Search

Background Improving the poor microenvironment of the joint cavity has great potential in the treatment of cartilage injury, and mesenchymal stem cells (MSCs)-derived exosomes (MSCs-Exos), with their inherent ability to modulate cellular behavior, are becoming a new cell-free therapy for cartilage repair. In this study, we aimed to investigate whether MSCs-Exos cultured on scaffolds of different dimensions could improve the poor joint cavity microenvironment caused by cartilage injury and explore the related mechanisms. Results The results of experiments in vitro showed that exosomes derived MSCs which cultured on three-dimension (3D) scaffolds (3D-Exo) has gain efficiency. 3D-Exo enhanced the biological functions of bone marrow mesenchymal stem cells (BMSCs), including proliferation, migration and chondrogenic differentiation. In addition, 3D-Exo can promote the macrophages toward M2 type and have the effect of protecting chondrocytes. In short-term animal experiments, compared with exosomes derived MSCs which cultured on two-dimension (2D) environment (2D-Exo), 3D-Exo have stronger ability to regulate the microenvironment of the joint cavity. Long-term animal studies have confirmed the therapeutic efficacy of 3D-Exo over 2D-Exo. Based on this, 3D-Exo were applied to the rat knee osteochondral defect model after adsorption in the micro-pores of the scaffold and combined with subsequent articular cavity injections, showing a more powerful cartilage repair ability. Conclusions 3D-Exo can better accelerate osteochondral defect repairing than 2D-Exo by upregulating the miRNAs related to cartilage repair. This offers a promising novel cell-free therapy for treating osteochondral defect repairing.

Mesenchymal stem/stromal cells (MSCs) are promising for the treatment of degenerative diseases and traumatic injuries. However, MSC engraftment is not always successful and requires a strong comprehension of the cytokines and their receptors that mediate the biological behaviors of MSCs. The effects of nerve growth factor (NGF) and its two receptors, TrkA and p75NTR, on neural cells are well studied. Increasing evidence shows that NGF, TrkA, and p75NTR are also involved in various aspects of MSC function, including their survival, growth, differentiation, and angiogenesis. The regulatory effect of NGF on MSCs is thought to be achieved mainly through its binding to TrkA. p75NTR, another receptor of NGF, is regarded as a novel surface marker of MSCs. This review provides an overview of advances in understanding the roles of NGF and its receptors in MSCs as well as the effects of MSC‐derived NGF on other cell types, which will provide new insight for the optimization of MSC‐based therapy., In this study, the modulatory effect of exogenous nerve growth factor (NGF) on mesenchymal stem/stromal cell (MSC) functions and the paracrine effects of MSC‐derived NGF on other cell types are discussed. In particular, the cytological functions and superiority of p75NTR+ MSCs as the basis for utilizing p75NTR as a surface marker to identify MSCs is presented.

Tissue engineering provides a promising avenue for treating cartilage defects. However, great challenges remain in the development of structurally and functionally optimized scaffolds for cartilage repair and regeneration. In this study, decellularized cartilage extracellular matrix (ECM) and waterborne polyurethane (WPU) were employed to construct WPU and WPU-ECM scaffolds by water-based 3D printing using low-temperature deposition manufacturing (LDM) system, which combines rapid deposition manufacturing with phase separation techniques. The scaffolds successfully achieved hierarchical macro‐microporous structures. After adding ECM, WPU scaffolds were markedly optimized in terms of porosity, hydrophilia and bioactive components. Moreover, the optimized WPU-ECM scaffolds were found to be more suitable for cell distribution, adhesion, and proliferation than the WPU scaffolds. Most importantly, the WPU-ECM scaffold could facilitate the production of glycosaminoglycan (GAG) and collagen and the upregulation of cartilage-specific genes. These results indicated that the WPU-ECM scaffold with hierarchical macro‐microporous structures could recreate a favorable microenvironment for cell adhesion, proliferation, differentiation, and ECM production. In vivo studies further revealed that the hierarchical macro‐microporous WPU-ECM scaffold combined with the microfracture procedure successfully regenerated hyaline cartilage in a rabbit model. Six months after implantation, the repaired cartilage showed a similar histological structure and mechanical performance to that of normal cartilage. In conclusion, the hierarchical macro‐microporous WPU-ECM scaffold may be a promising candidate for cartilage tissue engineering applications in the future.

Xenogeneic porcine fibrin sealant (PFS), derived from porcine blood, was used as a scaffold for cartilage tissue engineering. PFS has a porous microstructure, biocompatibility and degradation, and it provides a perfect extracellular matrix environment for the adhesion and proliferation of chondrocytes. Recently, PFS in combination with autologous chondrocytes (ACs) were used to study the microstructure of PFS scaffolds and promotion effect on the proliferation and migration of ACs. In this study, we investigated the effects of PFS in combination with ACs on the healing of cartilage defects in rabbits. A full‐thickness cartilage defect was made in the femoral trochlear in rabbits, subsequently, three surgical procedures were used to repair the defect, namely: the defect was treated with microfracture (MF group); the defect was filled with PFS alone (PFS group) or in combination with ACs (PFS + ACs group); the unrepaired cartilage defects served as the control group (CD group). Three and 6 months after the operation, the reparative effect was evaluated using medical imaging, gross scoring, pathological staining, biomechanical testing and biochemical examination. The PFS group showed a limited effect on defect repair, this result was significantly worse than the MF group. The best reparative effect was observed in the PFS + ACs group. These results hinted that PFS in combination with autologous chondrocytes has broad prospects for clinical applications in cartilage tissue engineering.

Cartilage is an important tissue that is widely found in joints, ears, nose and other organs. The limited capacity to regenerate makes cartilage reconstruction an urgent clinical demand. Due to the avascular nature of cartilage, we hypothesized that inhibition of vascularization contributes to cartilage formation. Here, we used VEGFa siRNA to inhibit the infiltration of the local vascular system. Optimized lipid nanoparticles were prepared by microfluidics for the delivery of siRNA. Then, we constructed a tissue engineering scaffold. Both seed cells and VEGFa siRNA-LNPs were loaded in a GELMA hydrogel. Subcutaneous implantation experiments in nude mice indicate that this is a promising strategy for cartilage reconstruction. The regenerated cartilage was superior, with significant upregulation of SOX9, COL-II and ACAN. This is attributed to an environment deficient in oxygen and nutrients, which facilitates cartilage formation by upregulating HIF-1α and FOXO transcription factors. In conclusion, a GelMA/Cells+VEGFa siRNA-LNPs scaffold was constructed to achieve superior cartilage regeneration.

Tissue engineering (TE) has brought new hope for articular cartilage regeneration, as TE can provide structural and functional substitutes for native tissues. The basic elements of TE involve scaffolds, seeded cells, and biochemical and biomechanical stimuli. However, there are some limitations of TE; what most important is that static cell culture on scaffolds cannot simulate the physiological environment required for the development of natural cartilage. Recently, bioreactors have been used to simulate the physical and mechanical environment during the development of articular cartilage. This review aims to provide an overview of the concepts, categories, and applications of bioreactors for cartilage TE with emphasis on the design of various bioreactor systems.

Due to the sophisticated hierarchical structure and limited reparability of articular cartilage (AC), the ideal regeneration of AC defects has been a major challenge in the field of regenerative medicine. As defects progress, they often extend from the cartilage layer to the subchondral bone and ultimately lead to osteoarthritis. Tissue engineering techniques bring new hope for AC regeneration. To meet the regenerative requirements of the heterogeneous and layered structure of native AC tissue, a substantial number of multilayered biomimetic scaffolds have been studied. Ideal multilayered scaffolds should generate zone-specific functional tissue similar to native AC tissue. This review focuses on the current status of multilayered scaffolds developed for AC defect repair, including design strategies based on the degree of defect severity and the zone-specific characteristics of AC tissue, the selection and composition of biomaterials, and techniques for design and manufacturing. The challenges and future perspectives of biomimetic multilayered scaffold strategies for AC regeneration are also discussed.

Background The dedifferentiation of chondrocytes and the unstable chondrogenic differentiation status of pluripotent mesenchymal stem cells (MSCs) are immense issues in cell-based articular cartilage repair and regenerative strategies. Here, to improve the cartilage characteristics of seed cells, a double biomimetic acellular cartilage extracellular matrix (ACECM)-oriented scaffold was used to mimic the cartilage microenvironment for human umbilical cord Wharton’s jelly-derived MSCs (hWJMSCs) and primary cartilage cells (pACs) to regenerate hyaline cartilage. Methods A double biomimetic ACECM-oriented scaffold was created from the cartilage extracellular matrix of pig articular cartilage using pulverization decellularization freeze-drying procedures. hWJMSCs and pACs were co-cultured at ratios of 50:50 (co-culture group, ACCC), 0:100 (ACAC group) and 100:0 (ACWJ group) in the ACECM-oriented scaffold, and the co-culture system was implanted in a caprine model for 6 months or 9 months to repair full-thickness articular cartilage defects. The control groups, which had no cells, comprised the blank control (BC) group and the ACECM-oriented scaffold (AC) group. Gross morphology and magnetic resonance imaging (MRI) as well as histological and biomechanical evaluations were used to characterize the cartilage of the repair area. Results Relative to the control groups, both the gross morphology and histological staining results demonstrated that the neotissue of the ACCC group was more similar to native cartilage and better integrated with the surrounding tissue. Measurements of glycosaminoglycan content and Young’s modulus showed that the repair areas had more abundant cartilage-specific content and significantly higher mechanical strength in the ACCC group than in the control groups, especially at 9 months. On MRI, the T2-weighted signal of the repair area was homogeneous, and the oedema signal disappeared almost completely in the ACCC group at 9 months. HLA-ABC immunofluorescence staining demonstrated that hWJMSCs participated in the repair and regeneration of articular cartilage and escaped surveillance and clearance by the caprine immune system. Conclusion The structure and components of double biomimetic ACECM-oriented scaffolds provided a cartilage-like microenvironment for co-cultured seed cells and enhanced the biomechanics and compositions of neotissue. This co-culture system has the potential to overcome the dedifferentiation of passage chondrocytes and the unstable chondrogenic differentiation status of MSCs.

