CeO2-Loaded Shear-Thinning Hydrogel Combined with Dental Pulp Stem Cells Modulates the Oxidative-Inflammatory Microenvironment To Enhance Facial Nerve Regeneration

Stem cell transplantation holds great promise for facial nerve repair, yet its efficacy is largely constrained by the excessive accumulation of reactive oxygen species (ROS) and the highly inflammatory microenvironment. Thus, developing bioactive scaffolds with robust antioxidant capacity for stem cell transplantation remains a challenge. In this study, an injectable and self-healing composite hydrogel composed of chitosan, graphene oxide, and cerium oxide nanoparticles (CeNPs) was developed to provide structural support for the neural conduit, create a favorable microenvironment for human dental pulp stem cells (hDPSCs), and effectively promote facial nerve regeneration. The hydrogel exhibited intrinsic shear-thinning, self-recovery, and self-healing properties, ensuring its adaptability to irregular nerve defects and suitability for minimally invasive delivery, while its ROS-scavenging activity effectively reshaped the injury microenvironment to mitigate oxidative stress and inflammatory responses in the transplanted cells. In vitro, the composite hydrogel promoted the specific migration of hDPSCs, while alleviating cellular oxidative damage by modulating the PI3K/AKT signaling pathway to facilitate M2 polarization of macrophages. In a facial nerve defect model, treatment with the hydrogel in combination with hDPSCs significantly improved neurological function and tissue regeneration, achieving morphological and functional outcomes comparable to those of autologous nerve grafts. Collectively, this CeNPs-integrated hydrogel provides adaptive structural support, modulates the injury microenvironment, and promotes stem cell migration, representing a promising bioactive platform with clinical translational potential for facial nerve repair.