Metabolic Syndrome and Tendon Disease: A Comprehensive Review.

Metabolic syndrome (MS) is a multifaceted pathological condition characterized by the atypical accumulation of various metabolic components such as central obesity or excess weight, hyperlipidemia, low-density lipoprotein (LDL), hypertension, and insulin resistance. Recently, MS has been recognized as a notable contributor to heart and circulatory diseases. In addition, with increasing research, the impact of MS on tendon repair and disease has gradually emerged. Recent studies have investigated the relationship between tendon healing and diseases such as diabetes, dyslipidemia, obesity, and other metabolic disorders. However, diabetes mellitus (DM), hypercholesterolemia, obesity, and various metabolic disorders often coexist and together constitute MS. At present, insulin resistance is considered the major pathological mechanism underlying MS, central obesity is regarded as the predominant factor responsible for it, and dyslipidemia and other metabolic diseases are known as secondary contributors to MS. This review aims to evaluate the current literature regarding the impact of various pathological conditions in MS on tendon recovery and illness, and to present a comprehensive overview of the effects of MS on tendon recovery and diseases, along with the accompanying molecular mechanisms.

Semi-Bone Tunnel Technique Using Double-Row Suture Bridge Combined With Platelet-Rich Plasma Hydrogel for Rotator Cuff Repair in a Rabbit Model.

BACKGROUND: The approach to managing the footprint area and reconstructing the tendon-bone interface (TBI) is critical for optimal healing. PURPOSE: To evaluate the outcomes of the semi-bone tunnel (SBT) technique using a double-row suture bridge combined with platelet-rich plasma (PRP) hydrogel for rotator cuff repair in a rabbit model. STUDY DESIGN: Controlled laboratory study. METHODS: A total of 48 New Zealand White rabbits were divided into 4 groups. The supraspinatus tendons were severed at the footprint to create a rotator cuff tear model in the surgical groups. Rabbits were treated with the traditional onto-surface repair (control group), SBT technique (SBT group), and SBT technique combined with PRP hydrogel implantation (SBT+PRP group). The rabbits without surgery were the normal group. At 8 weeks after surgery, macroscopic observation, magnetic resonance imaging (MRI) and micro-computed tomography (µCT) examinations, histological evaluations, and biomechanical tests were performed to assess the curative effects of the given treatments. RESULTS: The MRI results showed that the repaired supraspinatus tendon presented a uniform signal, minimal inflammatory response, and the lowest signal-to-noise quotient value in the SBT+PRP group. The µCT results suggested that the SBT technique did not reduce the local bone mineral density in the TBI area compared with the onto-surface repair technique. The histological staining results showed that the regenerated TBI in the SBT+PRP group had a 4-layer structure similar to the natural tissue. The highest values for biomechanical properties were observed in the SBT+PRP group, and there was no significant difference between the SBT+PRP group and normal group. CONCLUSION: The SBT technique presented a better tendon-bone healing effect for rotator cuff tear in the rabbit model compared with the traditional onto-surface repair technique. The specimens in the SBT+PRP group had a similar TBI structure and biomechanical properties to the natural tissue. CLINICAL RELEVANCE: The SBT technique can be an alternative surgical approach for rotator cuff repair, especially for moderate to large tears and cases requiring scaffold implantation.

Advances focusing on the application of decellularization methods in tendon-bone healing.

BACKGROUND: The tendon or ligament is attached to the bone by a triphasic but continuous area of heterogeneous tissue called the tendon-bone interface (TBI). The rapid and functional regeneration of TBI is challenging owing to its complex composition and difficulty in self-healing. The development of new technologies, such as decellularization, has shown promise in the regeneration of TBI. Several ex vivo and in vivo studies have shown that decellularized grafts and decellularized biomaterial scaffolds achieved better efficacy in enhancing TBI healing. However further information on the type of review that is available is needed. AIM OF THE REVIEW: In this review, we discuss the current application of decellularization biomaterials in promoting TBI healing and the possible mechanisms involved. With this work, we would like to reveal how tissues or biomaterials that have been decellularized can improve tendon-bone healing and to provide a theoretical basis for future related studies. KEY SCIENTIFIC CONCEPTS OF THE REVIEW: Decellularization is an emerging technology that utilizes various chemical, enzymatic and/or physical strategies to remove cellular components from tissues while retaining the structure and composition of the extracellular matrix (ECM). After decellularization, the cellular components of the tissue that cause an immune response are removed, while various biologically active biofactors are retained. This review further explores how tissues or biomaterials that have been decellularized improve TBI healing.