BackgroundMeniscus injury has a limited ability to heal itself and often results in the progression to osteoarthritis. Tissue engineering offers the possibility of regeneration of severely damaged meniscus. Immunomodulatory strategies based on biomaterials have a wide range of regenerative potential. Macrophages have a high degree of plasticity and will change in morphology and function under the influence of different tissues. M1 macrophages have pro-inflammatory properties, while M2 macrophages have tissue repair and remodeling functions. It has been reported many times that biological scaffolds induce M2 polarization, resulting in the increase of the M2: M1 macrophage phenotypic ratio, thereby promoting tissue repair. However, there is no report on meniscus repair and regenerative.ResultsIn this study, sodium tanshinone IIA sulfonate (STS) delivery Polycaprolactone (PCL)-meniscus extracellular matrix (MECM) based hydrogel hybrid scaffold was fabricated. PCL provides mechanical support, MECM based hydrogel provides a microenvironment conducive to cell proliferation and differentiation, and STS is used to control the phenotype of macrophages. In vitro experiments, we confirmed that STS could not only transform macrophages from M1 to M2 polarization but also prevent meniscal fibrochondrocytes (MFCs) from oxidative stress, apoptosis, and extracellular matrix degradation induced by inflammatory stimulation, thus having stronger proliferation activity. Results of subcutaneous implantation in vivo showed that hybrid scaffold could induce M2 polarization in the early stage. In addition, a hybrid scaffold seeded with MFCs could achieve good meniscus regeneration and chondroprotective effects in the rabbit.Conclusion STS delivery PCL-MECM based hydrogel hybrid scaffold promotes meniscal regeneration through controlling the phenotype of macrophage, which provides a new direction for tissue engineering meniscus regeneration.

According to different terrain characteristics, combined with the motion characteristics of wheeled and tracked mobile mechanisms, a reconfigurable wheel-track hybrid deformable wheel with multiple motion forms is proposed and developed. It is composed of a track, wheel body, slewing bearing, and conductive slip ring. In the wheel body, the deformation mechanism, braking mechanism, and turnover locking mechanism can make it realize four kinds of motion forms, such as wheeled form and triangular-tracked form. Based on the corresponding parameter model, the static and dynamic analysis of the deformation mechanism is carried out. Among them, the dynamic analysis puts forward two solutions to the rigid impact problem in the deformation process, and the second solution is systematically modeled. It is found that it can be expressed as a standard second-order system, and the simulation parameters are set according to its characteristics to verify the feasibility of the scheme.

Inferior healing and peritendinous adhesions are the major clinical problems following Achilles tendon injury, leading to impaired motor function and an increased risk of re-rupture. These complications are presumed to be inextricably linked to inflammation and fibroscar formation. Here, microRNA29a is identified as a promising therapeutic target for tendon injury through the cross-regulation of the immune response and matrix remodeling. MiR29a-LNPs were successfully prepared by microfluidic technology. They are then loaded into the core-shell nanofibers to achieve local delivery in the injured tendon, where the shell layer is composed of PELA for anti-adhesion. Our studies reveal that miR29a regulates collagen synthesis and NF-κB activation in tenocytes, and promotes macrophage polarization by inhibiting the inflammasome pathway. In vivo studies of the Achilles tendon-rupture model indicate the best repair in the miR29a group, as evidenced by superior collagen composition and alignment, higher mechanical strength, and better functional recovery. In conclusion, a functionalized anti-adhesive membrane that promotes nascent tendon matrix remodeling and improves the regenerative immune microenvironment is developed for the treatment of tendon injury.

Background The regeneration and repair of articular cartilage remains a major challenge for clinicians and scientists due to the poor intrinsic healing of this tissue. Since cartilage injuries are often clinically irregular, tissue-engineered scaffolds that can be easily molded to fill cartilage defects of any shape that fit tightly into the host cartilage are needed. Method In this study, bone marrow mesenchymal stem cell (BMSC) affinity peptide sequence PFSSTKT (PFS)-modified chondrocyte extracellular matrix (ECM) particles combined with GelMA hydrogel were constructed. Results In vitro experiments showed that the pore size and porosity of the solid-supported composite scaffolds were appropriate and that the scaffolds provided a three-dimensional microenvironment supporting cell adhesion, proliferation and chondrogenic differentiation. In vitro experiments also showed that GelMA/ECM-PFS could regulate the migration of rabbit BMSCs. Two weeks after implantation in vivo, the GelMA/ECM-PFS functional scaffold system promoted the recruitment of endogenous mesenchymal stem cells from the defect site. GelMA/ECM-PFS achieved successful hyaline cartilage repair in rabbits in vivo, while the control treatment mostly resulted in fibrous tissue repair. Conclusion This combination of endogenous cell recruitment and chondrogenesis is an ideal strategy for repairing irregular cartilage defects. Graphical Abstract

Articular cartilage (AC) injury repair has always been a difficult problem for clinicians and researchers. Recently, a promising therapy based on mesenchymal stem cells (MSCs) has been developed for the regeneration of cartilage defects. As endogenous articular stem cells, synovial MSCs (SMSCs) possess strong chondrogenic differentiation ability and articular specificity. In this study, a cartilage regenerative system was developed based on a chitosan (CS) hydrogel/3D-printed poly(e-caprolactone) (PCL) hybrid containing SMSCs and recruiting tetrahedral framework nucleic acid (TFNA) injected into the articular cavity. TFNA, which is a promising DNA nanomaterial for improving the regenerative microenvironment, could be taken up into SMSCs and promoted the proliferation and chondrogenic differentiation of SMSCs. CS, as a cationic polysaccharide, can bind to DNA through electrostatic action and recruit free TFNA after articular cavity injection in vivo. The 3D-printed PCL scaffold provided basic mechanical support, and TFNA provided a good microenvironment for the proliferation and chondrogenic differentiation of the delivered SMSCs and promoted cartilage regeneration, thus greatly improving the repair of cartilage defects. In conclusion, this study confirmed that a CS hydrogel/3D-printed PCL hybrid scaffold containing SMSCs could be a promising strategy for cartilage regeneration based on chitosan-directed TFNA recruitment and TFNA-enhanced cell proliferation and chondrogenesis.

The inflammatory response to chronic injury affects tissue regeneration and has become an important factor influencing the prognosis of patients. In previous stem cell treatments, it was revealed that stem cells not only have the ability for direct differentiation or regeneration in chronic tissue damage but also have a regulatory effect on the immune microenvironment. Stem cells can regulate the immune microenvironment during tissue repair and provide a good “soil” for tissue regeneration. In the current study, the regulation of immune cells by mesenchymal stem cells (MSCs) in the local tissue microenvironment and the tissue damage repair mechanisms are revealed. The application of the concepts of “seed” and “soil” has opened up new research avenues for regenerative medicine. Tissue engineering (TE) technology has been used in multiple tissues and organs using its biomimetic and cellular cell abilities, and scaffolds are now seen as an important part of building seed cell microenvironments. The effect of tissue engineering techniques on stem cell immune regulation is related to the shape and structure of the scaffold, the preinflammatory microenvironment constructed by the implanted scaffold, and the material selection of the scaffold. In the application of scaffold, stem cell technology has important applications in cartilage, bone, heart, and liver and other research fields. In this review, we separately explore the mechanism of MSCs in different tissue and organs through immunoregulation for tissue regeneration and MSC combined with 3D scaffolds to promote MSC immunoregulation to repair damaged tissues.

