Osteoarthritis, the most common degenerative joint disease, significantly impairs life quality and labor capability of patients. Synovial inflammation, initiated by HMGB1 (High mobility group box 1)-induced activation of macrophage, precedes other pathological changes. As an upstream regulator of NF-κB (nuclear factor-kappa B) and MAPK (mitogen-activated protein kinase) signaling pathway, TAK1 (TGF-β activated kinase 1) participates in macrophage activation, while its function in osteoarthritis remains unveiled. This study aims to investigate the role of TAK1 in the pathogenesis of osteoarthritis via both in vitro and in vivo approaches. We performed immunohistochemical staining for TAK1 in synovial tissue, both in osteoarthritis patients and healthy control. Besides, immunofluorescence staining for F4/80 as macrophage marker and TAK1 were conducted as well. TAK1 expression was examined in RAW264.7 macrophages stimulated by HMGB1 via qPCR (Quantitative polymerase chain reaction) and Western blotting, and the effect of TAK1 inhibitor (5z-7 oxozeaenol) on TNF-α production was evaluated by immunofluorescence staining. Further, we explored the influence of intra-articular shRNA (short hairpin RNA) targeting TAK1 on collagenase-induced osteoarthritis in mice. Immunohistochemical staining confirmed significant elevation of TAK1 in osteoarthritic synovium, and immunofluorescence staining suggested macrophages as predominant residence of TAK1. In HMGB1-stimulated RAW264.7 macrophages, TAK1 expression was up-regulated both in mRNA and protein level. Besides, TAK1 inhibitor significantly impairs the production of TNF-α by macrophages upon HMGB1 stimulation. Moreover, intra-articular injection of lentivirus loaded with shRNA targeting TAK1 (sh-TAK1) reduced peri-articular osteophyte formation in collagenase-induced osteoarthritis in mice. TAK1 exerts a potent role in the pathogenesis of osteoarthritis by mediating the activation of macrophages.
Intervertebral disc degeneration can lead to physical disability and significant pain, while the present therapeutics still fail to biochemically and biomechanically restore the tissue. Stem cell-based therapy in treating intervertebral disc (IVD) degeneration is promising while transplanting cells alone might not be adequate for effective regeneration. Recently, gene modification and 3D-printing strategies represent promising strategies to enhanced therapeutic efficacy of MSC therapy. In this regard, we hypothesized that the combination of thermosensitive chitosan hydrogel and adipose derived stem cells (ADSCs) engineered with modRNA encoding Interleukin − 4 (IL-4) can inhibit inflammation and promote the regeneration of the degenerative IVD. Rat ADSCs were acquired from adipose tissue and transfected with modRNAs. First, the kinetics and efficacy of modRNA-mediated gene transfer in mouse ADSCs were analyzed in vitro. Next, we applied an indirect co-culture system to analyze the pro-anabolic potential of IL-4 modRNA engineered ADSCs (named as IL-4-ADSCs) on nucleus pulposus cells. ModRNA transfected mouse ADSCs with high efficiency and the IL-4 modRNA-transfected ADSCs facilitated burst-like production of bio-functional IL-4 protein. In vitro, IL-4-ADSCs induced increased anabolic markers expression of nucleus pulposus cells in inflammation environment compared to untreated ADSCs. These findings collectively supported the therapeutic potential of the combination of thermosensitive chitosan hydrogel and IL-4-ADSCs for intervertebral disc degeneration management. Histological and in vivo validation are now being conducted.