Engineered exosomes: A promising strategy for tendon-bone healing.

BACKGROUND: Due to the spatiotemporal complexity of the composition, structure, and cell population of the tendon-bone interface (TBI), it is difficult to achieve true healing. Recent research is increasingly focusing on engineered exosomes, which are a promising strategy for TBI regeneration. AIM OF REVIEW: This review discusses the physiological and pathological characteristics of TBI and the application and limitations of natural exosomes in the field of tendon-bone healing. The definition, loading strategies, and spatiotemporal properties of engineered exosomes were elaborated. We also summarize the application and future research directions of engineered exosomes in the field of tendon-bone healing. KEY SCIENTIFIC CONCEPTS OF REVIEW: Engineered exosomes can spatially deliver cargo to targeted sites and temporally realize the sustained release of therapeutic molecules in TBI. This review expounds on the multidifferentiation of engineered exosomes for tendon-bone healing, which effectively improves the biological and biomechanical properties of TBI. Engineered exosomes could be a promising strategy for tendon-bone healing.

External stimulation: A potential therapeutic strategy for tendon-bone healing.

Injuries at the tendon-bone interface are very common in the field of sports medicine, and healing at the tendon-bone interface is complex. Injuries to the tendon-bone interface can seriously affect a patient's quality of life, so it is essential to restore stability and promote healing of the tendon-bone interface. In addition to surgical treatment, the healing of tendons and bones can also be properly combined with extracorporeal stimulation therapy during the recovery process. In this review, we discuss the effects of extracorporeal shock waves (ESWs), low-intensity pulsed ultrasound (LIPUS), and mechanical stress on tendon-bone healing, focusing on the possible mechanisms of action of mechanical stress on tendon-bone healing in terms of transcription factors and biomolecules. The aim is to provide possible therapeutic approaches for subsequent clinical treatment.

Comparison of Interobserver Agreement of Four Classification Systems for Lateral Clavicle Fractures between Two Groups of Surgeons: A Multicenter Study.

OBJECTIVE: Distal clavicle fracture classification directly affects the treatment decisions. It is unclear whether the classification systems implemented differ depending on surgeons' backgrounds. This study aimed to compare the interobserver agreement of four classification systems used for lateral clavicle fractures by shoulder specialists and general trauma surgeons. METHODS: Radiographs of 20 lateral clavicle fractures representing a full spectrum of adult fracture patterns were analyzed by eight experienced shoulder specialists and eight general trauma surgeons from 10 different hospitals. All cases were graded according to the Orthopedic Trauma Association (OTA), Neer, Jäger/Breitner, and Gongji classification systems. To measure observer agreement, Fleiss' kappa coefficient (κ) was applied and assessed. RESULTS: When only X-ray films were presented, both groups achieved fair agreement. However, when the 3D-CT scan images were provided, improved interobserver agreement was found in the specialist group when the OTA, Jäger/Breitner, and Gongji classification systems were used. In the generalist groups, improved agreement was found when using the Gongji classification system. In terms of interobserver reliability, the OTA, Neer, and Jäger/Breitner classification systems showed better agreement among shoulder specialists, while a slightly lower level of agreement was found using the Gongji classification system. For the OTA classification system, interobserver agreement had a mean kappa value of 0.418, ranging from 0.446 (specialist group) to 0.402 (generalist group). For the Neer classification system, interobserver agreement had a mean kappa value of 0.368, ranging from 0.402 (specialist group) to 0.390 (generalist group). For the Jäger/Breitner classification system, the inter-observer agreement had a mean kappa value of 0.380, ranging from 0.413 (specialist group) to 0.404 (generalist group). For the Gongji classification system, interobserver agreement had a mean kappa value of 0.455, ranging from 0.480 (specialist group) to 0.485 (generalist group). CONCLUSION: Generally speaking, 3D-CT scans provide a richer experience that can lead to better results in most classification systems of lateral clavicle fractures, highlighting the value of digitization and specialization in diagnosis and treatment. Competitive interobserver agreement was exhibited in the generalist group using the Gongji classification system, suggesting that the Gongji classification is suitable for general trauma surgeons who are not highly experienced in the shoulder field.