Heterogeneity of mesenchymal stem cells (MSCs) influences the cell therapy outcome and the application in tissue engineering. Also, the application of subpopulations of MSCs in cartilage regeneration remains poorly characterized. CD146+ MSCs are identified as the natural ancestors of MSCs and the expression of CD146 are indicative of greater pluripotency and self-renewal potential. Here, we sorted a CD146+ subpopulation from adipose-derived mesenchymal stem cells (ADSCs) for cartilage regeneration. Methods: CD146+ ADSCs were sorted using magnetic activated cell sorting (MACS). Cell surface markers, viability, apoptosis and proliferation were evaluated in vitro. The molecular signatures were analyzed by mRNA and protein expression profiling. By intra-articular injections of cells in a rat osteochondral defect model, we assessed the role of the specific subpopulation in cartilage microenvironment. Finally, CD146+ ADSCs were combined with articular cartilage extracellular matrix (ACECM) scaffold for long term (3, 6 months) cartilage repair. Results: The enriched CD146+ ADSCs showed a high expression of stem cell and pericyte markers, good viability, and immune characteristics to avoid allogeneic rejection. Gene and protein expression profiles revealed that the CD146+ ADSCs had different cellular functions especially in regulation inflammation. In a rat model, CD146+ ADSCs showed a better inflammation-modulating property in the early stage of intra-articular injections. Importantly, CD146+ ADSCs exhibited good biocompatibility with the ACECM scaffold and the CD146+ cell-scaffold composites produced less subcutaneous inflammation. The combination of CD146+ ADSCs with ACECM scaffold can promote better cartilage regeneration in the long term. Conclusion: Our data elucidated the function of the CD146+ ADSC subpopulation, established their role in promoting cartilage repair, and highlighted the significance of cell subpopulations as a novel therapeutic for cartilage regeneration.

Background: The repair of large bone defects remains challenging for orthopaedic surgeons. Bone grafting remains the method of choice; such grafts fill spaces and enhance bone repair. Therapeutic agents also aid bone healing. The objective of this study is to develop a composite bioactive scaffold composed of polylactide-coglycolide (PLGA) and tricalcium phosphate (TCP) (the basic carrier) incorporating osteogenic, bioactive magnesium metal powder (Mg). Method: Porous PLGA/TCP scaffolds incorporating Mg were fabricated using a low-temperature rapid-prototyping process. We term the PLGA/TCP/Mg porous scaffold (hereafter, PPS). PLGA/TCP lacking Mg served as the control material when evaluating the efficacy of PPS. A total of 36 New Zealand white rabbits were randomly divided into blank, PLGA/TCP (P/T) and PPS group, with 12 rabbits in each group. We established bone defects 15 mm in length in rabbit radii to evaluate the in vivo osteogenic potential of the bioactive scaffold in terms of the direct controlled release of osteogenic Mg ion during in vivo scaffold degradation. Radiographs of the operated radii were taken immediately after implantation and then at 2, 4, 8 and 12 weeks. Micro-computed tomography of new bone formation and remaining scaffold and histological analysis were performed at 4, 8, 12 weeks after operation. Results: X-ray imaging performed at weeks 4, 8 and 12 post-surgery revealed more newly formed bone within defects implanted with PPS and PLGA/TCP scaffolds than blank group (p < 0.05). And micro-computed tomography performed at weeks 4 and 8 after surgery revealed more newly formed bone within defects implanted with PPS scaffolds than PLGA/TCP scaffolds (p

Articular cartilage (AC) lesions are fairly common but remain an obstacle for clinicians and researchers due to their poor self-healing capacity. Recently, a promising therapy based on the recruitment of autologous mesenchymal stem cells (MSCs) has been developed for the regeneration of full-thickness cartilage defects in the knee joint. In this study, a 3D-bioprinted difunctional scaffold was developed based on aptamer HM69-mediated MSC-specific recruitment and growth factor-enhanced cell chondrogenesis. The aptamer, which can specifically recognize and recruit MSCs, was first chemically conjugated to the decellularized cartilage extracellular matrix and then mixed with gelatin methacrylate to form a photocrosslinkable bioink ready for 3D bioprinting. Together with the growth factor that promoted cell chondrogenic differentiation, the biodegradable polymer poly(e-caprolactone) was further chosen to impart mechanical strength to the 3D bioprinted constructs. The difunctional scaffold specifically recruited MSCs, provided a favorable microenvironment for cell adhesion and proliferation, promoted chondrogenesis, and thus greatly improved cartilage repair in rabbit full-thickness defects. In conclusion, this study demonstrated that 3D bioprinting of difunctional scaffolds could be a promising strategy for in situ AC regeneration based on aptamer-directed cell recruitment and growth-factor-enhanced cell chondrogenesis.

In recent years, silent speech recognition (SSR) based on surface electromyography (sEMG) has been proven practical and achieved successes in previous researches. The channel correlations hidden in sEMG data may work in SSR, which is rarely researched. This paper proposed to apply frame-based local binary pattern (LBP) in feature extraction of multichannel sEMG. Data are preprocessed after collection by human subjects to obtain clean signals. Then time domain (TD) features and BLP are both extracted as two feature sets, which are reduced in dimension by the method of Linear Discriminant Analysis (LDA). Random forest is used as the classifier to provide the recognitions. Experimental results show that TD obtain better result than LBP, which is exceeded by using TD and LBP simultaneously with a correct rate of 0.85. This proves LBP contains unique features in sEMG, indicating interactions in channels are promising in SSR.

The inspection space environment of indoor inspection robot in substation is complex and changeable. To acquire autonomous positioning and navigation of inspection robot in substation, which makes it difficult for indoor inspection robot to locate and identify images, this paper proposes a visual positioning method to solve the problem. The realization process of inspection robot vision navigation is to use the wireless detection RFID tag to roughly locate the robot, and use the target image information extracted by a camera to perform ranging, and judge the forward direction of the robot through image processing and pattern recognition. Finally, according to the information stored in the RFID tag, the task type of the robot in a certain position in the substation is determined and executed. The experiment runs in the actual substation environment, and the control algorithm can quickly complete the correction of the deviation from the predetermined track position. At the same time, it shows the characteristics of fast path recognition, accurate discrimination, with flexibility and portability.

Objectives CD49f is expressed on a variety of stem cells and has certain effects on their cytological functions, such as proliferation and differentiation potential. However, whether CD49f is expressed on the surface of adipose tissue‐derived mesenchymal stem cells (ADSCs) and its effect on ADSCs has not been clarified. Materials and methods The effects of in vitro culture passage and inflammatory factor treatment on CD49f expression and the adhesion ability of ADSCs from mice and rats were investigated. CD49f+ cells were selected from rat ADSCs (rADSCs) by magnetic‐activated cell sorting (MACS), and the cellular functions of CD49f+ ADSCs and unsorted ADSCs, including their clonogenic, proliferation, adipogenic and osteogenic differentiation, migration and anti‐apoptotic capacities, were compared. Results CD49f expression and the adhesion ability of ADSCs decreased with increasing in vitro culture passage number. TNF‐α and IFN‐γ treatment decreased CD49f expression but increased the adhesion ability of ADSCs. After CD49f was blocked with an anti‐CD49f antibody, the adhesion ability of ADSCs was decreased. No significant difference in clonogenic activity was observed between unsorted ADSCs and CD49f+ ADSCs. CD49f+ ADSCs had greater proliferation, adipogenic and osteogenic differentiation, migration and anti‐apoptotic capacities than unsorted ADSCs. Conclusion In the current study, the expression of CD49f on ADSCs was identified for the first time. The expression of CD49f on ADSCs was influenced by in vitro culture passage number and inflammatory factor treatment. Compared with unsorted ADSCs, CD49f + ADSCs exhibited superior cellular functions, thus may have great application value in mesenchymal stem cell (MSC)‐based therapies., Although mesenchymal stem cells (MSCs) is one of the most promising seed cells in tissue engineering, its application faces some problems, such as an insufficient cell source, cell senescence and the loss of ‘stemness’ during in vitro culture, and rapid cell death after in vivo transplantation. To address these issues, we isolated CD49f+ cells from ADSCs by magnetic activated cell sorting and confirmed that CD49f+ ADSCs possessed greater proliferation, multiple differentiation, migration and anti‐apoptotic potential than unsorted ADSCs. After treatment with anti‐CD49f antibody, ADSCs exhibited a significantly reduced adhesion ability. These results indicated that CD49f+ ADSCs have superior cellular functions and considerable application prospects.

Injury of articular cartilage can cause osteoarthritis and seriously affect the physical and mental health of patients. Unfortunately, current surgical treatment techniques that are commonly used in the clinic cannot regenerate articular cartilage. Regenerative medicine involving stem cells has entered a new stage and is considered the most promising way to regenerate articular cartilage. In terms of theories on the mechanism, it was thought that stem cell-mediated articular cartilage regeneration was achieved through the directional differentiation of stem cells into chondrocytes. However, recent evidence has shown that the stem cell secretome plays an important role in biological processes such as the immune response, inflammation regulation, and drug delivery. At the same time, the stem cell secretome can effectively mediate the process of tissue regeneration. This new theory has attributed the therapeutic effect of stem cells to their paracrine effects. The application of stem cells is not limited to exogenous stem cell transplantation. Endogenous stem cell homing and in situ regeneration strategies have received extensive attention. The application of stem cell derivatives, such as conditioned media, extracellular vesicles, and extracellular matrix, is an extension of stem cell paracrine theory. On the other hand, stem cell pretreatment strategies have also shown promising therapeutic effects. This article will systematically review the latest developments in these areas, summarize challenges in articular cartilage regeneration strategies involving stem cells, and describe prospects for future development.

