Polypyrrole Incorporation Modulates the Structural, Electrochemical, and Biological Performance of Oxidized Hyaluronic Acid Hydrogels

Abstract

Skin wound repair involves coordinated cellular activities regulated by both biochemical and bioelectrical cues. In this study, an electroactive hydrogel system based on oxidized hyaluronic acid (oxi-HA) crosslinked with adipic dihydrazide (ADH) and incorporated with polypyrrole (PPy) was developed and systematically evaluated. The effects of PPy incorporation on hydrogel structure, physicochemical properties, electrochemical behavior, and cellular responses were investigated. FTIR and SEM analyses confirmed successful PPy incorporation within the oxi-HA network, while preserving an interconnected porous structure at low PPy content. Increasing PPy concentration reduced swelling capacity and altered degradation behavior, indicating a transition toward a denser network. Electrochemical measurements demonstrated a PPy-dependent increase in conductivity and electrochemical behavior, accompanied by increased peak-to-peak separation (ΔE_p) at higher PPy content, indicating changes in electrochemical behavior that warrant further investigation. In vitro studies showed that hydrogels with moderate PPy incorporation (PPy-4) maintained high cytocompatibility (> 95%) and supported fibroblast proliferation, whereas excessive PPy content was associated with reduced cell viability. Under daily low-intensity electrical stimulation (20 μA, 5 min/day), PPy-4 hydrogels further enhanced fibroblast proliferation, migration, and upregulated wound-healing–related gene expression (PDGF-A, FGF-2, and TGF-β1). These results indicate that the incorporation of in situ polymerized PPy modulates the structural and electrochemical properties of oxi-HA hydrogels and is associated with composition-dependent differences in cellular responses under electrical stimulation. This study provides an in vitro proof-of-concept for the development of oxi-HA/PPy/ADH hydrogel systems with composition-dependent electroactive properties.