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Tendinopathy is a common musculoskeletal disorder which results in chronic pain and reduced performance. The therapeutic effect of stem cell derived-small extracellular vesicles (sEVs) for tendinopathy has been validated in recent years. However, whether large extracellular vesicles (lEVs), another subset of extracellular vesicles, possesses the ability for the improvement of tendinopathy remains unknown. Here, we showed that lEVs secreted from iPSC-derived MSCs (iMSC-lEVs) significantly mitigated pain derived from tendinopathy in rats. Immunohistochemical analysis showed that iMSC-lEVs regulated the heterogeneity of infiltrated macrophages and several inflammatory cytokines in rat tendon tissue. Meanwhile

Aim: This study aimed to explore the effect of small extracellular vesicles from induced pluripotent stem cell-derived mesenchymal stem cells (iMSC-sEVs) on acute pain and investigate the underlying mechanisms. Materials & methods: The pathology of tendons was accessed by hematoxylin and eosin staining, immunohistochemical and immunofluorescent staining. The pain degree was measured by pain-related behaviors. In vitro, we performed β-hexosaminidase release assay, RT-qPCR, toluidine blue staining, ELISA and RNA sequencing. Results: iMSC-sEVs effectively alleviated acute pain in tendinopathy as well as inhibiting activated mast cell infiltration and interactions with nerve fibers in vivo. In vitro, iMSC-sEVs reduced the degranulation of mast cells and the expression of proinflammatory cytokines and genes involved in the HIF-1 signaling pathway. Conclusion: This study demonstrated that iMSC-sEVs relieved tendinopathy-related pain through inhibiting mast cell activation via the HIF-1 signaling pathway.

Mesenchymal stem cell (MSCs)‐based therapies have shown a promised result for intervertebral disc degeneration (IVDD) treatment. However, its molecular mechanisms remain unclear. Exosomes involve cell‐cell communication via transference of its contents among different cells, and the present potential effect on cell death regulation. This study aimed to investigate the role of MSCs‐derived exosomes on IVDD formation. Here, we first found the NLRP3‐mediated nucleus pulposus cell (NP cell) pyroptosis was activated in the IVDD mice model and lipopolysaccharide (LPS)‐induced model. However, MSCs treatment could inhibit NP cell pyroptosis in vitro. We then isolated MSCs‐derived exosomes by differential centrifugation and identified the characteristics. Secondly, we investigated the function of MSCs‐derived exosomes on LPS‐induced NP cell pyroptosis. Finally, we presented evidence that MSCs‐derived exosomal miR‐410 was a crucial regulator of pyroptosis. Results showed that MSCs‐derived exosomes play an anti‐pyroptosis role by suppressing the NLRP3 pathway. Moreover, it suggested that this effect was attributed to miR‐410, which was derived from MSCs‐exosomes and could directly bind to NLRP3mRNA. In conclusion, for the first time, we demonstrated that MSCs‐exosome treatment may inhibit pyroptosis and could be a promising therapeutic strategy for IVDD.

Background Small extracellular vesicles (sEV) secreted by mesenchymal stem cells (MSC) derived from human induced pluripotent stem cells (iPSC, iMSC-sEV) are considered to have great potential in treating ischemic diseases. Angiogenesis play an important role in post-stroke recovery. However, no studies have yet been conducted to systemically examine the effect and the underlying mechanism of iMSC-sEV on angiogenesis under brain ischemia conditions. Methods Ischemic stroke model was performed in rats induced by middle cerebral artery occlusion (MCAO), and the pro-angiogenic capacity of iMSC-sEV was measured. The in vitro effects of iMSC-sEV on the migration and tube formation of endothelial cells were investigated, respectively. Autophagy and autophagy-related signaling pathway were detected in vivo and in vitro. Results We found that iMSC-sEV significantly reduced infarct volume, enhanced angiogenesis, and alleviated long-term neurological deficits in rats after stroke. We also demonstrated that iMSC-sEV increased migration and tube formation of endothelial cells in vitro. A further mechanism study revealed that the pro-angiogenic effect of iMSC-sEV was correlated with a reduction in autophagy. Furthermore, iMSC-sEV significantly activated signal transducer and activator of transcription 3 (STAT3), and suppression of STAT3 abolished iMSC-sEV-induced inhibition of autophagy and promotion of angiogenesis in vivo and in vitro. Conclusions Taken together, our data indicate that iMSC-sEV promote angiogenesis after ischemic stroke, potentially, by inhibiting autophagy, a process that is partially dependent on STAT3 activation.