Since articular cartilage lacks blood vessels, nerves, and lymph tissue, its ability to repair itself is limited. Once damaged, it can lead to joint swelling and pain, accelerating the progression of osteoarthritis. Complete regeneration of hyaline cartilage with good mechanical properties remains an elusive goal, despite the many technologies available today. The inflammatory milieu created by cartilage damage is critical for chondrocyte death and hypertrophy, extracellular matrix breakdown, ectopic bone formation, and the progression of cartilage injury to osteoarthritis. In the inflammatory microenvironment, MSCs undergo aberrant differentiation, and chondrocytes begin to convert or dedifferentiate into cells with a fibroblast phenotype, resulting in fibrocartilage with poor mechanical qualities. All of these suggest that inflammatory problems may be a major stumbling block to cartilage repair. To produce a milieu conducive to cartilage regeneration, multi-dimensional management of the joint inflammatory microenvironment in place and time is required. Therefore, it is of great significance to elucidate the immune microenvironment of cartilage repair and regeneration after injury. This review provides a brief overview of:（1）the pathogenesis of cartilage injury（2）immune cells in cartilage injury and repair（3）effects of inflammatory cytokines on cartilage repair;（4）clinical strategies for the treatment of cartilage defects（5）strategies for targeted immunoregulation in cartilage repair and regeneration.

Articular cartilage is susceptible to damage, but its self-repair is hindered by its avascular nature. Traditional treatment methods are not able to achieve satisfactory repair effects, and the development of tissue engineering techniques has shed new light on cartilage regeneration. Mesenchymal stem cells (MSCs) are one of the most commonly used seed cells in cartilage tissue engineering. However, MSCs tend to lose their multipotency, and the composition and structure of cartilage-like tissues formed by MSCs are far from those of native cartilage. Thus, there is an urgent need to develop strategies that promote MSC chondrogenic differentiation to give rise to durable and phenotypically correct regenerated cartilage. This review provides an overview of recent advances in enhancement strategies for MSC chondrogenic differentiation, including optimization of bioactive factors, culture conditions, cell type selection, coculture, gene editing, scaffolds, and physical stimulation. This review will aid the further understanding of the MSC chondrogenic differentiation process and enable improvement of MSC-based cartilage tissue engineering.

Despite intensive effort was made to regenerate injured meniscus by cell-free strategies through recruiting endogenous stem/progenitor cells, meniscus regeneration remains a great challenge in clinic. In this study, we found decellularized meniscal extracellular matrix (MECM) preserved native meniscal collagen and glycosaminoglycans which could be a good endogenous regeneration guider for stem cells. Moreover, MECM significantly promoted meniscal fibrochondrocytes viability and proliferation, increased the expression of type II collagen and proteoglycans in vitro. Meanwhile, we designed 3D-printed polycaprolactone (PCL) scaffolds which mimic the circumferential and radial collagen orientation in native meniscus. Taken these two advantages together, a micro-structure and micro-environment dually biomimetic cell-free scaffold was manipulated. This cell-free PCL-MECM scaffold displayed superior biocompatibility and yielded favorable biomechanical capacities closely to native meniscus. Strikingly, neo-menisci were regenerated within PCL-MECM scaffolds which were transplanted into knee joints underwent medial meniscectomy in rabbits and sheep models. Histological staining confirmed neo-menisci showed meniscus-like heterogeneous staining. Mankin scores showed PCL-MECM scaffold could protect articular cartilage well, and knee X-ray examination revealed same results. Knee magnetic resonance imaging (MRI) scanning also showed some neo-menisci in PCL-MECM scaffold group. In conclusion, PCL-MECM scaffold appears to optimize meniscus regeneration. This could represent a promising approach worthy of further investigation in preclinical applications., Graphical abstract Image 1, Highlights • 3D-printed PCL scaffolds could mimic the circumferential and radial collagen orientation in native meniscus. • PCL-MECM scaffold displayed superior biocompatibility and yielded favorable biomechanical capacities. • PCL-MECM scaffold appears to optimize meniscus regeneration in both rabbit and sheep meniscus repairing model. • PCL-MECM scaffold may represent a promising approach worthy of further investigation in preclinical applications.

Tissue engineering provides a promising avenue for treating cartilage defects. However, great challenges remain in the development of structurally and functionally optimized scaffolds for cartilage repair and regeneration. In this study, decellularized cartilage extracellular matrix (ECM) and waterborne polyurethane (WPU) were employed to construct WPU and WPU-ECM scaffolds by water-based 3D printing using low-temperature deposition manufacturing (LDM) system, which combines rapid deposition manufacturing with phase separation techniques. The scaffolds successfully achieved hierarchical macro‐microporous structures. After adding ECM, WPU scaffolds were markedly optimized in terms of porosity, hydrophilia and bioactive components. Moreover, the optimized WPU-ECM scaffolds were found to be more suitable for cell distribution, adhesion, and proliferation than the WPU scaffolds. Most importantly, the WPU-ECM scaffold could facilitate the production of glycosaminoglycan (GAG) and collagen and the upregulation of cartilage-specific genes. These results indicated that the WPU-ECM scaffold with hierarchical macro‐microporous structures could recreate a favorable microenvironment for cell adhesion, proliferation, differentiation, and ECM production. In vivo studies further revealed that the hierarchical macro‐microporous WPU-ECM scaffold combined with the microfracture procedure successfully regenerated hyaline cartilage in a rabbit model. Six months after implantation, the repaired cartilage showed a similar histological structure and mechanical performance to that of normal cartilage. In conclusion, the hierarchical macro‐microporous WPU-ECM scaffold may be a promising candidate for cartilage tissue engineering applications in the future., Graphical abstract Image 1, Highlights • Hierarchical macro‐microporous scaffolds could be fabricated by low-temperature deposition manufacturing. • Waterborne polyurethane (WPU) scaffolds were optimized by adding decellularized cartilage extracellular matrix (ECM). • The WPU-ECM scaffold provided a suitable microenvironment for cell attachment, proliferation, and differentiation in vitro. • The paradigm of WPU-ECM scaffold and microfracture (MF) has great potential for clinical application in cartilage repair.

The meniscus plays a critical role in maintaining knee joint homeostasis. Injuries to the meniscus, especially considering the limited self-healing capacity of the avascular region, continue to be a challenge and are often treated by (partial) meniscectomy, which has been identified to cause osteoarthritis. Currently, meniscus tissue engineering focuses on providing extracellular matrix (ECM)-mimicking scaffolds to direct the inherent meniscal regeneration process, and it has been found that various stimuli are essential. Numerous bioactive factors present benefits in regulating cell fate, tissue development, and healing, but lack an optimal delivery system. More recently, bioengineers have developed various polymer-based drug delivery systems (PDDSs), which are beneficial in terms of the favorable properties of polymers as well as novel delivery strategies. Engineered PDDSs aim to provide not only an ECM-mimicking microenvironment but also the controlled release of bioactive factors with release profiles tailored according to the biological concerns and properties of the factors. In this review, both different polymers and bioactive factors involved in meniscal regeneration are discussed, as well as potential candidate systems, with examples of recent progress. This article aims to summarize drug delivery strategies in meniscal regeneration, with a focus on novel delivery strategies rather than on specific delivery carriers. The current challenges and future prospects for the structural and functional regeneration of the meniscus are also discussed. Impact statement Meniscal injury remains a clinical Gordian knot owing to the limited healing potential of the region, restricted surgical approaches, and risk of inducing osteoarthritis. Existing tissue engineering scaffolds that provide mechanical support and a favorable microenvironment also lack biological cues. Advanced polymer-based delivery strategies consisting of polymers incorporating bioactive factors have emerged as a promising direction. This article primarily reviews the types and applications of biopolymers and bioactive factors in meniscal regeneration. Importantly, various carrier systems and drug delivery strategies are discussed with the hope of inspiring further advancements in this field.

The purpose of this study was to investigate the feasibility of adipose-derived stem cells (ADSCs) as the seed cells of cartilage tissue engineering. ADSCs were isolated from adipose tissue that was harvested under sterile conditions from the inguen fold of porcines and cultured in vitro. Acellular cartilage extracellular matrix (ACECM) scaffolds of pigs were then constructed. Moreover, inflammatory cells, as well as cellular and humoral immune responses, were detected using hematoxylin and eosin staining staining, immunohistochemical staining, and western blot analysis. The results showed that the cartilage complex constructed by ADSCs and ACECM through tissue engineering successfully repaired the cartilage defect of the pig knee joint. The in vivo repair experiment showed no significant difference between chondrocytes, ADSCs, and induced ADSCs, indicating that ADSCs do not require in vitro induction and have the potential for chondrogenic differentiation in the environment around the knee joint. In addition, pig-derived acellular cartilage scaffolds possess no obvious immune inflammatory response when used in xenotransplantation. ADSCs may serve as viable seed cells for cartilage tissue engineering.

