Three Birds, One Stone: An Osteo-Microenvironment Stage-Regulative Scaffold for Bone Defect Repair through Modulating Early Osteo-Immunomodulation, Middle Neovascularization, and Later Osteogenesis.

In order to repair critical-sized bone defects, various polylactic acid-glycolic acid (PLGA)-based hybrid scaffolds are successfully developed as bone substitutes. However, the byproducts of these PLGA-based scaffolds are known to acidify the implanted site, inducing tiresome acidic inflammation. Moreover, these degradation productions cannot offer an osteo-friendly microenvironment at the implanted site, matching natural bone healing. Herein, inspired by bone microenvironment atlas of natural bone-healing process, an osteo-microenvironment stage-regulative scaffold (P80/D10/M10) is fabricated by incorporating self-developed decellularized bone matrix microparticles (DBM-MPs) and multifunctional magnesium hydroxide nanoparticles (MH-NPs) into PLGA with an optimized proportion using low-temperature rapid prototyping (LT-RP) 3D-printing technology. The cell experiments show that this P80/D10/M10 exhibits excellent properties in mechanics, biocompatibility, and biodegradability, meanwhile superior stimulations in osteo-immunomodulation, angiogenesis, and osteogenesis. Additionally, the animal experiments determined that this P80/D10/M10 can offer an osteo-friendly microenvironment in a stage-matched pattern for enhanced bone regeneration, namely, optimization of early inflammation, middle neovascularization, and later bone formation. Furthermore, transcriptomic analysis suggested that the in vivo performance of P80/D10/M10 on bone defect repair is mostly attributed to regulating artery development, bone development, and bone remodeling. Overall, this study reveals that the osteo-microenvironment stage-regulative scaffold provides a promising treatment for bone defect repair.

Autophagy in sarcopenia: Possible mechanisms and novel therapies.

With global population aging, age-related diseases, especially sarcopenia, have attracted much attention in recent years. Characterized by low muscle strength, low muscle quantity or quality and low physical performance, sarcopenia is one of the major factors associated with an increased risk of falls and disability. Much effort has been made to understand the cellular biological and physiological mechanisms underlying sarcopenia. Autophagy is an important cellular self-protection mechanism that relies on lysosomes to degrade misfolded proteins and damaged organelles. Research designed to obtain new insight into human diseases from the autophagic aspect has been carried out and has made new progress, which encourages relevant studies on the relationship between autophagy and sarcopenia. Autophagy plays a protective role in sarcopenia by modulating the regenerative capability of satellite cells, relieving oxidative stress and suppressing the inflammatory response. This review aims to reveal the specific interaction between sarcopenia and autophagy and explore possible therapies in hopes of encouraging more specific research in need and unlocking novel promising therapies to ameliorate sarcopenia.

HYBID in osteoarthritis: Potential target for disease progression.

HYBID is a new hyaluronan-degrading enzyme and exists in various cells of the human body. Recently, HYBID was found to over-express in the osteoarthritic chondrocytes and fibroblast-like synoviocytes. According to these researches, high level of HYBID is significantly correlated with cartilage degeneration in joints and hyaluronic acid degradation in synovial fluid. In addition, HYBID can affect inflammatory cytokine secretion, cartilage and synovium fibrosis, synovial hyperplasia via multiple signaling pathways, thereby exacerbating osteoarthritis. Based on the existing research of HYBID in osteoarthritis, HYBID can break the metabolic balance of HA in joints through the degradation ability independent of HYALs/CD44 system and furthermore affect cartilage structure and mechanotransduction of chondrocytes. In particular, in addition to HYBID itself being able to trigger some signaling pathways, we believe that low-molecular-weight hyaluronan produced by excess degradation can also stimulate some disease-promoting signaling pathways by replacing high-molecular-weight hyaluronan in joints. The specific role of HYBID in osteoarthritis is gradually revealed, and the discovery of HYBID raises the new way to treat osteoarthritis. In this review, the expression and basic functions of HYBID in joints were summarized, and reveal potential role of HYBID as a key target in treatment for osteoarthritis.

An update on recent progress of the epidemiology, etiology, diagnosis, and treatment of acute septic arthritis: a review.