Quantitative ultrasound (QUS) is a promising tool to estimate bone structure characteristics and predict fragile fracture. The aim of this pilot cross-sectional study was to evaluate the performance of a multi-channel residual network (MResNet) based on ultrasonic radiofrequency (RF) signal to discriminate fragile fractures retrospectively in postmenopausal women. RF signal and speed of sound (SOS) were obtained using an axial transmission QUS at one‐third distal radius for 246 postmenopausal women. Based on the involved RF signal, we conducted a MResNet, which combines multi-channel training with original ResNet, to classify the high risk of fragility fractures patients from all subjects. The bone mineral density (BMD) at lumber, hip and femoral neck acquired with DXA was recorded on the same day. The fracture history of all subjects in adulthood were collected. To assess the ability of the different methods in the discrimination of fragile fracture, the odds ratios (OR) calculated using binomial logistic regression analysis and the area under the receiver operator characteristic curves (AUC) were analyzed. Among the 246 postmenopausal women, 170 belonged to the non-fracture group, 50 to the vertebral group, and 26 to the non-vertebral fracture group. MResNet was discriminant for all fragile fractures (OR = 2.64; AUC = 0.74), for Vertebral fracture (OR = 3.02; AUC = 0.77), for non-vertebral fracture (OR = 2.01; AUC = 0.69). MResNet showed comparable performance to that of BMD of hip and lumbar with all types of fractures, and significantly better performance than SOS all types of fractures.Methods
Results
Total joint replacement (TJR) was one of the most revolutionary breakthroughs in joint surgery. The majority studies had shown that most implants could last about 25 years, anyway, there is still variation in the longevity of implants. In US, for all the hip revisions from 2012 to 2017 in the United States, 12.0% of the patients were diagnosed as aseptic loosening. Variable studies have showed that any factor that could cause a systemic or partial bone loss, might be the risk of periprosthetic osteolysis and aseptic loosening. Breast cancer is the most frequent malignancy in women, more than 2.1 million women were newly diagnosed with breast cancer, 626,679 women with breast cancer died in 2018. It's been reported that the mean incidence of THA was 0.29% for medicare population with breast cancer in USA, of which the incidence was 3.46% in Norwegian. However, the effects of breast cancer chemotherapy and hormonotherapy, such as aromatase inhibitors (AI), significantly increased the risk of osteoporosis, and had been proved to become a great threat to hip implants survival. In this case, a 46-year-old female undertook chemotherapy and hormonotherapy of breast cancer 3 years after her primary THA, was diagnosed with aseptic loosening of the hip prosthesis. Her treatment was summarized and analyzed. Breast cancer chemotherapy and hormonotherapy might be a threat to the stability of THA prosthesis. More attention should be paid when a THA paitent occurred with breast cancer. More studies about the effect of breast cancer treatments on skeleton are required.
As peri-prosthetic aseptic loosening is one of the main causes of implant failure, inhibiting wear particles induced macrophages inflammation is considered as a promising therapy for AL to expand the lifespan of implant. Here, we aim at exploring the role of p110δ, a member of class IA PI3K family, and Krüppel-like factor 4 (KLF4) in titanium particles (TiPs) induced macrophages-inflammation and osteolysis. Firstly, IC87114, the inhibitor of p110δ and siRNA targeting p110δ were applied and experiments including ELISA and immunofluorescence assay were conducted to explore the role of p110δ. Sequentially, KLF4 was predicted as the transcription factor of p110δ and the relation was confirmed by dual luciferase reporter assay. Next, assays including RT-PCR, western blotting and flow cytometry were performed to ensure the specific role of KLF4. Finally, TiPs-induced mice cranial osteolysis model was established, and micro-CT scanning and immunohistochemistry assay were performed to reveal the role of p110δ and KLF4 in vivo. Here, we found that p110δ was upregulated in TiPs-stimulated macrophages. The inhibition of p110δ or knockdown of p110δ could significantly dampen the TiPs-induced secretion of TNFα and IL-6. Further mechanistic studies confirmed that p110δ was responsible for TNFα and IL-6 trafficking out of Golgi complex without affecting their expression in TiPs-treated macrophages. Additionally, we explored the upstream regulators and confirmed that Krüppel-like factor 4 (KLF4) was the transcription repressor of p110δ. Apart from that, KLF4, targeted by miR-92a, could also attenuate TiPs-induced inflammation by mediating NF-κB pathway and M1/M2 polarization. By the establishment of TiPs-induced mice cranial osteolysis model, we found that KLF4 knockdown exacerbated TiPs-induced osteolysis which was strikingly ameliorated by knockdown of p110δ. In summary, our study suggests the key role of miR-92a/KLF4/p110δ signal in TiPs-induced macrophages inflammation and osteolysis.
