A Biomimetic Nanocomposite Hydrogel Cross-Linked by Calcium Phosphate Oligomers for Bone Regeneration

Conventional gelatin (Gel) and alginate hydrogels possess excellent biocompatibility. Their high water content and three-dimensional porous structure mimic the extracellular matrix, facilitating nutrient transport and metabolic waste removal. However, their application in bone tissue engineering is hindered by insufficient mechanical strength, rapid degradation, and weak osteogenic activity. In this study, we developed a self-cross-linking hydrogel (GOP hydrogel) reinforced with calcium phosphate oligomers (CPO). The network was formed via a Schiff base reaction between periodate-oxidized sodium alginate (OSA) and gelatin, with small-sized CPO acting as an inorganic cross-linker to enhance intermolecular bonding and strengthen the polymeric network. The composite hydrogel was characterized by scanning electron microscopy (SEM) and X-ray diffraction (XRD), and its mechanical properties, degradation behavior, and swelling capacity were evaluated. The GOP hydrogel exhibited excellent biocompatibility, supported cell viability and osteogenic differentiation, and promoted vascularized healing in critical-sized calvarial defects in rats. With the incorporation of CPO, the hydrogels exhibited enhanced mechanical strength, regulated degradation and swelling, and improved mineralization and osteogenic activity. These findings indicate that the GOP hydrogel meets the key requirements for bone tissue engineering scaffolds and holds considerable promise for bone regeneration applications.