Acute septic arthritis is on the rise among all patients. Acute septic arthritis must be extensively assessed, identified, and treated to prevent fatal consequences. Antimicrobial therapy administered intravenously has long been considered the gold standard for treating acute osteoarticular infections. According to clinical research, parenteral antibiotics for a few days, followed by oral antibiotics, are safe and effective for treating infections without complications. This article focuses on bringing physicians up-to-date on the most recent findings and discussions about the epidemiology, etiology, diagnosis, and treatment of acute septic arthritis. In recent years, the emergence of antibiotic-resistant, particularly aggressive bacterial species has highlighted the need for more research to enhance treatment approaches and develop innovative diagnosis methods and drugs that might combat better in all patients. This article aims to furnish radiologists, orthopaedic surgeons, and other medical practitioners with contemporary insights on the subject matter and foster collaborative efforts to improve patient outcomes. This review represents the initial comprehensive update encompassing patients across all age groups.

Metformin Prevents or Delays the Development and Progression of Osteoarthritis: New Insight and Mechanism of Action.

For over 60 years, metformin has been widely prescribed by physicians to treat type 2 diabetes. Along with more in-depth research on metformin and its molecular mechanism in recent decades, metformin has also been proposed as an effective drug to prevent or delay musculoskeletal disorders, including osteoarthritis (OA). The occurrence and development of OA are deemed to be associated with the impaired mitochondrial functions of articular chondrocytes. Metformin can activate the pathways and expressions of both AMPK and SIRT1 so as to protect the mitochondrial function of chondrocytes, thereby promoting osteoblast production. Moreover, the clinical significance of the metformin combination therapy in preventing OA has also been demonstrated. This review aimed to comprehensively summarize the current research progress on metformin as a proposed drug for OA prevention or treatment.

Exosomes secreted by hypoxia-stimulated bone-marrow mesenchymal stem cells promote grafted tendon-bone tunnel healing in rat anterior cruciate ligament reconstruction model.

Background: After anterior cruciate ligament (ACL) reconstruction in clinic, firm and rapid integration of the grafted tendon into the bone tunnel remains a challenge. Exosomes from hypoxia-treated stem cells are beneficial for promoting angiogenesis and then coupling with osteogenesis. Therefore, exosomes from hypoxia-cultured bone-marrow mesenchymal stem cells (Hypo-Exos) may be a cell-free therapy for enhancing graft-bone incorporation after ACL reconstruction. Methods: Exosomes from normoxia-cultured bone-marrow mesenchymal stem cells (Norm-Exos) or Hypo-Exos were respectively cultured with human umbilical vein endothelial cells (HUVECs) for in-vitro evaluating their functions in HUVECs proliferation, migration, and tube formation. A total of 87 rats with single-bundle ACL reconstructions in the right knee were randomly allocated into 3 different treatments: phosphate-buffered saline (PBS) with the adhesive hydrogel injection as control (Ctrl), Norm-Exos with the adhesive hydrogel injection (Norm-Exos), and Hypo-Exos with the adhesive hydrogel injection (Hypo-Exos). At postoperative weeks 2, 4, or 8, the ACL graft-bone integrations were evaluated. Results: Hypo-Exos was a better stimulator for in-vitro HUVECs proliferation, migration, and tube formation compared to PBS or Norm-Exos. Hypo-Exos within the adhesive hydrogel could be sustained-released at least 14 days around the peri-graft site. Radiologically, at week 4 or 8, femoral or tibial bone tunnel areas (BTA), as well as bone volume/total volume ratio (BV/TV) of the femoral or tibial peri-graft bone in the Hypo-Exos group, improved significantly better than these parameters of the Ctrl and Norm-Exos groups (P<0.05 for all). Histologically, the grafted tendon-bone interface in the Hypo-Exos group showed significantly higher histologic scores at week 4 or 8 as compared with the other groups (P<0.05 for all). Immunofluorescent staining verified that type H vessels were more abundant in the Hypo-Exos group when compared to the Ctrl or Norm-Exos group at week 2. Biomechanically, the Hypo-Exos group exhibited a significantly heightened failure load compared with the Ctrl and Norm-Exos groups (P<0.05 for all) at 8 weeks. Meanwhile, the stiffness in the Hypo-Exos group was the greatest among the three groups. Conclusion: Peri-graft Hypo-Exos injection accelerates grafted tendon-bone tunnel integration after ACL reconstruction by improving peri-graft bone microarchitecture.

A Slotted Decellularized Osteochondral Scaffold With Layer-Specific Release of Stem Cell Differentiation Stimulators Enhances Cartilage and Bone Regeneration in Osteochondral Defects in a Rabbit Model.

