Metal-Substituted Hydroxyapatite Nanoparticles as Antimicrobial and Osteogenic Biomaterials for Hard-Tissue Applications

Bacterial colonization and biofilm formation on orthopedic and dental implants remain major clinical complications, while conventional systemic antibiotics are often limited by poor penetration into biofilms and infected bone. These limitations have motivated the development of biomaterials with intrinsic antibacterial activity. Hydroxyapatite (HA), a major inorganic component of bone and teeth, possesses excellent biocompatibility, osteoconductivity, and bone-bonding ability but exhibits limited inherent antibacterial activity. Incorporation of therapeutic metal ions, including Ag+, Cu2+, Zn2+, Ti4+, Co2+, Ga3+, Sr2+, and Ce3+, has therefore emerged as a promising strategy for developing multifunctional HA-based biomaterials. This review critically examines the crystal-chemical basis of metal-ion incorporation into HA and discusses how ionic radius, oxidation state, charge-compensation mechanisms, dopant concentration, and synthesis conditions influence lattice occupancy, physicochemical properties, and biological performance. The antibacterial activity of metal-substituted and metal-modified HA systems generally involves interconnected mechanisms, including bacterial membrane damage, intracellular metabolic disruption, interference with enzymes and nucleic acids, reactive oxygen species (ROS)-mediated oxidative stress, and inhibition of bacterial adhesion and biofilm formation. Ag-, Cu-, Zn-, and Ga-containing HA systems show the most consistently reported antibacterial effects, although their efficacy and cytocompatibility depend strongly on dopant concentration and ion-release kinetics. Co-substituted HA may combine antibacterial activity with angiogenic and osteogenic stimulation, whereas Sr-substituted HA is primarily osteogenic and anti-resorptive, with variable antibacterial performance. Ti-modified HA and TiO2/HA composites exhibit predominantly photoactive antibacterial behavior, while Ce-substituted HA shows concentration-, oxidation-state-, and synthesis-dependent biological effects. The review also evaluates protein adsorption, osteogenic and angiogenic signaling, macrophage-mediated immunomodulation, biological safety, and representative commercial and translational applications. Overall, metal-substituted HA represents a versatile platform for infection-resistant and regenerative hard-tissue biomaterials, provided that composition, phase structure, ion release, antibacterial efficacy, and cytocompatibility are systematically co-optimized before clinical translation.