Background: Acute pain is the primary symptom of tendinopathy, and mast cells activation is a nonnegligible cause. Currently, safe and effective treatment for acute pain in tendinopathy is still lacking. This study was aimed to explore the analgesic effect of iPSC-derived mesenchymal stem cell-derived small extracellular vesicles (iMSC-sEVs) on acute pain and further investigate the underlying mechanisms in tendinopathy. Methods: A rat tendinopathy model was established and then treated with iMSC-sEVs or PBS for 4 weeks. The pathology of tendinopathy was accessed by H&E staining and immunohistochemical analysis 2 and 4 weeks after treatment. Then we measured pain-related behaviors 4 weeks after treatment. Double immunofluorescent staining on tendon sections for tryptase and PGP9.5 was conducted to assess whether iMSC-sEVs inhibit mast cells activation in tendinopathy. To further investigate the potential mechanism, RBL-2H3 cells were stimulated with substance P to mimic tendinopathy condition in vitro. The effect of iMSC-sEVs on inhibiting mast cells activation was measured by b-Hexosaminidase release assay, RT-qPCR, Toluidine blue staining and ELISA. RNA-seq was performed to analyze the related global changes and discover the underlying mechanism. Results: iMSC-sEVs effectively reduced inflammation, thereby alleviating acute pain in tendinopathy as reflected by histological analysis and pain-related behaviors. Moreover, iMSC-sEVs inhibited activated mast cell infiltration and interactions with nerve fibers in tendinopathy. In vitro study showed that the expression of proinflammatory cytokines and the degranulation of mast cells induced by substance P were reduced upon iMSC-sEVs treatment. Transcriptome analysis revealed that iMSC-sEVs treatment down-regulated the expression of genes involved in the HIF-1 signaling pathway.Conclusion: Overall, this study demonstrated that iMSC-sEVs relieved tendinopathy-related pain through inhibiting mast cells activation partly via the HIF-1 signaling pathway. These findings provide a novel treatment strategy for pain derived from tendinopathy and unravel the molecular mechanism underlying the application of iMSC-sEVs on mast cells.

Background: As life expectancy increases for lung cancer patients who develop bone metastases, the need for personalized local treatment for bone metastases is expanding.Methods: Lung cancer patients with bone metastases were treated by a multidisciplinary team via surgery, percutaneous osteoplasty, or radiation. The pre- and post-treatment visual analog scale (VAS) and Quality of Life (QoL) scores were analyzed. QoL at 12 weeks was the main outcome. Treatment-related costs and overall survival time (OS) were collected. We used machine learning to develop and test models to predict which patients should receive local treatment. Models discrimination were evaluated by the area under curve (AUC), and the best one was used for validation in clinical use. Results: Under the direction of a multidisciplinary team, 161 patients in the training set, and 32 patients in the test set underwent local treatment. A decision tree model included VAS scale, bone metastases character, Frankel classification, Mirels score, age, driver gene, aldehyde dehydrogenase 2, and enolase 1 expression had a best AUC of 0.92 (95%CI 0.89 to 0.94), and 36 patients in a validation set underwent local treatment guided by the model. Improved QoL and VAS scores were observed at 12 weeks after local treatment in training, test, and validation sets (p < 0.05), with no significant differences among the three datasets. There were no significant differences in mean costs among the three datasets in the four treatment groups. OS was 18.03±0.45 months and did not significantly differ among treatment groups or the three datasets. Conclusions: Local treatment not only had no negative influence on OS but also provided significant pain relief and improved QoL. QoL, OS or costs did not significantly differ between patients whose treatment was guided by a multidisciplinary team or machine learning model. Our machine learning model using clinical data can help guide clinicians to make local treatment decisions to improve patients’ QoL.Trial registration: No. ChiCRT-ROC-16009501

