Calcium Phosphate Ceramics Research Articles

The impact of the physicochemical properties of calcium phosphate ceramics on biocompatibility and osteogenic differentiation of mesenchymal stem cells

ObjectiveIn this study we have focused on biocompatibility and osteoinductive capacity analysis of self-manufactured single-phase (HAP) and two-phase (HAP and β-ТСР) bioactive ceramics with various chemical modifications (Fig. 1).ResultsWe demonstrate a reduction in solubility for all analyzed composite after the treatment with H2O and H2O2, accompanied by an enhancement in adsorption activity. This modification also resulted in an increase in micro- and macroporosity, along with a rise in the open porosity. Adipose-derived mesenchymal stromal cells demonstrated excellent cell adhesion and survival when cultured with these ceramics. Calcium phosphate ceramics (H-500, HT-500, and HT-1 series) stimulated alkaline phosphatase expression, promoted calcium deposition, and enhanced osteopontin expression in ADSCs, independently inducing osteogenesis without additional osteogenic stimuli. These findings underscore the promising potential of HAP-based bioceramics for bone regeneration/reconstruction.Graphical

Porous titanium/hydroxyapatite interpenetrating phase composites with optimal mechanical and biological properties for personalized bone repair

This study introduces the first fabrication of porous titanium/hydroxyapatite interpenetrating phase composites achieved through an innovative processing method. The approach combines additive manufacturing of a customized titanium skeleton with the infiltration of an injectable hydroxyapatite foam, followed by in situ foam hardening at physiological temperature. This biomimetic process circumvents ceramic sintering and metal casting, effectively avoiding the formation of secondary phases that can impair mechanical performance. Hydroxyapatite foams, prepared using two foaming agents (polysorbate 80 and gelatine), significantly reinforce the titanium skeleton while preserving the microstructural characteristics essential for osteoinductive properties. The strengthening mechanisms rely on the conformation of the foams to the titanium surface, thereby enabling a stable mechanical interlocking and effective interfacial stress transfer. This, combined with the mechanical constriction of phases, enhances damage tolerance and mechanically reliability of the interpenetrating phase composites. In addition, the interpenetrating phase composites feature a network of concave pores with an optimal size for bone repair, support human osteoblasts proliferation, and exhibit mechanical properties compatible with bone, offering a promising solution for the efficient and personalized reconstruction of large bone defects. The results demonstrate a significant advancement in composite fabrication, integrating the benefits of additive manufacturing for bone repair with the osteogenic capacity of calcium phosphate ceramics.

Polysaccharide-Based Composite Systems in Bone Tissue Engineering: A Review.

In recent years, a growing demand for biomaterials has been observed, particularly for applications in bone regenerative medicine. Bone tissue engineering (BTE) aims to develop innovative materials and strategies for repairing and regenerating bone defects and injuries. Polysaccharides, due to their biocompatibility, biodegradability as well as bioactivity, have emerged as promising candidates for scaffolds or composite systems in BTE. Polymers combined with bioactive ceramics can support osteointegration. Calcium phosphate (CaP) ceramics can be a broad choice as an inorganic phase that stimulates the formation of new apatite layers. This review provides a comprehensive analysis of composite systems based on selected polysaccharides used in bone tissue engineering, highlighting their synthesis, properties and applications. Moreover, the applicability of the produced biocomposites has been analyzed, as well as new trends in modifying biomaterials and endowing them with new functionalizations. The effects of these composites on the mechanical properties, biocompatibility and osteoconductivity were critically analyzed. This article summarizes the latest manufacturing methods as well as new developments in polysaccharide-based biomaterials for bone and cartilage regeneration applications.

