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Yang N.,Peking University | Cui Y.,Peking University | Tan J.,Peking University | Fu X.,Peking University | And 4 more authors.
Journal of Bone and Mineral Metabolism | Year: 2014

The aim of this study was to evaluate the effects and explore the mechanism of a local injection of a single dose of simvastatin as a strategy to strengthen target bone. Simvastatin was injected into the femurs (5 or 10 mg) or caudal vertebrae (1 or 2 mg) of ovariectomized rats, with an equal volume of vehicle injected as a control. Bone mineral density (BMD), bone microstructure and strength were evaluated at 1 and 5 months post-injection for the femurs and at 12 days post-injection for the vertebrae. Bone mass, adipocyte numbers and Runx2 expression were also examined using histology and immunohistochemistry. Compared with controls, simvastatin significantly increased BMD, bone volume fraction (BV/TV), improved bone microstructural parameters and bone strength in the femurs at both time points (all P < 0.01). Simvastatin-treated femurs contained fewer adipocytes and a higher Runx2 expression. For the caudal vertebrae, simvastatin significantly improved BV/TV, bone microstructures, and bone strength (all P < 0.01) as compared with controls. In conclusion, local injection of a single dose of simvastatin induces early onset and long-lasting bone augmentation in osteoporotic bone, significantly improving BMD, and bone microstructure and biomechanical strength. Simvastatin induces Runx2 expression, which may function to induce osteogenesis and inhibit adipogenesis as an underlying mechanism to augment bone mass. © The Japanese Society for Bone and Mineral Research and Springer 2013. Source


Yueyi C.,Peking University | Xiaoguang H.,Peking University | Jingying W.,Peking University | Quansheng S.,Peking University | And 5 more authors.
Biomaterials | Year: 2013

Local statins implant has been shown to promote bone healing, the underlying mechanisms are unclear. The purpose of this study was to test the effect of local simvastatin implant on bone defect healing; to evaluate the mobilization, migration, and homing of bone marrow-derived mesenchymal stem cells (BMSCs) and endothelial progenitor cells (EPCs) induced by simvastatin. We found that local simvastatin implant increased bone formation by 51.8% (week 6) and 64.8% (week 12) compared with polyglycolic acid controls (P<0.01), as verified by X-ray, CT, and histology. Simvastatin increased migration capacity of BMSCs and EPCs invitro (P<0.05). Local simvastatin implant increased mobilization of EPCs to the peripheral blood by 127% revealed by FACS analysis (P<0.01), and increased osteogenic BMSCs to the peripheral blood dramatically revealed by Alizarin Red-S staining for mineralized nodules formation. Pre-transplanted GFP-transfected BMSCs as a tracing cell and bioluminescence imaging revealed that local simvastatin implant recruited GFP-labeled BMSC. Also, local simvastatin implant induced the HIF-1α and BMP-2 expression. In conclusion, local simvastatin implantation promotes bone defect healing, where the underlying mechanism appears to involve the higher expression of HIF-1α and BMP-2, thus recruit autogenous osteogenic and angiogenetic stem cells to the bone defect area implanted with simvastatin. © 2013 Elsevier Ltd. Source


Tan J.,Peking University | Tan J.,Beijing Key Laboratory of Spinal Diseases | Yang N.,Peking University | Fu X.,Peking University | And 10 more authors.
Medical Science Monitor | Year: 2015

Background: Statins have been reported to promote bone formation. However, taken orally, their bioavailability is low to the bones. Implant therapies require a local repair response, topical application of osteoinductive agents, or biomaterials that promote implant fixation. Material/Methods: The present study evaluated the effect of a single local injection of simvastatin on screw fixation in an ovariectomized rat model of osteoporosis. Results: Dual-energy X-ray absorptiometry, micro-computed tomography, histology, and biomechanical tests revealed that 5 and 10 mg simvastatin significantly improved bone mineral density by 18.2% and 22.4%, respectively (P<0.05); increased bone volume fraction by 51.0% and 57.9%, trabecular thickness by 16.4% and 18.9%, trabeculae number by 112.0% and 107.1%, and percentage of osseointegration by 115.7% and 126.3%; and decreased trabeculae separation by 34.1% and 36.6%, respectively (all P<0.01). Bone mineral apposition rate was significantly increased (P<0.01). Furthermore, implant fixation was significantly increased (P<0.05), and bone morphogenetic protein 2 (BMP2) expression was markedly increased. Local injection of a single dose of simvastatin also promoted angiogenesis. Vessel number, volume, thickness, surface area, and vascular volume per tissue volume were significantly increased (all P<0.01). Vascular endothelial growth factor (VEGF), VEGF receptor- 2, von Willebrand factor, and platelet endothelial cell adhesion molecule-1 expression were enhanced. Conclusions: A single local injection of simvastatin significantly increased bone formation, promoted osseointegration, and enhanced implant fixation in ovariectomized rats. The underlying mechanism appears to involve enhanced BMP2 expression and angiogenesis in the target bone. © Med Sci Monit. Source


