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Background: Carpal Tunnel Syndrome (CTS) is an idiopathic fibrotic disorder. Fibrosis in the subsynovial connective tissues (SSCT) of CTS and many other fibrotic diseases is mediated by Transforming growth factor β (TGF-β). Recently monocyte chemoattractant protein-1 (MCP-1) a cytokine involved in cellular recruitment has been suggested to regulate TGF-β activity. It is related to the onset of diseases which are caused by fibrosis, such as idiopathic pulmonary fibrosis, renal fibrosis, and systemic scleroderma. In this study, we evaluated the effect of the MCP-1 synthesis inhibitor, Bindarit, on primary cultures of fibroblasts from the SSCT of five CTS patients., Methods: Fibroblasts were treated with Bindarit (10 μM, 50 μM, 100 μM, or 300 μM). Responses to inhibitors were evaluated by regulation of CTS fibrosis-associated genes, fibrosis gene array and Smad luciferase reporter assay. We also assessed the combination effect of Bindarit and SD208, a TGF-β receptor type 1 inhibitor on TGF-β signaling., Results: Collagen type III A1 (Col3), connective tissue growth factor (CTGF), and SERPINE1 expression were significantly down-regulated by Bindarit (300 μM) compared to vehicle control. In the fibrosis array, expression of inhibin beta E chain precursor (INHBE), beta actin (ACTB), endothelin 1 (EDN1) and hypoxanthine phosphoribosyltransferase 1 (HPRT1) were significantly down-regulated, and integrin beta-3 (ITGB3) was significantly up-regulated by Bindarit (300 μM). Smad signal transduction activation was significantly down-regulated by Bindarit (300 μM) and/or SD208 (1 μM) with TGF-β1 compared to vehicle control with TGF-β1., Conclusions: These results suggest that Bindarit in combination with SD208 may be beneficial as medical therapy for the SSCT fibrosis associated with CTS., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Carpal tunnel syndrome commonly occurs in individuals working in occupations that involve use of vibrating manual tools or tasks with highly repetitive and forceful manual exertion. In recent years, carpal tunnel syndrome has been evaluated by ultrasound imaging that monitors median nerve movement. Conventional image analysis methods, such as the active contour model, are typically used to expedite automatic segmentation of the median nerve, but these usually suffer from an arduous manual intervention. We propose a new convolutional neural network framework for localization and segmentation of the median nerve, called DeepNerve, that is based on the U-Net model. DeepNerve integrates the characteristics of MaskTrack and convolutional long short-term memory to effectively locate and segment the median nerve. On the basis of experimental results, the proposed model achieved high performance and generated average Dice measurement, precision, recall and F-score values of 0.8975, 0.8912, 0.9119 and 0.9015, respectively. The segmentation results of DeepNerve were significantly improved in comparison with those of conventional active contour models. Additionally, the results of Student's t-test revealed significant differences in four deformation measurements of the median nerve, including area, perimeter, aspect ratio and circularity. We conclude that the proposed DeepNerve not only generates satisfactory results for localization and segmentation of the median nerve, but also creates more promising measurements for applications in clinical carpal tunnel syndrome diagnosis., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Fibroblast behavior and cell-matrix interactions of cells from normal and idiopathic carpal tunnel syndrome (CTS) subsynovial connective tissue (SSCT) with and without Triamcinolone Acetonide (TA) were compared in this study. A cell-seeded gel contraction model was applied to investigate the effect of steroid treatment on SSCT fibroblast gene expression and function., Methods: SSCT cells were obtained from CTS patients and fresh cadavers. Cells were isolated by mechanical and collagenase digestion. Collagen gels (1 mg/ml) were prepared with SSCT cells (1 × 10 6 /mL). A sterile Petri dish with a cloning ring in the center was prepared. The area between the ring and outer dish was filled with cell-seeded collagen solution and gelled for 1 h. The gel was released from the outer way of the petri dish to allow gel contraction. Cell seeded gels were treated with 10 M triamcinolone acetonide (TA) or vehicle (DMSO) in modified MEM. Every 4 h for 3 days the contracting gels were photographed and areas calculated. Duplicate contraction tests were performed with each specimen, and the averages were used in the analyses, which were conducted using two-factor analysis of variance in a generalized linear model framework utilizing generalized estimating equations (GEE) to account for the correlation between samples. The contraction rate was determined by the area change over time, and the decay time constant was calculated. A customized mechanical test system was used to determine gel stiffness and tensile strength. Gene expression was assessed using Human Fibrosis and Cell Motility PCR arrays., Results: TA-treated gels had a significantly higher contraction rate, tensile strength and stiffness than the untreated gels. Proteinases involved in remodeling had increased expression in TA-treated gels of the patient group. Pro-fibrotic genes and ECM regulators, such as TGF-β, collagens and integrins, were down-regulated by TA, indicating that TA may work in part by decreasing fibrotic gene expression., Conclusions: This study showed that TA affects cell-matrix interaction and suppresses fibrotic gene expression in the SSCT cells of CTS patients.