Circular RNA (circRNA) is involved in the regulation of articular cartilage degeneration induced by inflammatory factors or oxidative stress. In a previous study, we found that the expression of Minus RNA sequencing, fluorescence in situ hybridization, and quantitative real-time polymerase chain reaction (qRT-PCR) were used to detect the expression of Aims
Methods
Developmental dysplasia of the hip (DDH) is a complex musculoskeletal disease that occurs mostly in children. This study aimed to investigate the molecular changes in the hip joint capsule of patients with DDH. High-throughput sequencing was used to identify genes that were differentially expressed in hip joint capsules between healthy controls and DDH patients. Biological assays including cell cycle, viability, apoptosis, immunofluorescence, reverse transcription polymerase chain reaction (RT-PCR), and western blotting were performed to determine the roles of the differentially expressed genes in DDH pathology.Aims
Methods
The aim of this meta-analysis was to assess the prognosis after early functional rehabilitation or traditional immobilization in patients who underwent operative or nonoperative treatment for rupture of the Achilles tendon. PubMed, Embase, Web of Science, and Cochrane Library were searched for randomized controlled trials (RCTs) from their inception to 3 June 2020, using keywords related to rupture of the Achilles tendon and rehabilitation. Data extraction was undertaken by independent reviewers and subgroup analyses were performed based on the form of treatment. Risk ratios (RRs) and weighted mean differences (WMDs) (with 95% confidence intervals (CIs)) were used as summary association measures.Aims
Methods
To explore a novel machine learning model to evaluate the vertebral fracture risk using Decision Tree model and train the model by Bone Mineral Density (BMD) of different compartments of vertebral body. We collected a Computed Tomography image dataset, including 10 patients with osteoporotic fracture and 10 patients without osteoporotic fracture. 40 non-fracture Vertebral bodies from T11 to L5 were segmented from 10 patients with osteoporotic fracture in the CT database and 53 non-fracture Vertebral bodies from T11 to L5 were segmented from 10 patients without osteoporotic fracture in the CT database. Based on the biomechanical properties, 93 vertebral bodies were further segmented into 11 compartments: eight trabecular bone, cortical shell, top and bottom endplate. BMD of these 11 compartments was calculated based on the HU value in CT images. Decision tree model was used to build fracture prediction model, and Support Vector Machine was built as a compared model. All BMD data was shuffled to a random order. 70% of data was used as training data, and 30% left was used as test data. Then, training prediction accuracy and testing prediction accuracy were calculated separately in the two models. The training accuracy of Decision Tree model is 100% and testing accuracy is 92.14% after trained by BMD data of 11 compartments of the vertebral body. The type I error is 7.14% and type II error is 0%. The training accuracy of Support Vector Machine model is 100% and the testing accuracy is 78.57%. The type I error is 17.86% and type II error is 3.57%. The performance of vertebral body fracture prediction using Decision Tree is significantly higher than using Support Vector Machine. The Decision Tree model is a potential risk assessment method for clinical application. The pilot evidence showed that Decision Tree prediction model overcomes the overfitting drawback of Support Vector Machine Model. However, larger dataset and cohort study should be conducted for further evidence.