Hypoxia-mimicking scaffolds with controlled release of DMOG and PTHrP to promote cartilage regeneration via the HIF-1α/YAP signaling pathway.

Efficiently driving chondrogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) while avoiding undesired hypertrophy remains a challenge in the field of cartilage tissue engineering. Here, we report the sequential combined application of dimethyloxalylglycine (DMOG) and parathyroid hormone-related protein (PTHrP) to facilitate chondrogenesis and prevent hypertrophy. To support their delivery, poly(lactic-co-glycolic acid) (PLGA) microspheres were fabricated using a double emulsion method. Subsequently, these microspheres were incorporated onto a poly(l-lactic acid) (PLLA) scaffold with a highly porous structure, high interconnectivity and collagen-like nanofiber architecture to construct a microsphere-based scaffold delivery system. These functional constructs demonstrated that the spatiotemporally controlled release of DMOG and PTHrP effectively mimicked the hypoxic microenvironment to promote chondrogenic differentiation with phenotypic stability in a 3D culture system, which had a certain correlation with the interaction between hypoxia-inducible Factor 1 alpha (HIF-1α) and yes-associated protein (YAP). Subcutaneous implantation in nude mice revealed that the constructs were able to maintain cartilage formation in vivo at 4 and 8 weeks. Overall, this study indicated that DMOG and PTHrP controlled-release PLGA microspheres incorporated with PLLA nanofibrous scaffolds provided an advantageous 3D hypoxic microenvironment for efficacious and clinically relevant cartilage regeneration and is a promising treatment for cartilage injury.

Extracellular Vesicles from Hypoxic Pretreated Urine-Derived Stem Cells Enhance the Proliferation and Migration of Chondrocytes by Delivering miR-26a-5p.

OBJECTIVE: Stem-cell therapy is a promising treatment for cartilage defects. The newly identified urine-derived stem cells (USCs), which have multipotency and sufficient proliferative ability, are promising candidates for several tissue engineering therapies. In this study, we investigated the role of USC extracellular vehicles (EVs) in promoting the proliferation and migration of chondrocytes. DESIGN: USCs were characterized by measuring induced multipotent differentiation and flow cytometry analysis of surface marker expression. The EVs were isolated from USCs under normoxic conditions (nor-EVs) and hypoxic conditions (hypo-EVs). Transmission electron microscopy and western blot analysis characterized the EVs. The chondrocytes were cultured in the USC-EVs. CCK-8 assay and EdU staining detected the proliferation of chondrocytes, and transwell assay detected their migration. miR-26a-5p expression in EVs was detected by quantitative real-time polymerase chain reaction (qRT-PCR). The target relationship of miR-26a-5p and phosphatase and tensin homolog (PTEN) was predicted and confirmed. The roles of EVs-miR-26a-5p and PTEN on the proliferation and migration of chondrocytes were also investigated. RESULTS: Hypo-EVs showed a superior effect in promoting the proliferation and migration of chondrocytes than nor-EVs. Mechanistically, USC-EVs delivered miR-26a-5p into chondrocytes to overexpress miR-26a-5p. PTEN was identified as an miR-26a-5p target in chondrocytes. The effects of EVs-miR-26a-5p on promoting the proliferation and migration of chondrocytes were mediated by its regulation of PTEN. CONCLUSION: Our study suggested that hypoxic USC-EVs may represent a promising strategy for osteoarthritis by promoting the proliferation and migration of chondrocytes via miR-26a-5p transfer.

A new biomechanical classification system for split fractures of the humeral greater tuberosity: guidelines for surgical treatment.

