Clinical Implication of Glenohumeral and Subacromial Synovitis in Rotator Cuff Tears.

Background: Synovitis of the glenohumeral (GH) joint and the subacromial (SA) space is commonly observed during arthroscopic rotator cuff surgery. Purpose: To investigate the distribution, severity, and clinical implications of synovitis in the GH joint and SA space in patients with a full-thickness rotator cuff tear (RCT). Study Design: Case series; Level of evidence, 4. Methods: Data were retrospectively collected from 207 patients with a full-thickness RCT who underwent arthroscopic repair. Preoperative parameters used in the clinical assessment included pain, range of motion (ROM), muscle strength, and functional scores. Macroscopic assessment of synovitis was performed intraoperatively in the 3 regions of interest (ROIs) of the GH joint and 4 ROIS of the SA space using an evaluation system. The distribution and severity of synovitis and the association between synovitis and clinical assessment were evaluated. Results: Synovitis was more severe in the GH joint than in the SA space (P < .001). Synovitis in the posterior GH joint and the lateral SA space, where most of the rotator cuff was located, was the most severe area among the ROIs of the GH joint and the SA space, respectively (P < .05). All types of pain, except for pain at rest, were associated with synovitis in the posterior GH joint (P < .05). All ROM measures were associated with synovitis in the posterior and inferior GH joint (|r| > 0.20; P < .05 for both). The strength of the supraspinatus and the infraspinatus was associated with synovitis in the posterior GH joint (P < .05). Shoulder function was associated with synovitis in the posterior and inferior GH joint and more in the posterior GH joint (P < .05 for both). Synovitis in the SA space was not associated with any of the clinical parameters. Conclusion: Synovitis in the posterior GH joint was the most severe form of synovitis in the GH joint in patients with a full-thickness RCT. Synovitis in the posterior GH joint was closely associated with increased pain and decreased ROM, muscle strength, and functional score. Synovitis in the SA space was milder and not associated with any clinical parameters.

Implications of Axis Inhibition Protein 2 in Breast Cancer Progression.

BACKGROUND/AIM: Although axis inhibition protein 2 (Axin2) has been reported to act as a tumour suppressor, recent findings suggest that it exhibits oncogenic effects by mediating Snail1-induced epithelial-mesenchymal transition (EMT) in breast cancer cells. EMT is a crucial biological process involved in the initiation of metastasis in cancer progression. This study elucidated the biological significance and mechanism of Axin2 in breast cancer using transcriptomic and molecular techniques. MATERIALS AND METHODS: The expression of Axin2 and Snail1 in MDA-MB-231 breast cancer cells was determined by western blotting analysis, and the role of Axin2 in breast cancer tumorigenesis was investigated in xenograft mouse models constructed using pLKO-Tet-shAxin2-transfected triple negative (TN) breast cancer cells. Additionally, the expression levels of EMT markers were determined using qRT-PCR, and clinical data were analysed using Kaplan-Meier (KM) plotter and The Cancer Genome Atlas (TCGA). RESULTS: Axin2 knockdown significantly decreased (p<0.001) the proliferation of MDA-MB-231 cells in vitro and attenuated (p<0.05) the tumorigenic potential of the cells in vivo. Moreover, Axin2 knockdown significantly increased the relative mRNA levels of epithelial markers but decreased the expression of mesenchymal markers in MDA-MB-231 cells. CONCLUSION: Axin2 may be involved in the progression of breast cancer, particularly triple-negative breast cancer, through the regulation of Snail1-induced EMT, making it a potential therapeutic target.

Prognostic factors affecting structural integrity after arthroscopic rotator cuff repair: a clinical and histological study.