Whether to perform hybrid surgery (HS) in contrast to anterior cervical discectomy and fusion (ACDF) when treating patients with multilevel cervical disc degeneration remains a controversial subject. To resolve this we have undertaken a meta-analysis comparing the outcomes from HS with ACDF in this condition. Seven databases were searched for studies of HS and ACDF from inception of the study to 1 September 2019. Both random-effects and fixed-effects models were used to evaluate the overall effect of the C2-C7 range of motion (ROM), ROM of superior/inferior adjacent levels, adjacent segment degeneration (ASD), heterotopic ossification (HO), complications, neck disability index (NDI) score, visual analogue scale (VAS) score, Japanese Orthopaedic Association (JOA) score, Odom’s criteria, blood loss, and operating and hospitalization time. To obtain more credible results contour-enhanced funnel plots, Egger’s and Begg’s tests, meta-regression, and sensitivity analyses were performed.Aims
Methods
The objective of this study was to investigate the association of four single-nucleotide polymorphisms (SNPs) of the cannabinoid receptor 2 ( Chinese patients with OP were recruited between March 2011 and December 2015 from our hospital. In this study, a total of 1267 post-menopausal female patients (631 OP patients and 636 control patients) were selected. The mean age of all subjects was 69.2 years (sd 15.8). A generalized multifactor dimensionality reduction (GMDR) model and logistic regression model were used to examine the interaction between SNP and obesity on OP. For OP patient-control haplotype analyses, the SHEsis online haplotype analysis software (Objectives
Methods
Irrigation is the cornerstone of treating skeletal infection by eliminating pathogens in wounds. A previous study shows that irrigation with normal saline (0.9%) and ethylenediaminetetraacetic acid (EDTA) could improve the removal of We established three wound infection models (skin defect, bone-exposed, implant-exposed) by inoculating the wounds with a variety of representative drug-resistant bacteria including methicillin-resistant Objectives
Methods
Radiologic signs such as radiolucent lines around the implant, hardware fracture or displacement and periosteal reaction have been considered suggestive of implant-associated infection. The goal of this study is to assess the correlation of these signs with confirmed internal fixation-associated infection evaluated in a prospective cohort. We evaluated the radiologic appearance of preoperative standard x-ray images in 421 surgeries performed in 380 patients with internal fixation device in place (56.8% male, mean age 53 ± 17 years). This prospective study was performed in a large single center for musculoskeletal surgery from 2013–2017. Infection was suspected preoperatively in only 23.8% of the surgeries. The most common indications for surgeries in which infection was not suspected were nonunion (84 cases) and symptomatic hardware (57 cases). All removed implants were sent to sonication for biofilm removal and detection. In addition, several peri-implant tissue samples were collected. Radiographs were analyzed in a blinded fashion for signs of radiolucent lines around the implant before removal, hardware fracture or displacement, and soft periosteal reactions suggestive of infection. Diagnosis was established according to the IDSA criteria for PJI. Contingency tables were constructed to determine sensitivity and specificity, and to perform Chi-square tests to compare the presence of infection with radiological signs of infection.Aim
Method
Unexpected positive infections are distinct entity in prosthetic revision surgery. The prevalence and characteristics of unexpected positive cultures in internal fixation are however less established. The aim of this study was to describe the prevalence and characteristics of unexpected diagnosis of infection in a prospective cohort of revision surgeries following internal fixation. We reviewed the microbiological results following 356 surgeries that included partial or complete removal of internal fixation, performed in 328 patients (54% male, mean age 53 ± 17 years), in which infection was not initially suspected. This prospective study was performed in a large single center for musculoskeletal surgery from 2013–2017. The implants most commonly removed were plate and/or screws (281 cases, 78,9%), followed by intramedullary nails (64 cases, 18,0%). The main indications for surgery were nonunion (89 cases, 25%) and symptomatic hardware (70 cases, 19,7%). All removed implants were sonicated, and tissue cultures were obtained depending on the surgeon's criteria. Diagnosis of infection was established by the presence of 2 or more positive tissue cultures (1 with a highly virulent microorganism), or ≥ 50 colony-forming units found in the sonication fluid.Aim
Method
Although single-stage revision has attracted a lot of attention due to less socioeconomic cost, this technique is not widely used throughout the world due to strict indications. In this situation, we report our outcome on single-stage revision combined with selective direct intra-articular antibiotic infusion for chronic infected THA, especially for patients with culture-negative hip, fungal infections and multidrug-resistant organism. We retrospectively reviewed 131 patients with chronic infected THA between January 2010 and February 2017 who underwent single-stage revision, including soakage of surgical area with 0.5% aqueous betadine, pouring powdered vancomycin or imipenem into the medullary cavity. For patients with culture-negative hip, fungal infections and multidrug-resistant organism, a direct intra-articular infusion of pathogens-sensitive antibiotics via three-branch catheter were performed postoperatively. Recurrence of infection and clinical outcomes were evaluated. One hundred and fifteen patients were followed-up for an average of 4.5 years (range, 1.2–8 years). Of the 115 patients, 103 patients (89.6%) required no additional surgical or medical treatment for recurrence of infection. A recurrent infection was observed in 4 of the 23 patients (17.4%) with culture-negative infected hip. One of 4 fungal infections was relapse and the success rate in patients with multidrug-resistant organism was 84.2% (16/19). The mean postoperative Harris hip score was 81 points (63 to 92; p < 0.05) at the most recent assessment. Treatment of chronic infected THA by single-stage revision combined with selective direct intra-articular antibiotic infusion can be fairly effective, even for patients with relative “contraindication” of this approach.