BACKGROUND: Owing to the disappointing regenerative ability of osteochondral tissue, without treatment an osteochondral defect would progress to osteoarthritis. This situation motivates the need for new strategies to enhance the regeneration of osteochondral defects. PURPOSE: To develop a tissue-engineering scaffold by tethering bone morphogenetic protein 2 (BMP2) and transforming growth factor beta 3 (TGFß3) in a layer-specific manner on a slotted decellularized osteochondral matrix (SDOM) and to evaluate the efficacy of this scaffold for osteochondral regeneration. STUDY DESIGN: Controlled laboratory study. METHODS: Normal osteochondral tissue from the rabbit patellofemoral groove was sectioned into a slot shape and decellularized for fabricating an SDOM. The collagen-binding domain (CBD) was fused into the N-terminus of BMP2 or TGFß3 to synthesize 2 recombinant growth factors (GFs) (CBD-BMP2 or CBD-TGFß3), which were tethered to the bone layer and cartilage layer, respectively, of the SDOM to prepare a tissue-engineering scaffold (namely, CBD-GFs/SDOM). After examining the influence of the CBD-GFs/SDOM on the viability and layer-specific differentiation of bone marrow mesenchymal stem cells in vitro, we determined the regeneration potential of the CBD-GFs/SDOM on osteochondral regeneration in a rabbit model. A total of 72 New Zealand White rabbits with a cylindrical osteochondral defect in the patellofemoral groove were randomly assigned to 3 groups: defect only (control [CTL] group), defect patched with an SDOM (SDOM group), and defect patched with the CBD-GFs/SDOM (CBD-GFs/SDOM group). At 6 or 12 weeks postoperatively, the rabbits were euthanized to harvest the knee joint, which was then evaluated via gross observation, micro-computed tomography, histological staining, and mechanical testing. RESULTS: In vitro, the CBD-GFs/SDOM was noncytotoxic, showed high biomimetics with normal osteochondral tissue, was suitable for cell adhesion and growth, and had good layer-specific ability in inducing stem cell differentiation. Macroscopic images showed that the CBD-GFs/SDOM group had significantly better osteochondral regeneration than the CTL and SDOM groups had. Micro-computed tomography demonstrated that much more bony tissue was formed at the defect sites in the CBD-GFs/SDOM group compared with the defect sites in the CTL or SDOM group. Histological analysis showed that the CBD-GFs/SDOM group had a significant enhancement in osteochondral regeneration at 6 and 12 weeks postoperatively in comparison with the CTL or SDOM group. At 12 weeks postoperatively, the mechanical properties of reparative tissue were significantly better in the CBD-GFs/SDOM group than in the other groups. CONCLUSION: The CBD-GFs/SDOM is a promising scaffold for osteochondral regeneration. CLINICAL RELEVANCE: The findings of this study indicated that the CBD-GFs/SDOM is an excellent candidate for reconstructing osteochondral defects, which may be translated for clinical use in the future.

Constructing Injectable Bone-Forming Units by Loading a Subtype of Osteoprogenitors on Decellularized Bone Matrix Powders for Bone Regeneration.

Bone defects resulting from trauma or tumor are one of the most challenging problems in clinical settings. Current tissue engineering (TE) strategies for managing bone defects are insufficient, owing to without using optimal osteoconductive material and seeding cells capable of superior osteogenic potential; thus their efficacy is instable. Herein, a novel TE strategy was developed for treating bone defects. First, the decellularized bone matrix (DBM) was manufactured into powders, and these DBM powders preserved the ultrastructural and compositional properties of native trabecular bone, are non-cytotoxic and low-immunogenic, and are capable of inducing the interacted stem cells differentiating into osteogenic lineage. Then, a subtype of osteoprogenitors was isolated from mouse long bones, and its high osteogenic potential was identified in vitro. After that, we constructed a "bone-forming unit" by seeding the special subtype of osteoprogenitors onto the DBM powders. In vivo performance of the "bone-forming units" was determined by injecting into the defect site of a mouse femoral epiphysis bone defect model. The results indicated that the "bone-forming unit" was capable of enhancing bone defect healing by regulating new bone formation and remodeling. Overall, the study establishes a protocol to construct a novel "bone-forming unit," which may be an alternative strategy in future bone TE application.

Comparative evaluation of pinning and cast fixation vs. external fixation after lateral closing-wedge osteotomy for cubitus varus in children.

