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High strength porous titanium implants are widely used for the reconstruction of craniofacial defects because of their similar mechanical properties to those of bone. The recent introduction of electron beam melting (EBM) technique allows a direct digitally enabled fabrication of patient specific porous titanium implants, whereas both their in vitro and in vivo biological performance need further investigation. In the present study, we fabricated porous Ti6Al4V implants with controlled porous structure by EBM process, analyzed their mechanical properties, and conducted the surface modification with biomimetic approach. The bioactivities of EBM porous titanium in vitro and in vivo were evaluated between implants with and without biomimetic apatite coating. The physical property of the porous implants, containing the compressive strength being 163 - 286 MPa and the Young's modulus being 14.5-38.5 GPa, is similar to cortical bone. The in vitro culture of osteoblasts on the porous Ti6Al4V implants has shown a favorable circumstance for cell attachment and proliferation as well as cell morphology and spreading, which were comparable with the implants coating with bone-like apatite. In vivo, histological analysis has obtained a rapid ingrowth of bone tissue from calvarial margins toward the center of bone defect in 12 weeks. We observed similar increasing rate of bone ingrowth and percentage of bone formation within coated and uncoated implants, all of which achieved a successful bridging of the defect in 12 weeks after the implantation. This study demonstrated that the EBM porous Ti6Al4V implant not only reduced the stress-shielding but also exerted appropriate osteoconductive properties, as well as the apatite coated group. The results opened up the possibility of using purely porous titanium alloy scaffolds to reconstruct specific bone defects in the maxillofacial and orthopedic fields.

Although three-dimensional (3D) β-tricalcium phosphate (β-TCP) scaffolds serve as promising bone graft substitutes for the segmental bone defect treatment, no consensus has been achieved regarding their optimal 3D architecture. In this study, we has systematically compared four types of β-TCP bone graft substitutes with different 3D architectures, including two types of porous scaffolds, one type of tubular scaffolds and one type of solid scaffolds, for their efficacy in treating segmental bone defect in a rabbit model. Our study has demonstrated that when compared to the traditional porous and solid scaffolds, tubular scaffolds promoted significantly higher amount of new bone formation in the defect regions as shown by X-ray, micro CT examinations and histological analysis, restored much greater mechanical properties of the damaged bone evidenced by the biomechanical testing, and eventually achieved the complete union of segmental defect. Moreover, the implantation of tubular scaffolds enhanced the neo-vascularization at the defect region with higher bone metabolic activities than others, as indicated by the bone scintigraphy assay. This study has further the current knowledge regarding the profound influence of overall 3D architecture of β-TCP scaffolds on their in vivo defect healing performance and illuminated the promising potential use of tubular scaffolds as effective bone graft substitute in treating large segmental bone defects.

As cortical bone has a hierarchical structure, the macroscopic bone strength may be affected by the alterations of mineral crystal and collagen, which are main components of cortical bone. Limited studies focused on the time related alterations of these two components in osteoporosis, and their contributions to bone mechanics at tissue level and whole-bone level. Therefore, the purpose of this study was to elucidate the time related changes of mineral and collagen in cortical bone of ovariectomized (OVX) rabbits, and to relate these changes to cortical bone nanomechanics and macromechanics. 40 Rabbits (7-month-old) were randomly allocated into two groups (OVX and sham). OVX group received bilateral ovariectomy operation. Sham group received sham-OVX operation. Cortical bone quality of five rabbits in each group were assessed by DXA, μCT, nanoindentation, Fourier transform infrared (FTIR) spectroscopy and biomechanical tests (3-point bending of femoral midshaft) at pre-OVX, 4, 6, and 8 weeks after OVX. As time increased from pre-OVX to 8 weeks, the mineral to matrix ratio decreased with time, while both collagen crosslink ratio and crystallinity increased with time in OVX group. Elastic modulus and hardness measured by nanoindentation, whole-bone strength measured by biomechanical tests all decreased in OVX group with time. Bone material properties measured by FTIR correlated well with nano or whole-bone level mechanics. However, bone mineral density (BMD), structure, tissue-level and whole-bone mechanical properties did not change with age in sham group. Our study demonstrated that OVX could affect the tissue-level mechanics and bone strength of cortical bone. And this influence was attributed to the time related alterations of mineral and collagen properties, which may help us to design earlier interventions and more effective treatment strategies on osteoporosis.

