, and we review the measurement toolkit — voltage-sensitive dyes, patch-clamp electrophysiology, genetically encoded voltage indicators, and ion-channel/gap-junction expression assays — available to directly test the hypothesis rather than infer it from differentiation outcomes alone. A worked case study, drawn from a matched anionic/cationic/zwitterionic/neutral poly(ethylene glycol) diacrylate interpenetrating-network hydrogel panel, illustrates how these principles translate into a concrete fabrication and validation pipeline. We close by mapping the current evidentiary gaps in the field, offering a research roadmap for establishing fixed-charge density as a validated, power-free bioelectric design parameter, and surveying the journals in bioelectricity, biomaterials, and stem cell biology where this convergent literature is actively being published. Taken together, the evidence reviewed here indicates that charge-mediated bioelectric signaling is a physically plausible and experimentally tractable, but not yet directly demonstrated, mechanism for hydrogel-based control of stem cell fate — positioning it as one of the more intriguing open questions at the interface of soft-matter physics and regenerative biology.
Source: ChemRxiv
Author: Augustine Odibo
Institution: Villanova University
Language: English
Subfield: Biomaterials
Field: Materials Science
Domain: Physical Sciences
Open Access status: green
OpenAlex ID: W7204783433