Neuro-Instructive Hydrogels - A Key to Sensory Innervation in Oral Tissues: A Comprehensive Review

Current treatments for oral tissue defects restore structure but rarely restore sensory nerves. Tissues without innervation lose protective reflexes and long-term stability. This review examines neuro-instructive hydrogels designed to guide nerve regeneration in oral tissues. We discuss four design mechanisms: physical cues that direct axon growth, spatiotemporal release of neurotrophic signals, regulation of oral stem cells and Schwann cells, and immunomodulation that supports a pro-regenerative niche. We then map these mechanisms onto three clinical scenarios: regeneration of the dentin-pulp complex, reconstruction of innervated jawbone, and repair of oral mucosal nerves. The oral environment imposes specific constraints (saliva, chewing forces, and a rich microbiome) that call for wet-adhesive, antibacterial, and mechanically adaptable designs. Bioprinting offers a route to patient-specific constructs with controlled architecture, and emerging tools such as stimuli-responsive release and machine learning guided formulation may further improve precision. Key next steps include scalable production under Good Manufacturing Practice, large-animal validation, and objective clinical endpoints for sensory recovery. The central goal is to move oral tissue repair from structural filling toward restoration of sensation.