Recent clinical studies indicated that angiotensin receptor blockers (ARBs) would decrease the risk of bone fractures in the elderly populations. There is little known about the role of the ARBs in the process of fracture healing. The purpose of the present study was to verify the hypothesis that systemic treatment with telmisartan has the ability to promote fracture healing. In this study, femur fractures were produced in 96 mature male BALB/c mice. Animals were treated with the ARBs telmisartan or vehicle. Fracture healing was analysed after 2, 5 and 10 weeks postoperatively using X-ray, biomechanical testing, histomorphometry, immunohistochemistry and micro-computed tomography (micro-CT). Radiological analysis showed the diameter of the callus in the telmisartan treated animals was significantly increased when compared with that of vehicle treated controls after two weeks of fracture healing. The radiologically observed promotion of callus formation was confirmed by histomorphometric analyses, which revealed a significantly increased amount of bone formation when compared with vehicle-treated controls. Biomechanical testing further showed a significantly greater peak torque at failure, and a higher torsional stiffness in telmisartan-treated animals compared with controls. There was an increased fraction of PCNA-positive cells and VEGF-positive cells in telmisartan-treated group compared with vehicle-treated controls. From the three-dimensional reconstruction of the bony callus, telmisartan-treated group significantly increased the values of BV/TV by 21.7% and CsAr by 26.0% compared to the vehicle-treated controls at 5 weeks post-fracture. In summary, we demonstrate in the current study that telmisartan could promote fracture healing in a mice model via increasing mechanical strength and improving microstructure. The most mechanism is probably by an increase of cell proliferation and neovascularization associated with a decreased VEGF expression in hypertrophic chondrocytes.

The basic strategy to construct tissue engineered bone graft (TEBG) is to combine osteoblastic cells with three dimensional (3D) scaffold. Based on this strategy, we proposed the \"Totally Vitalized TEBG\" (TV-TEBG) which was characterized by abundant and homogenously distributed cells with enhanced cell proliferation and differentiation and further investigated its biological performance in repairing segmental bone defect. In this study, we constructed the TV-TEBG with the combination of customized flow perfusion seeding/culture system and β-tricalcium phosphate (β-TCP) scaffold fabricated by Rapid Prototyping (RP) technique. We systemically compared three kinds of TEBG constructed by perfusion seeding and perfusion culture (PSPC) method, static seeding and perfusion culture (SSPC) method, and static seeding and static culture (SSSC) method for their in vitro performance and bone defect healing efficacy with a rabbit model. Our study has demonstrated that TEBG constructed by PSPC method exhibited better biological properties with higher daily D-glucose consumption, increased cell proliferation and differentiation, and better cell distribution, indicating the successful construction of TV-TEBG. After implanted into rabbit radius defects for 12 weeks, PSPC group exerted higher X-ray score close to autograft, much greater mechanical property evidenced by the biomechanical testing and significantly higher new bone formation as shown by histological analysis compared with the other two groups, and eventually obtained favorable healing efficacy of the segmental bone defect that was the closest to autograft transplantation. This study demonstrated the feasibility of TV-TEBG construction with combination of perfusion seeding, perfusion culture and RP technique which exerted excellent biological properties. The application of TV-TEBG may become a preferred candidate for segmental bone defect repair in orthopedic and maxillofacial fields.

This study was aimed at elucidating the temporal changes of microarchitectural and mechanical parameters of cancellous bone in the osteoporotic rabbit model induced by ovariectomy (OVX) combined with glucocorticoid (GC) administration. Osteoporotic (OP) group received bilateral OVX combined with injections of GC, while sham group only received sham operation. Cancellous bone quality in vertebrae and femoral condyles in each group was assessed by DXA, μCT, nanoindentation, and biomechanical tests at pre-OVX and 4, 6, and 8 weeks after injection. With regard to femoral condyles, nanoindentation test could detect significant decline in tissue modulus and hardness at 4 weeks. However, BMD and microarchitecture of femoral condylar cancellous bone changed significantly at 6 weeks. In vertebrae, BMD, microarchitecture, nanoindentation, and biomechanical tests changed significantly at 4 weeks. Our data demonstrated that temporal changes of microarchitectural and mechanical parameters of cancellous bone in the osteoporotic rabbit were significant. The temporal changes of cancellous bone in different anatomical sites might be different. The nanoindentation method could detect the changes of bone quality at an earlier stage at both femoral condyle and vertebra in the osteoporotic rabbit model than other methods (μCT, BMD).