BACKGROUND: Tendon degeneration contributes to rotator cuff tears; however, its role in postoperative structural integrity is poorly understood. The purpose of this study was to investigate the factors associated with postoperative structural integrity after rotator cuff repair, particularly focusing on the histology of tendons harvested intraoperatively. METHODS: A total of 56 patients who underwent primary arthroscopic rotator cuff repair between 2009 and 2011 were analyzed. A 3-mm-diameter sample of supraspinatus tendons was harvested en bloc from each patient after minimal debridement of the torn ends. Tendon degeneration was assessed using seven histological parameters on a semi-quantitative grading scale, and the total degeneration score was calculated. One-year postoperative magnetic resonance imaging was used to classify the patients based on retear. RESULTS: The total degeneration scores in the healed and retear groups were 13.93±2.03 and 14.08±2.23 (P=0.960), respectively. Arthroscopically measured anteroposterior (AP) tear sizes in the healed and retear groups were 24.30±12.35 mm and 36.42±25.23 mm (P=0.026), respectively. Preoperative visual analog scale pain scores at rest in the healed and retear groups were 3.54±2.37 and 5.16±2.16 (P=0.046), respectively. Retraction sizes in the healed and retear groups were 16.02±7.587 mm and 22.33±13.364 mm (P=0.037), respectively. The odds of retear rose by 4.2% for every 1-mm increase in AP tear size (P=0.032). CONCLUSIONS: The postoperative structural integrity of the rotator cuff tendon was not affected by tendon degeneration, whereas the arthroscopically measured AP tear size of the rotator cuff tendon was an independent predictor of retear.

Degenerative tendon matrix induces tenogenic differentiation of mesenchymal stem cells.

PURPOSE: Mesenchymal stem cells (MSCs) react dynamically with the surrounding microenvironment to promote tissue-specific differentiation and hence increase targeted regenerative capacity. Extracellular matrix (ECM) would be the first microenvironment to interact with MSCs injected into the tissue lesion. However, degenerative tissues would have different characteristics of ECM in comparison with healthy tissues. Therefore, the influence of degenerative ECM on tissue-specific differentiation of MSCs and the formation of matrix composition need to be considered for the sophisticated therapeutic application of stem cells for tissue regeneration. METHODS: Human degenerative tendon tissues were obtained from patients undergoing rotator cuff repair and finely minced into 2 ~ 3 mm fragments. Different amounts of tendon matrix (0.005 g, 0.01 g, 0.025 g, 0.05 g, 0.1 g, 0.25 g, 0.5 g, 1 g, and 2 g) were co-cultured with bone marrow MSCs (BM MSCs) for 7 days. Six tendon-related markers, scleraxis, tenomodulin, collagen type I and III, decorin, and tenascin-C, osteogenic marker, alkaline phosphatase (ALP), and chondrogenic marker, aggrecan (ACAN), were analyzed by qRT-PCR. Cell viability and senescence-associated beta-galactosidase assays were performed. The connective tissue growth factor was used as a positive control. RESULTS: The expressions of six tendon-related markers were significantly upregulated until the amount of tendon matrix exceeded 0.5 g, the point where the mRNA expressions of all six genes analyzed started to decrease. The tendon matrix exerted an inhibitory effect on ACAN expression but had a negligible effect on ALP expression. Cell viability did not change significantly over the culture period. The amount of tendon matrix exceeding 0.01 g significantly increased the SA-ßgal activity of BM MSCs. CONCLUSION: This study successfully demonstrated tendon ECM-stimulated tenogenesis of BM MSCs through an indirect co-culture system without the use of exogenous growth factors and the alteration of cellular viability. In contrast to the initial hypothesis, the tenogenesis of BM MSCs induced with the degenerative tendon matrix accompanied cellular senescence.

Arthroscopic supraspinatus advancement for retracted rotator cuff tears: a technical note.

Irreparable rotator cuffs with retracted torn ends remain a significant challenge for most shoulder surgeons. Since repairs are preferable to reconstruction or replacement whenever possible, studies for anatomical reductions with minimal tension and secure fixation are important. In this study, the authors introduce an arthroscopic supraspinatus advancement (ASSA) procedure for retracted rotator cuff tears that could not be adequately reduced to the original footprint. Using modified long, narrow, curved Cobb elevators, procedures can be performed through lateral portals without any additional skin incision. Following meticulous stepwise three-compartment elevation procedures based on the supraspinatus insertion anatomy, the supraspinatus muscle could be safely elevated from the fossa and sufficiently advanced laterally. The authors suggest that ASSA could be a useful procedure for management of challenging retracted rotator cuff tears by maximizing lateral excursions that could convert irreparable tears to reparable tears in select patients.