Objective Developmental dysplasia of the hip (DDH) is the most common skeletal development in children and could result in secondary osteoarthritis. This study aims to clarify the alternations of subchondral trabecular bone remodeling and microstructural properties during the development of DDH, and the potential influence of these alternations on the overlying cartilage degeneration and DDH progression. Design Traditional straight-leg swaddling method was adopted to establish DDH model in newborn Sprague Dawley rats. Hip joint specimens from normal or DDH rats were used. Typical features of DDH in radiological examination were observed by x-ray analysis. Micro–computed tomography analysis was applied to evaluate the microstructural properties of subchondral bone at postnatal weeks 2, 4, and 6. Histological and immunohistochemical analyses were adopted to appraise subchondral bone remodeling activity and cartilage degeneration. The associations among subchondral bone, articular cartilage, and DDH severity were analyzed via multiple linear regression analysis. Results Compared with control group, the subchondral bone in DDH group displayed a gradual trend of deteriorated microstructure and worsening biomechanical properties along with aberrant bone remodeling, which might be responsible for the inhibition of stress transmission from the articular cartilage to the subchondral bone and thus leading to the cartilage degeneration and accelerated DDH progression. Conclusions Our findings indicate that alternations of subchondral trabecular bone in a time-dependent manner could contribute to the DDH progression and the amelioration on subchondral bone might be a favorable therapeutic candidate for DDH.

Vascular dementia (VD) is one of the most common types of dementia, however, the intrinsic mechanism is unclear and there is still lack of effective medications. In this study, the VD rats exhibit a progressive cognitive impairment, as well as a time‐related increasing in hippocampal neural stem cells (H‐NSCs) senescence, lost and neurogenesis decline. Then, embryonic stem cell‐derived small extracellular vesicles (ESC‐sEVs) are intravenously injected into VD rats. ESC‐sEVs treatment significantly alleviates H‐NSCs senescence, recovers compromised proliferation and neuron differentiation capacity, and reverses cognitive impairment. By microarray analysis and RT‐qPCR it is identified that several miRNAs including miR‐17‐5p, miR‐18a‐5p, miR‐21‐5p, miR‐29a‐3p, and let‐7a‐5p, that can inhibit mTORC1 activation, exist in ESC‐sEVs. ESC‐sEVs rejuvenate H‐NSCs senescence partly by transferring these miRNAs to inhibit mTORC1 activation, promote transcription factor EB (TFEB) nuclear translocation and lysosome resumption. Taken together, these data indicate that H‐NSCs senescence cause cell depletion, neurogenesis reduction, and cognitive impairment in VD. ESC‐sEVs treatment ameliorates H‐NSCs senescence by inhibiting mTORC1 activation, and promoting TFEB nuclear translocation and lysosome resumption, thereby reversing senescence‐related neurogenesis dysfunction and cognitive impairment in VD. The application of ESC‐sEVs may be a novel cell‐free therapeutic tool for patients with VD, as well as other aging‐related diseases., Hippocampal neural stem cells (H‐NSCs) senescence causes their loss and neurogenesis decline, resulting in cognitive impairment in vascular dementia (VD). Embryonic stem cells derived small extracellular vesicles (ESC‐sEVs) can rejuvenate H‐NSCs senescence by transferring miRNAs including miR‐17‐5p, miR‐18a‐5p, miR‐21‐5p, miR‐29a‐3p, and let‐7a‐5p to inhibit mTORC1 activation, and promote transcription factor EB nuclear translocation and lysosome resumption, which reverses senescence‐related neurogenesis dysfunction and cognitive impairment in VD.

Background Osteosarcoma (OS) is one of the most common types of primary bone tumors which poses negative effects on the bones of both young children and adolescents. LncRNA LINC00472 has been reported to be involved with poor prognostics in breast cancer and ovarian cancer. As a new lncRNA, its role in OS remains to be elusive. Herein, we are focused to explore its regulatory mechanism in the development of OS. Methods qRT-PCR was utilized to examine the expressions of LINC00472 and miR-300 in OS tissues and cell lines. OS cell lines of U2OS and MG63 were used to investigate the biological function of LINC00472. Xenograft tumor model was built in nude mice with MG63 cells. Results The expressions of LINC00472 were inhibited in OS tissues and cells, and were negatively related to the expressions of miR-300. LINC00472 directly targeted miR-300. FOXO1 was inhibited in OS tissues and its expressions were negatively related to the expressions of miR-300. LINC00472 over-expressions decreased cell proliferation abilities and colony formation abilities. These effects were mediated by miR-300. The silence of LINC00472 and over-expressions of miR-300 suppressed FOXO1 expressions. LINC00472 greatly reduced tumor growth in vivo and this effect was attenuated by miR-300 mimic. Conclusions From all the experiments and observations, we demonstrated that LINC00472 could be a potential tumor suppressor in OS through interacting with miR-300 and FOXO1.

