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Some compositional and structural features of mature bone mineral particles remain unclear. They have been described as calcium-deficient and hydroxyl-deficient carbonated hydroxyapatite particles in which a fraction of the PO 4 3− lattice sites are occupied by HPO 4 2− ions. The time has come to revise this description since it has now been proven that the surface of mature bone mineral particles is not in the form of hydroxyapatite but rather in the form of hydrated amorphous calcium phosphate. Using a combination of dedicated solid-state nuclear magnetic resonance techniques, the hydrogen-bearing species present in bone mineral and especially the HPO 4 2− ions were closely scrutinized. We show that these HPO 4 2− ions are concentrated at the surface of bone mineral particles in the so-called amorphous surface layer whose thickness was estimated here to be about 0.8 nm for a 4-nm thick particle. We also show that their molar proportion is much higher than previously estimated since they stand for about half of the overall amount of inorganic phosphate ions that compose bone mineral. As such, the mineral-mineral and mineral-biomolecule interfaces in bone tissue must be driven by metastable hydrated amorphous environments rich in HPO 4 2− ions rather than by stable crystalline environments of hydroxyapatite structure.

Nanocrystalline apatites are major constituents of hard tissues, and attempts are made worldwide to prepare synthetic analogs. However the impact of synthesis/postsynthesis parameters is often disregarded. Based on an updated knowledge on such compounds, we inspected the effects of synthesis parameters (maturation time, temperature, pH, nature of counter-ions) and post-treatments (re-immersion in aqueous media, thermal treatment) on physicochemical characteristics. Great modifications were noticed during the 3 first days of maturation, where a progressive evolution of the apatite phase (localized in the core of the nanocrystals) toward stoichiometry was observed at the expense of the non-apatitic surface layer which progressively disappears. Similar trends were also evidenced for maturation run under increasing temperatures, studied here in the range 20–100 °C. pH impacted more specifically the chemical composition. The nature of the counter-ion in the starting phosphate salt influenced composition and nonstoichiometry, depending on its (in)ability to be incorporated in the lattice. Freeze-drying allowed to preserve a high surface reactivity, although further evolutions were noticed after re-immersion. Effects of a thermal treatment of dried samples were unveiled, suggesting a denaturation of the hydrated layer on the nanocrystals. This work underlines the necessity of a good control of synthesis/postsynthesis parameters for the production of biomimetic apatites.

Calcium phosphate apatites are inorganic compounds encountered in many different mineralized tissues. Bone mineral, for example, is constituted of nanocrystalline nonstoichiometric apatite, and the production of “analogs” through a variety of methods is frequently reported. In another context, the ability of solid surfaces to favor the nucleation and growth of “bone-like” apatite upon immersion in supersaturated fluids such as SFB is commonly used as one evaluation index of the “bioactivity” of such surfaces. Yet, the compounds or deposits obtained are not always thoroughly characterized, and their apatitic nature is sometimes not firmly assessed by appropriate physicochemical analyses. Of particular importance are the “actual” conditions in which the precipitation takes place. The precipitation of a white solid does not automatically indicate the formation of a “bone-like carbonate apatite layer” as is sometimes too hastily concluded: “all that glitters is not gold.” The identification of an apatite phase should be carefully demonstrated by appropriate characterization, preferably using complementary techniques. This review considers the fundamentals of calcium phosphate apatite characterization discussing several techniques: electron microscopy/EDX, XRD, FTIR/Raman spectroscopies, chemical analyses, and solid state NMR. It also underlines frequent problems that should be kept in mind when making “bone-like apatites.”

Bone is a natural mineral-organic nanocomposite protecting internal organs and allowing mobility. Through the ages, numerous strategies have been developed for repairing bone defects and fixing fractures. Several generations of bone repair biomaterials have been proposed, either based on metals, ceramics, glasses, or polymers, depending on the clinical need, the maturity of technologies, and knowledge of the natural constitution of the bone tissue to be repaired. The global trend in bone implant research is shifting toward osteointegrative, bioactive and possibly stimuli-responsive biomaterials and, where possible, resorbable implants that actively promote the regeneration of natural bone tissue. In this mini-review, the fundamentals of bone healing materials and clinical challenges are summarized and commented on with regard to progressing scientific discoveries. The main types of bone-healing materials are then reviewed, and their specific relevance to the field is reminded, with the citation of reference works. In the final part, we highlight the promise of hybrid organic-inorganic bioactive materials and the ongoing research activities toward the development of multifunctional or stimuli-responsive implants. This contribution is expected to serve as a commented introduction to the ever-progressing field of bone regeneration and highlight trends of future-oriented research.

