Biomolecules in intrafibrillar collagen mineralization: Mechanisms, biomimetic analogs, and translational contexts

Intrafibrillar collagen mineralization (IFM) is a fundamental process in the formation of vertebrate hard tissues such as bone and dentin. Although non-collagenous proteins (NCPs) are recognized as key physiological regulators of this process, diverse biomolecules beyond NCPs are increasingly recognized as important regulators of IFM. These biomolecules participate in different stages of mineralization, ranging from establishing membrane-associated and physicochemical conditions permissive for mineral deposition to stabilizing amorphous calcium phosphate precursors and modulating collagen interfaces. In parallel, biomimetic analogs inspired by these natural regulators have been developed to reproduce or optimize their mineralization-regulating functions in vitro. In this review, we summarize current advances in biomolecule-guided IFM, covering metabolites, biomacromolecules, and representative synthetic analogs, and discuss how different classes of biomolecules regulate IFM through distinct mechanisms. We further highlight translationally relevant contexts, particularly demineralized dentin and collagen-based scaffolds for bone regeneration. Finally, we discuss current challenges in linking intracellular regulation with extracellular mineralization, controlling ectopic calcification risk, and developing biomolecule-inspired materials for hard tissue repair and regeneration.