Optimizing silicon doping levels for enhanced osteogenic and angiogenic properties of 3D-printed biphasic calcium phosphate scaffolds: An in vitro screening and in vivo validation study

Biphasic calcium phosphate (BCP) ceramics are valued for their osteoconductive properties but have limited osteogenic and angiogenic activities, which restricts their clinical utility in bone defect repair. Silicon doping has emerged as an effective strategy to enhance these biological functions of BCP. However, the biological impact of BCP is influenced by the level of silicon doping, necessitating determination of the optimal concentration to maximize efficacy in bone repair. This study investigated the effects of silicon doping on both the physicochemical and biological properties of BCP, with a specific focus on osteogenic and angiogenic potentials. Results indicated that silicon doping exceeding 4 mol.% led to the formation of α-TCP, accelerating BCP degradation, enhancing silicon ion release, and promoting mineralization product formation. Simultaneously, silicon doping increased the porosity of BCP scaffolds, which typically reduces their compressive strength. Nevertheless, scaffolds doped with ≤4 mol.% silicon maintained compressive strengths exceeding 2 MPa. In vitro biological experiments indicated that higher levels of silicon doping (≥6 mol.%) partially inhibited the successful differentiation of stem cells and the vascularization of endothelial cells. Optimal conditions for promoting osteogenic differentiation and angiogenesis were identified between 2 and 4 mol.% silicon doping, with an optimal level of approximately 4 mol.%. Subsequent in vivo experiments confirmed that BCP scaffolds doped with 4 mol.% silicon effectively promoted vascularization and new bone formation, highlighting their potential for clinical bone defect repair.

Triply periodic minimal surfaces structured biphasic calcium phosphate bio-scaffolds with controllable porous struts from digital light processing of Pickering emulsion

Hierarchically porous biphasic calcium phosphate (BCP) ceramics with triply periodic minimal surface structure and porous framework have been fabricated by digital light processing (DLP) using dual-phase Pickering emulsion as the paste. The pristine hydroxyapatite and β-tricalcium phosphate particles were separately modified by dispersant firstly to obtain photosensitive Pickering emulsion with suitable rheological properties and stability for DLP printing. The porous structure has been well regulated by dispersant content, and ethylene glycol content. The resulting BCP ceramics exhibited a hierarchical pore structure consisting of interconnected micropores ranging from 1.13 μm to 8.98 μm and model-designed pores of nearly 500 μm, demonstrating excellent compressive strength of 4.83 MPa at a porosity of 60 %. In vitro biological experiments revealed that rat bone marrow mesenchymal stem cells exhibited good proliferation and adhesion ability on the BCP bio-scaffolds, thereby enhancing their application potential in bone regenerative medicine.

Variations of chemical, physical, mechanical properties, and biological and antimicrobial effectiveness of Ti alloys by coating with CaP doped with different amounts of Zn via micro-arc oxidation (MAO) technique

Titanium alloys are preferred metals as implant materials due to their advantageous combination of low density and high biocompatibility. However, the augmentation of implant surfaces with calcium-based coatings becomes essential to regulate corrosion rates and enhance the osteoconductive properties of the implant material. In this study, titanium alloys, specifically Ti6Al4V, underwent a transformative process wherein they were coated with calcium phosphate (CaP) ceramics doped with zinc (Zn) via micro-arc oxidation (MAO) technique, using varying concentrations of Zn compound in the electrolyte solutions. The chemical and physical properties of the freshly prepared samples were analyzed, both initially and after culturing them with Saos-2 cells. Furthermore, the antimicrobial efficacy against E. coli was examined. The findings unveiled the remarkable efficiency of the MAO technique in forming an uniformly distributed coat on Ti6Al4V, thereby enhancing its mechanical resilience and biocompatibility, depending upon the preparation parameters employed. It was shown that Zn doped calcium coating is very efficient to regulate various parameters such as corrosion rate and mechanical strength, and an increase in Zn content exhibited a favorable impact on cell attachment and antimicrobial efficacy. Surface modification of metallic implants via MAO technique can be applied in the production of advanced implant materials.