Injuries to articular cartilage (AC) can lead to cartilage degeneration without timely and proper treatments and ultimately results in osteoarthritis. Regenerative medicine and tissue engineering techniques are emerging as promising approaches for AC regeneration and repair. Typically, AC regenerative medicine and tissue engineering can be divided into two categories, cell-based tissue engineering and cell-homing tissue engineering techniques, based on the involvement of seed cells. Although numerous cell-based techniques can regenerate and repair cartilage lesions to some extent, existing strategies are still restricted by limited cell sources, excessive costs, risks of disease transmission and complex manufacturing practices. However, cell-homing tissue engineering strategies avoid these drawbacks and offer great promise for in situ AC regeneration. These strategies rely on the recruitment of endogenous stem/progenitor cells, host tissue stimulation, and functional responses and thus can provide new insights into in situ cartilage regeneration. This review provides a brief overview of the status of cell-homing tissue engineering strategies; the subpopulations, distribution and migration routes of native joint-resident stem/progenitor cells for regenerating cartilage; chemoattractants that induce enhanced endogenous cell homing; and drug delivery systems and biofunctionalized scaffolds that are indispensable for facilitating in situ AC regeneration and repair.

The West Qinling orogen in central China contains dozens of world-class sediment-hosted gold deposits, but the ages of these deposits and their relation to regional tectonism, magmatism, and metamorphism are poorly understood. Zaozigou, in the western zone of the Xiahe-Hezuo district, is one of the larger deposits in the orogen with 142 t Au at an average grade of 2.69 g/t. It is hosted in a middle Triassic turbidite sequence and swarm of crosscutting ilmenite-series intermediate to felsic dikes. Ore bodies are localized along subvertical, NE- or NS-striking faults. Gold occurs in fine-grained arsenian pyrite and arsenopyrite disseminated in hydrothermally altered sedimentary and igneous rocks and in subordinate sulfide-quartz-ankerite veinlets. Such mineralization is locally crosscut and overprinted by NW-striking, gently-dipping, auriferous stibnite-quartz veins. Zircon grains from gold mineralized granodiorite and quartz diorite porphyry dikes have U-Pb ages of 248.9 ± 1.4 to 244.8 ± 1.4 Ma, whereas a post-ore diorite porphyry dike has a U-Pb age of 237.5 ± 1.4 Ma. Two samples of sericite associated with disseminated arsenian pyrite and arsenopyrite in sedimentary and igneous host rocks yield plateau ages of 245.6 ± 1.0 Ma and 242.1 ± 1.0 Ma, that are bracketed by the zircon U-Pb ages on pre- and post-ore dikes. Field relationships and geochronological results, thus, constrain magmatism and gold mineralization at the early Triassic. Previous work has shown that the Au-Cu skarns and intrusion-related gold deposits exposed at a deeper level in the eastern zone of the Xiahe-Hezuo district are genetically related to early-middle Triassic ilmenite series intrusions generated in an extensional back-arc setting during rollback of the subducted paleo-Tethyan slab. Our U-Pb and Ar/Ar data show that the large Zaozigou gold deposit in the western zone of the Xiahe-Hezuo district is broadly coeval with the Au-Cu skarn and intrusion-related gold deposits in the eastern zone. This temporal consistency provides additional support for a genetic link between gold mineralization and magmatism in the Xiahe-Hezuo district. As such, this district may represent the only reduced intrusion related gold system in the West Qinling Orogen.

Low vascularization in meniscus limits its regeneration ability after injury, and tissue engineering is the most promising method to achieve meniscus regeneration. In this study, we fabricated a kind of composite scaffold by decellularized meniscus extracellular matrix/polycaprolactone (DMECM/PCL) electrospinning fibers and porous DMECM, in which DMECM/PCL fibers were used as reinforcing component. The tensile modulus of the composite scaffold in longitudinal and crosswise directions were 8.5 ± 1.9 and 2.3 ± 0.3 MPa, respectively. Besides that, the DMECM/PCL electrospinning fibers enhanced suture resistance of the composite scaffold more than 5 times than DMECM scaffold effectively. In vitro cytocompatibility showed that the porous structure provided by DMECM component facilitated meniscus cells’ proliferation. DMECM was also the main component to regulate cell behaviors, which promoted meniscus cells expressing extracellular matrix related genes such as COL I, COL II, SOX9 and AGG. Rabbits with total meniscectomy were used as animal model to evaluated the composited scaffolds performance in vivo at 3 and 6 months. Results showed that rabbits with scaffold implanting could regenerate neo-menisci in both time points. The neo-menisci had similar histology structure and biochemical content with native menisci. Although neo-menisci had inferior tensile modulus than native ones, its modulus was improved with implanting time prolonging. MRI imaging showed the signal of neo-meniscus in the body is clear, and X-ray imaging of knee joints demonstrated the implantation of scaffolds could relief joint space narrowing. Moreover, rabbits with neo-menisci had better cartilage condition in femoral condyle and tibial plateau compared than meniscectomy group. Statement of Significance We fabricated the meniscus scaffold by combining porous decellularized meniscus extracellular matrix (DMECM) and DMECM/PCL electrospinning fibers together, which used the porous structure of DMECM, and the good tensile property of electrospinning fibers. We believe single material cannot satisfy increasing needs of scaffold. Therefore, we combined not only materials but also fabrication methods together to develop scaffold to make good use of each part. DMECM in electrospinning fibers also made these two components possible to be integrated through crosslinking. Compared to existing meniscus scaffold, the composite scaffold had (1) soft structure and extrusion would not happen after implantation, (2) ability to be trimmed to suitable shape during surgery, and (3) good resistance to suture.

Articular cartilage defects have very limited self-repair potential, and traditional bone marrow-stimulating therapy is not effective. Cartilage tissue engineering using bone marrow mesenchymal stem cells (BMSCs) and adipose tissue-derived mesenchymal stem cells (ADSCs) is considered an attractive treatment for cartilage lesions and osteoarthritis. However, studies proved that both BMSCs and ADSCs have their own advantages and shortcomings, including their sources, isolation methods, characterizations and differentiation potential. Understanding the properties and differences between ADSCs and BMSCs is important for clinical application in cartilage regeneration. This review provides an overview of BMSCs and ADSCs based on their characterization, isolation. Then, we summarized their differentiation potential in different experimental conditions. Finally, we discuss the applications of BMSCs and ADSCs in scaffold-free and scaffold-based cartilage tissue engineering. Based on different properties of BMSCs and ADSCs, and patient's physical condition, a more suitable therapeutic strategy can be selected.

The Triassic West Qinling orogen, which formed by the continental collision between the South China block and North China craton following the subduction and closure of the paleo-Tethyan ocean, hosts numerous gold deposits that have commonly considered as products of metamorphic dehydration during the oceanic subduction and subsequent continental collision. However, whether or not there are gold deposits that are genetically related to regional magmatism remains poorly understood. Here we present mineralogical, compositional, and geochronological data of the Dewulu Au-Cu skarn deposit in the Xiahe-Hezuo district to understand the ore genesis and its genetic link to many coeval sediment-hosted disseminated and magmatic-hosted vein gold deposits in the same district, which collectively reveal a possible intrusion-related gold system. The Dewulu Au-Cu skarn deposit in the eastern zone of the Xiahe-Hezuo district is associated with the early Triassic I-type, ilmenite-series Dewulu quartz diorite pluton that intrudes Permian marine clastic and carbonate rocks. Ore-related hydrothermal biotite separates yield a well-defined 40Ar/39Ar plateau age of 239.9 ± 1.4 Ma (2σ), which agrees with a previous zircon U-Pb age (238.6 ± 1.5 Ma at 2σ) of the Dewulu quartz diorite and thus demonstrates a temporal and likely genetic link between the two. Both prograde and retrograde skarn assemblages are well developed in the Dewulu Au-Cu deposit. Prograde garnet and pyroxene are compositionally dominated by grossularite and hedenbergite, respectively, indicating a reduced skarn system. Au-Cu mineralization is largely represented by the arsenopyrite-loellingite-chalcopyrite-pyrrhotite-bornite assemblage and is associated with retrograde skarns. Gold is mostly hosted in arsenopyrite, loellingite and chalcopyrite, and has close textural relations with native bismuth or bismuthides. Mineral stability relationships and fluid inclusion microthermometric data confirm that the prograde skarns formed at a low oxygen fugacity, high temperature (> 630 °C), and a depth range of 2.9 to 6.5 km. Arsenopyrite and chlorite geothermometers indicate that the retrograde skarns and late quartz-sulfide-calcite assemblages formed at 550 to 345 °C and