Infection is a potentially disastrous complication of total knee arthroplasty (TKA). Although advances in surgical technique and antibiotic prophylaxis have reduced the incidence of infection to approximately 1% in primary TKA, there is still a substantial number of patients. Treatment options include antibiotic suppression, irrigation and debridement with component retention (with or without polyethylene exchange), one-stage or two-stage revision, resection arthroplasty and rarely arthrodesis or amputation. Salvage of prostheses has always been associated with low rates of success. It was reported a success rate of 27% for open debridement. It is suitable for selective cases where infection occurs within the first 4–6 weeks of primary TKA or in the setting of acute hematogenous gram positive infection with stable implants. With the advances in arthroscopic technique, arthroscopy after TKA has become an accepted method to assess and manage the complications of TKA. Arthroscopic treatment for infected TKA was reported and the successful rate was similar or better than open debridement in selected situations. We used arthroscopic debridement combined with continuous antibiotic irrigation and suction to treat acute presentation of infected TKA with acceptable result. From 2010∼2013, we has performed arthroscopic debridement and continuous antibiotic irrigation system for seven patients with infected TKA. All of the seven patients had no open wounds nor sinuses and no radiological evidence of prosthetic instability or evidence of osteomyelitis. Most of the surgical intervention was performed within two weeks from the onset of symptoms. Arthroscopic debridement was performed with a shaver using a multiportal technique (anterolateral, anteromedial, superolateral, superomedial, posterolateral, posteromedial) and a continuous antibiotic irrigation system was used to dilutes concentration of the causative microorganism and keep high local bactericidal concentration of antibiotics. We evaluated the efficacy by using follow up of the C-reactve protein (CRP) test, erythrocyte sedimentation rate (ESR) test and physical examination. Successful treatment was defined as prosthesis retention without recurrent infection by the final follow-up. Six of seven infected TKA were cured without recurrence at a mean follow-up of 23 months (range, 6–41 months). One case with rheumatoid arthritis under long-term steroid therapy had recurred after episode of upper respiratory tract infection for 3 times. However, the infection was controlled by arthroscopic debridement and retention of the prosthesis was achieved. We emphasize the importance of posterior portal to ensure adequate arthroscopic debridement. It is imperative to make early diagnosis and treatment for infected TKA. We should make more effort to preserve the prosthesis in acute infection(within 2 weeks). With the advantage of minimal morbidity, arthroscopic treatement shoulder be an alternative to open debridement.