3D printing calcium phosphate ceramics with high osteoinductivity through pore architecture optimization

The osteoinductivity of 3D printed calcium phosphate (CaP) ceramics has a large gap compared with those prepared by conventional foaming methods, and improving the osteoinductivity of 3D printing CaP ceramics is crucial for successful application in bone regeneration. Pore architecture plays a critical role in osteoinductivity. In this study, CaP ceramics with a hexagonal close-packed (HCP) spherical pore structure were successfully fabricated using DLP printing technology. Additionally, octahedral (Octahedral), diamond (Diamond), and helical (Gyroid) structures were constructed with similar porosity and macropore diameter. CaP ceramics with the HCP structure exhibited higher compression strength (8.39 ± 1.82 MPa) and lower permeability (6.41 × 10−11 m2) compared to the Octahedral, Diamond, and Gyroid structures. In vitro cellular responses indicated that the macropore architecture strongly influenced the local growth rate of osteoblast-formed cell tissue; cells grew uniformly and formed circular rings in the HCP group. Furthermore, the HCP group promoted the expression of osteogenic genes and proteins more effectively than the other three groups. The outstanding osteoinductivity of the HCP group was confirmed in canine intramuscular implantation studies, where the new bone area reached up to 8.02 ± 1.94 % after a 10-week implantation. Additionally, the HCP group showed effective bone regeneration in repairing femoral condyle defects. Therefore, our findings suggest that 3D printed CaP bioceramics with an HCP structure promote osteoinductivity and can be considered as candidates for personalized precise treatment of bone defects in clinical applications. Statement of significance1. 3D printing BCP ceramics with high osteoinductivity were constructed through pore architecture optimization.2. BCP ceramics with HCP structure exhibited relatively higher mechanical strength and lower permeability than those with Octahedral, Diamond and Gyroid structures.3. BCP ceramics with HCP structure could promote the osteogenic differentiation of MC3T3-E1, and showed the superior in-vivo osteoinductivity and bone regeneration comparing with the other structures.

Osteo-immunomodulatory effects of macrophage-derived extracellular vesicles treated with biphasic calcium phosphate ceramics on bone regeneration

Literature on osteoimmunology has demonstrated that macrophages have a great influence on biomaterial-induced bone formation. However, there are almost no reports clarifying the osteo-immunomodulatory capacity of macrophage-derived extracellular vesicles (EVs). This study comprehensively investigated the effects of EVs derived from macrophages treated with biphasic calcium phosphate (BCP) ceramics (BEVs) on vital events associated with BCP-induced bone formation such as immune response, angiogenesis, and osteogenesis. It was found that compared with EVs derived from macrophages alone (control, CEVs), BEVs preferentially promoted macrophage polarization towards a wound-healing M2 phenotype, enhanced migration, angiogenic differentiation, and tube formation of human umbilical vein endothelial cells, and induced osteogenic differentiation of mesenchymal stem cells. Analysis of 15 differentially expressed microRNAs (DEMs) related to immune, angiogenesis, and osteogenesis suggested that BEVs exhibited good immunomodulatory, pro-angiogenic, and pro-osteogenic abilities, which might be attributed to their specific miRNA cargos. These findings not only deepen our understanding of biomaterial-mediated osteoinduction, but also suggest that EVs derived from biomaterial-treated macrophages hold great promise as therapeutic agents with desired immunomodulatory capacity for bone regeneration.

Histomorphological assessment of the germanium-doped calcium phosphate ceramics on reparative osteogenesis in rabbits with systemic osteoporosis