The Xiahe-Hezuo district in the West Qinling orogen contains numerous Au-(As-Sb) and Cu-Au-(W) deposits. The district is divided into eastern and western zones by the Xiahe-Hezuo Fault. The western zone is exposed at a shallow level and contains sediment-hosted disseminated Au-(As-Sb) deposits, whereas the eastern zone is exposed at a deeper level and contains Cu-Au-(W) skarn and lode gold deposits within or close to granitic intrusions. The Laodou gold deposit in the eastern zone consists of auriferous quartz-sulfide-tourmaline and minor quartz-stibnite veins that are structurally controlled by fault zones transecting the Laodou quartz diorite porphyry stock and enveloped by potassic and phyllic alteration. Both the veins and alteration halos commonly contain quartz, sericite, tourmaline, pyrite, and arsenopyrite, with minor galena, sphalerite, chalcopyrite, tetrahedrite, and enargite. Gold occurs mainly as invisible gold in pyrite or arsenopyrite and locally as inclusions less than 50 μm in diameter. The zircon U-Pb age of 247.6 ± 1.3 Ma (2σ) on the host quartz diorite porphyry and the sericite 40Ar/39Ar plateau ages of 249.1 ± 1.6 and 249.0 ± 1.5 Ma (2σ) on two ore-related hydrothermal sericite samples are within analytical errors of one another. At the formation temperature (275 °C) inferred from microthermometric measurements of fluid inclusion, sericite and tourmaline yield calculated δDH2O values of −70 to −45‰ and δ 18OH2O of 5.8 to 9.7‰, while quartz yields calculated δ 18OH2O values of 5.1∼5.7‰. Hydrothermal tourmaline in quartz-sulfide-tourmaline veins has δ 11B of −11.2 to −0.9‰ (mean of −6.3‰) that are similar to the values of magmatic tourmaline (−8.9 to −5.5‰ with a mean of −6.8‰) in the host quartz diorite porphyry. The δ 34S values of sulfide minerals range from −5.9 to +5.8‰ with a mean of −0.6‰ that is typical of magmatic sulfur. Pyrite from hydrothermally altered quartz diorite porphyry and quartz-sulfide-tourmaline veins have relatively homogeneous lead isotopic compositions, compatible with granitic intrusions in the district. The geochronological and isotopic data combined support a magmatic origin for the Laodou gold deposit, most likely formed from fluids exsolved from the Laodou quartz diorite porphyry or associated intrusive phases at deeper levels beneath the stock. Orogenic and Carlin-like gold deposits in the West Qinling orogen have been commonly thought to have formed from metamorphic fluids. This study, however, highlights the role of magmatic-derived fluids in the formation of lode gold deposits. Synthesis of geochronological, geological, and geochemical data on magmatic rocks and ore deposits in and surrounding the Xiahe-Hezuo district indicates that gold mineralization predominantly occurred within a subduction-related magmatic arc prior to collision between the Yangtze and North China cratons that produced the West Qinling orogen.

OBJECTIVE: Electrospinning technique was used to manufacture polycaprolactone (PCL)/collagen typeⅠ nanofibers orientated patches and to study their physical and chemical characterization, discussing their feasibility as synthetic patches for rotator cuff repairing. METHODS: PCL patches were prepared by electrospinning with 10% PCL electrospinning solution (control group) and PCL/collagen typeⅠorientated nanofibers patches were prepared by electrospinning with PCL electrospinning solution with 25% collagen type Ⅰ(experimental group). The morphology and microstructure of the two patches were observed by gross and scanning electron microscopy, and the diameter and porosity of the fibers were measured; the mechanical properties of the patches were tested by uniaxial tensile test; the composition of the patches was analyzed by Fourier transform infrared spectroscopy; and the contact angle of the patch surface was measured. Two kinds of patch extracts were co-cultured with the third generation of rabbit tendon stem cells. Cell counting kit 8 (CCK-8) was used to detect the toxicity and cell proliferation of the materials. Normal cultured cells were used as blank control group. Rabbit tendon stem cells were co-cultured with the two patches and stained with dead/living cells after 3 days ofin vitro culture, and laser confocal scanning microscopy was used to observe the cell adhesion and activity on the patch. RESULTS: Gross and scanning electron microscopy showed that the two patch fibers were arranged in orientation. The diameter of patch fibers in the experimental group was significantly smaller than that in the control group (t=26.907, P=0.000), while the porosity in the experimental group was significantly larger than that in the control group (t=2.506, P=0.032). The tensile strength and Young’s modulus of the patch in the experimental group were significantly higher than those in the control group (t=3.705, P=0.029; t=4.064, P=0.034). Infrared spectrum analysis showed that PCL and collagen type Ⅰ were successfully mixed in the experimental group. The surface contact angle of the patch in the experimental group was (73.88±4.97)°, which was hydrophilic, while that in the control group was (128.46±5.10) °, which was hydrophobic. There was a significant difference in the surface contact angle between the two groups (t=21.705, P=0.002). CCK-8 test showed that with the prolongation of culture time, the cell absorbance (A) value increased gradually in each group, and there was no significant difference between the experimental group and the control group at each time point (P>0.05). Laser confocal scanning microscopy showed that rabbit tendon stem cells could adhere and grow on the surface of both patches after 3 days of culture. The number of cells adhered to the surface of the patches in the experimental group was more than that in the control group, and the activity was better. CONCLUSION: PCL/ collagen type Ⅰ nanofibers orientated patch prepared by electrospinning technology has excellent physical and chemical properties, cell adhesion, and no cytotoxicity. It can be used as an ideal scaffold material in tendon tissue engineering for rotator cuff repair in the future.

Osteoarthritis (OA) is a type of chronic joint disease that is characterized by the degeneration and loss of articular cartilage and hyperplasia of the synovium and subchondral bone. There is reasonable knowledge about articular cartilage physiology, biochemistry, and chondrocyte metabolism. However, the etiology and pathogenesis of OA remain unclear and need urgent clarification to guide the early diagnosis and treatment of OA. Extracellular vesicles (EVs) are small membrane-linking particles that are released from cells. In recent decades, several special biological properties have been found in EV, especially in terms of cartilage. Autophagy plays a critical role in the regulation of cellular homeostasis. Likewise, more and more research has gradually focused on the effect of autophagy on chondrocyte proliferation and function in OA. The synthesis and release of EV are closely associated with autophagy. At the same time, both EV and autophagy play a role in OA development. Based on the mechanism of EV and autophagy in OA development, EV may be beneficial in the early diagnosis of OA; on the other hand, the combination of EV and autophagy-related regulatory drugs may provide insight into possible OA therapeutic strategies.

The West Qinling orogen, central China is endowed with dozens of world-class sediment-hosted gold deposits, most of which have formed from metamorphic fluids released from Paleozoic sedimentary rocks during the Triassic collisional orogeny. Here we present trace element and sulfur isotope data of gold-bearing pyrite and arsenopyrite, along with oxygen and hydrogen isotopes of ore-related sericite, to show that the Early Triassic Zaozigou gold deposit (142 t) in the Xiahe-Hezuo district may have contrasting origin. Gold mineralization at Zaozigou is dominated by fine-grained pyrite and arsenopyrite disseminations (Py1 and Asp1) in hydrothermally altered Triassic flysch and, less significantly, in Early Triassic granitoid dike swarm. The disseminated ores are overprinted by quartz-sulfide-ankerite-sulfide vein/veinlets, which contain less abundant, coarser pyrite and arsenopyrite (Py2 and Asp2) and are less economically significant. Gold occurs as invisible gold in fine-grained arsenian pyrite and arsenopyrite of the disseminated ores, with subordinate native gold grains locally observed in the quartz-sulfide-ankerite vein/veinlets. The two types of pyrite (Py1 vs. Py2) and arsenopyrite (Asp1 vs. Asp2) are consistently enriched in As, Au, Co, Ni, Mn, Cu, Zn, Ag, Sb, W, Pb, Te, and Bi and have well comparable δ34S values ranging from −12.0‰ to −5.5‰. Grain-scale variation has been observed for Au and other trace elements both in Py1 and Py2, likely reflecting changes in physio-chemical conditions such as fO2, fS2 and temperature due to fluid-rock interactions and/or fluid mixing. The δ34S values are broadly consistent with sulfur isotopic compositions of many Early Triassic ilmenite-series intrusions in the Xiahe-Hezuo district, and thus suggest a magmatic sulfur derivation from the reduced magmas that have assimilated carbonaceous sedimentary rocks. The δD and δ18O values of ore-fluids calculated from isotopic compositions of ore-related sericite range from −56 to −76‰ and 10.1 to 12.4‰, respectively, indicating a magmatic fluids exsolved from the above-mentioned ilmenite-series magma or a mixture of such as fluid with a metamorphic derived component. Synthesis of geochronological and geochemical data throughout the Xiahe-Hezuo district led us to conclude that the Zaozigou gold deposits can be considered as a shallow-seated, distal product of a reduced intrusion-related gold system.

Meniscus injuries are very common in the knee joint. Treating a damaged meniscus continues to be a scientific challenge in sport medicine because of its poor self-healing potential and few clinical therapeutic options. Tissue engineering strategies are very promising solutions for repairing and regenerating a damaged meniscus. Meniscus is exposed to a complex biomechanical microenvironment, and it plays a crucial role in meniscal development, growth, and repairing. Over the past decades, increasing attention has been focused on the use of biomechanical stimulus to enhance biomechanical properties of the engineered meniscus. Further understanding the influence of mechanical stimulation on cell proliferation and differentiation, metabolism, relevant gene expression, and pro/anti-inflammatory responses may be beneficial to enhance meniscal repair and regeneration. On the one hand, this review describes some basic information about meniscus; on the other hand, we sum up the various biomechanical stimulus based strategies applied in meniscus tissue engineering and how these factors affect meniscal regeneration. We hope this review will provide researchers with inspiration on tissue engineering strategies for meniscus regeneration in the future.

