Polyphosphate in Bone Tissue Engineering: From Molecular Mechanisms to Material Design.

Polyphosphate (PolyP) is an inorganic polymer composed of orthophosphate units linked by high-energy phosphate anhydride bonds, widely found in various organisms from bacteria to mammals. In recent years, PolyP has attracted widespread attention in the field of bone tissue engineering due to its unique biological characteristics, possessing both osteoinductive activity and metabolic energy supply functions. This article systematically reviews the molecular structure, physicochemical properties, and multiple mechanisms by which PolyP promotes osteogenic differentiation, as well as biomaterial design strategies based on PolyP. PolyP can synergistically promote osteogenic differentiation through multiple mechanisms, including by acting as a phosphate donor, providing metabolic energy, regulating signaling pathways such as Wnt/β-catenin, and modulating the osteoprotegerin/receptor activator of nuclear factor κB ligand (OPG/RANKL) balance. In terms of material design, PolyP can form nano/microparticles with metal ions such as Ca2+, Sr2+, and Mg2+ and can also be compounded with polymers to construct various forms such as hydrogels, bone cement, and three-dimensional (3D)-printed scaffolds. Preclinical studies have shown that PolyP-incorporated materials exhibit excellent osteogenic performance and biocompatibility in bone defect repair, and preliminary clinical studies have also confirmed its feasibility. This article aims to provide a comprehensive overview of the current applications of PolyP-incorporated materials and delineate future directions, challenges, and necessary pathways for their clinical translation.