High-performance bioceramics are required for preventing failure and prolonging the life-time of bone grafting scaffolds and osseous implants. The proper identification and development of materials with extended functionalities addressing socio-economic needs and health problems constitute important and critical steps at the heart of clinical research. Recent findings in the realm of ion-substituted hydroxyapatite (HA) could pave the road towards significant developments in biomedicine, with an emphasis on a new generation of orthopaedic and dentistry applications, since such bioceramics are able to mimic the structural, compositional and mechanical properties of the bone mineral phase. In fact, the fascinating ability of the HA crystalline lattice to allow for the substitution of calcium ions with a plethora of cationic species has been widely explored in the recent period, with consequent modifications of its physical and chemical features, as well as its functional mechanical and in vitro and in vivo biological performance. A comprehensive inventory of the progresses achieved so far is both opportune and of paramount importance, in order to not only gather and summarize information, but to also allow fellow researchers to compare with ease and filter the best solutions for the cation substitution of HA-based materials and enable the development of multi-functional biomedical designs. The review surveys preparation and synthesis methods, pinpoints all the explored cation dopants, and discloses the full application range of substituted HA. Special attention is dedicated to the antimicrobial efficiency spectrum and cytotoxic trade-off concentration values for various cell lines, highlighting new prophylactic routes for the prevention of implant failure. Importantly, the current in vitro biological tests (widely employed to unveil the biological performance of HA-based materials), and their ability to mimic the in vivo biological interactions, are also critically assessed. Future perspectives are discussed, and a series of recommendations are underlined.

Synthetic physiological fluids are currently used as a first in vitro bioactivity assessment for bone grafts. Our understanding about the interactions taking place at the fluid–implant interface has evolved remarkably during the last decade, and does not comply with the traditional International Organization for Standardization/final draft International Standard 23317 protocol in purely inorganic simulated body fluid. The advances in our knowledge point to the need of a true paradigm shift toward testing physiological fluids with enhanced biomimicry and a better understanding of the materials’ structure-dissolution behavior. This will contribute to “upgrade” our vision of entire cascades of events taking place at the implant surfaces upon immersion in the testing media or after implantation. Starting from an osteoinductive bioglass composition with the ability to alleviate the oxidative stress, thin bioglass films with different degrees of polymerization were deposited onto titanium substrates. Their biomineralization activity in simulated body fluid and in a series of new inorganic–organic media with increasing biomimicry that more closely simulated the human intercellular environment was compared. A comprehensive range of advanced characterization tools (scanning electron microscopy; grazing-incidence X-ray diffraction; Fourier-transform infrared, micro-Raman, energy-dispersive, X-ray photoelectron, and surface-enhanced laser desorption/ionization time-of-flight mass spectroscopies; and cytocompatibility assays using mesenchymal stem cells) were used. The information gathered is very useful to biologists, biophysicists, clinicians, and material scientists with special interest in teaching and research. By combining all the analyses, we propose herein a step forward toward establishing an improved unified protocol for testing the bioactivity of implant materials.

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