BACKGROUND: Cubitus varus has been regarded as a poor functional and cosmetic consequence of supracondylar humerus fracture in children. The aim of this study was to assess the clinical and radiologic outcomes of cubitus varus treatments based on fixation methods: Kirschner (K)-wire and cast fixation or external fixation. METHODS: Forty consecutive patients with cubitus varus secondary to supracondylar fractures were retrospectively enrolled between October 2015 and December 2018. Following lateral closing-wedge osteotomy, those undergoing K-wire and cast fixation were included in group A (n = 21) and those who were treated with external fixation comprised group B (n = 19). We measured the bony union, elbow joint range of motion, and carrying angle. The clinical and radiographic results were assessed according to the Bellemore criteria. RESULTS: No significant difference was found between the 2 groups in terms of age, gender, operation duration, union time, and postoperative elbow range of motion (P > .05). A significant difference was noted, however, in postoperative carrying angle and results according to Bellemore criteria in group B (P < .05). No nonunion, myositis ossificans, or neurovascular injury was found at follow-up in the 2 groups. In group A, revision surgery was needed for residual varus in 1 patient and lateral condylar prominence was found in 2 patients. In group B, a superficial pin-site infection occurred in 2 patients, who were treated successfully with oral antibiotics. CONCLUSIONS: Both K-wire and external fixation after lateral closing-wedge osteotomy are reliable and effective for the treatment of cubitus varus in children. Compared with the K-wire method, external fixation achieves better functional and cosmetic results with a shorter learning curve.

Mg(OH)2 nanoparticles enhance the antibacterial activities of macrophages by activating the reactive oxygen species.

Infection often causes disastrous consequences in all fields of clinical medicine, especially orthopedics. Hence, critical efforts are being made to engineer novel nanomaterials for the treatment of orthopedic infections due to the high biocompatibility and antibacterial properties they possess. The purpose of this study was to investigate the antibacterial effects of magnesium hydroxide (Mg(OH)2 ) nanoparticles (NPs) in vitro and determine their possible mechanisms of action. In this study, Escherichia coli was selected as the pathogenic bacteria and it was found that Mg(OH)2 NPs significantly inhibited the growth of E. coli by promoting nucleic acid leakage, inhibiting protein synthesis, and suppressing the metabolic activity. The minimum inhibitory concentration for these bacteria was determined to be 4.4 µg/ml. In vitro flow cytometry and immunofluorescence tests indicated that Mg(OH)2 NPs induced the macrophages to generate reactive oxygen species to kill the bacteria. To understand the mechanisms involved in this process, western blotting was performed and it was found that Mg(OH)2 NPs activated the phosphatidylinositol-3-kinase/serine-threonine kinase (PI3K/Akt) signaling pathway of macrophages to enhance their phagocytosis with no obvious cytotoxicity. Thus, Mg(OH)2 NPs are a suitable choice to develop promising agents or coating materials for the treatment of clinically widespread infections in view of their safety, biocompatibility, and powerful antibacterial properties.

Compression screws and buttress plate versus compression screws only for Hoffa fracture in Chinese patients: a comparative study.

OBJECTIVE: To compare compression screws and buttress plate (CS plus BP) with compression screws only (CS) in treating patients with Hoffa fracture. METHODS: This retrospective study included Chinese patients with Hoffa fracture treated by open reduction and internal fixation. Radiographs and clinical outcomes (range of movement [ROM], bone union and Knee Society Score [KSS]) were compared between patients treated using CS plus BP versus CS only. RESULTS: At 4 months following surgery, significantly better outcomes were shown in the CS plus BP group ( n = 24) versus CS only group ( n = 21) regarding ROM (120.4 ± 5.2° versus 110 ± 7.1°) and KSS (85.5 ± 4.1 versus 79.7 ± 3.3). At the 12-month follow-up, significantly better outcomes were maintained in the CS plus BP versus CS only group regarding ROM (126.2 ± 7.4° versus 120.5 ± 8.2°) and KSS (88.3 ± 4.6 versus 84.2 ± 4.0). At the final follow-up, all patients had normal fracture healing and no malunion, nonunion or reduction loss. CONCLUSIONS: Fixation with CS plus BP for Hoffa fracture is effective and reliable, and may provide more adequate stability and better outcomes versus CS only.

CXCR4-mediated osteosarcoma growth and pulmonary metastasis is suppressed by MicroRNA-613.

Osteosarcoma is the most common primary bone malignancy. Recently, studies showed chemokine receptor 4 (CXCR4) played a critical role in osteosarcoma. However, the regulation of CXCR4 is not fully understood. microRNAs are short, non-coding RNAs that play an important roles in post-transcriptional regulation of gene expression in a variety of diseases including osteosarcoma. miR-613 is a newly discovered miRNA and has been reported to function as a tumor suppressor in many cancers. In this study, we confirmed that both Stromal Cell-Derived Factor (SDF-1) and CXCR4 could be prognostic markers for osteosarcoma. Meanwhile this study found that SDF-1/CXCR4 pathway regulated osteosarcoma cells proliferation, migration and reduced apoptosis. Besides, we demonstrated that miR-613 was significantly downregulated in osteosarcoma patients. Elevated expression of miR-613 directly suppressed CXCR4 expression and then decreased the proliferation, migration and induced apoptosis of osteosarcoma cells. Moreover, our study found that CXCR4 promoted the development of lung metastases and inhibition of CXCR4 by miR-613 reduced lung metastases. These data indicated that CXCR4 mediated osteosarcoma cell growth and lung metastases and this effect can be suppressed by miR-613 through directly downregulating CXCR4.

