Bioelectronic Direct Current Stimulation at the Transition Between Reversible and Irreversible Charge Transfer

Many biological processes rely on endogenous electric fields (EFs), including tissue regeneration, cell development, wound healing, and cancer metastasis. Mimicking these biological EFs by applying external direct current stimulation (DCS) is therefore the key to many new therapeutic strategies. During DCS, the charge transfer from electrode to tissue relies on a combination of reversible and irreversible electrochemical processes, which may generate toxic or bio-altering substances, including metal ions and reactive oxygen species (ROS). Poly(3,4-ethylenedioxythiophene) (PEDOT) based electrodes are emerging as suitable candidates for DCS to improve biocompatibility compared to metals. This work addresses whether PEDOT electrodes can be tailored to favor reversible biocompatible charge transfer. To this end, different PEDOT formulations and their respective back electrodes are studied using cyclic voltammetry, chronopotentiometry, and direct measurements of H₂O₂ and O₂. This combination of electrochemical methods sheds light on the time dynamics of reversible and irreversible charge transfer and the relationship between capacitance and ROS generation. The results presented here show that although all electrode materials investigated generate ROS, the onset of ROS can be delayed by increasing the electrode's capacitance via PEDOT coating, which has implications for future bioelectronic devices that allow longer reversibly driven pulse durations during DCS.