To explore the degradation of AZ31 magnesium alloy and poly (lactic-co-glycolic acid) (PLGA) in the femoral condyle, and then evaluate the laws of degradation of AZ31 magnesium alloy by Micro-CT images and data.?Forty 3-month-old male New Zealand white rabbits (weighing, 2.5 kg) were randomly divided into 4 groups, 10 rabbits each group. Forty micro-arc-oxidized AZ31 magnesium alloy pins and 40 PLGA pins were implanted into the right and left femoral condyle, respectively. Micro-CT images and data analysis were used to evaluate the degradation at 4, 8, 12, and 16 weeks after operation (n=10). Degradation was evaluated by weight difference between pre-and post-implantation. The inflammatory response was observed around the implants by HE staining. The weight loss of magnesium alloy and Micro-CT results were compared.?The Micro-CT images showed that PLGA pins had gray low signal, which was similar to the soft tissue around. At 4 weeks after operation, no signs of degradation were observed, and there were little corrosion pitting on the magnesium alloy. At 8 weeks, corrosion pitting gradually expanded, the boundary between the longitudinal axis and the cross section became blurred; at 16 weeks, corrosion pitting became bigger, and the boundary was discontinuous. Micro-CT quantitative analysis showed that the volume fraction of magnesium pins decreased slowly at 4 and 8 weeks; it was significantly lower at 12 and 16 weeks than 4 and 8 weeks (P0.05). The magnesium cylinder mineral density continuously decreased during the study period, it had a rapidly speed from 12 to 16 weeks (P0.05). However, the magnesium CT image density showed a slight change (P0.05). The surface-to-volume ratio of the pins constantly increased, and the ratio was significantly larger at 12 and 16 weeks than 4 and 8 weeks, and at 16 weeks than 12 weeks (P0.05). There was more and more corrosion pitting on the surface with time, which resulted in a decrease in the radius that mean trabecular thickness gradually decreased, showing significant difference between different time points after 8 weeks (P0.05). The weight loss detection showed that the degradation of magnesium pin and PLGA gradually increased with time (P0.05), and the degradation rate of magnesium pin was significantly lower than that of PLGA at 8-12 weeks (P0.05), but the degradation rate of magnesium pin was higher than that of PLGA at 16 weeks. At each time point, the weight loss of magnesium alloy was similar to that by Micro-CT, but mass fraction was lower than volume fraction and had significant differences at 8, 12, and 16 weeks (P0.05). HE staining revealed that slight inflammatory response was observed around the magnesium pins at 4 weeks, and inflammatory reaction gradually reduced with time and disappeared at 16 weeks, but no inflammatory reaction was seen around PLGA.?Micro-CT has the advantages of non-trauma, in vivo detection, quantitative analysis, and precise data in evaluating the degradation of AZ31 magnesium alloy. Regarding the degradation of the magnesium alloy and PLGA in vivo, the degradation rate is slow in the early stage, and then increases with time. The degradation of PLGA is faster and earlier but it is then overtaken by AZ31 magnesium alloy at 16 weeks. During the degradation, the density of the magnesium has almost no change. The biomaterials can not firmly attach to the surrounding tissues due to inadequate holding forces.比较镁合金与聚乳酸-羟基乙酸共聚物[poly（lactic-co-glycolic acid），PLGA]在体内降解情况，同时采用Micro-CT深入研究镁合金体内降解规律。.取3月龄雄性新西兰大白兔40只，分别于右侧和左侧股骨髁钻孔植入40个表面微弧氧化处理的AZ31镁合金棒（镁棒）和40个PLGA棒。术后4、8、12、16周各处死10只动物，取出双侧股骨髁，采用Micro-CT扫描及生成数据定量评价植入物降解情况；然后取出植入物清洗、烘干后称重，与术前重量差值作为植入物降解量；HE染色观察局部炎性反应情况。并将镁合金的失重情况与Micro-CT的评价结果进行对比。.Micro-CT扫描示，PLGA棒不显影。术后4周镁棒几乎无降解痕迹，有少量腐蚀点；术后8周在4周原有腐蚀点基础上逐步扩大，纵轴与横截面交界边缘变得模糊；至术后16周镁棒表面腐蚀面积更大，边缘已不连续。Micro-CT定量分析示：术后4、8周镁棒体积分数下降缓慢；术后12、16周较术后4、8周降低明显，16周最低，差异均有统计学意义（P0.05）。术后随时间延长镁矿物密度持续降低，12～16周降低速度最快，第8周后各时间点间比较差异均有统计学意义（P0.05）；而镁CT图像密度随术后时间延长变化很小（P0.05）。术后随时间延长镁棒表面积与体积比持续增加，术后12、16周明显高于4、8周，且16周高于12周（P0.05）。术后随时间延长，镁棒表面腐蚀点越来越多，导致横截面半径减小，即平均骨小梁厚度逐渐降低，8周后各时间点间差异均有统计学意义（P0.05）。失重法检测示：术后随时间延长，两种材料降解量均逐渐增加（P0.05）；术后8、12周，镁棒降解量均显著低于PLGA棒（P0.05），但术后16周时镁棒降解量已超过PLGA棒。将各时间点镁棒质量分数与Micro-CT方法得出的体积分数进行比较，结果显示两个指标的变化趋势相近，但各时间点镁棒质量分数均低于体积分数，且在第8、12、16周差异有统计学意义（P0.05）。HE染色示，术后4周镁棒周围可见轻度炎性反应，但随时间延长炎性反应逐渐减轻，至16周时已未见炎性反应；而PLGA周围一直无炎性反应。.采用Micro-CT检测镁合金降解情况具有无创、可活体检测、定量、精确的优势。镁合金和PLGA在体内均随时间推移而逐步腐蚀，经历先缓慢后加速的持续降解过程；PLGA在体内降解则更早、更快，至16周时镁合金降解量已超过PLGA，镁合金密度在降解过程中无明显变化。镁合金在金属与原骨之间产生新生骨桥欠充分，仍缺乏足够的无缝连接能力。.

The meniscus plays a vital role in protecting the articular cartilage of the knee joint. The inner two-thirds of the meniscus are avascular, and injuries to this region often fail to heal without intervention. The use of tissue engineering and regenerative medicine techniques may offer novel and effective approaches to repairing meniscal injuries. Meniscal tissue engineering and regenerative medicine typically use one of two techniques, cell-based or cell-free. While numerous cell-based strategies have been applied to repair and regenerate meniscal defects, these techniques possess certain limitations including cellular contamination and an increased risk of disease transmission. Cell-free strategies attempt to repair and regenerate the injured tissues by recruiting endogenous stem/progenitor cells. Cell-free strategies avoid several of the disadvantages of cell-based techniques and, therefore, may have a wider clinical application. This review first compares cell-based to cell-free techniques. Next, it summarizes potential sources for endogenous stem/progenitor cells. Finally, it discusses important recruitment factors for meniscal repair and regeneration. In conclusion, cell-free techniques, which focus on the recruitment of endogenous stem and progenitor cells, are growing in efficacy and may play a critical role in the future of meniscal repair and regeneration.

Meniscus injuries are very common and still pose a challenge for the orthopedic surgeon. Meniscus injuries in the inner two-thirds of the meniscus remain incurable. Tissue-engineered meniscus strategies seem to offer a new approach for treating meniscus injuries with a combination of seed cells, scaffolds, and biochemical or biomechanical stimulation. Cell- or scaffold-based strategies play a pivotal role in meniscus regeneration. Similarly, biochemical and biomechanical stimulation are also important. Seed cells and scaffolds can be used to construct a tissue-engineered tissue; however, stimulation to enhance tissue maturation and remodeling is still needed. Such stimulation can be biomechanical or biochemical, but this review focuses only on biochemical stimulation. Growth factors (GFs) are one of the most important forms of biochemical stimulation. Frequently used GFs always play a critical role in normal limb development and growth. Further understanding of the functional mechanism of GFs will help scientists to design the best therapy strategies. In this review, we summarize some of the most important GFs in tissue-engineered menisci, as well as other types of biological stimulation.

Articular cartilage lacks a blood supply and nerves. Hence, articular cartilage regeneration remains a major challenge in orthopedics. Decellularized extracellular matrix- (ECM-) based strategies have recently received particular attention. The structure of native cartilage exhibits complex zonal heterogeneity. Specifically, the development of a tissue-engineered scaffold mimicking the aligned structure of native cartilage would be of great utility in terms of cartilage regeneration. Previously, we fabricated oriented PLGA/ACECM (natural, nanofibrous, articular cartilage ECM) composite scaffolds. In vitro, we found that the scaffolds not only guided seeded cells to proliferate in an aligned manner but also exhibited high biomechanical strength. To detect whether oriented cartilage regeneration was possible in vivo, we used mesenchymal stem cell (MSC)/scaffold constructs to repair cartilage defects. The results showed that cartilage defects could be completely regenerated. Histologically, these became filled with hyaline cartilage and subchondral bone. Moreover, the aligned structure of cartilage was regenerated and was similar to that of native tissue. In conclusion, the MSC/scaffold constructs enhanced the structure-specific regeneration of hyaline cartilage in a rabbit model and may be a promising treatment strategy for the repair of human cartilage defects.