Effect of Quality of Repair on Clinical and Structural Outcomes of Rotator Cuff Repair.

BACKGROUND: Anatomic repair of a torn rotator cuff tendon on the greater tuberosity (GT) is an important surgical goal in rotator cuff repair. However, few studies have investigated whether the efforts made to maximize coverage of the GT are associated with the clinical and structural outcomes after rotator cuff repair surgery. PURPOSE: To investigate whether the quality of repair at the time of surgery is associated with clinical and structural outcomes after surgery and to identify factors influencing the quality of repair. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Data were retrospectively collected from 141 patients who underwent arthroscopic rotator cuff repair between 2008 and 2016. All repairs were classified according to the amount of postoperative GT coverage: A, complete coverage of the GT (n = 96); B, incomplete coverage, comprising more than half of GT (n = 27); C, incomplete coverage, comprising less than half of the GT (n = 16); and D, exposure of the glenohumeral joint (n = 2). All patients underwent magnetic resonance imaging 1 year after surgery. Clinical outcomes and structural integrity based on Sugaya classification were assessed 2 years and 1 year after surgery, respectively. Preoperative factors associated with the postoperative GT coverage (measured at the close of surgery) were identified using a multivariable proportional odds cumulative logit model. RESULTS: The forward flexion strength in group A (10.3 ± 4.6 lb) was significantly greater than that in group C (6.5 ± 3.7 lb) (P = .003) 2 years after surgery. The postoperative Constant score in group A (76.6 ± 11.5) was greater than that in group C (66.7 ± 15.6) (P = .018). The number of cases that showed retearing of the repaired tendon was as follows: group A (5/96; 5.2%), group B (7/27; 25.9%), and group C (10/16; 62.5%). There was no significant difference in the changes of pain visual analog scale scores among groups 2 years after surgery (all P > .05). Also, there was no significant difference in the changes of range of motion in all directions among groups 2 years after surgery (all P > .05). Patients with preoperative GT coverage B included in the postoperative GT coverage groups through surgery were as follows: group A (23/45; 51.1%), group B (17/45; 37.8%), and group C (5/45; 11.1%). Preoperative GT coverage was the only independent factor that was associated with GT coverage in multivariable analysis. CONCLUSION: Quality of repair, measured as the extent of postoperative GT coverage at the time of surgery, was associated with clinical and structural outcomes after rotator cuff repair surgery.

Florid Reactive Periostitis of the Clavicle: A Case Report.

Florid reactive periostitis (FRP) is a rare benign fibro-osseous proliferation, occurring mostly in the short tubular bones of hands and rarely in the long tubular bones. We report a surgically confirmed case of FRP involving the clavicle in a 26-year-old male. On MRI scans, a soft tissue mass with T2 high signal intensity was found that originated from the periosteum of the clavicle and included surrounding a periosteal elevation and perilesional soft tissue edema. Strong contrast enhancement was noted inside the mass and along the periosteum involving more than half of the circumference of the clavicle. Serial radiographs revealed a soft tissue mass without mineralization that turned into an ossified mass with a solid periosteal reaction within a month.

Minimal Cube Explant Provides Optimal Isolation Condition of Mesenchymal Stem Cells from Umbilical Cord.

