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Osteoporotic femur fractures are the most common fragility fracture and account for approximately one million injuries per year. Local intervention by intra-marrow injection is potentially a good choice for preventing osteoporotic bone loss when the osteoporotic femoral fracture was treated. Previously, it was shown that trace element co-doped calcium phosphate (teCaP) implants could stimulate osteoporotic bone marrow mesenchymal stem cell activity in vitro and bone regeneration in femoral bone defects in osteoporotic animal models. They hypothesized that local intra-marrow injection of teCaP particles could improve bone function because the teCaP can sustain release of biologically essential inorganic minerals and improve bone remodeling in osteoporosis. The teCaP and CaP particles were synthesized in simulated body fluid with and without adding silicon, zinc and strontium ions. Female rats (8 months) were ovariectomized (OVX) or sham-operated, and then intervened in the femoral marrow space at 12 months old. Groups include: (1) saline water; (2) CaP particles; and (3) teCaP particles. After 2-3 months of intervention, the sham groups showed higher bone mineral density (MBD) in the femur, and teCaP group increased the BMD in the OVX groups. The compressive strength of the OVX-teCaP group was significantly higher than that in the OVX-CaP group. Significant differences between OVX-teCaP and OVX-CaP groups were found for bone mineral microarchitecture, bone mineral density, and trace mineral content, but not for feces composition. These results confirm the teCaP particles could suppress osteoporotic bone loss by local intramarrow injection. Therefore, this biomaterial could be used as a next-generation combination treatment for osteoporotic trauma and osteoporosis itself. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1422-1432, 2017., (© 2017 Wiley Periodicals, Inc.)

Some Ca-Mg-silicate ceramics have been widely investigated to be highly bioactive and biodegradable, whereas their osteogenic potential and especially biomechanical response in the early stage in vivo are scarcely demonstrated. Herein, the osteogenesis capacity and mechanical evolution of the akermanite (Ca 2 MgSi 2 O 7 ) porous materials manufactured by ceramic ink writing three-dimensional printing technique were investigated systematically in a critical size femur defect model, in comparison with the clinically available β-tricalcium phosphate porous bioceramic. Such three-dimensional printed akermanite scaffolds possess fully interconnected pores of ∼280 × 280 µm in size and over 50% porosity with appreciable compressive strength (∼71 MPa), that is 7-fold higher than that of the β-tricalcium phosphate porous bioceramics (∼10 MPa). After 6 weeks and 12 weeks of implantation, the percentage of newly formed bone and more new bone was observed in the akermanite group as compared with the β-tricalcium phosphate group (p < 0.01). Moreover, significant higher mRNA expressions of osteogenic genes were detected in the akermanite group by PCR analysis (p < 0.01). The in vivo mechanical strength decreased during the process of implantation, but maintained a relative high level (∼14 MPa) which was still higher than that of the host cancellous bone (5-10 MPa) at 12 weeks post-implantation. On the contrary, the β-tricalcium phosphate scaffold always exhibited a very low mechanical strength (∼8 MPa). These results suggest that the three-dimensional printed akermanite scaffolds are promising for the bone tissue regeneration and repair of load-bearing bone defects., (© The Author(s) 2016.)

The chitosan/alginate-trace element-codoped octacalcium phosphate/nano-sized bioactive glass (CS/ALG-teOCP/nBG) composite membranes were prepared by a layer-by-layer coating method for the functional requirement of guided bone regeneration (GBR). The morphology, mechanical properties and moisture content of the membranes was studied by scanning electron microscopy (SEM) observation, mechanical and swelling test. The results showed that the teOCP/nBG distributed uniformly in the composite membranes, and such as-prepared composite membrane exhibited an excellent tensile strength, accompanying with mechanical decay with immersion in aqueous medium. Cell culture and MTT assays showed that the surface microstructure and the ion dissolution products from teOCP/nBG components could enhance the cell proliferation, and especially the composite membranes was suitable for supporting the adhesion and growth behavior of human bone marrow mesenchymal stem cells (hBMSCs) in comparison with the CS/ALG pure polymer membranes. These results suggest that the new CS/ALG-teOCP/nBG composite membrane is highly bioactive and biodegradable, and favorable for guiding bone regeneration.

