Inflammation and Regeneration in the Dentine-Pulp Complex: Where are we now and where are we going?

INTRODUCTION: To develop new regenerative endodontic procedures (REPs) we require an understanding of the basic biology of the dentin-pulp complex and its behavior in health, disease and healing. Clinicians and scientific research partnerships are essential for this field to advance. Translational-targeted tissue regenerative approaches can then be identified, developed in tandem with the development of novel next-generation diagnostics. Combined, these advancements will improve clinical outcomes. METHODS: This narrative review aims to summarize developments over recent decades in the field of dentin-pulp complex biology focusing on our understanding of the intersection between inflammation and regeneration. RESULTS: Our knowledge of inflammation and regeneration in the pulp has rapidly expanded. As carious disease progresses the microflora changes, pulpal cells detect this infection and mount a defensive immune response. The cytokines released orchestrate immune cell infiltration and activation, with cells such as neutrophils utilizing their antimicrobial armamentarium, including the release of Neutrophil Extracellular Traps (NETs). This response although defensive, can be double-edged, leading to detrimental effects on the host tissue. Damaged tissue signals, combined with bacterial components, then activate molecular pathways, such as the inflammasome, which further exacerbate immune activity. In individuals with systemic diseases, such as type-2-diabetes (T2D), the chronic inflammation can accelerate tissue aging and potentially increase pulpal mineralization events. Epigenetic and immunotherapeutic compounds have been shown to modulate inflammation and enable innate regenerative responses. The use of high-quality preclinical laboratory-based in vitro, ex vivo and animal models is however essential to underpin the next stages of evidence-based clinical translation. Enhanced knowledge of the molecular response during pulpitis has the potential to facilitate accurate objective diagnosis and guide the most appropriate treatments. CONCLUSION: Sustained collaboration between scientist and clinicians with a translational-focus will continue to increase our understanding of the association between inflammation and regeneration within the dentin-pulp complex. Further research in this area will lead to clinical benefit in the form of new point-of-care diagnostics and therapeutics.