Advancing dentin biomimetic mineralization: From non-collagenous proteins to multifunctional material design

Dentin biomimetic mineralization, particularly intrafibrillar mineralization, is crucial for restoring the biomechanical properties of demineralized dentin and enhancing the restoration interface. Non-collagenous proteins (NCPs) may regulate dentin biomineralization through various mechanisms, among which the polymer-induced liquid-precursor (PILP) is widely accepted. This review provides a comprehensive overview of cutting-edge strategies and materials that mimic the functions of NCPs in order to achieve effective dentin biomimetic mineralization. Beginning with the natural biomineralization process of dentin, the advantages of biomimetic mineralization are elaborated in this review, followed by a classification and discussion of various biomimetic agents, such as polyelectrolytes, peptides, poly(amidoamine) (PAMAM) dendrimers, and metal ions. Specifically, polyelectrolytes efficiently stabilize mineral precursors using their charge properties, allowing them to adapt to a wide range of mineralization microenvironments; peptides achieve dual targeting of collagen binding and mineralization regulation by precisely mimicking functional domains of NCPs; PAMAM dendrimers provide abundant nucleation sites through their highly branched structures while also serving as carriers; and metal ions enhance mineralization effects by modulating the lattice and activating additional bioactivities. Additionally, this review clarifies the underlying mechanisms and relative effectiveness of biomimetic strategies and proposes future directions, including modular integrated platforms, intelligent microenvironment-responsive mineralization systems, and clinical translation validation. These insights and perspectives are crucial for the development of next-generation therapeutic materials for dentin regeneration and repair. STATEMENT OF SIGNIFICANCE: This review integrates four classes of biomimetic agents, polyelectrolytes, peptides, poly(amidoamine) (PAMAM) dendrimers, and metal ions, and critically evaluates those designed to mimic non-collagenous proteins (NCPs), examining mechanisms such as the polymer-induced liquid-precursor (PILP) process. It sheds light on design principles for biomimetic materials and offers insights into biomaterial-living system interactions by examining structural and biological responses in native tissues. These multifunctional material designs are important for restoring dentin's hierarchical structure from nanoscale to macroscale, while achieving unique advantages in multifunctional reinforcement and tissue regeneration.