Magnesium has been investigated as a biodegradable metallic material. Increased concentrations of Mg 2+ around magnesium implants due to biodegradation contribute to its satisfactory osteogenic capacity. However, the mechanisms underlying this process remain elusive. We propose that activation of the PI3K/Akt signalling pathway plays a role in the Mg 2+ -enhanced biological behaviours of osteoblasts. To test this hypothesis, 6, 10 and 18 mM Mg 2+ was used to evaluate the stimulatory effect of Mg 2+ on osteogenesis, which was assessed by evaluating cell adhesion, cell viability, ALP activity, extracellular matrix mineralisation and RT-PCR. The expression of p-Akt was also determined by western blotting. The results showed that 6 and 10 mM Mg 2+ elicited the highest stimulatory effect on cell adhesion, cell viability and osteogenic differentiation as evidenced by cytoskeletal staining, MTT assay results, ALP activity, extracellular matrix mineralisation and expression of osteogenic differentiation-related genes. In contrast, 18 mM Mg 2+ had an inhibitory effect on the behaviour of osteoblasts. Furthermore, 10 mM Mg 2+ significantly increased the phosphorylation of Akt in osteoblasts. Notably, the aforementioned beneficial effects produced by 10 mM Mg 2+ were abolished by blocking the PI3K/Akt signalling pathway through the addition of wortmannin. In conclusion, these results demonstrate that 6 mM and 10 mM Mg 2+ can enhance the behaviour of osteoblasts, which is at least partially attributed to activation of the PI3K/Akt signalling pathway. Furthermore, a high concentration (18 mM Mg 2+ ) showed an inhibitory effect on the biological behaviour of osteoblasts. These findings advance the understanding of cellular responses to biodegradable metallic materials and may attract greater clinical interest in magnesium.

The purpose of this study was to investigate the therapeutic effects of crocin on ovariectomy-induced osteoporosis in rats. Female Sprague-Dawley rats were randomly assigned to a sham-operated group (sham) and five ovariectomy (OVX) subgroups, that is, OVX with vehicle (OVX), OVX with 17β-estradiol (E 2, 25 μg/kg/day), and OVX with graded crocin doses (5, 10, or 20 mg/kg/day). Daily oral administration of E 2 or crocin started 4 weeks after OVX and lasted for 16 weeks. Our results showed that crocin dose-dependently inhibited the BMD reduction of L4 vertebrae and femurs caused by OVX and prevented the deterioration of trabecular microarchitecture, which were accompanied by a significant decrease in skeletal remodeling as evidenced by the lower levels of bone turnover markers. Furthermore, crocin reversed the oxidative stress status in both serum and bone tissue. The present study indicates that the administration of crocin at higher doses over a 16-week period can prevent OVX-induced osteoporosis in rats without hyperplastic effects on the uterus, which may, at least partially, be attributed to crocin’s antioxidative property. In brief, crocin is a natural alternative for postmenopausal osteoporosis treatment in elderly women.

: Mechanisms underlying the compromised bone formation in type 1 diabetes mellitus (T1DM), which causes bone fragility and frequent fractures, remain poorly understood. Recent advances in organ-specific vascular endothelial cells (ECs) identify type H blood vessel injury in the bone, which actively direct osteogenesis, as a possible player. : T1DM was induced in mice by streptozotocin (STZ) injection in two severity degrees. Bony endothelium, the coupling of angiogenesis and osteogenesis, and bone mass quality were evaluated. Insulin, antioxidants, and NADPH oxidase (NOX) inhibitors were administered to diabetic animals to investigate possible mechanisms and design therapeutic strategies. : T1DM in mice led to the holistic abnormality of the vascular system in the bone, especially type H vessels, resulting in the uncoupling of angiogenesis and osteogenesis and inhibition of bone formation. The severity of osteopathy was positively related to glycemic levels. These pathological changes were attenuated by early-started, but not late-started, insulin therapy. ECs in diabetic bones showed significantly higher levels of reactive oxygen species (ROS) and NOX 1 and 2. Impairments of bone vessels and bone mass were effectively ameliorated by treatment with anti-oxidants or NOX2 inhibitors, but not by a NOX1/4 inhibitor. GSK2795039 (GSK), a NOX2 inhibitor, significantly supplemented the insulin effect on the diabetic bone. : Diabetic osteopathy could be a chronic microvascular complication of T1DM. The impairment of type H vessels by NOX2-mediated endothelial oxidative stress might be an important contributor that can serve as a therapeutic target for T1DM-induced osteopathy.

Although three-dimensional (3D) [beta]-tricalcium phosphate ([beta]-TCP) scaffolds serve as promising bone graft substitutes for the segmental bone defect treatment, no consensus has been achieved regarding their optimal 3D architecture. In this study, we has systematically compared four types of [beta]-TCP bone graft substitutes with different 3D architectures, including two types of porous scaffolds, one type of tubular scaffolds and one type of solid scaffolds, for their efficacy in treating segmental bone defect in a rabbit model. Our study has demonstrated that when compared to the traditional porous and solid scaffolds, tubular scaffolds promoted significantly higher amount of new bone formation in the defect regions as shown by X-ray, micro CT examinations and histological analysis, restored much greater mechanical properties of the damaged bone evidenced by the biomechanical testing, and eventually achieved the complete union of segmental defect. Moreover, the implantation of tubular scaffolds enhanced the neo-vascularization at the defect region with higher bone metabolic activities than others, as indicated by the bone scintigraphy assay. This study has further the current knowledge regarding the profound influence of overall 3D architecture of [beta]-TCP scaffolds on their in vivo defect healing performance and illuminated the promising potential use of tubular scaffolds as effective bone graft substitute in treating large segmental bone defects.