Bone fractures are mostly urgent in nature, complex in pathogenetic, diagnostic and therapeutic aspects, and reparative osteogenesis is multimodal and depends on the balanced and reciprocal interaction of many factors. The results of histological studies for osteoreplacement of bone defects in rabbits with systemic osteoporosis are presented. The purpose of the work is histomorphological evaluation of bone regenerates after osteoreplacement with germanium-doped hydroxyapatite ceramics in rabbits with secondary osteoporosis. Experimental osteoporosis in rabbits (n=18) was induced by administration of 0.4% dexamethasone solution. In animals of the experimental group, bone defects were replaced with granules of hydroxyapatite ceramics doped with germanium, and in animals of the control group, they healed under a blood clot. Histological sections were made on a rotary microtome with a thickness of 5 to 10 μm and stained with Weigert's iron hematoxylin and 1% alcohol-based eosin solution (manufactured by Diapath, Italy). On the 60th day of reparative osteogenesis in the animals of the experimental group, the site of the bone defect was flled with compact bone tissue with minor remnants of spongy bone tissue. Slightly expanded Haversian canals were noted. In the control group, the defect site was flled with coarse and spongy bone tissue. Bone beams of various thicknesses with a small number of osteoblasts and single walled osteocytes were visualized. A signifcant number of osteocyte lacunae were empty due to the process of osteocyte lysis. Haversian canals are signifcantly dilated with a small number of vessels. Also, lacunae of bone tissue resorption and acellular areas were observed on histological specimens. Histomorphological assessment of bone regenerates confrms the realization of osteoconductive, osteointegrative and osteoinductive properties of calcium-phosphate ceramics doped with germanium in conditions of osteoporotic fractures of tubular bones. Keywords: systemic osteoporosis, bone fractures, cancellous and compact bone tissue, histological sections, histomorphological changes, rabbits.

Enhancing Transparency in Non-Cubic Calcium Phosphate Ceramics: Effect of Starting Powder, LiF Doping, and Spark Plasma Sintering Parameters

Our objective is to achieve a new good-quality and mechanically durable high-transparency material that, when activated by rare earth ions, can be used as laser sources, scintillators, or phosphors. The best functional transparent ceramics are formed from high-symmetry systems, mainly cubic. Considering hexagonal hydroxyapatite, which shows anisotropy, the particle size of the initial powder is extremely important and should be of the order of several tens of nanometers. In this work, transparent micro-crystalline ceramics of non-cubic Ca10(PO4)6(OH)2 calcium phosphate were fabricated via Spark Plasma Sintering (SPS) from two types of nanopowders i.e., commercially available (COM. HA) and laboratory-made (LAB. HA) via the hydrothermal (HT) protocol. Our study centered on examining how the quality of sintered bodies is affected by the following parameters: the addition of LiF sintering agent, the temperature during the SPS process, and the quality of the starting nanopowders. The phase purity, microstructure, and optical transmittance of the ceramics were investigated to determine suitable sintering conditions. The best optical ceramics were obtained from LAB. HA nanopowder with the addition of 0.25 wt.% of LiF sintered at 1000 °C and 1050 °C.

Study of biphasic calcium phosphate (BCP) ceramics of tilapia fish bones by age

Biphasic calcium phosphate (BCP), consisting of bioceramics such as HAp + β-TCP and Ca10(PO4)6(OH)2 + Ca3(PO4)2, is a popular choice for optimizing performance due to its superior biological reabsorption and osseointegration. In this study, BCP was produced by calcining the bones of tilapia fish (Oreochromis niloticus) reared in net cages and slaughtered at an age ranging from 15 to 420 days. The bones were cleaned and dried, calcined at 900 °C for 8 h, and then subjected to high-energy grinding for 3 h to produce BCP powders. After the calcination process, the crystalline phase’s hydroxyapatite (HAp) and/or beta-tricalcium phosphate (β-TCP) were present in the composition of the bioceramic. The age-dependent variation in phase composition was confirmed by complementary vibrational spectroscopy techniques, revealing characteristic peaks and bands of the bioceramic. This variation was marked by an increase in HAp phase and a decrease in β-TCP phase. Thermogravimetric Analysis (TGA) and Differential Thermal Analysis (DTA) from 25 to 1400 °C showed the characteristic mass losses of the material, with a greater loss observed for younger fish, indicating the complete removal of organic components at temperatures above 600 °C. Comparison of the results obtained by X-Ray Diffraction (XRD) and Rietveld refinement with Raman spectroscopy showed excellent agreement. These results showed that with temperature and environment control and adequate fish feeding, it is possible to achieve the desired amounts of each phase by choosing the ideal age of the fish. This bioceramic enables precise measurement of HAp and β-TCP concentrations and Ca/P molar ratio, suitable for medical orthopedics and dentistry.

