Multimodal in vitro biocompatibility assessment of functionalized PEDOT neural interfaces

Conductive polymers such as poly(3,4-ethylenedioxythiophene):polystyrene sulfonate (PEDOT:PSS) have emerged as promising neural interface materials due to their favorable electrochemical and mechanical properties. However, biological assessment of new bioelectrode coatings remains dependent on conventional cytotoxicity assays and animal studies, providing limited insight into cell-material interactions. Here, we present a multimodal in vitro framework for evaluating the biocompatibility of functionalized PEDOT coatings as neural interfaces. Standard PEDOT:PSS, functionalized PEDOT:polydopamine (PDA), and PEDOT:dopamine-grafted hyaluronic acid (DAHA) coatings were characterized electrochemically and assessed using SH-SY5Y cells through viability measurements, profilometry, 3D reconstruction, immunofluorescence imaging, and targeted gene expression analysis. While all coatings support cell viability, substrate-dependent differences were observed in cellular organization, multicellular aggregation, extracellular-matrix- and focal-adhesion-associated architecture, and the expression of genes related to cell-matrix interactions and intercellular communication. Our findings demonstrate mechanistic insights surpassing conventional tests, a valuable intermediate step to guide material development prior to in vivo experiments.