Fibrosis of the subsynovial connective tissue (SSCT) in carpal tunnel syndrome (CTS) patients is increasingly recognized as an important aspect of CTS pathophysiology. In this study, we evaluated the effect of blocking profibrotic pathways in fibroblasts from the SSCT in CTS patients. Fibroblasts were stimulated with transforming growth factor β1 (TGF-β1), and then treated either with a specific fibrosis pathway inhibitor targeting TGF-β receptor type 1 (TβRI), platelet-derived growth factor receptor (PDGFR), epidermal growth factor receptor (EGFR), or vascular endothelial growth factor receptor (VEGFR). Fibrosis array and quantitative real-time polymerase chain reaction of fibrotic genes were evaluated. Array gene expression analysis revealed significant down-regulation of multiple fibrotic genes after treatment with TβRI, PDGFR, and VEGFR inhibitors. No array fibrotic genes were significantly down-regulated with EGFR inhibition. Further gene expression analysis of known CTS fibrosis markers collagen type I A2 (Col1), collagen type III A1 (Col3), connective tissue growth factor (CTGF), and SERPINE1 showed significantly down-regulation after TβRI inhibition. In contrast, VEGFR inhibition significantly down-regulated CTGF and SERPINE1, whereas, PDGFR and EGFR inhibition significantly down-regulated Col3. Taken together the inhibition of TβRI appears to be the primary mediator of fibrotic gene expression in fibroblasts from CTS patients. TGF-β/Smad activity was further evaluated, and as expected inhibition of Smad activity was significantly down-regulated after inhibition of TβRI, but not with PDGFR, VEGFR, or EGFR inhibition. These results indicate that local therapies specifically targeting TGF-β signaling alone or in combination offer the potential of a novel local antifibrosis therapy for patients with CTS., (© 2017 Wiley Periodicals, Inc.)

Carpal tunnel pressure is a key factor in the etiology of carpal tunnel syndrome. Numerous approaches have been conducted to measure carpal tunnel pressure. However, most techniques are invasive and take time and effort. We have developed an innovative approach to noninvasively assess the tunnel pressure by using the ultrasound surface wave elastography (USWE) technique. In a previous study it was shown that the shear wave speed in a tendon increased linearly with increasing tunnel pressure enclosed the tendon in a simple tendon model. This study aimed to examine the relationship between the carpal tunnel pressure and the shear wave speeds inside and outside the carpal tunnel in a human cadaveric model. The result showed that the shear wave speed inside the carpal tunnel increased linearly with created carpal tunnel pressure, while the shear wave speed outside the carpal tunnel remained constant. These findings suggest that noninvasive measurement of carpal tunnel pressure is possible by measuring the shear wave speed in the tendon. After fully establishing this technology and being applicable in clinic, it would be useful in the diagnosis of carpal tunnel syndrome. For that reason, further validation with this technique in both healthy controls and patients with carpal tunnel syndrome is required. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:477-483, 2018., (© 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

Noninflammatory subsynovial connective tissue (SSCT) fibrosis with nerve compression is a prominent feature of carpal tunnel syndrome (CTS). Studies have shown that SSCT matrix synthesis and material property changes in CTS are associated with increased activity of transforming growth factor (TGF)-β1. The aim of this study were to (1) investigate the ability of SSCT fibroblasts from CTS patients and unaffected individuals to contract a collagen gel ring and (2) determine how the addition of TGF-β1 affects this ability. SSCT fibroblasts from three normal cadavers and three age-matched female patients who had undergone surgery for CTS were used. Results showed patient cell-seeded gels had a significantly higher contraction rate (p < 0.001) than control cells, and fully contracted gel rings possessed a significantly higher tensile strength (p = 0.003) and stiffness (p < 0.001). Furthermore, TGF-β1 significantly intensified contraction rate (p < 0.001), tensile strength (p < 0.001), and stiffness (p < 0.001). In conclusion, SSCT cells from normal donors and CTS patients contract collagen gel rings differently, and this ability is affected by TGF-β1 treatment. This cell-seeded collagen gel model may be useful for developing new methods of stopping or eliminating the effect of TGF-β1 on the SSCT fibroblasts and surrounding matrix, which might aid in the identification of medical treatment for CTS., (© 2014 Wiley Periodicals, Inc.)

