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One of the most widely used materials for bone graft substitution is β‐Tricalcium phosphate (β‐TCP; β-Ca 3 (PO 4) 2). β-TCP is typically produced by sintering in air or vacuum. During this process, evaporation of phosphorus (P) species occurs, leading to the formation of a calcium-rich alkaline layer. It was recently shown that the evaporation of P species could be prevented by co-sintering β-TCP with dicalcium phosphate (DCPA; CaHPO 4 ; mineral name: monetite). The aim of this study was to see how a change of sintering atmosphere could affect the physico-chemical and biological properties of β-TCP. For this purpose, three experimental groups were considered: β‐TCP cylinders sintered in air and subsequently polished to remove the surface layer (control group); the same polished cylinders after subsequent annealing at 500 °C in air to generate a calcium-rich alkaline layer (annealed group); and finally, β‐TCP cylinders sintered in a monetite-rich atmosphere and subsequently polished (monetite group). XPS analysis confirmed that cylinders from the annealed group had a significantly higher Ca/P molar ratio at their surface than that of the control group while this ratio was significantly lower for the cylinders from the monetite group. Sintering β‐TCP in the monetite-rich atmosphere significantly reduced the grain size and increased the density. Changes of surface composition affected the activity of osteoclasts seeded onto the surfaces, since annealed β-TCP cylinders were significantly less resorbed than β-TCP cylinders sintered in the monetite-rich atmosphere. This suggests that an increase of the surface Ca/P molar ratio leads to a decrease of osteoclastic resorption. Minimal changes of surface and bulk (< 1%) composition have major effects on the ability of osteoclasts to resorb β-tricalcium phosphate (β-TCP), one of the most widely used ceramics for bone substitution. The results presented in this study are thus important for the calcium phosphate community because (i) β-TCP may have up to 5% impurities according to ISO and ASTM standards and still be considered to be "pure β-TCP", (ii) β-TCP surface properties are generally not considered during biocompatibility assessment and (iii) a rationale can be proposed to explain the various inconsistencies reported in the literature on the biological properties of β-TCP. [Display omitted] [ABSTRACT FROM AUTHOR]

β-tricalcium phosphate (β-TCP) is one the most used and potent synthetic bone graft substitute. It is not only osteoconductive, but also osteoinductive. These properties, combined with its cell-mediated resorption, allow full bone defects regeneration. Its clinical outcome is sometimes considered to be "unpredictable", possibly due to a poor understanding of β-TCP physico-chemical properties: β-TCP crystallographic structure is not fully uncovered; recent results suggest that sintered β-TCP is coated with a Ca-rich alkaline phase; β-TCP apatite-forming ability and osteoinductivity may be enhanced by a hydrothermal treatment; β-TCP grain size and porosity are strongly modified by the presence of minute amounts of β-calcium pyrophosphate or hydroxyapatite impurities. The aim of the present article is to provide a critical, but still rather comprehensive review of the current state of knowledge on β-TCP, with a strong focus on its synthesis and physico-chemical properties, and their link to the in vivo response. The present review documents the richness, breadth, and interest of the research devoted to β-tricalcium phosphate (β-TCP). β-TCP is synthetic, osteoconductive, osteoinductive, and its resorption is cell-mediated, thus making it one of the most potent bone graft substitutes. This comprehensive review reveals that there are a number of aspects, such as surface chemistry, crystallography, or stoichiometry deviations, that are still poorly understood. As such, β-TCP is still an exciting scientific playground despite a 50 year long history and > 200 yearly publications. Image, graphical abstract [ABSTRACT FROM AUTHOR]

Several mechanisms proposed to explain the osteoinductive potential of calcium phosphates involve surface mineralization ("bioactivity") and mention the occurrence of concentration gradients between the inner and the outer part of the implanted material. Determining the evolution of the local chemical environment occurring inside the pores of an implanted bone graft substitute (BGS) is therefore highly relevant. A quantitative and fast method was developed to measure the chemical changes occurring within the pores of β-Tricalcium Phosphate (β-TCP) granules incubated in a simulated body fluid. A factorial design of experiment was used to test the effect of particle size, specific surface area, microporosity, and purity of the β-TCP granules. Large pH, calcium and phosphate concentration changes were observed inside the BGS and lasted for several days. The kinetics and magnitude of these changes (up to 2 pH units) largely depended on the processing and properties of the granules. Interestingly, processing parameters that increased the kinetics and magnitude of the local chemical changes are parameters considered to favor calcium phosphate osteoinduction, suggesting that the model might be useful to predict the osteoinductive potential of BGSs. Recent results suggest that in situ mineralization of biomaterials (polymers, ceramics, metals) might be key in their ability to trigger ectopic bone formation. This is the reason why the effect on in situ mineralization of various synthesis parameters of β-tricalcium phosphate granules was studied (size, microporosity, specific surface area, and Ca/P molar ratio). To the best of our knowledge, this is the first article devoted to the chemical changes occurring within the pores of a bone graft substitute. We believe that the manuscript will prove to be highly important in the design and mechanistic understanding of drug-free osteoinductive biomaterials. Image, graphical abstract [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract The efficiency of calcium phosphate (CaP) bone substitutes can be improved by tuning their resorption rate. The influence of both crystal orientation and ion doping on resorption is here investigated for beta-tricalcium phosphate (β-TCP). Non-doped and Mg-doped (1 and 6 mol%) sintered β-TCP samples were immersed in acidic solution (pH 4.4) to mimic the environmental conditions found underneath active osteoclasts. The surfaces of β-TCP samples were observed after acid-etching and compared to surfaces after osteoclastic resorption assays. β-TCP grains exhibited similar patterns with characteristic intra-crystalline pillars after acid-etching and after cell-mediated resorption. Electron BackScatter Diffraction analyses, coupled with Scanning Electron Microscopy, Inductively Coupled Plasma–Mass Spectrometry and X-Ray Diffraction, demonstrated the influence of both grain orientation and doping on the process and kinetics of resorption. Grains with c -axis nearly perpendicular to the surface were preferentially etched in non-doped β-TCP samples, whereas all grains with simple axis (a , b or c) nearly normal to the surface were etched in 6 mol% Mg-doped samples. In addition, both the dissolution rate and the percentage of etched surface were lower in Mg-doped specimens. Finally, the alignment direction of the intra-crystalline pillars was correlated with the preferential direction for dissolution. Statement of significance The present work focuses on the resorption behavior of calcium phosphate bioceramics. A simple and cost-effective alternative to osteoclast culture was implemented to identify which material features drive resorption. For the first time, it was demonstrated that crystal orientation, measured by Electron Backscatter Diffraction, is the discriminating factor between grains, which resorbed first, and grains, which resorbed slower. It also elucidated how resorption kinetics can be tuned by doping β-tricalcium phosphate with ions of interest. Doping with magnesium impacted lattice parameters. Therefore, the crystal orientations, which preferentially resorbed, changed, explaining the solubility decrease. These important findings pave the way for the design of optimized bone graft substitutes with tailored resorption kinetics. [ABSTRACT FROM AUTHOR]