Interplay of stiffness and conductivity in modulating host immune reactions to conductive hydrogels

Electrically conductive hydrogels (ECHs) that combine mechanical softness with electrical conductivity are emerging as promising materials for implantable electronics and tissue engineering. However, the individual and combined influences of their mechanical and electrical properties on the host immune system remain poorly understood. In this study, we independently controlled stiffness and conductivity in graphene oxide–polyacrylamide (GO/PAAm) hydrogels by varying crosslinker concentration and chemical reduction and examined their effects on macrophage polarization and tissue responses in vitro and in vivo. Four hydrogels with independently tunable stiffness and conductivity were fabricated: low-conductivity soft (LS), low-conductivity rigid (LR), high-conductivity soft (HS), and high-conductivity rigid (HR). Rigid ECHs consistently induced pro-inflammatory macrophage activation and promoted fibrotic collagen deposition. In contrast, conductivity attenuated inflammation in the early stages, regardless of stiffness. Notably, conductivity amplified stiffness-dependent immune responses: high-conductivity soft ECHs suppressed fibrosis, while high-conductivity rigid ECHs exhibited the most severe fibrotic responses. Our studies reveal a previously unrecognized interplay between stiffness and conductivity in shaping early-stage immune reactions to ECHs, providing vital insights for the rational design of immune-compatible ECHs for implantable biomedical devices.