Fibrosis of the subsynovial connective tissue (SSCT) is a predominant feature of carpal tunnel syndrome (CTS). While the nature of CTS has been extensively studied, little is known about the etiology of this disease. We investigated SSCT tissue from patients with CTS and control subjects using fibrosis arrays and cell culture analysis. Twofold changes in fibrotic gene expression were found in multiple genes from patient SSCT using fibrosis arrays. This data was confirmed via qRT-PCR on a subset of genes; collagen I (Col1), collagen III (Col3), connective tissue growth factor (CTGF), transforming growth factor β (TGF-β), and SMAD3 (P < 0.05) which significantly corroborate the fold changes found in the fibrosis arrays. To further explore the nature of SSCT fibrosis, cells were isolated from patient and control tissue. Col1, Col3, TGF-β, and SMAD3 were highly expressed in patient SSCT fibroblasts as compared to control (P < 0.05). Further, fibrotic genes expression was decreased by inhibiting TGF-β receptor I (TβRI) activity (P < 0.05). TGF-β second messenger SMAD activity was significantly activated in SSCT fibroblasts from patients and this activation was abrogated by inhibiting TβRI signaling (P < 0.05). These findings suggest that blocking TGF-β signaling may be an important therapeutic approach to treating the underlying fibrosis of SSCT in CTS patients., (© 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

Fibrosis of the subsynovial connective tissue (SSCT) in the carpal tunnel is the most common histological finding in carpal tunnel syndrome (CTS). Fibrosis may result from damaged SSCT. Previous studies found that with low-velocity (2 mm/s), tendon excursions can irreversibly damage the SSCT. We investigated the effect of tendon excursion velocity in the generation of SSCT damage. Nine human cadaver wrists were used. Three repeated cycles of ramp-stretch testing were performed simulating 40%, 60%, 90%, and 120% of the middle finger flexor tendon superficialis physiological excursion with an excursion velocity of 60 mm/s. Energy and force were calculated and normalized by values obtained in the first cycle for each excursion level. Data were compared with low-velocity excursion data. For high-velocity excursions, a significant drop in the excursion energy ratio was first observed at an excursion level of 60% physiological excursion (p < 0.024) and that for low-velocity excursions was first observed at 90% physiological excursion (p < 0.038). Furthermore, the energy ratio was lower at 60% for high velocities (p ≤ 0.039). Increasing velocity lowers the SSCT damage threshold. This finding may be relevant for understanding the pathogenesis of SSCT fibrosis, such as that accompanying CTS, and a relationship with occupational factors., (© 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

ABSTRACT Carpal tunnel syndrome (CTS) is a peripheral neuropathy characterized by non-inflammatory fibrosis of the subsynovial connective tissues (SSCT). A rabbit model of CTS was developed to test the hypothesis that SSCT fibrosis causes the neuropathy. We used a cell-seeded collagen-gel contraction model to characterize the fibrosis in this model in terms of cellular mechanics, specifically to compare the ability of SSCT cells from the rabbit model and normal rabbits to contract the gel, and to assess the effect of transforming growth factor-β1,which is upregulated in CTS, on these cells. SSCT fibrosis was induced in six retired breeder female rabbits which were sacrificed at 6 weeks ( N = 3) and 12 weeks ( n = 3). An additional two rabbits served as controls. SSCT was harvested according to a standard protocol. Gels seeded with SSCT cells from rabbits sacrificed at 6 weeks had significantly higher tensile strength ( p < 0.001) and Young's modulus ( p < 0.001) than gels seeded with cells from rabbits sacrificed at 12 weeks or control animals. TGF-β1 significantly increased the decay time constant ( p < 0.001), tensile strength ( p < 0.001), and Young's modulus ( p < 0.001) regardless of the cell source. This model may be useful in screening therapeutic agents that may block SSCT fibrosis, identifying possible candidates for CTS treatment. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:668-674, 2015. [ABSTRACT FROM AUTHOR]