Effect of Posterior Cruciate Ligament Rupture on Biomechanical and Histological Features of Lateral Femoral Condyle.

BACKGROUND The aim of this study was to investigate bone mineral density (BMD) and the biomechanical and histological effects of posterior cruciate ligament (PCL) rupture on the lateral femoral condyle. MATERIAL AND METHODS Strain on different parts of the lateral femoral condyle from specimens of normal adult knee joints, including 12 intact PCLs, 6 ruptures of the anterolateral bundle, 6 ruptures of the postmedial bundle, and 12 complete ruptures, was tested when loaded with different loads on the knee at various flexion angles. Lateral femoral condyles were also collected randomly from both the experimental side in which the PCLs were transected and the control side from 4 sets of 12 matched-mode pairs of rabbits at 4, 8, 16, and 24 weeks after surgery, and their BMD and morphological and histological changes were observed. RESULTS Partial and complete rupture of the PCL may cause an abnormal load on all parts of the lateral femoral condyle with any axial loading at all positions. Noticeable time-dependent degenerative histological changes of the lateral femoral condyle were observed in the rabbit model of PCL rupture. All of the PCL rupture groups had a higher expression of matrix metalloproteinase-7 (MMP-7) and collagen type II than the control group at all time points (P<0.05), but no significant difference in BMD (P>0.05). CONCLUSIONS Rupture of the PCL may trigger a coordinated response of lateral femoral condyle degeneration in a time-dependent manner, to which the high level of expression of MMP-7 and collagen type II could contribute.

Percutaneous compression plate versus dynamic hip screw for treatment of intertrochanteric hip fractures: A overview of systematic reviews and update meta-analysis of randomized controlled trials.

PURPOSE: Intertrochanteric hip fractures lead to high morbidity and mortality rates. As a minimally invasive technique, many studies reported the efficacy of PCCP for the treatment of intertrochanteric fractures, but the controversy still existed in some outcomes. The purpose of this study was to evaluate the efficacy of PCCP and DHS by a overview of systematic reviews and well-designed, comprehensive update meta-analysis. METHODS: PUBMED, SCOPUS, CCRCT, WANFANG and CNKI database were searched in all languages published up to April 2016. Systematic reviews and randomized controlled trials reporting outcomes of PCCP and DHS for intertrochanteric fractures were included. Meta-analyses comparing the two techniques were performed according to the Cochrane Handbook. RESULTS: Five original trials and four systematic reviews met the inclusion criteria. Meta-analyses showed that the blood loss [SMD = -2.35, 95%CI(-4.26--0.44)], transfusion volume [SMD = -0.26, 95%CI(-0.47--0.06)] and complications [RR = 0.33, 95%CI(0.14-0.77)] was statistically less in PCCP group than DHS group while there was no significant difference between two groups in mortality rate, transfusion rate and length of hospital day. CONCLUSIONS: PCCP is recommended to treat intertrochanteric hip fractures as an alternative minimally invasive method. More high-quality, randomized controlled trials that are adequately powered are needed to further evaluate the efficacy of PCCP and DHS.

Lipoic acid prevents steroid-induced osteonecrosis in rabbits.

The objective of this study was to investigate in vivo effects of lipoic acid (LA) in preventing steroid-induced osteonecrosis and the possible pathway in a rabbit model. Sixty rabbits were divided into 2 groups: rabbits were intraperitoneally injected with LA aqueous solution at 36 mg/kg of body weight per day for 4 weeks in Group A and rabbits were injected with physiologic saline (PS) as a control in Group B. At 2 weeks after starting treatment, they were intramuscularly injected once with 20 mg/kg of methylprednisolone acetate (MPSL). The femora were histopathologically examined for the presence of osteonecrosis. The plasma levels of total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), glutathione (GSH), endothelin (ET) and malondialdehyde (MDA) were assayed at 2 weeks after the injection of MPSL. The incidence of osteonecrosis was significantly higher in Group B (73.1%) than in Group A (20.8%). The GSH level was higher in Group A than in Group B after the LA injection. The plasma MDA and ET levels were lower in Group A than in Group B at 2 weeks after the MPSL administration. Lipoic acid can prevent the development of steroid-induced osteonecrosis in rabbits. Inhibited oxidative stress and amendment of vascular endothelial dysfunction is a possible mechanism for this effect.