Additional file 6: Figure S6. Stat3 inactivation inhibites iMSC-sEV-induced angiogenesis. (A-D) Rats were intravenously treated with vehicle (500ul, PBS), iMSC-sEV (1 × 1011 particles in 500 μL PBS), or iMSC-sEV with stattic (3.75 mg/kg) 4 h after MCAO, EdU was i.p. injected at day 3, 5, and 7 to label proliferated cells. (A) Representative images of CD31+EdU+ endothelial cells in the peri-infarct area. Arrow head, double-labeled proliferated cells. Scale bar = 100 μm. (B) Quantification of CD31+EdU+ endothelial cells normalized to that in sham group. N = 3–5 per group. (C) Representative of CD31+DAPI+ endothelial cells in the peri-infarct zone. Scale bar = 400 μm. (D) Quantification of CD31+ vascular density normalized to that in Sham group. N = 3–5 per group.

Additional file 4: Figure S4. Identification of HUVECs and in vitro uptake of iMSC-sEV by HUVECs. (A-C) Representative immunofluorescence images of CD31 (green), vWF (green), and α-SMA (red) in HUVECs. Scale bar =100 μm. (D) Representative immunofluorescence images of HUVECs cultured with Dil labeled iMSC-sEV (red) or Dil alone (control). The Dil-labeled iMSC-sEV were visible in the perinuclear region of recipient cells. HUVECs in the control group showed no fluorescence signal. Scale bar =30 μm.

Additional file 5: Figure S5. Inhibition of autophagy decreases migration and tube formation in HUVECs after OGD. HUVECs were challenged with 8 h OGD with the addition of 3-MA (5 mM) or vehicle (PBS) and migration and tube formation were analyzed 24 h after reoxygenation. HUVECs cultured under the normoxia condition without treatment were set as control. (A) Representative images of crystal violet staining in the transwell assay. Scale bar = 25 μm. (B) Quantification analysis of migration rate normalized to control group. N = 3–5 per group. (G) Representative images of the tube formation assay. Scale bar = 25 μm. (H) Quantification analysis of the tube length normalized to control group. N = 3–5 per group. Data are presented as mean ± SD. *P

Additional file 3: Figure S3. Treatment of iMSC-sEV increases the blood vessel density after ischemic stroke. CD31 immunofluorescence staining was utilized to evaluate blood vessel density 7 days after MCAO. (A) Representative images of CD31 positive endothelial cells and DAPI staining in the peri-infarct area. Scale bar = 400 μm. (B) ROI and quantification of CD31+ blood vessel density. N = 3–5 per group. Data are presented as mean ± SD. *P

Additional file 1: Figure S1. Phenotypic characteristics of iMSC. (A) Flow cytometry analysis of the surface antigen profile of iMSC. (B-D) Representative images of Alizarin Red staining (B), Oil Red O staining (C), and Toluidine Blue staining (D) for the evaluation of osteogenesis, adipogenesis, and chondrogenesis in iMSC. Scale bar = 25 μm.

Additional file 2: Figure S2. In vivo uptake of iMSC-sEV after stroke. (A) One single dose of vehicle (PBS, 500 μL) or DiR labeled iMSC-sEV (DiR-iMSC-sEV, 1 × 1011 particles in 500 μL PBS) were administered through tail veil injection in rats 4 h after MCAO and images were captured 6 h after administration. Representative fluorescence images of rats brain in the vehicle and DiR-iMSC-sEV group. IL: ipsilateral side. CL: contralateral side. (B-C) Dio labeled iMSC-sEV (Dio-iMSC-sEV) were administered intravenously 24 h after MCAO, and rats were sacrificed 24 h after injection. (B) Illustration of experimental design. (C) Representative images of Dio-iMSC-sEV (green) in the ipsilateral and contralateral side of the brain. Yellow dashed line: outline for blood vessel. Red arrow head: Dio-iMSC-sEV around the nucleus in the cytoplasm. Scale bar = 50 μm.

