Crosslinked hyaluronic acid-doped polypyrrole: Stable, nonbiofouling implantable bioelectrodes for in vivo signal recording

Implantable bioelectrodes with biomimetic and antibiofouling properties are essential for reliable long-term signal acquisition in biomedical applications. Hyaluronic acid (HA), a natural biopolymer, has been incorporated into conductive polymers such as polypyrrole (PPy) to produce biomimetic bioelectrodes with enhanced biocompatibility. However, the poor enzymatic stability of HA limits the longevity of HA-doped PPy (PPy/HA) electrodes, resulting in fibrosis and the loss of signal sensitivity. In this study, we developed PPy electrodes doped with crosslinked HA (PPy/cHA) to improve their enzymatic resistance and electrochemical stability in vivo. PPy/HA electrodes were prepared via electrochemical polymerization and subsequently treated with 1,4-butanediol diglycidyl ether to covalently crosslink the surface-exposed HA moieties. This post-crosslinking did not significantly alter the surface morphology, hydrophilicity, impedance, or nonfouling properties of the electrodes. Importantly, upon hyaluronidase treatment, the PPy/HA electrodes exhibited increased impedance and fibroblast adhesion, whereas PPy/cHA retained its original physicochemical and antibiofouling characteristics. Subcutaneous implantation in mice for three weeks revealed significantly reduced fibrotic tissue around the PPy/cHA electrodes. Furthermore, electrocardiogram monitoring revealed that compared to controls, the PPy/cHA electrodes sustained stable signal transmission with a higher signal-to-noise ratio over three weeks. These results highlight the potential of the PPy/cHA electrodes as reliable, nonbiofouling, and implantable bioelectrodes for diverse biomedical applications.