Reconceptualizing gingival keratinization: from epithelial autonomy to artificial intelligence-driven therapeutic...

Gingival keratinization is critical for homeostasis of periodontal health, which has been previously thought to be connective tissue (CT) driven. Recent data refute that model instead of supporting it, implicating epithelial-intrinsic factors and local environmental signals as the dominant regulators of keratinization. This review critically appraises the role of CT in gingival keratinization and other possible mechanisms. A comprehensive review was conducted on literature from animal models, human case studies, and genetic research comparing the classical CT-directed model with recent hypotheses emphasizing keratinocyte autonomy. Studies on heterotopic gingival grafts, growth factor signaling, and keratinocyte differentiation were analyzed to assess the relative contributions of CT and epithelial factors in keratinization. Artificial intelligence driven predictive modelling was utilised to assess gingival keratinization. Analysis revealed that keratinization is not solely dictated by the CT. Instead, epithelial factors such as local signaling molecules, growth factors (TGF-β, KGF), and intrinsic genetic regulation of keratinocytes also play a dominant role. Studies on keratinocyte behaviour in the absence of CT support this hypothesis, suggesting epithelial differentiation occurs independently of CT signals. This review shifts the paradigm of gingival keratinization from a CT-driven model to an epithelial-mediated process. These findings have significant implications for periodontal regenerative therapies, emphasizing the modulation of epithelial factors over conventional CT grafting techniques for more effective soft tissue regeneration.