Summary Stem cells, with their therapeutic potential in tissue repair and regeneration, have been widely used in translational medicine. Recent evidence suggests that the beneficial effects are mediated largely by their paracrine actions rather than the engraftment and differentiation at the injured sites. Extracellular vesicles (EVs), actively released from cells, play important roles in cell-to-cell communication and display multiple functions in tissue regeneration. In the present report, we will briefly review the current knowledge related to the therapeutic potential of EVs, particularly stem cell or progenitor cell-derived ones for promoting tissue repair and regeneration, and focus on the restorative properties of exosomes/microvesicles in cutaneous wound healing, bone regeneration, hindlimb ischemia, and vascular injury repair.

The regeneration of articular cartilage, which scarcely shows innate self-healing ability, is a great challenge in clinical treatment. Stem cell-derived exosomes (SC-Exos), an important type of extracellular nanovesicle, exhibit great potential for cartilage regeneration to replace stem cell-based therapy. Cartilage regeneration often takes a relatively long time and there is currently no effective administration method to durably retain exosomes at cartilage defect sites to effectively exert their reparative effect. Therefore, in this study, we exploited a photoinduced imine crosslinking hydrogel glue, which presents excellent operation ability, biocompatibility and most importantly, cartilage-integration, as an exosome scaffold to prepare an acellular tissue patch (EHG) for cartilage regeneration. It was found that EHG can retain SC-Exos and positively regulate both chondrocytes and hBMSCs in vitro. Furthermore, EHG can integrate with native cartilage matrix and promote cell deposition at cartilage defect sites, finally resulting in the promotion of cartilage defect repair. The EHG tissue patch therefore provides a novel, cell-free scaffold material for wound repair.

CEP hypertrophy is one of the characteristics of intervertebral disc degeneration (IDD). LIG exerts a protective effect on IDD in animal model. The effect of LIG on CEP hypertrophy is further investigated in the present study. Cells were isolated from hypertrophic samples obtained from patients during vertebral fusion surgery. Cellular proliferation and the expression of type I collagen (Col I) and TGF-β1 were tested. In the bipedal rats, the edges of the CEP and the sizes of noncartilaginous outgrowth, as well as the expression of osteogenic markers, Col1a, ALP, Runx2, and TGF-β1, were detected. Within two passages, the condensed hypertrophic CEP cells exhibited osteogenic capacity by bony-like nodules and ALP positive staining, along with increased expression of Col I and TGF-β1. LIG inhibited proliferation of CEP cells and downregulated the expression of Col I and TGF-β1in vitro. Furthermore, LIG attenuated CEP hypertrophy on the lumbar spine of bipedal rats by reducing Col1a, ALP, Runx2, and TGF-β1 mRNA expression and TGF-β1 distributionin vivo. We concluded LIG exerted a preventive effect on CEP hypertrophy via suppression of TGF-β1 levels. This information could be used to develop alternative therapeutic methods to treat spinal CEP hypertrophy.

Introduction Many studies have suggested that the vitamin D receptor polymorphism BsmI might be associated with the risk of osteoporosis development in post-menopausal women. However, the results have been inconsistent. The aim of this meta-analysis was to derive a more precise evaluation of the relationship. Material and methods Published literature from PubMed, EMBASE and the CNKI database was searched. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of any association. Results Ten case-control studies were included with a total of 1,403 osteoporosis cases and 2,144 healthy controls. In the overall analysis, no significant association was found between BsmI polymorphism and osteoporosis risk (BB vs. bb: OR = 0.76, 95% CI = 0.39-1.48; BB vs. Bb: OR = 0.90, 95% CI = 0.71-1.15; dominant model: OR = 1.20, 95% CI = 0.74-1.93; recessive model: OR = 0.83, 95% CI = 0.53-1.30). In the subgroup analysis by ethnicity, the results showed similar result that BsmI polymorphism m had no association with osteoporosis. Conclusions Results from the current meta-analysis suggest that vitamin D receptor BsmI polymorphism may not be a risk factor for osteoporosis in post-menopausal women.

