The Neural Symphony in the Periodontium: Health, Inflammation, and Regeneration.

Periodontal nerves, comprising sensory, sympathetic, and parasympathetic fibers, are essential components of the periodontium. Beyond their classic sensory and proprioceptive functions, these neural networks actively modulate periodontal immune responses, bone remodeling, and tissue regeneration. They orchestrate tissue homeostasis by releasing specific neuropeptides, neurotransmitters, and neurotrophic factors. The progression of periodontitis is intimately linked to neural dysregulation, where proinflammatory mediators (e.g., excessive substance P and sympathetic catecholamines) overpower protective signals (e.g., calcitonin gene-related peptide and parasympathetic acetylcholine). Conversely, successful periodontal regeneration requires the restoration of this neural equilibrium. Nerve terminals rapidly sprout into osteogenic zones during early repair. Subsequently, their spatiotemporally patterned signaling suppresses osteoclastogenesis and promotes the osteogenic differentiation of stem cells. Crucially, these local neural networks function as a bidirectional conduit linking the periodontium to the central nervous system: systemic stressors (eg, sleep deprivation and chronic stress) can compromise ganglionic autophagy or trigeminal function to exacerbate periodontal bone loss, while periodontal pathogens can reciprocally exploit these pathways to induce central neuroinflammation. Recognizing this interconnected oral-neural-brain axis not only explains why certain periodontitis-susceptible patients remain refractory to conventional therapies but also highlights the broader impact of periodontal inflammation on neurodegenerative risk. Furthermore, nerve-targeted strategies, including neurotrophin-functionalized biomaterials, local neuropeptide delivery, and bioelectric neuromodulation, offer promising approaches to resolving refractory inflammation, restoring periodontal integrity, and concurrently mitigating the risk of associated central neuroinflammation. In this review, we comprehensively characterize the spatiotemporal plasticity of periodontal nerves under physiological and pathological conditions. We dissect the molecular mechanisms linking neural signaling to periodontal immunity and repair, and highlight how integrating neurobiology into periodontology could advance the development of next-generation regenerative medicine.