Biphasic calcium phosphate (BCP) bioceramics (hydroxyapatite/tricalcium phosphate, or HA/TCP) for tissue engineering and drug delivery systems is a unique know-how. A mechanical mixture of HA and TCP does not lead to such bioactive ceramics. The wet elaboration conditions of calcium-deficient apatite (CDA) or CDHA, followed by sintering, converts it into TCP and HA. The dissolution precipitation of nano-sized needle-like crystals at the surface of BCP occurs on time at body temperature. Combining several technics of characterization [scanning electron microscopy (SEM), transmission electron microscopy (TEM), energy-dispersive x-ray spectroscopy (EDX), Brunauer-Emmett-Teller method (BET), chemical analysis, x-ray diffraction (XRD), Fourier transformed infrared spectroscopy (FTIR)], we demonstrated an evolution on time of the HA/β-TCP. The current paper describes the crystallographic evolution of initial β-TCP rhombohedral crystallographic structure to microsized needle-like layer corresponding to apatitic TCP form. This phenomenon leads to an increase of the HA/TCP ratio, since hexagonal apatitic TCP is similar to hexagonal HA. However, the Ca/P ratio (reflecting the chemical composition HA/TCP) remains unchanged. Thus, the high reactivity of BCP involves dynamic evolution from rhombohedral to hexagonal structure, but not a chemical change. The dynamic process is reversible by calcination. These events are absolutely necessary for smart scaffolds in bone regeneration and orthobiology.

The crystal deposition is constituted of biological apatites. However, ectopic calcifications are also observed and may represent severe injuries for the patient. Ectopic calcifications, most periarticular, articular, dental, or visceral, are essentially constituted of calcium phosphate, as opposed to the calculi. The variability of the inorganic phase of ectopic calcifications explains the extensive and uncoordinated literature on the subject. Biological examinations are needed to diagnose a general pathology favoring metastatic calcifications. During acute crisis, there is a biological inflammatory syndrome. Pathological study shows deposits of calcific ma-terial surrounded by necrosis and inflammatory cells. Calcified tissues are fixed in ethanol to avoid demineralization, and are embedded in methyl methacrylate. X-ray radiographs of shoulder periarticular calcification can reveal enormous calcification in the bursa, with or without destructive arthropathy, associated with numerous "apatite-like" precipitations. The role of ions of biological interest, like Mg, must be determined, due to their suspected role in calcification and crystal maturation.

Due to their osteoconductive and inductive properties, a variety of calcium phosphate (CaP) scaffolds are commonly used in orthopaedics as graft material to heal bone defects. In this study, we have used two CaP scaffolds with different hydroxyapatite (HA) and β-tricalcium phosphate (β-TCP) ratios (MBCP®; 60/40 and MBCP+ ®; 20/80) to investigate their intrinsic capacity to favour human bone marrow stem cells (hBMSCs) osteogenic differentiation capacity. We report that MBCP+ ® showed in in vitro culture model a higher rate of calcium ion release in comparison with MBCP®. In two defined coculture systems, the hBMSC seeded onto MBCP+ ® presented an increased amount of VEGF secretion, resulting in an enhanced endothelial cell proliferation and capillary formation compared with hBMSC seeded onto MBCP®. When both ceramics combined with hBMSC were implanted in a nude mouse model, we observed a faster osteogenic differentiation and enhancement mature bone deposition sustained by the presence of a vast host vasculature within the MBCP+ ® ceramics. Bone formation was observed in samples highly positive to the activation of calcium sensing receptor protein (CaSr) on the surface of seeded hBMSC that also shown higher BMP-2 protein expression. With these data we provide valuable insights in the possible mechanisms of ossification and angiogenesis by hBMSC that we believe to be primed by calcium ions released from CaP scaffolds. Evidences could lead to an optimization of ceramic scaffolds to prime bone repair.

We report the novel use of a tuneable, non‐integrating viral gene delivery system to bone that can be combined with clinically approved biomaterials in an 'off‐the‐shelf' manner. Specifically, a doxycycline inducible Tet‐on adenoviral vector (AdTetBMP‐2) in combination with mesenchymal stromal cells (MSCs), fibrin and a biphasic calcium phosphate ceramic (MBCP®) was used to repair large bone defects in nude rats. Bone morphogenetic protein‐2 (BMP‐2) transgene expression could be effectively tuned by modification of the doxycycline concentration. The effect of adenoviral BMP‐2 gene delivery upon bone healing was investigated in vivo in 4 mm critically sized, internally fixated, femoral defects. MSCs were transduced either by direct application of AdTetBMP‐2 or by pre‐coating MBCP granules with the virus. Radiological assessment scores post‐mortem were significantly improved upon delivery of AdTetBMP‐2. In AdTetBMP‐2 groups, histological analysis revealed significantly more newly formed bone at the defect site compared with controls. Newly formed bone was vascularized and fully integrated with nascent tissue and implanted biomaterial. Improvement in healing outcome was achieved using both methods of vector delivery (direct application vs. pre‐coating MCBP). Adenoviral delivery of BMP‐2 enhanced bone regeneration achieved by the transplantation of MSCs, fibrin and MBCP in vivo. Importantly, our in vitro and in vivo data suggest that this can be achieved with relatively low (ng/ml) levels of the growth factor. Our model and novel gene delivery system may provide a powerful standardized tool for the optimization of growth factor delivery and release for the healing of large bone defects. Copyright © 2016 John Wiley & Sons, Ltd.