Calcium phosphate ceramic-induced osteoimmunomodulation: Submicron-surface-treated macrophage-derived exosomes driving osteogenesis

The development of osteoimmunology has highlighted the crucial role of biomaterial surface topography in modulating macrophage responses, subsequently affecting bone formation. However, the underlying mechanism remains largely unexplored. This study introduced two biphasic calcium phosphate (BCP) ceramics with different surface architecture, finding that compared to micron-scale counterparts (BCP2, ∼3.07 μm), BCP with submicron-scale structure (BCP1, ∼0.66 μm) enhanced ectopic bone formation and facilitated M2 macrophage polarization in vivo. Previous studies have focused predominantly on soluble cytokines secreted by macrophages, the significance of exosomes in intercellular communication has been overlooked. This study isolated exosomes from macrophages treated with either submicron- or micron-scale surfaces, designated as B1-Exos and B2-Exos, respectively. Notably, B1-Exos could significantly improve osteogenic differentiation of mesenchymal stem cells (MSCs), potentially attributable to miRNA cargos within these exosomes. SmallRNA sequencing, western blotting, qRT-PCR, and bioinformatics analyses indicated that submicron-sized BCP1 ceramic markedly elevated miR-142a-5p levels in macrophage-derived exosomes, activating the PTEN/AKT signaling pathway, and consequently guiding the differentiation of MSCs towards osteoblast lineage. These findings not only deepen our understanding of the biomaterial-mediated osteoinduction mechanism, but also inform the design of bone repair materials with specialized surface design for proper immunomodulation to initiate osteogenesis.

Macrophage Intracellular “Calcium Oscillations” Triggered Through In Situ Mineralization Regulate Bone Immunity to Facilitate Bone Repair

AbstractBioceramics are vital for treating bone defects, and bioactive glasses (exemplified by 45S5) and calcium phosphate ceramics (CaPs, exemplified by tricalcium phosphate [β‐TCP]) are extensively explored. β‐TCP exhibits superior biocompatibility, degradability, and osteoconductive properties than 45S5; however, it lacks bioactivity, such as mineralization capability. To harness the synergies of both, four 3D printing bioceramic scaffolds: 45S5, 70% 45S5 + 30% TCP, 30% 45S5 + 70% TCP, and TCP, are manufactured. Furthermore, the investigation elucidates the correlation between their in situ mineralization capabilities and the intracellular calcium oscillations within macrophages and determines how they impact macrophage phenotypic transitions. Notably, during bioceramic degradation, there is an initial rise followed by a decline in calcium ion concentration, which results in intracellular calcium ion oscillations within macrophages. In the 70% 45S5 + 30% TCP group, early release of calcium ions promotes M1 macrophage polarization. Subsequently, rapid in situ mineralization causes a decrease in extracellular calcium ions, thus accelerating the transition of M1 to M2 macrophages and facilitating bone repair. The present study reveals a novel mechanism through which bioceramics modulate macrophage polarization, offers new insights into the initial foreign body response to bioceramics and presents a perspective on expeditious progression toward tissue repair.

Synthetic biomaterials based on hydroxyapatite and tricalcium phosphate: analysis of current clinical trials