BACKGROUND: Split fractures of the humeral greater tuberosity (HGT) are common injuries. Although there are numerous surgical treatments for these fractures, no classification system combining clinical and biomechanical characteristics has been presented to guide the choice of fixation method. METHODS: We created a standardised fracture of the HGT in 24 formalin-fixed cadavers. Six were left as single-fragment fractures (Group A), six were further prepared to create single-fragment with medium size full-thickness rotator cuff tear (FT-RCT) fractures (Group B), six were cut to create multi-fragment fractures (Group C), and six were cut to create multi-fragment with FT-RCT fractures (Group D). Each specimen was fixed with a shortened proximal humeral internal locking system (PHILOS) plate. The fixed fractures were subjected to load and load-to-failure tests and the differences between groups analysed. RESULTS: The mean load-to-failure values were significantly different between groups (Group A, 446.83 ± 38.98 N; Group B, 384.17 ± 36.15 N; Group C, 317.17 ± 23.32 N and Group D, 266.83 ± 37.65 N, P < 0.05). The load-to-failure values for fractures with a greater tuberosity displacement of 10 mm were significantly different between each group (Group A, 194.00 ± 29.23 N; Group B, 157.00 ± 29.97 N; Group C, 109.00 ± 17.64 N and Group D, 79.67.83 ± 15.50 N; P < 0.05). These findings indicate that fractures with a displacement of 10 mm have different characteristics and should be considered separately from other HGT fractures when deciding surgical treatment. CONCLUSIONS: Biomechanical classification of split fractures of the HGT is a reliable method of categorising these fractures in order to decide surgical treatment. Our findings and proposed system will be a useful to guide the choice of surgical technique for the treatment of fractures of the HGT.

Combination of graphene oxide and platelet-rich plasma improves tendon-bone healing in a rabbit model of supraspinatus tendon reconstruction.

The treatment of rotator cuff tear is one of the major challenges for orthopedic surgeons. The key to treatment is the reconstruction of the tendon-bone interface (TBI). Autologous platelet-rich plasma (PRP) is used as a therapeutic agent to accelerate the healing of tendons, as it contains a variety of growth factors and is easy to prepare. Graphene oxide (GO) is known to improve the physical properties of biomaterials and promote tissue repair. In this study, PRP gels containing various concentrations of GO were prepared to promote TBI healing and supraspinatus tendon reconstruction in a rabbit model. The incorporation of GO improved the ultrastructure and mechanical properties of the PRP gels. The gels containing 0.5 mg/ml GO (0.5 GO/PRP) continuously released transforming growth factor-ß1 (TGF-ß1) and platelet-derived growth factor (PDGF)-AB, and the released TGF-ß1 and PDGF-AB were still at high concentrations, ∼1063.451 pg/ml and ∼814.217 pg/ml, respectively, on the 14th day. In vitro assays showed that the 0.5 GO/PRP gels had good biocompatibility and promoted bone marrow mesenchymal stem cells proliferation and osteogenic and chondrogenic differentiation. After 12 weeks of implantation, the magnetic resonance imaging, micro-computed tomography and histological results indicated that the newly regenerated tendons in the 0.5 GO/PRP group had a similar structure to natural tendons. Moreover, the biomechanical results showed that the newly formed tendons in the 0.5 GO/PRP group had better biomechanical properties compared to those in the other groups, and had more stable TBI tissue. Therefore, the combination of PRP and GO has the potential to be a powerful advancement in the treatment of rotator cuff injuries.

Long Non-Coding RNA (lncRNA) Small Nucleolar RNA Host Gene 15 (SNHG15) Alleviates Osteoarthritis Progression by Regulation of Extracellular Matrix Homeostasis.