Implant-related infection (IRI) is closely related to the local immunity of peri-implant tissues. The generation of reactive oxygen species (ROS) in activated macrophages plays a prominent role in the innate immune response. In previous studies, we indicated that implant wear particles promote endotoxin tolerance by decreasing the release of proinflammatory cytokines. However, it is unclear whether ROS are involved in the damage of the local immunity of peri-implant tissues. In the present study, we assessed the mechanism of local immunosuppression using titanium (Ti) particles and/or lipopolysaccharide (LPS) to stimulate RAW 264.7 cells. The results indicate that the Ti particles induced the generation of a moderate amount of ROS through nicotinamide adenine dinucleotide phosphate oxidase-1 (NOX-1), but not through catalase. Pre-exposure to Ti particles inhibited ROS generation and extracellular regulated protein kinase (ERK) activation in LPS-stimulated macrophages. These findings indicate that chronic stimulation by Ti particles may lead to a state of oxidative stress and persistent inflammation, which may result in the attenuation of the immune response of macrophages to bacterial components such as LPS. Eventually, immunosuppression develops in peri-implant tissues, which may be a risk factor for IRI.
This study demonstrated that Sclerostin monoclonal antibody (Scl-Ab) enhanced bone healing in the rat osteotomy model. Scl-Ab increased callus size, callus bone volume fraction, rate of callus bone formation and fracture callus strength. Sclerostin is a protein secreted by osteocytes and is characterized as a key inhibitor of osteoblast-mediated bone formation. Previous studies demonstrated that treatment with a sclerostin monoclonal antibody (Scl-Ab) results in significantly increased bone formation, bone mass and strength in rat closed fracture model (1–2). However, the effects of Scl-Ab on healing of open fracture model have not yet been reported in rats. Previously in ORS and ASBMR Annual Meeting, we have reported that Scl-Ab promoted the open fracture healing at week 3 and week 6 post-fracture. Here we extended our investigation for up to week 9 with additional histological assessments and dynamic histomorphometric analysis to investigate the effects of systemic administration of Scl-Ab on a later phase of fracture repair.Summary Statement
Introduction
The use of tapered junctions in primary hip arthroplasty has excellent results. Large heads are being used to mitigate dislocation and optimize range of motion. The prevalence of larger heads, coupled with recent findings regarding corrosion artifacts at tapered surfaces, has spurred growing interest when considering revision rates. The purpose of this study was to determine if correlations exist between severity of corrosion artifacts and head size, head offset, time Retrieved hip arthroplasty devices with CoCrMo or oxidized zirconium (OxZr) heads were investigated for corrosion artifacts in this study. Female tapered surfaces were scored independently by a panel according to the Goldberg system for assessment of corrosion. Exclusion criteria included less than 1 week INTRODUCTION:
METHODS:
One of the recent advances in the hard-on-hard hip arthroplasty is the development of a new material of diffusion hardened oxidised zirconium (DHOxZr). The DHOxZr material consists of a ceramic layer on the top surface which is supported by a thick oxygen diffusion hardened (DH) zone underneath. With the desired properties of metal substrate, ceramic surface and a gradient structure of the oxygen diffusion zone, the DHOxZr-on-DHOxZr bearing combination is expected to produce low wear and minimal metal ions. This can possibly address the concerns associated with metal hypersensitivity associated with metal on metal bearings and fracture risk associated with ceramics. The aim of this study was to evaluate the wear of DHOxZr-on-DHOxZr as a possible hard on hard bearing combination in hips. Three pairs of 50 mm DHOxZr prototype hip joint devices, each consisting of a DHOxZr modular head and a DHOxZr liner were wear tested in a ProSim hip joint simulator under standard testing conditions used by the Implant Development Centre (IDC), Smith & Nephew, Leamington Spa for 5 million cycles (Mc). The flexion/extension was 30° and 15°. The internal/external rotation was ± 10°. The force was Paul-type stance phase loading, with a maximum load of 3 kN and a standard ISO swing phase load of 0.3 kN. The test frequency was 1 Hz. Gravimetric analysis was carried out at 0, 0.5, 1, 2, 3, 4 & 5 million cycles. The lubricant was new born calf serum with 2 g/l sodium azide concentration diluted with de-ionised water to achieve average protein concentration of 20 g/l. Lubricant was changed every 0.25Mc during the first million cycles of the test and at every 0.33 Mc from 1 to 5Mc.INTRODUCTION
METHODS