BACKGROUND Few studies have investigated systemic inflammation levels in degenerative cervical myelopathy (DCM). This study evaluated the concentration of inflammatory cytokines in DCM patients and assessed whether they can predict symptom severity. MATERIAL AND METHODS A total of 40 consecutive DCM patients and 10 healthy volunteers were included in this study. Concentrations of interleukin (IL)-1β, IL-6, interferon-γ, and tumor necrosis factor-α were compared between DCM patients and normal controls. Spearman's correlation coefficient was used to examine relationships of cytokines with age, body mass index (BMI), symptom duration, and symptom severity. A DCM compression rat model was established to examine the levels of inflammatory cytokines in serum and cerebrospinal fluid (CSF). RESULTS Serum level of IL-6 is significantly higher in DCM patients compared with normal people (0.8±0.5 pg/ml vs. 0.5±0.3 pg/ml, P=0.036). Positive correlations were found between IL-6 levels with BMI (r=0.519; P=0.001) and symptom severity (ρ=-0.556, P

Osteosarcoma (OS) is the most common primary malignancy of the bone affecting children and adolescents. Copine 1 (CPNE1) is a highly conserved calcium-dependent phospholipid-binding protein and may function in regulating signal transduction and membrane trafficking. In the present study, we investigated CPNE1 expression in osteosarcoma tissues and cells, and studied the effects of small interfering RNA (siRNA)-targeting CPNE1 on proliferation, metastasis and chemosensitivity of the osteosarcoma cells. The results demonstrated that CPNE1 was highly expressed in the osteosarcoma tissues and cell lines. Moreover, functional investigations confirmed that CPNE1 knockdown significantly inhibited cell proliferation, colony formation, invasion and metastasis in Saos-2 and HOS cells. Western blot analysis indicated that CPNE1 silencing downregulated the expression of many proteins associated with tumorigenesis and development, including Ras, MEK-1/2, WNT1, β-catenin, cyclin A1, IRAK2 and cIAP2. In addition, CPNE1 downregulation enhanced the sensitivity of Saos-2 cells towards cisplatin and adriamycin. The present study provides deep insight into the clinical use of lentiviral-mediated CPNE1 silencing for osteosarcoma therapy.

The repair of articular cartilage injury is a great clinical challenge. Platelet-rich plasma (PRP) has attracted much attention for the repair of articular cartilage injury, because it contains various growth factors that are beneficial for wound repair. However, current administration methods of PRP have many shortcomings, such as unstable biological fixation and burst release of growth factors, all of which complicate its application in the repair of articular cartilage and compromise its therapeutic efficacy. In this study, based on our previously reported photoinduced imine crosslinking (PIC) reaction, we developed an in situ photocrosslinkable PRP hydrogel glue (HNPRP) through adding a photoresponsive hyaluronic acid (HA-NB) which could generate aldehyde groups upon light irradiation and subsequently react with amino groups, into autologous PRP. Our study showed that HNPRP hydrogel glue was cytocompatible and could be conveniently and rapidly prepared in situ, forming a robust hydrogel scaffold. In addition, our results demonstrated that HNPRP hydrogel not only achieved controlled release of growth factors, but also showed strong tissue adhesive ability. Therefore, HNPRP hydrogel was quite suitable for cartilage defect regeneration. Our further in vitro experiment showed that HNPRP hydrogel could promote the proliferation and migration of chondrocytes and bone marrow stem cells (BMSCs). In vivo testing using a rabbit full-thickness cartilage defect model demonstrated that HNPRP hydrogel could achieve integrative hyaline cartilage regeneration and its therapeutic efficacy was better than thrombin activated PRP gel. Statement of Significance In this study, we have developed a photocrosslinkable platelet rich plasma (PRP) – complexed hydrogel glue (HNPRP) for cartilage regeneration. The in situ formed HNPRP hydrogel glue showed not only the controlled release ability of growth factors, but also strong tissue adhesiveness, which could resolve the current problems in clinical application of PRP. Furthermore, HNPRP hydrogel glue could promote integrative hyaline cartilage regeneration, and its reparative efficacy for cartilage defect was better than thrombin activated PRP gel. This study provided not only an effective repair material for cartilage regeneration, but also developed an advanced method for PRP application.

Zirconia/graphene nanosheets (ZrO 2 /GNs) composite coatings were prepared using a plasma spraying technique. Microscopic observations showed that the GNs additives (1 wt%) were homogeneously distributed in the ZrO 2 matrix and most of them were anchored at the splat interface. The results of wear test indicated that the ZrO 2 /GNs composite coating exhibited excellent wear resistance and low friction coefficient with the addition of GNs. The wear rate of ZrO 2 /GNs coating reduced to 1.17×10 −6 mm 3 /N m at 100 N, which corresponded to a 50% decrease compared with the pure ZrO 2 coating. Interestingly, a GNs-rich transfer layer was observed on the wear track of ZrO 2 /GNs coating by field-emission scanning electron microscope (FESEM), energy dispersive spectroscopy (EDS), transmission electron microscope (TEM) and micro-Raman spectroscopy. This layer protected the ZrO 2 /GNs composite coatings from severe wear by brittle microfracture, which significantly improved their tribological performance.