Biomolecule-ion interactions that occur during changes in pH value are a crucial but poorly investigated area that underlies the aggregation of inorganic nanocrystals. Meanwhile, the disorderly growth of calcium phosphate (CaP) nanocrystals is an obstacle that limits its practical applications. Herein, we have demonstrated for the first time that a simple two-step pH-adjustment process for a gelatin hydrosol reaction medium can modulate the ordered self-assembly of trace-element-doped CaP nanocrystals into porous beads. Two methods are used to adjust the initial pH value of gelatin hydrosol: One is to firstly adjust the pH value to 3.0 and then to 4.0 with acid/base solutions, whilst the other is to directly adjust the pH value to 4.0 with acid. Spherical CaP porous beads are rapidly produced through the two-step pH-adjustment process, whereas the one-step pathway results in disorderly CaP aggregates. We believe that the introduction of additives for pH adjustment is the dominant factor in disturbing the electrokinetic parameters and for driving the self-assembly of nanocrystals, whereas the nucleation of CaP nanocrystals prior to assembly is caused by the relaxation/condensation of the polypeptide network, owing to the increase in pH value on the introduction of the basic calcium salt. This method is facile and rapid and these highly bioactive porous beads are particularly promising for use in hard-tissue repair, tissue engineering, and drug delivery., (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Supplementation of individual micronutrient is inadequate for maintaining bone function because single micronutrient can not contribute significantly a positive remodeling balance., Objective: We developed the highly integrated, stably dietary multi-micronutrients with good bioavailability and low adverse effect on the improvement of bone consolidation in osteoporosis., Methods: The trace element-codoped calcium phosphate (teCaP) particles were prepared in the modified body fluid and carefully evaluated. Rats, aged 3 months, were ovariectomized and when 6 month intervened with the conditioned, low, moderate, and high teCaP diets., Results: The teCaP particles showed highly dissolvable in stomach juice-mimicing acidic solutions. Three months after intervention, the body weight increase showed remarkable differences among the low teCaP diet (~52 g), moderate teCaP diet (~34 g) and high teCaP diet (~23 g) group. In particular, the intake of moderate teCaP greatly improved the retention of trace elements in femural bone for better protection against the skeletal weakening, and resulted in a significant increase of bone mineral density (104.06%) in comparison with the conventional high calcium plus vitamin D3 diet (Control group)., Conclusions: These investigations improve our understanding of micronutrient retention on bone consolidation in osteoporotic bone tissue, and also provide new mild wet-chemical approach to prepare potent nutritionally effective edible complements to synergistically relieve bone degeneration and prevent osteoporosis.