Introduction To date, a wide variety of synthetic materials, including metals, polymers and ceramics, have been proposed and used as a substitute for bone grafts in the field of traumatology/orthopedics, neurosurgery and oral and maxillofacial surgery (OMFS). However, the most studied materials are calcium phosphate ceramics (CPC), in particular hydroxyapatite and tricalcium phosphate, as well as their mixtures, called byphasic calcium phosphates. This interest stems from the fact that the main component of bone is the apatite mineral calcium phosphate. Hydroxyapatite and tricalcium phosphate are among the most commonly used and effective synthetic substitutes for bone grafts. They have not only osteoconductive properties, but also osteoinductive. These properties, combined with cell-mediated resorption, ensure complete regeneration of bone defects. This study will analyze existing clinical trials, registered on the clinicaltirals.gov website, on the use of hydroxyapatite and tricalcium phosphate in the field of traumatology and orthopedics, neurosurgery and OMFS.Aim To identify the potential for clinical use, as well as possible side effects, of CPC as a replacement for bone grafts.Materials and methods The search strategy was to use material from the clinicaltrials.gov website, which focused on key terms such as hydroxyapatite, tricalcium phosphate, hydroxyapatite and tricalcium phosphate, traumatology and orthopedics, maxillofacial surgery, dentistry, neurosurgery, bone, и diseases of the musculoskeletal system.Results and discussion As of November 2022, there were approximately 85 clinical trials with hydroxyapatite application, approximately 49 clinical trials with tricalcium phosphate, and approximately 16 clinical trials with the hydroxyapatite/tricalcium phosphate combination. Most of the studies were Phase 1-2, Phase 2, or Phase 4. Most focused on tibial trauma therapy, osteoporosis/osteopenia, alveolar bone resorption, and spinal surgery. It was found that full results were published only in 3, 7 and 2 clinical trials on the use of hydroxyapatite, tricalcium phosphate and their combination, respectfully. All clinical trials had similar preparation methods and all of those clinical trials produced positive results without serious side effects.Conclusion There is a wide potential for clinical use of CPC as synthetic bone graft substitutes without reports of serious side effects. Many preclinical and clinical studies are currently underway on the use of hydroxyapatite and tricalcium phosphate, and their future results will further explore their clinical potential.

Low-Temperature Calcium Phosphate Ceramics Can Modulate Monocytes and Macrophages Inflammatory Response In Vitro.

Creating bioactive materials for bone tissue regeneration and augmentation remains a pertinent challenge. One of the most promising and rapidly advancing approaches involves the use of low-temperature ceramics that closely mimic the natural composition of the extracellular matrix of native bone tissue, such as Hydroxyapatite (HAp) and its phase precursors (Dicalcium Phosphate Dihydrate-DCPD, Octacalcium Phosphate-OCP, etc.). However, despite significant scientific interest, the current knowledge and understanding remain limited regarding the impact of these ceramics not only on reparative histogenesis processes but also on the immunostimulation and initiation of local aseptic inflammation leading to material rejection. Using the stable cell models of monocyte-like (THP-1ATRA) and macrophage-like (THP-1PMA) cells under the conditions of LPS-induced model inflammation in vitro, the influence of DCPD, OCP, and HAp on cell viability, ROS and intracellular NO production, phagocytosis, and the secretion of pro-inflammatory cytokines was assessed. The results demonstrate that all investigated ceramic particles exhibit biological activity toward human macrophage and monocyte cells in vitro, potentially providing conditions necessary for bone tissue restoration/regeneration in the peri-implant environment in vivo. Among the studied ceramics, DCPD appears to be the most preferable for implantation in patients with latent inflammation or unpredictable immune status, as this ceramic had the most favorable overall impact on the investigated cellular models.

Effect of Addition of ZrO2 on Biaxial Flexural Strength of Calcium Phosphate Ceramics

The aim of this study is to investigate the effect of addition of ZrO2 on the biaxial flexural strength (BFS) of ceramics fabricated using a conventional powder technology. Various compositions of hydroxyapatite (HAp) Ca10(PO4)6(OH)2 and zirconia powder ZrO2, ranging from 10 to 90 wt% ZrO2, were prepared using a wet mixing process. Ten compacts (13.5mm3mm) were made for each group, pressed and sintered in air at sintering temperatures from 1100 to 1450oC for up to 12 hours. The bulk density, porosity, linear shrinkage and BFS. The porosity reduced and linear shrinkage increased with increasing sintering temperature and amounts of zirconia, whereas the sintering time had little effect. The highest mean value achieved for the BFS was 26920 MPa for a composition of 70% ZrO2 and 30% HAp fired at 1450oCfor 6 hours. From the experimental results can be conclude that sintering temperature and composition affect densification behaviour of calcium phosphate/ ZrO2 composites. The BFS increases with a reduction of porosity and increases with both sintering temperature and additions of ZrO2. It was noted that there is considerable scope for improvement in the BFS values by reducing the porosity of these composites.