BACKGROUND: Enzymatic digestion and explant method have been widely used for isolating umbilical cord-derived mesenchymal stem cells (UC MSCs), although there is still a strong need for robust protocols for optimal isolation for large-scale stem cell banks. This study aims to establish an explant method for clinical scale production of MSCs from human UC tissue and to characterize UC MSCs isolated and cultured with the explant method. METHODS: UC MSCs were isolated by enzymatic digestion, minimal cube explant (MCE) 1-2, MCE 2-4, and MCE 10 and cultured, respectively. Also, human antibody array and basic fibroblast growth factor (bFGF) secretion in conditioned medium (CM) was analyzed. The cells were evaluated initial cell number, colony forming unit-fibroblast (CFU-F), proliferation capacity, CD marker expression, and multi-lineage differentiation. SA-ß-gal assay as well as expression of p16, p21 and p53 was performed by RT-PCR. RESULTS: MCE 2-4 is the most optimized method for isolation of small umbilical cord-derived fast proliferating cells (smumf cells) with the greatest number. MCE 2-4 had the highest secretion of various bioactive factors including bFGF. The MCE 2-4 provided significantly higher CD146 expression than enzymatic digestion, and that expression was maintained until P20. The gene expression of p16, p21, and p53 of smumf cells did not change until P10 and SA-ß-gal activity did not increase until P14. CONCLUSION: This study demonstrated that MCE 2-4 provided an optimal environment to isolate MSCs with quantity and quality from human whole UC tissue through secretion of various bioactive factors inherent to UC.

CTRP3 exacerbates tendinopathy by dysregulating tendon stem cell differentiation and altering extracellular matrix composition.

Tendinopathy, the most common disorder affecting tendons, is characterized by chronic disorganization of the tendon matrix, which leads to tendon tear and rupture. The goal was to identify a rational molecular target whose blockade can serve as a potential therapeutic intervention for tendinopathy. We identified C1q/TNF-related protein-3 (CTRP3) as a markedly up-regulated cytokine in human and rodent tendinopathy. Overexpression of CTRP3 enhanced the progression of tendinopathy by accumulating cartilaginous proteoglycans and degenerating collagenous fibers in the mouse tendon, whereas CTRP3 knockdown suppressed the tendinopathy pathogenesis. Functional blockade of CTRP3 using a neutralizing antibody ameliorated overuse-induced tendinopathy of the Achilles and rotator cuff tendons. Mechanistically, CTRP3 elicited a transcriptomic pattern that stimulates abnormal differentiation of tendon stem/progenitor cells and ectopic chondrification as an effect linked to activation of Akt signaling. Collectively, we reveal an essential role for CTRP3 in tendinopathy and propose a potential therapeutic strategy for the treatment of tendinopathy.

Comparative analysis of intra-articular injection of steroid and/or sodium hyaluronate in adhesive capsulitis: prospective, double-blind, randomized, placebo-controlled study.

BACKGROUND: Few studies have reported the effects of simultaneous injections of corticosteroid (CS) and hyaluronic acid (HA) on adhesive capsulitis (AC) of the shoulder. This study investigated the synergistic effects of simultaneous intra-articular injections of CS and compared them to those of CS or HA alone. METHOD: Sixty patients with AC were enrolled in this randomized, placebo-controlled trial. The participants were divided into 4 groups: saline, CS, HA, and CS with HA groups. The primary outcome measure was changes in the Shoulder Pain and Disability Index (SPADI) scores at one month. The secondary outcome measures included changes in pain, range of motion, muscle strength, and additional shoulder functional scores at 1 day, 1 week, and 1, 3, and 6 months after injection. RESULTS: After 1 month, changes of the SPADI scores were significantly higher in the CS with HA group (-58.4%) than those in the saline (-7.7%) and HA (-14.4%) groups. The score changed more in the CS with HA group than that in the CS group (-43.7%), but there was no significant difference. In the changes in pain, the CS with HA group showed significantly better and faster effects than the saline and HA groups. In the changes of range of motion, functional scores, the CS with HA group showed better results than the saline and HA groups. CONCLUSION: In the treatment of AC, the simultaneous injection of CS and HA was more effective in improving SPADI scores at one month after injection than a single injection of CS or HA.

Allogenic Pure Platelet-Rich Plasma Therapy for Adhesive Capsulitis: A Bed-to-Bench Study With Propensity Score Matching Using a Corticosteroid Control Group.

