Scalable Synthesis of Copper-Incorporated Amorphous Calcium Phosphate Nanoparticles with Antibacterial Activity and Osteogenesis-Related Potential

Calcium phosphate materials have garnered significant attention in oral tissue engineering applications due to their good biocompatibility and osteogenic potential. However, bacterial infections resulting from the polymicrobial oral environment frequently undermine their bone-regenerative efficiency. This study utilized a simple and controllable wet chemical method to synthesize a series of amorphous calcium phosphate (ACP) nanoparticles with adjustable Cu 2+ incorporated content (0.1%–20%). The nanoparticles can be macroscopically prepared in a short period of time at normal temperature and pressure, demonstrating their potential for large-scale preparation. Through the coordination effect of poly(acrylic acid) on Cu 2+ and the coprecipitation process, Cu 2+ was uniformly incorporated into the calcium phosphate matrix, while the crystallization transformation of calcium phosphate was effectively inhibited. The antibacterial experimental results showed that the antibacterial performance of the material showed obvious dependence on the amount of Cu 2+ incorporated. Among them, 5% Cu 2+ -incorporated ACP maintains good cytocompatibility and achieved an inhibition rate of more than 99% against representative Gram-positive and Gram-negative oral pathogens, indicating its suitability as a material platform for biomedical applications. Subsequently, we extended this nanoparticle system into several representative formulation forms, including sprays, hydrogels, and 3D-printed scaffolds, to illustrate its formulation flexibility and potential for clinical translation. Ion release studies demonstrated sustained and pH-dependent Cu 2+ /Ca 2+ release behavior, suggesting that Cu-incorporated ACP and its hydrogel composites may provide prolonged antibacterial activity together with sustained osteogenesis-related potential, while ALP staining further confirmed its retained osteogenesis-related activity.