Effects of void defects on the mechanical properties of biphasic calcium phosphate nanoparticles: A molecular dynamics investigation

Porous biphasic calcium phosphate (BCP) ceramics are widely used in bone tissue engineering, and the mechanical properties of BCP implants must be reliable. However, the effects of pore structure (e.g., shape and size) on the mechanical properties are not well understood. In this study, we used molecular dynamics simulations to investigate the influence of pore shape and size on the mechanical behavior of BCP nanoparticles. BCP void models with cylindrical and cuboid pores ranging from 2 to 16 nm in diameter were constructed, and the elastic moduli were calculated. In addition, uniaxial tensile and compressive tests were performed on the models. We found that the pore size had a more significant impact on the mechanical properties of BCP than pore shape. Further, the elastic moduli decreased nonlinearly with increasing pore size. In addition, the tensile and compressive strength also decreased with the increase in pore size, but the ductility improved. Furthermore, deformation and fracture were more likely to occur near the pores and at the phase interfaces as a result of high atomic local strain in the calcium-deficient hydroxyapatite area. The results of this work reveal the effects of pore parameters on the mechanical properties of porous BCP at the nanometer level, which may aid the design of improved porous and multiphase CaP-based biomaterials for bone regeneration.

Microscopy to discern cells behaviour on different nano/microstructured calcium phosphates ceramics

Microscopy to discern cells behaviour on different nano/microstructured calcium phosphates ceramics

PI3K/AKT/mTOR signaling regulates BCP ceramic-induced osteogenesis.

An increasing number of studies demonstrate that biphasic calcium phosphate (BCP) ceramics can induce bone regeneration. However, the underlying molecular mechanisms involved are still poorly understood. This work was proposed to investigate how PI3K/AKT/mTOR signaling influenced the osteogenesis mediated by BCP ceramics. The results showed that incubation with BCP ceramics promoted the proliferation of murine bone marrow-derived mesenchymal stem cells (BMSCs) in a time-dependent manner. The resulting cell proliferation was then suppressed by the selective inhibition of either PI3K, AKT, or mTOR signaling activation. Next, we confirmed that BCP ceramics up-regulated the phosphorylation levels of AKT and mTOR in BMSCs, suggesting the ability of BCP ceramics to drive the activation of PI3K/AKT/mTOR signaling in BMSCs. Furthermore, the blockade of PI3K/AKT/mTOR signaling prevented BCP ceramics-induced osteogenic differentiation and pro-angiogenesis of BMSCs by down-regulating the expression of genes encoding OPN, RUNX2 or VEGF. Moreover, the PI3K/AKT/mTOR signaling blockade suppressed stem cell infiltration and new bone formation in the implants following intra-muscular implantation of BCP ceramics in mice. Therefore, our results suggested that PI3K/AKT/mTOR signaling played a critical regulatory role in BCP ceramic-induced osteogenesis.

Research progress on biodegradable magnesium phosphate ceramics in orthopaedic applications.

To overcome critical size bone defects, calcium phosphate (CaP)-based ceramics have been widely explored. The compositional similarity with bone matrix and degradability are the main reasons for their selection in orthopaedic biomaterials. However, the low solubility rate under in vivo conditions raises concerns about these CaP groups, particularly hydroxyapatite (HA) and tricalcium phosphate (TCP) ceramics. Therefore, reliable and suitable degradable ceramics for bone defect repair are always an important research direction for researchers. The magnesium phosphate (MgP) group of bioceramics has been studied for orthopaedic applications and is comparatively new compared to traditional CaP ceramics. The role of magnesium in different biochemical processes, such as DNA stabilization, bone density maintenance, regulating Ca and Na ion channels, and cell proliferation and differentiation enhancement, is a key parameter for the development of MgP bioceramics. This article aims to give a comprehensive review of MgP ceramics in bone tissue engineering. Here, we have highlighted several preparation techniques, the existence of porosity, and the impact of metal ion doping on MgP bioceramics. Finally, in vitro and in vivo responses of MgP bioceramics in bone formation are discussed.