Tympanoplasty is the reference for cholesteatoma treatment in ear, nose, and throat (ENT surgery), with the realization of a closing technique, which preserves the external auditory canal. An insufficient pneumatisation is an element favoring the occurrence and recurrence of cholesteatoma. In a prospective clinical pilot study, we have realized the reconstruction of the mastoid cortical bone by a Micro Macroporous Biphasic Calcium Phosphate bioceramics disks (MBCPTM Biomatlante France) using the closed technique, in order to maintain or increase the mastoid pneumatisation. Eleven patients were used for this study, and some of them have a sample collection for histomorphometry and histopathological analysis. Bone regeneration at the expense of the bioceramic was observed. The size and shape of the disk was not preserved due to the large resorption and bone ingrowth at the expense of the implant. However 6 patients presented cholesteatoma recurrence. The MBCPTM disks are able to reconstruct the mastoid cortical and maintain the mastoid pneumatisation contrarily to the technique of filling the mastoid cavity. However, the high rate of cholesteatoma recurrence observed in our study, confirmed the interest to fill mastoid that suppress airspace posterior cavities.

Bioceramics draw attention in bone tissue engineering field since their biomimetic properties regarding bone attribute. In this context, a concept of smart bioceramics granules made of Hydroxyapatite have been set up, enhancing surface area available to body fluids containing proteins and cell adhesion for bone forming respectively thanks to microporosities and macropore concavities. New “hollow shell” granules were developed and assessed by physico-chemical characterizations, in-vitro experiments and in-vivo implantation in comparison with classical round granules. This new original galenic formulation showed promising potential in cell carrying and osteoconduction matter.

Bioceramics is a relatively new field; it did not exist until the beginning of 1970, when these materials were shown to restore osteoarticular and dental functions, as well as act as a replacement material for autografts and allograft bone reconstructions. Bioceramics used to replace, repair, or reconstruct human body parts or complex living tissues have differences in their chemical nature, properties, and applications, such as the use of alumina for hip prosthesis versus CaP bioceramics for bone regeneration. Alumina is classified as an inert bioceramic, while CaP bioceramics are considered bioactive biomaterials, able to be absorbed or bond directly with bone. This review concentrates on the development and use of bioceramics and biocomposites and is limited to CaP bioceramics. Bioactive bioceramics are recommended for use as an alternative or additive to autogenous bone for various procedures: orthopedic and dental applications, scaffolds for tissue engineering, vectors for gene therapy, and as a drug delivery system. There are two physical properties of bioceramics that are considered important for optimal biological performance, which includes bioceramic-cell interactions, bioceramic resorption, the bioceramic-tissue interface, and new bone formation. These fundamental properties are interconnecting macroporosity and appropriate microporosity. CaP bioceramics are a recent development in bone surgery that act as a replacement for auto- and allografts, which have been engineered less than 100 years from the first medical applications and less than 30 years from the initial manufacturing of medical devices and experiments with bone regeneration. Bioactive bioceramics have largely contributed to this revolution in medicine. Numerous innovations in this field are now appearing; it is the beginning of bioceramics and not the “has-been medical device”.

There are numerous clinical indications for bone grafts. The ideal graft material should favor bone apposition and growth while simultaneously being degraded by body fluids and cells. Ultimately, the material should be replaced by mature bone tissue within a healing period of weeks. Because autologous and allogenic bone grafts fulfill some of these requirements, these biological materials are routinely used by clinicians. However, biological materials have intrinsic limitations. Harvesting autologous bone requires a second surgical site, which can cause complications, the material is limited in quantity, and it may lead to immunogenic rejection or transfer certain pathogens and viruses [1-3]. For these reasons, researchers and clinicians have developed synthetic bone substitutes. Our approach has focused on composite biomaterials that combine bioceramics with hydrogels to replace and regenerate bone tissue in osseous defects.

