Biomarker-Based Classification of Periapical Tissue Healing: Resolution and Regeneration: Systematic Review

Periapical healing is a biologically complex process that extends beyond the resolution of clinical symptoms or radiographic findings. Understanding the molecular events underlying this process may improve diagnostic interpretation and guide therapeutic strategies. To identify and classify molecular biomarkers associated with periapical tissue healing, with emphasis on their roles in inflammatory resolution and tissue regeneration.

A systematic review was undertaken in accordance with PRISMA 2020 guidelines. Literature searches were performed in PubMed only covering January 2014 to April 2025. From 110 records screened, 60 full texts were assessed and 28 studies met inclusion criteria (clinical and experimental papers reporting molecular markers linked with periapical healing). Data were extracted on study design, intervention and biomarker direction of change.

Biomarkers were grouped into 3 overlapping categories: (1) Resolution phase - downregulation of tumour necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and matrix metalloproteinase-9 (MMP-9), along-side upregulation of regulatory and anti-inflammatory molecules including interleukin-10 (IL-10) and fork-head box P3 (FOXP3). (2) Regeneration phase was characterised by increased expression of osteogenic and angiogenic markers such as Runt-related transcription factor 2 (RUNX2), vascular endothelial growth factor A (VEGFA), dentin matrix protein-1 (DMP1) and osteocalcin (OCN). (3) Dual-role markers: Several biomarkers exhibited dual roles, contributing to both immune regulation and tissue regeneration depending on treatment context and healing stage such as FOXP3, osteoprotegerin (OPG) and epidermal growth factor receptor (EGFR) acting across both phases. Conventional endodontic therapy predominantly induced resolution-associated biomarker patterns, whereas regenerative protocols preferentially enhanced osteogenic and angiogenic signalling.

Periapical healing involves overlapping phases of inflammatory resolution and tissue regeneration, each characterised by distinct molecular patterns. A biomarker-based classification may improve understanding of healing dynamics and support a biologically informed definition of endodontic success.