Strength training using patients’ desired force level is helpful to improve training effect and promote rehabilitation. Generally, force levels are recognized by applying EMG or biomechanical information, these methods were not suitable for patients who lost important muscle groups or have weakened muscle functions. This paper proposed a method for identifying force level based on cerebral hemoglobin information, rather than the information depending on limbs. Ten subjects performed pedaling movement in three force levels. Features were extracted in both the time-domain and frequency-domain, with deoxygenated hemoglobin (deoxy) and the difference between oxygenated hemoglobin (oxy) and deoxy as parameters. Important frequency bands (0.01-0.03Hz, 0.03-0.06Hz, 0.06-0.09Hz, 0.09-0.12Hz) were confirmed by performing power spectrum density analysis. And significant measure channels were selected by performing one-way analyses of variance on three time periods around the start of movement. Force level was recognized by applying extreme learning machine (ELM). The corresponding precision rate was up to 78.7%. The proposed identification method was not restricted to the existence of limbs or the strength of limb information. It was realized based on brain information recorded in a real movement environment; it is helpful to realize the desired force level of subjects and to provide a control command for rehabilitation training equipment.

The scaffold is a key element in cartilage tissue engineering. The components of Wharton’s jelly are similar to those of articular cartilage and it also contains some chondrogenic growth factors, such as insulin-like growth factor I and transforming growth factor-β. We fabricated a tissue-engineered cartilage scaffold derived from Wharton’s jelly extracellular matrix (WJECM) and compared it with a scaffold derived from articular cartilage ECM (ACECM) using freeze-drying. The results demonstrated that both WJECM and ACECM scaffolds possessed favorable pore sizes and porosities; moreover, they showed good water uptake ratios and compressive moduli. Histological staining confirmed that the WJECM and ACECM scaffolds contained similar ECM. Moreover, both scaffolds showed good cellular adherence, bioactivity, and biocompatibility. MTT and DNA content assessments confirmed that the ACECM scaffold tended to be more beneficial for improving cell proliferation than the WJECM scaffold. However, RT-qPCR results demonstrated that the WJECM scaffold was more favorable to enhance cellular chondrogenesis than the ACECM scaffold, showing more collagen II and aggrecan mRNA expression. These results were confirmed indirectly by glycosaminoglycan and collagen content assessments and partially confirmed by histology and immunofluorescent staining. In conclusion, these results suggest that a WJECM scaffold may be favorable for future cartilage tissue engineering.

The present study aims to investigate the feasibility of tissue-engineered cartilage constructed in vivo and in vitro by dynamically culturing adipose-derived stem cells (ADSCs) with an articular cartilage acellular matrix in a bioreactor and subsequently implanting the cartilage in nude mice. ADSCs were proliferated, combined with three dimensional scaffolds (cell density: 5 × 10(7)/mL) and subsequently placed in a bioreactor and culture plate for 3 weeks. In the in vivo study, complexes cultured for 1 week under dynamic or static states were subcutaneously implanted into nude mice and collected after 3 weeks. Indicators such as gross morphology, histochemistry and immunohistochemistry were examined. In the in vitro study, histological observation showed that most scaffolds in the dynamic group were absorbed, and cell proliferation and matrix secretion were significant. Positive staining of safranin-O and alcian blue II collagen stain in the dynamic group was significantly stronger than that in the static culture group. In the in vivo study, cartilage-like tissues formed in the specimens of the two groups. Histological examination showed that cell distribution in the dynamic group was relatively more uniform than in the static group, and matrix secretion was relatively stronger. Bioreactor culturing can promote ADSC proliferation and cartilage differentiation and is thus a suitable method for constructing tissue-engineered cartilage in vivo.

Controlling rehabilitation training using patients' desired motion states is helpful to motivate their active participation, and further to improve training effect. Generally, motion states are recognized by applying EMG or biomechanics information, these methods have great limitations for the patients who lost important muscle groups or have weakened muscle functions. This paper proposed a method for identifying motion intention based on cerebral hemoglobin information. Nine subjects performed bicycling movement in three velocity levels. One-way analyses of variance on the difference between oxygenated hemoglobin (oxyHb) and deoxygenated hemoglobin (deoxyHb) were performed. Features in time-domain and frequency-domain were extracted respectively. The features were used to recognize speed by applying extreme learning machine (ELM). The corresponding precision rate was up to 74.1%. Since the proposed identification method is realized based on brain information recorded in a real movement environment, it is helpful to realize autonomous control of rehabilitation training equipment.

The Shagou vein-type Ag-Pb-Zn deposit in the Xiong’ershan district, southern margin of the North China craton, is hosted within amphibolite facies metamorphic rocks of the Late Archean to early Paleoproterozoic Taihua Group. The Ag-Pb-Zn veins are localized in NE- to NNE-trending brittle faults and typically display symmetrical zoning consisting of siderite, quartz + sphalerite, galena, and quartz + calcite from the margin toward the center of each vein. Ore-related hydrothermal alteration is well developed on both sides of the veins, dominated by silicification, sericitization, chloritization, and carbonatization. Sericite separates extracted from a major Ag-Pb-Zn vein yield a 40 Ar/ 39 Ar plateau age of 140.0 ± 1.0 Ma (1 σ ) and isochron age of 141.1 ± 1.6 Ma (1 σ ), indicating that mineralization occurred at the beginning of Early Cretaceous. Field and textural relationships indicate four hydrothermal stages marked by assemblages of quartz + siderite (stage I), quartz + sphalerite + ankerite (stage II), quartz + galena + silver minerals + ankerite (stage III), and quartz + calcite (stage IV), respectively. Silver minerals are abundant in all veins and are composed of, in paragenetic order, argentiferous tetrahedrite, polybasite, jalpaite, argentite, and native silver. These silver minerals commonly occur as replacements of galena, chalcopyrite, and other sulfides, or as fillings of microfractures in sulfides and quartz. Microthermometric measurements of primary fluid inclusions in quartz, carbonates, and sphalerite from various hydrothermal stages indicate that ore minerals were deposited at intermediate temperatures (267°–157°C) from aqueous-carbonic to aqueous fluids with moderate salinities (7.2–15.9 wt % NaCl equiv). Coexisting galena-sphalerite pair yields sulfur isotope equilibrium temperatures of 205° to 267°C, consistent with the overall homogenization temperatures of fluid inclusions. The microthermometric data also indicate that both fluid mixing and fluid-rock interaction were important mechanisms for ore precipitation. Carbonate minerals (siderite, ankerite, calcite) spanning the entire mineralization history have δ 13 C V-PDB values of −5.2 to −1.4‰ and δ 18 O V-SMOW of 10.9 to 15.0‰, corresponding to calculated values for the ore fluids of −6.5 to −1.8‰ and 1.4 to 5.4‰, respectively. δ 34 S V-CDT values of sulfide minerals (pyrite, sphalerite, galena) range from 1.1 to 5.5‰, consistent with a deep-seated sulfur source. Galena separates have 206 Pb/ 204 Pb ratios of 17.472 to 17.813, 207 Pb/ 204 Pb ratios of 15.411 to 15.498, and 208 Pb/ 204 Pb ratios of 38.178 to 38.506. The isotope data, together with geological and geochronological evidence, favor a primary metamorphic source for sulfur and other components in the ore fluids. A synthesis of available data suggests that the Shagou deposit is a typical vein-type Ag-Pb-Zn deposit that formed under an extensional geodynamic setting associated with tectonic reactivation of the North China craton during the late Mesozoic, a time period that is manifested by pervasive magmatism, widespread formation of metamorphic core complexes, and development of faulted basins throughout the eastern part of the craton. Metamorphic devolatilization of the Meso-Neoproterozoic marine sedimentary rocks previously subducted beneath the Xiong’ershan district, facilitated by extensive magmatism and elevated heat flow due to lithospheric extension, could have provided large amounts of ore fluids responsible for the Ag-Pb-Zn mineralization. The NE- to NNE-trending faults affiliated with the transcrustal Machaoying fault may have acted as pathways for the upward migration of deep-seated metamorphic fluids. Mixing of the metamorphically derived fluids with meteoric waters ultimately resulted in deposition of the Ag-Pb-Zn veins in brittle extensional structures.

The histological features of cartilage call attention to the fact that cartilage has a little capacity to repair itself owing to the lack of a blood supply, nerves, or lymphangion. Stem cells have emerged as a promising option in the field of cartilage tissue engineering and regenerative medicine and could lead to cartilage repair. Much research has examined cartilage regeneration utilizing stem cells. However, both the potential and the limitations of this procedure remain controversial. This review presents a summary of emerging trends with regard to using stem cells in cartilage tissue engineering and regenerative medicine. In particular, it focuses on the characterization of cartilage stem cells, the chondrogenic differentiation of stem cells, and the various strategies and approaches involving stem cells that have been used in cartilage repair and clinical studies. Based on the research into chondrocyte and stem cell technologies, this review discusses the damage and repair of cartilage and the clinical application of stem cells, with a view to increasing our systematic understanding of the application of stem cells in cartilage regeneration; additionally, several advanced strategies for cartilage repair are discussed.