The commercial offer for bioceramic bone substitutes is very large, however, the prerequisites for applications in bone reconstruction and tissue engineering, are most often absent. The main criteria being: on the one hand physico-chemical features providing surgeons with an injectable and/or shapeable biomaterial; on the second hand the multi-scale bioactivity leading to osteoconduction and osteoinduction properties. In order to obtain greater suitability according to the nature of the bone defect to be treated, new bone regeneration technologies, “smart scaffolds” must be developed and optimize to support suitable Ortho Biology.

Bioceramic bone substitutes made of calcium phosphate are numerous, but their chemical composition alone do not ensure that they will behave as a ‘‘smart scaffold’’. This article describes the proprietary MBCPTM technology developed by Biomatlante S.A., building on the expertise of R. Legeros (University of New York, USA) and G. Daculsi (University of Nantes, France), the inventors of Biphasic Calcium Phosphate (BCP) in the 80’s. At the core of Biomatlante expertise lays a holistic approach of engineering biomaterials with biomimetic properties. This paper reports correlations between the physicochemical properties of BCP scaffolds and the induced biological responses as well as raising the crucial importance of controlling all critical aspects behind the conception of a biomaterial, namely materials science, biology and medicine.

Solid-state transformation of CDA at high temperature has been investigated using TEM microscopy and diffraction from sintered biphasic calcium phosphate (hydroxyapatite-HA, and beta-tricalcium phosphate-TCP). Microcrystals, between 200nm and 800nm approximately, separated by grain boundaries were found to be either HA-HA or TCP-TCP, but not HA-TCP, suggesting that heteroepitaxial growth is very unlikely between these two orthophosphates. TEM-correlated EDX elemental analysis also demonstrated a higher ionic substitution (Na, Mg) of TCP phase.

Various bioceramics or xenograft has been used to avoid autograft. However, there are large differences in the chemistry, the micro- and macrostructure, and consequently the performance in terms of resorption, absorption, and regeneration of physiological bone. The differences in such available bioceramics were reported and critical data presented. Recent developments related to CaP scaffolds including improvements in terms of engineering chemistry, surface properties, microstructure, and porosities, which lead them to be considered as being bioinstructive rather than osteoconductive scaffolds, have opened up new opportunities for bone regenerative technologies. Not only are some of these CaP bioceramics scaffolds osteoinductive in their own right, but evidence also supports the hypothesis that specific engineering bioceramics have a direct influence on the differentiation and proliferation of human mesenchymal stem cells (hMSCs). Tissue engineering, new bioactive molecules, and new surgical technologies increase the potential application of CaP bioceramics as carriers of these cells and also as scaffolds capable of guiding the behavior of these cells and the efficiency of bone regeneration. If the smart bioinstructive CaP scaffold technology led to a higher efficacy of CaP scaffolds, it would allow further surgical applications in bone tissue regeneration. The mechanical properties required for bone ingrowth and bone remodeling and mechanotransduction must be explored to allow for development of new generation scaffolds.

Physico-chemical characteristics impact directly or indirectly the bioactive properties of biomaterials, it is then essential to correlate it with their effect in vivo. A panel of biomaterials available on the market, based on Hydroxyapatite (HA) and Tricalcium phosphate (β-TCP) is studied in terms of surface area, hydrophilicity, porosity, zeta potential, crystalline phases and density. This study highlights the dispersity of commercial calcium phosphates (CaP) properties, and demonstrates how the quality criteria required for such bone substitute based on biomimicry concept, whose pores distribution is certainly the more relevant, are often incompletely or not respected according to literature.

Restoring alveolar bone following tooth extraction or pathological diseases is important, and recent efforts have been made to overcome the use of autografts during dental implantation. Although micro-macroporous biphasic calcium phosphate (MBCPTM) has performed well in orthopedic procedures, few studies have investigated its use in dentistry. Here, we report a greater than eight-year clinical follow-up of bone regeneration using MBCPTM after sinus grafting. MBCPTM technology is a unique mixture of hydroxyapatite and β-tricalcium phosphate, which displays both macroporosity and microporosity. A total of 25 patients (33 implantation sites) were evaluated by X-rays, and their pre-operative and immediate post-operative bone heights were measured. After approximately six months, dental implantation was performed. Subsequently, X rays were performed each year, and bone height was measured. In all cases, radio-opacity of the implantation area decreased with time, indicating resorption and bone ingrowth at the expense of the MBCPTM material. After one year, the implantation area had the appearance of physiological bone and <11% of height loss was observed. Strikingly, the newly formed bone was preserved after 78 years of follow-up, with only <14% of height loss recorded. We demonstrate that sinus grafting followed by dental implantation with a resorbable and bioactive synthetic bone graft material (MBCPTM technology) safely and efficiently supports dental implantation.