The quantification of neurofibrillary tangles (NFTs) using specific PET tracers can facilitate the diagnosis of Alzheimer's disease (AD) and allow monitoring of disease progression and treatment efficacy. [(18)F]-THK523 has shown high affinity and selectivity for tau pathology. However, its high retention in white matter, which makes simple visual inspection difficult, may limit its use in research or clinical settings. In this paper, we optimized the automated radiosynthesis of [(11)C]-TKF and evaluated its biodistribution and toxicity in C57 mice. [(11)C]-TKF can be made by reaction precursor with [(11)C]MeOTf or (11)CH₃I, but [(11)C]MeOTf will give us higher labeling yields and specific activity. [(11)C]-TKF presented better brain uptake in normal mouse than [(18)F]-THK523 (3.23% ± 1.25% ID·g(-1) vs. 2.62% ± 0.39% ID·g(-1) at 2 min post-injection). The acute toxicity studies of [(11)C]-TKF were unremarkable.

Background Recently, accumulating evidence has shown that exosomes, the naturally secreted nanocarriers of cells, can exert therapeutic effects in various disease models in the absence of parent cells. However, application of exosomes in bone defect repair and regeneration has been rarely reported, and little is known regarding their underlying mechanisms. Methods Exosomes derived from human-induced pluripotent stem cell-derived mesenchymal stem cells (hiPS-MSC-Exos) were combined with tricalcium phosphate (β-TCP) to repair critical-sized calvarial bone defects, and the efficacy was assessed by histological examination. We evaluated the in vitro effects of hiPSC-MSC-Exos on the proliferation, migration, and osteogenic differentiation of human bone marrow-derived mesenchymal stem cells (hBMSCs) by cell-counting, scratch assays, and qRT-PCR, respectively. Gene expression profiling and bioinformatics analyses were also used to identify the underlying mechanisms in the repair. Results We found that the exosome/β-TCP combination scaffolds could enhance osteogenesis as compared to pure β-TCP scaffolds. In vitro assays showed that the exosomes could release from β-TCP and could be internalized by hBMSCs. In addition, the internalization of exosomes into hBMSCs could profoundly enhance the proliferation, migration, and osteogenic differentiation of hBMSCs. Furthermore, gene expression profiling and bioinformatics analyses demonstrated that exosome/β-TCP combination scaffolds significantly altered the expression of a network of genes involved in the PI3K/Akt signaling pathway. Functional studies further confirmed that the PI3K/Akt signaling pathway was the critical mediator during the exosome-induced osteogenic responses of hBMSCs. Conclusions We propose that the exosomes can enhance the osteoinductivity of β-TCP through activating the PI3K/Akt signaling pathway of hBMSCs, which means that the exosome/β-TCP combination scaffolds possess better osteogenesis activity than pure β-TCP scaffolds. These results indicate that naturally secreted nanocarriers-exosomes can be used as a bioactive material to improve the bioactivity of the biomaterials, and that hiPS-MSC-Exos combined with β-TCP scaffolds can be potentially used for repairing bone defects.

Primers used for quantitative real-time PCR (qRT-PCR) analysis. Figure S1. Characterization of hiPS-MSCs. (A) Flow cytometry analysis of the cell surface markers in hiPS-MSCs. (B) The qRT-PCR results for OCN, Sox9, and LPL after 7Â days in culture with osteo-, chondro-, and adipogenic mediun. ANOVA, *pâ