Bone is a natural nanocomposite. Its mineral component is nanocrystalline calcium phosphate apatite, whose synthetic biomimetic analogs can be prepared by wet chemistry. The initially formed crystals, whether biological or synthetic, exhibit very peculiar physicochemical features. In particular, they are nanocrystalline, nonstoichiometric, and hydrated. The surface of the nanocrystals is covered by a non-apatitic hydrated layer containing mobile ions, which may explain their exceptional surface reactivity. For their precipitation in vivo or in vitro, for their evolution in solution, for the 3D organization of the nanocrystals, and for their consolidation to obtain bulk ceramic materials, water appears to be a central component that has not received much attention. In this mini-review, we explore these key roles of water on the basis of physicochemical and thermodynamic data obtained by complementary tools including FTIR, XRD, ion titrations, oxide melt solution calorimetry, and cryo-FEG-SEM. We also report new data obtained by DSC, aiming to explore the types of water molecules associated with the nanocrystals. These data support the existence of two main types of water molecules associated with the nanocrystals, with different characteristics and probably different roles and functions. These findings improve our understanding of the behavior of bioinspired apatite-based systems for biomedicine and also of biomineralization processes taking place in vivo, at present and in the geologic past. This paper is thus intended to give an overview of the specificities of apatite nanocrystals and their close relationship with water.

Bone infections are a key health challenge with dramatic consequences for affected patients. In dentistry, periodontitis is a medically compromised condition for efficient dental care and bone grafting, the success of which depends on whether the surgical site is infected or not. Present treatments involve antibiotics associated with massive bacterial resistance effects, urging for the development of alternative antibacterial strategies. In this work, we established a safe-by-design bone substitute approach by combining bone-like apatite to peroxide ions close to natural in vivo oxygenated species aimed at fighting pathogens. In parallel, bone-like apatites doped with Ag+ or co-doped Ag+/peroxide were also prepared for comparative purposes. The compounds were thoroughly characterized by chemical titrations, FTIR, XRD, SEM, and EDX analyses. All doped apatites demonstrated significant antibacterial properties toward four major pathogenic bacteria involved in periodontitis and bone infection, namely Porphyromonas gingivalis (P. gingivalis), Aggregatibacter actinomycetemcomitans (A. actinomycetemcomitans), Fusobacterium nucleatum (F. nucleatum), and S. aureus. By way of complementary tests to assess protein adsorption, osteoblast cell adhesion, viability and IC50 values, the samples were also shown to be highly biocompatible. In particular, peroxidated apatite was the safest material tested, with the lowest IC50 value toward osteoblast cells. We then demonstrated the possibility to associate such doped apatites with two biocompatible polymers, namely gelatin and poly(lactic-co-glycolic) acid PLGA, to prepare, respectively, composite 2D membranes and 3D scaffolds. The spatial distribution of the apatite particles and polymers was scrutinized by SEM and µCT analyses, and their relevance to the field of bone regeneration was underlined. Such bio-inspired antibacterial apatite compounds, whether pure or associated with (bio)polymers are thus promising candidates in dentistry and orthopedics while providing an alternative to antibiotherapy.

Biomimetic apatites exhibit a high reactivity allowing ion substitutions to modulate their in vivo response. We developed a novel approach combining several bioactive ions in a spatially controlled way in view of subsequent releases to address the sequence of events occurring after implantation, including potential microorganisms’ colonization. Innovative micron-sized core-shell particles were designed with an external shell enriched with an antibacterial ion and an internal core substituted with a pro-angiogenic or osteogenic ion. After developing the proof of concept, two ions were particularly considered, Ag+ in the outer shell and Cu2+ in the inner core. In vitro evaluations confirmed the cytocompatibility through Ag-/Cu-substituting and the antibacterial properties provided by Ag+. Then, these multifunctional “smart” particles were embedded in a polymeric matrix by freeze-casting to prepare 3D porous scaffolds for bone engineering. This approach envisions the development of a new generation of scaffolds with tailored sequential properties for optimal bone regeneration.