Tan J.,Peking University | Fu X.,Peking University | Sun C.G.,Peking University | Sun C.G.,Beijing Key Laboratory of Spinal Diseases | And 18 more authors.
Osteoporosis International | Year: 2016

Summary: The ultimate goal of osteoporosis treatment is prevention of fragile fracture. Local treatment targeting specific bone may decrease the incidence of osteoporotic fractures. We developed an injectable, thermosensitive simvastatin/poloxamer 407 hydrogel; a single CT-guided percutaneous intraosseous injection augmented vertebrae in ovariectomized minipigs. Introduction: The greatest hazard associated with osteoporosis is local fragility fractures. An adjunct, local treatment might be helpful to decrease the incidence of osteoporotic fracture. Studies have found that simvastatin stimulates bone formation, but the skeletal bioavailability of orally administered is low. Directly delivering simvastatin to the specific bone that is prone to fractures may reinforce the target bone and reduce the incidence of fragility fractures. Methods: We developed an injectable, thermosensitive simvastatin/poloxamer 407 hydrogel, conducted scanning electron microscopy, rheological, and drug release analyses to evaluate the delivery system; injected it into the lumbar vertebrae of ovariectomized minipigs via minimally invasive CT-guided percutaneous vertebral injection. Three months later, BMD, microstructures, mineral apposition rates, and strength were determined by DXA, micro-CT, histology, and biomechanical test; expression of VEGF, BMP2, and osteocalcin were analyzed by immunohistochemistry and Western blots. Results: Poloxamer 407 is an effective controlled delivery system for intraosseous-injected simvastatin. A single injection of the simvastatin/poloxamer 407 hydrogel significantly increased BMD, bone microstructure, and strength; the bone volume fraction and trabecular thickness increased nearly 150 %, bone strength almost doubled compared with controls (all P < 0.01); and induced higher expression of VEGF, BMP2, and osteocalcin. Conclusions: CT-guided percutaneous vertebral injection of a single simvastatin/poloxamer 407 thermosensitive hydrogel promotes bone formation in ovariectomized minipigs. The underlying mechanism appears to involve the higher expression of VEGF and BMP-2. © 2015, International Osteoporosis Foundation and National Osteoporosis Foundation. Source


Xiu P.,Peking University | Xiu P.,Beijing Key Laboratory of Spinal Diseases | Jia Z.,Peking University | Lv J.,Peking University | And 15 more authors.
ACS Applied Materials and Interfaces | Year: 2016

3D printed porous titanium (Ti) holds enormous potential for load-bearing orthopedic applications. Although the 3D printing technique has good control over the macro-sturctures of porous Ti, the surface properties that affect tissue response are beyond its control, adding the need for tailored surface treatment to improve its osseointegration capacity. Here, the one step microarc oxidation (MAO) process was applied to a 3D printed porous Ti6Al4V (Ti64) scaffold to endow the scaffold with a homogeneous layer of microporous TiO2 and significant amounts of amorphous calcium-phosphate. Following the treatment, the porous Ti64 scaffolds exhibited a drastically improved apatite forming ability, cyto-compatibility, and alkaline phosphatase activity. In vivo test in a rabbit model showed that the bone in-growth at the untreated scaffold was in a pattern of distance osteogenesis by which bone formed only at the periphery of the scaffold. In contrast, the bone in-growth at the MAO-treated scaffold exhibited a pattern of contact osteogenesis by which bone formed in situ on the entire surface of the scaffold. This pattern of bone in-growth significantly increased bone formation both in and around the scaffold possibly through enhancement of bone formation and disruption of bone remodeling. Moreover, the implant surface of the MAO-treated scaffold interlocked with the bone tissues through the fabricated microporous topographies to generate a stronger bone/implant interface. The increased osteoinetegration strength was further proven by a push out test. MAO exhibits a high efficiency in the enhancement of osteointegration of porous Ti64 via optimizing the patterns of bone in-growth and bone/implant interlocking. Therefore, post-treatment of 3D printed porous Ti64 with MAO technology might open up several possibilities for the development of bioactive customized implants in orthopedic applications. © 2016 American Chemical Society. Source

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