The present work describes a novel nanocrystalline, multidoped hydroxyapatite featuring excellent eukaryotic versus prokaryotic cell selectivity, attested by excellent osteoinductive character and evaluated with human stem cells, and anti-infective ability, tested against different pathogens. Physicochemical analysis and transmission electron microscopy (TEM)/scanning STEM observations highlighted that such enhanced biological features are related to the lower crystallinity level and increased surface charge of hydroxyapatite, both induced by multiple-ion doping. Specifically, the lattice substitution of Ca 2+ with Zn 2+ promotes the segregation of Ca 2+ and doping Mg 2+ cations to a less-ordered surface layer, thus promoting dynamic ion absorption/release acting as bioactive signals for cells and exerting an antiproliferative effect on all tested pathogens. These findings open the design of new biodevices, combining regenerative ability and effective microbial inhibition without using any antibiotic drugs. This is extremely important to circumvent bacterial resistance to antibiotics, which is today considered as one of the biggest threats to global health.

In the present work, hydroxyapatite (HA) nanoparticles doped with Mg 2+ , Sr 2+ , and Zn 2+ ions are developed by wet neutralization method and then sintered at 1,250 • C to obtain bulk consolidated materials. Physicochemical and microstructural analyses show that the presence of doping ions in the HA structure induced the formation of βTCP as secondary phase, during the sintering process, and we found that this effect is depending on the stability of the various doping ions in the hydroxyapatite lattice itself. We also found that the formation of βTCP as secondary phase, in turn, confines the grain growth of HA induced by the high-temperature sintering process, thus leading to a strong increase of the flexural strength of the bulk materials, according to Hall-Petchlike law. Furthermore, we found that the doping ions enter also in the structure of the βTCP phase; besides the grain growth confinement, also the solubility and ion release ability of the final materials were enhanced. In addition to ameliorate the mechanical performance, the described phenomena also activate multiple biofunctionalities: (i) ability to upregulate various genes involved in the osteogenesis, as obtained by human adipose stem cells culture and evaluated by array technology; (ii) enhanced resistance to the adhesion and proliferation of Gram+ and Gram-bacterial strains. Hence, our results open a perspective for the use of sintered multiple ion-doped HA to develop ceramic biodevices, such as plates, screws, or other osteosynthesis media, with enhanced strength, osteointegrability, and the ability to prevent post-surgical infections.