BACKGROUND Growing evidence suggests that long non-coding RNAs (lncRNAs), as decoys of microRNAs (miRNAs), are involved in osteoarthritis (OA) progression, but the potential mechanism of lncRNA SNHG15 in OA remains unknown. Thus, the present study explored the molecular mechanism of SNHG15 in OA progression. MATERIAL AND METHODS OA chondrocytes were created by 20 ng/ml IL-1ß stimulation, and the experimental OA model was created by destabilization of the medial meniscus (DMM) surgery. Cartilage histomorphology was observed by safranin and fast green double dyeing. The relationships between SNHG15 and miR-7, KLF4, and miR-7 were determined by dual-luciferase assay or RNA immunoprecipitation (RIP). Immunofluorescence was used to detect the expressions of Ki67, collagen II, and Aggrecan. Moreover, SNHG15, miR-7, KLF4, MMP3, ADAMTS5, COL2A1, Aggrecan, and ß-catenin expressions were assessed by qRT-PCR or Western blot. The methylation status of SNHG15 promoter was evaluated by MS-PCR. RESULTS Underexpression of KLF4 and SHNG15 and overexpression of miR-7 were found in human OA knee cartilage tissues and IL-1ß-stimulated OA chondrocytes. SHNG15 overexpression significantly inhibited ECM degradation and promoted chondrocyte formation of OA chondrocytes. Furthermore, SNHG15 regulated KLF4 expression by sponging miR-7. Further analysis found that SNHG15 significantly inhibited b-catenin in OA chondrocytes. SNHG15 had a higher level of methylation in human OA tissues than in normal cartilage tissues. CONCLUSIONS Our results revealed that SNHG15 alleviated OA progression by regulating ECM homeostasis, which provides a promising target for OA therapy.

Effect of Hyperbaric Oxygen on Tissue Damage and Expression of Adhesion Molecules and C3 in a Rat Model of Renal Ischemia-Reperfusion Injury After Kidney Transplantation.

BACKGROUND The aim of this study was to investigate the protective effect and mechanism of hyperbaric oxygen (HBO) in a rat model of renal ischemia-reperfusion injury following kidney transplantation. MATERIAL AND METHODS Sprague Dawley rats were randomly divided into 3 groups (n=18): sham group, kidney transplantation group, and HBO treatment group. Six rats in each group were sacrificed at 1, 3, and 5 hours after reperfusion, and serum and renal tissue were then collected. The serum creatinine levels and histopathological changes of the renal tissue were detected. ICAM-1, VCAM-1, and C3 expression levels were also detected by immunohistochemical staining or real-time polymerase chain reaction. RESULTS Renal function was damaged in the kidney transplantation group and the HBO treatment group compared with sham group (P<0.05). Renal histopathological changes, including tubular cell swelling, tubular dilatation, and hyaline casts, were remarkably reduced in the HBO treatment group compared to the kidney transplantation group. In the immunohistochemical examination, the expression levels of ICAM-1, VCAM-1, and C3 were obviously increased in the kidney transplantation group and the HBO treatment group; moreover, the levels in the HBO treatment group were significantly lower than in the kidney transplantation group (P<0.05). In addition, the ICAM-1 and C3 mRNA levels were increased in the kidney transplantation group and HBO treatment group, but the levels of in the HBO treatment group them were significantly decreased compared to the kidney transplantation group that at 3 and 5 hours after reperfusion (P<0.05). CONCLUSIONS HBO treatment exerted a protective effect on renal function through inhibition of adhesion molecule overexpression and complement system activation in a rat model of renal ischemia-reperfusion injury after kidney transplantation.

Treatment of Atlantoaxial Tuberculosis with Neurological Impairment: A Systematic Review.

BACKGROUND: Tuberculosis (TB) in the atlantoaxial joint is a rare disease. However, the treatment of atlantoaxial TB with neurologic impairment is controversial. The aim of this review is to provide clinical outcomes of surgical and nonsurgical management of atlantoaxial TB. METHODS: Databases including PubMed, Embase, and the Cochrane Central Register of Controlled Trials were searched for English literature describing the treatment of atlantoaxial TB with neurologic deficits. The outcomes of conservative and surgical treatment approaches, including treatment failure, death, changes in neurologic impairment, and complications, were compared by performing odds ratio (OR) analysis. RESULTS: Overall, 24 studies (247 patients) meeting the inclusion criteria were analyzed. Ninety-four patients (38%) were treated conservatively and 153 (62%) patients were treated surgically. The rate of poor outcomes was greater in the conservative group (14.89%) than in the surgery group (1.3%) (OR, 0.081; 95% confidence interval [CI], 0.016-0.39).There was no significant difference in mortality between the conservative (1.06%) and surgery (3.27%) groups (OR, 3.28; 95% CI, 0.494-27.381). There was no significant difference in muscle power improvement between the 2 treatments (conservative, 95.7%; surgery:, 94.8%; OR, 1.353; 95% CI, 0.291-4.925). CONCLUSIONS: Conservative and surgical treatments both significantly improved neurologic deficits in most patients. Compared with conservative treatment, surgical treatment reduced treatment failures without significantly increasing the rates of neurologic deficit improvement or mortality.