A large amount of research in orthopedic and maxillofacial domains is dedicated to the development of bioactive 3D scaffolds. This includes the search for highly resorbable compounds, capable of triggering cell activity and favoring bone regeneration. Considering the phosphocalcic nature of bone mineral, these aims can be achieved by the choice of amorphous calcium phosphates (ACPs). Because of their metastable property, these compounds are however to-date seldom used in bulk form. In this work, we used a non-conventional “cold sintering” approach based on ultrafast low-pressure RT compaction to successfully consolidate ACP pellets while preserving their amorphous nature (XRD). Complementary spectroscopic analyses (FTIR, Raman, solid-state NMR) and thermal analyses showed that the starting powder underwent slight physicochemical modifications, with a partial loss of water and local change in the HPO42- ion environment. The creation of an open porous structure, which is especially adapted for non-load bearing bone defects, was also observed. Moreover, the pellets obtained exhibited sufficient mechanical resistance allowing for manipulation, surgical placement and eventual cutting/reshaping in the operation room. Three-dimensional porous scaffolds of cold-sintered reactive ACP, fabricated through this low-energy, ultrafast consolidation process, show promise toward the development of highly bioactive and tailorable biomaterials for bone regeneration, also permitting combinations with various thermosensitive drugs.

Layered Double Hydroxides (LDHs) are inorganic compounds of relevance to various domains, where their surface reactivity and/or intercalation capacities can be advantageously exploited for the retention/release of ionic and molecular species. In this study, we have explored specifically the applicability in the field of bone regeneration of one LDH composition, denoted “MgFeCO3”, of which components are already present in vivo, so as to convey a biocompatibility character. The propensity to be used as a bone substitute depends, however, on their ability to allow the fabrication of 3D constructs able to be implanted in bone sites. In this work, we display two appealing approaches for the processing of MgFeCO3 LDH particles to prepare (i) porous 3D scaffolds by freeze-casting, involving an alginate biopolymeric matrix, and (ii) pure MgFeCO3 LDH monoliths by Spark Plasma Sintering (SPS) at low temperature. We then explored the capacity of such LDH particles or monoliths to interact quantitatively with molecular moieties/drugs in view of their local release. The experimental data were complemented by computational chemistry calculations (Monte Carlo) to examine in more detail the mineral–organic interactions at play. Finally, preliminary in vitro tests on osteoblastic MG63 cells confirmed the high biocompatible character of this LDH composition. It was confirmed that (i) thermodynamically metastable LDH could be successfully consolidated into a monolith through SPS, (ii) the LDH particles could be incorporated into a polymer matrix through freeze casting, and (iii) the LDH in the consolidated monolith could incorporate and release drug molecules in a controlled manner. In other words, our results indicate that the MgFeCO3 LDH (pyroaurite structure) may be seen as a new promising compound for the setup of bone substitute biomaterials with tailorable drug delivery capacity, including for personalized medicine.

Critical bone defect repair remains a major medical challenge. Developing biocompatible materials with bone-healing ability is a key field of research, and calcium-deficient apatites (CDA) are appealing bioactive candidates. We previously described a method to cover activated carbon cloths (ACC) with CDA or strontium-doped CDA coatings to generate bone patches. Our previous study in rats revealed that apposition of ACC or ACC/CDA patches on cortical bone defects accelerated bone repair in the short term. This study aimed to analyze in the medium term the reconstruction of cortical bone in the presence of ACC/CDA or ACC/10Sr-CDA patches corresponding to 6 at.% of strontium substitution. It also aimed to examine the behavior of these cloths in the medium and long term, in situ and at distance. Our results at day 26 confirm the particular efficacy of strontium-doped patches on bone reconstruction, leading to new thick bone with high bone quality as quantified by Raman microspectroscopy. At 6 months the biocompatibility and complete osteointegration of these carbon cloths and the absence of micrometric carbon debris, either out of the implantation site or within peripheral organs, was confirmed. These results demonstrate that these composite carbon patches are promising biomaterials to accelerate bone reconstruction.