Background context Removal of cervical dumbbell tumors can be particularly challenging because of unique exposure requirements and proximity of the vertebral artery (VA). There are no reports describing the treatment of giant cervical spine dumbbell tumors (CSDTs). Purpose To introduce an extensive posterolateral approach to CSDTs involving total lateral mass resection and laminectomy. Study design Prospective study of all the patients with multilevel CSDTs treated by this new procedure between December 2002 and March 2006. Patient sample Sixteen patients (3 men and 13 women) with CSDTs underwent the procedure we describe. The follow-up periods ranged from 9 to 51 months (average 9 months). Average age at surgery was 45 years (range 23–68 years). Outcome measures Axial symptoms and Japanese Orthopedic Association scores were recorded. Pre- and postoperative ranges of neck motion were measured on lateral flexion and extension radiographs. Methods After making a midline incision, we preferred exposing the extraforaminal component of the tumor before performing a semilaminectomy and lateral mass resection. Any lateral extension of a tumor can be attained by detachment of the adjacent three or more segments of the lateral mass muscle insertion. The most lateral portion can be separated beneath the tumor's superficial muscle flap, and then when the tumor is retracted medially, the whole portion of the lateral component can be totally exposed. We then performed total lateral mass resection and laminectomy to expose the tumor at the foramina and cervical canal. Results We were able to completely resect the tumors in every patient. The average duration of surgery was 150 minutes. Blood loss was minimal (average 400 mL). All patients were monitored for a minimum of 9 months (range 9–51 months; mean 28 months). The follow-up period was uneventful, and no patients developed spinal instability. Conclusions Extensive posterolateral exposure enables surgeons to reach the lateralmost portion of CSDTs and also facilitates septation of the VA and resection of vertebral body encroachment of the tumor.

BACKGROUND To evaluate the pain, quality of life (QOL), and limb function of patients after en bloc resection of solitary metastatic bone cancer in the limbs. MATERIAL/METHODS A total of 27 patients with solitary metastatic bone cancer in the limbs were recruited. All these patients underwent limb-salvage surgery with en bloc resection of the metastatic tumor. Pain and QOL were evaluated before and after surgery. Pain was assessed with a 10-point scale before and 1 month after surgery. The QOL was evaluated with the SF-30 scale before and 3 months after surgery. Limb function was evaluated with the Musculoskeletal Tumor Society scale (MSTS) 3 months after surgery. Follow-up was performed for 6~31 months (mean: 16.15 ± 7.47 months). RESULTS All procedures were successfully performed. Post-operative complications were found in 6 patients, including incision infection, prosthesis dislocation, deep vein thrombosis, and pulmonary infection. The pain score before and 1 month after surgery was 6.85 ± 3.11 and 1.26 ± 0.81, respectively, indicating obvious improvement (t=9.978, P

Background Osteoarthritis (OA) is the most common joint disease worldwide. In the past decade, mesenchymal stem cells (MSCs) have been used widely for the treatment of OA. A potential mechanism of MSC-based therapies has been attributed to the paracrine secretion of trophic factors, in which exosomes may play a major role. In this study, we aimed to compare the effectiveness of exosomes secreted by synovial membrane MSCs (SMMSC-Exos) and exosomes secreted by induced pluripotent stem cell-derived MSCs (iMSC-Exos) on the treatment of OA. Methods Induced pluripotent stem cell-derived MSCs and synovial membrane MSCs were characterized by flow cytometry. iMSC-Exos and SMMSC-Exos were isolated using an ultrafiltration method. Tunable resistive pulse-sensing analysis, transmission electron microscopy, and western blots were used to identify exosomes. iMSC-Exos and SMMSC-Exos were injected intra-articularly in a mouse model of collagenase-induced OA and the efficacy of exosome injections was assessed by macroscopic, histological, and immunohistochemistry analysis. We also evaluated the effects of iMSC-Exos and SMMSC-Exos on proliferation and migration of human chondrocytes by cell-counting and scratch assays, respectively. Results The majority of iMSC-Exos and SMMSC-Exos were approximately 50–150 nm in diameter and expressed CD9, CD63, and TSG101. The injection of iMSC-Exos and SMMSC-Exos both attenuated OA in the mouse OA model, but iMSC-Exos had a superior therapeutic effect compared with SMMSC-Exos. Similarly, chondrocyte migration and proliferation were stimulated by both iMSC-Exos and SMMSC-Exos, with iMSC-Exos exerting a stronger effect. Conclusions The present study demonstrated that iMSC-Exos have a greater therapeutic effect on OA than SMMSC-Exos. Because autologous iMSCs are theoretically inexhaustible, iMSC-Exos may represent a novel therapeutic approach for the treatment of OA. Electronic supplementary material The online version of this article (doi:10.1186/s13287-017-0510-9) contains supplementary material, which is available to authorized users.