Hyperbaric Oxygenation Protects Against Ischemia-Reperfusion Injury in Transplanted Rat Kidneys by Triggering Autophagy and Inhibiting Inflammatory Response.

BACKGROUND Ischemia-reperfusion injury (IRI) is a clinically common pathologic process defined as the inability to improve neuronal function. This study aimed to investigate the pathological mechanism of IRI and to explore effects of hyperbaric oxygenation (HBO) on autophagy and inflammatory response in IRI. MATERIAL AND METHODS Ninety Sprague-Dawley (SD) rats were randomly divided into a Sham group, a kidney transplant group (Trans), and a kidney transplant plus HBO treatment group (Trans+HBO). The kidney was harvested from the donor and transplanted to recipient rats according to a previously reported study. Rats were anesthetized using pentobarbital-natrium, and the kidney was resected and fixed in 4% paraformaldehyde. Serum creatinine (Scr) was detected using an automatic biochemical analyzer. The interleukin-6 (IL-6) level was assessed using enzyme-linked immunosorbent assay (ELISA). LC-3 was examined using indirect immunofluorescence assay and immunochemistry assay. LC-3 mRNA levels were analyzed using real-time PCR (RT-PCR). RESULTS The kidney transplant IRI model was successfully established. Scr and IL-6 levels were significantly increased in the Trans group (P<0.05). HBO significantly enhanced Scr and IL-6 levels. Scr was positively correlated with IL-6 levels (r-0.607, P<0.05). HBO increased LC-3 protein and mRNA expression in kidney-transplanted rats compared to the Sham and Trans group (P<0.05). Moreover, immunofluorescence assay also showed that LC-3 protein mainly distributes along renal tubular epithelial cells in a linear manner. CONCLUSIONS Autophagy dysfunction and inflammatory response after renal transplantation play important roles in processes of IRI. HBO treatment protects against the renal injury of IRI in renal tissues at the early stage, which may be triggered by the IL-6 pathway.

Impact of immunosuppressive agents on the expression of indoleamine 2,3-dioxygenase, heme oxygenase-1 and interleukin-7 in mesangial cells.

Chronic allograft nephropathy (CAN) is a major cause of graft loss following kidney transplantation and may result from the interactions of various immune and non-immune factors. The aim of the present study was to establish an in vitro model of glomerular mesangial cell injury in order to examine the gene expression levels of indoleamine 2,3-dioxygenase (IDO), heme oxygenase-1 (HO-1) and interleukin-7 (IL-7) in mesangial cells during the healing process as well as to investigate the effects of various immunosuppressants on the expression of these genes. The HBZY-1 glomerular mesangial cell line was pre-treated in vitro with cytochalasin B for 2 h to induce reversible damage. Following the pre-treatment, the HBZY-1 cells were divided into five groups: Blank control group, cyclosporine A (CsA) group, tacrolimus (Tac) group, mycophenolate mofetil (MMF) group and rapamycin (RAPA) group. After treating the mesangial cells with each immunosuppressive drug for 6, 12 or 24 h, the mRNA and protein expression levels of IDO, HO-1 and IL-7 were examined using reverse transcription quantitative polymerase chain reaction (RT-qPCR), western blot and immunohistochemical analyses. The results showed that expression levels of HO-1 were significantly upregulated in response to treatment with CsA, FK506, RAPA and MMF, whereas the expression levels of IL-7 were markedly downregulated by treatment with the above immunosuppressants. CsA, FK506 and MMF significantly enhanced the expression levels of IDO, whereas RAPA exhibited no apparent effect on IDO. The present study may contribute to the understanding of the pathogenesis of CAN and provide novel strategies for the prevention and treatment of CAN.