Non-collagenous protein analog-induced biomimetic mineralization strategy to restore the dentin interface

Dentin biomineralization is a gene-regulated, cytokine-mediated, programmed process by mineralized cells to form highly ordered hydroxyapatite (HAP) crystals encapsulating dentin matrix, ultimately creating a stable dentin interface. Repairing dentin damage caused by irreversible demineralization has been a significant challenge in dental regenerative medicine due to dentin's limited biomineralization capacity. It is well established that non-collagenous proteins (NCPs)-collagen interactions and NCPs-crystal interactions influence the nucleation, deposition, arrangement, and assembly of HAP crystals during the biomineralization process. Inspired by this process, NCP analogs can be used as a biomimetic template to stabilize the intermediate mineral phases of biomineralization to achieve collagen fibrils' hierarchical mineralization in dentin. In addition, specific functional groups can be introduced to achieve antimicrobial, anti-enzymatic, cross-linking and tissue regeneration functions to restore the microstructure and mechanical properties of demineralized dentin. Therefore, designing and developing NCP analogs are currently a hot topic in dentin biomimetic restorations. However, most existing reviews have only focused on the mineralizing effect of NCP analogs and have rarely summarized their additional functions and applications at the dentin interface. This review first summarizes the basic principles of dentin biomineralization and biomimetic mineralization and then focuses on the common classifications of NCP analogs and newly introduced functional properties. It finally discusses the applications and limitations of NCP analogs in dentin interface, providing a theoretical basis for applying NCP analogs in the minimally invasive treatment of demineralized dentin.