Bisphosphonates (BPs) are a class of synthetic pyrophosphate analogs that can prevent the loss of bone mass, given orally to treat postmenopuasal osteoporosis. It is not clear yet if the benefits of BPs include the possibility of affecting bone apatitic precursors transition for bone consolidation except for encouraging osteoclasts to undergo apoptosis. Furthermore, the complexity of the in vivo system makes it difficult to isolate and study such extracellular topographical cues that trigger bone turnover response. Herein, we proposed a wet-chemical approach employing alendronate sodium (AS) as a guide of hydroxyapatite (HA) precursor growth and conversion which was initiated from the nucleantion of octacalcium phosphate (OCP) in a cell membrane-mimicking surfactant micelle aqueous system. The nanocrystal clusters of dicalcium phosphate dihydrate (DCPD) and OCP nanocryatals were readily precipitated within a relatively narrow AS concentration range (2-8 μM). However, such low concentrations of AS seemed to stabilize the more acidic phases, and to delay the transformation into HA, to an extent which increased on increasing AS concentration. In contrast, at a slight higher concentrations (16-32 μM), AS promoted HA precipitation after ageing for 1h. It was found that the effect of AS on the phase selectivity of apatitic precursors was concentration-dependent within a prolonged ageing time stage (0.5-168 h). The AS-assisted reactions in vitro offer an expedient way to understand the underlying implementarity between bone and BPs for bone consolidation, and to improve our understanding of benefit of BP dosages on bone turnover and trauma healing., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The promising future of calcium phosphates (CaP) as a group of biomedical materials with a wide range of functions, might ultimately depend on tuning their composition and microstructure. However, the disorderly growth and aggregation of CaP nanocrystals limit their practical application. This paper reports a strategy for designing polypeptide/trace elements (TE), dual mediating the self-assembly of octacalcium phosphate (OCP) nanocrystals, with multilayered porous cross section and TE dilute doping. Intriguing advantages such as bead morphology, mesoporous structure, tunable diameter (20-1,000 μm) and TE contents, biodegradability and bioactivity are obtained. The microcomputerized-tomography reconstruction reveals an interconnective macroporous architecture and a void volume of over 49.02% for the nearly close-packed bead scaffolds. The specific surface area and average mesopore size are 89.73 m(2)g(-1) and 2.75 nm for the 180 μm diameter bead group, and those of 500 μm diameter beads are 130.17 m(2)g(-1) and 3.69 nm, respectively. It is demonstrated that the bead production mechanism is a multistep process including liquid-like precursor formation, nanocrystal nucleation and aggregation, aggregate combination and bead growth. Such a multilayer structure of TE-OCP porous beads would have adequate physical strength to maintain their shape, in contrast to the physical weakness of pure OCP hollow shell. The beads exhibit good biocompatibility and degradability and encourage bone mineralization in the early stage in vivo. This study demonstrates the feasibility of developing highly porous calcium phosphate giant beads via biomimetic self-assembly for direct application in reconstructive surgery and other widespread applications such as tissue engineering and drug delivery., (Copyright © 2011 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Research in the field of orthopedic implantology is currently focused on developing methodologies to potentiate osseointegration and to expedite the reestablishment of full functionality. We have developed a simple biomimetic approach for preparing trace elements-codoped calcium phosphate (teCaP) coatings on a titanium substrate. The reaction proceeded via low-thermal incubation in trace elements (TEs)-added simulated body fluid (teSBF) at 90 and 120 °C. The x-ray photoelectron spectroscopy, x-ray diffraction and energy-dispersive x-ray analyses demonstrated that the teCaP coating was the composite of hydroxyapatite and whitlockite, simultaneously doped with magnesium, strontium, zinc and silicon. The addition of polyaspartic acid and TEs into SBF significantly densified the coating. The incubation temperature is another important factor controlling the coating precipitation rate and bonding strength. An incubation temperature of 120 °C could accelerate the coating precipitation and improve the interface bonding strength. The in vitro cell culture investigation indicated that the teCaP coating supported the adhesion and spreading of ovariectomized rat mesenchymal stem cells (rMSCs) and particularly, promoted rMSCs proliferation compared to the CaP coating prepared in SBF. Collectively, from such a biomimetic route there potentially arises a general procedure to prepare a wide range of bioactive teCaP coatings of different composition for osteoporotic osteogenic cells activation response.

The multiple biologically active trace element delivery remains a problem in regeneration medicine and tissue engineering. A novel approach to fabricate the biologically active trace elements assembly in a core-shell system for cooperative controlled-release has been proposed. Firstly, using a pH-dependent electrostatic interaction, zinc and strontium ions were incorporated into the silica gel nanospheres. Subsequently a porous octacalcium phosphate (OCP) shell was coated on the nanospheres tailored by poly(acrylate sodium) molecules. In vitro test shows that this hierarchical multilayered nanostructure can achieve a shell-/pH-dependent controlled-release of silicon, strontium and zinc ions. The wet-chemical route to selective synthesis of the core-shell Silica@OCP system may provide a general model to develop cooperative encapsulation of biologically active ions in a silica-based system by using layer-by-layer assembly technique for controlled-release in biomedical areas.