Biological mechanisms governing the periodontal regenerative microenvironment: cellular crosstalk, extracellular matrix remodelling, and immunomodulation.

Periodontal regeneration is no longer viewed as the simple replacement of lost alveolar bone, but as the reprogramming of a diseased regenerative niche. Predictable repair requires coordinated reconstruction of cementum, periodontal ligament (PDL), and alveolar bone within a chronically infected, inflamed, and mechanically loaded microenvironment. Unlike regeneration in bone, skin or muscle, periodontal regeneration requires reconstruction of an integrated cementum-PDL-bone unit. Success therefore depends not on repair of a single tissue compartment, but on coordinated cementogenesis, PDL fibre insertion, alveolar bone remodelling, vascularization, immune resolution and restoration of load-bearing tooth support. Here, we synthesize current evidence on the cellular, matrix-based, and biomaterial mechanisms that regulate this process. Periodontal ligament stem cells, PDL fibroblasts, macrophages, endothelial cells, osteoclast-lineage cells, and resident progenitors form interconnected signalling networks mediated by cytokines, chemokines, extracellular vesicles, apoptotic bodies, mitochondrial signals, metabolites, and extracellular matrix cues. In periodontitis, these networks are disrupted by microbial dysbiosis, persistent inflammation, oxidative stress, stromal senescence, metabolic dysfunction, osteoclastogenesis, and collagen degradation, collectively limiting osteogenesis, cementogenesis, angiogenesis, and PDL fibre organization. Effective regeneration should therefore proceed through staged control of infection, resolution of inflammation without loss of host defence, restoration of stem-cell fitness, recruitment of vascular and mesenchymal progenitors, and matrix remodelling toward functional tissue integration. Responsive biomaterials, including hydrogels, metal-organic frameworks, nanozymes, vesicle-based platforms, and bioelectric or piezoelectric matrices, may help couple local pathological cues to controlled therapeutic release. Clinical translation will require standardized disease models, spatial and single-cell biomarkers, mechanism-defined potency assays, and endpoints that measure cementum-PDL-bone integration rather than bone fill alone.