BACKGROUND: While platelet-rich plasma (PRP) has been widely studied for musculoskeletal disorders, few studies to date have reported its use for adhesive capsulitis (AC). Fully characterized and standardized allogenic PRP may provide clues to solve the underlying mechanism of PRP with respect to synovial inflammation and thus may clarify its clinical indications. PURPOSE: To clinically evaluate the safety and efficacy of a fully characterized pure PRP injection in patients with AC and to assess the effects of pure PRP on synoviocytes with or without inflammation in vitro. STUDY DESIGN: Controlled laboratory study and cohort study; Level of evidence, 3. METHODS: For the clinical analysis, a total of 15 patients with AC received an ultrasonography-guided intra-articular PRP injection and were observed for 6 months. Pain, range of motion (ROM), muscle strength, shoulder function, and overall satisfaction in the patients were evaluated using questionnaires at 1 week as well as at 1, 3, and 6 months after the PRP injection and results were compared with the results of a propensity score-matched control group that received a corticosteroid injection (40 mg triamcinolone acetonide). For the in vitro analysis, synoviocytes were cultured with or without interleukin-1ß (IL-1ß) and PRP. The gene expression of proinflammatory and anti-inflammatory cytokines as well as matrix enzymes and their inhibitors was evaluated. RESULTS: At 6-month follow-up, pure PRP significantly decreased pain and improved ROM, muscle strength, and shoulder function to levels comparable with those after a corticosteroid injection. All pain values, strength measurements, and functional scores significantly improved up to 6 months in the PRP group, but these measures improved up to 3 months and then were decreased at 6 months in the corticosteroid group. ROM was significantly improved in the 2 groups at 6 months compared with baseline. Allogenic PRP did not cause adverse events. For the in vitro findings, PRP induced inflammation but significantly improved the IL 1ß-induced synovial inflammatory condition by decreasing proinflammatory cytokines such as IL-1ß, tumor necrosis factor-α, IL-6, cyclooxygenase-2, and microsomal prostaglandin E synthase-1 and decreased matrix enzymes (matrix metalloproteinase-1, -3, and -13 as well as a disintegrin and metalloproteinase with thrombospondin motifs-4 and -5) and further increasing anti-inflammatory cytokines such as vasoactive intestinal peptide. CONCLUSION: This study showed that PRP decreased pain and improved shoulder ROM and function to an extent comparable with that of a corticosteroid in patients with AC. Allogenic pure PRP acted in a pleiotropic manner and decreased proinflammatory cytokines only in the inflammatory condition. CLINICAL RELEVANCE: Allogenic PRP could be a treatment option for the inflammatory stage of AC.

Effects of corticosteroids and platelet-rich plasma on synoviocytes in IL-1ß-induced inflammatory condition.

AIMS: Corticosteroid injections are used to treat shoulder pain. Platelet-rich plasma (PRP) is known to have anti-inflammatory and anabolic effects, as well as cytoprotective effects against corticosteroids. Thus, this study was to investigate the effects of co-treatment of corticosteroid and PRP on anti-inflammatory and matrix homeostasis of synoviocytes in IL-1ß-induced inflammatory conditions. MATERIALS AND METHODS: Synoviocytes were cultured with 1 ng/mL IL-1ß, 1 µM dexamethasone, and 10% (vol/vol) Platelet-poor plasma (PPP), PRP200, PRP1000, and PRP4000 X 103/µL. Gene expressions of pro-inflammatory and anti-inflammatory cytokines, degradative enzymes, and their inhibitors were evaluated and protein synthesis of degradative enzymes and their inhibitors were also examined. RESULTS: Corticosteroid modulated anti-inflammatory and pro-inflammatory cytokines, and subsequent PRP treatment did not interfere with the effect of a corticosteroid and modulated the gene expressions of cytokines such as TNF-α and IL-4, which were not regulated by the corticosteroid alone. Gene expressions and protein expressions of degradative enzymes and their inhibitors were suppressed by corticosteroid. Additional PRPs did not alter the gene expression and protein regulated by the corticosteroid and inhibited the gene expression of ADAMTS-5 and protein synthesis of MMP-9 and ADAMTS-5, which were not modulated by the corticosteroid alone. CONCLUSION: Corticosteroid regulated the inflammation and synovial homeostasis. When PRP and the corticosteroid were used together, it exhibited synergistic effects on synoviocytes by regulating the parts that were not controlled by corticosteroid alone while not interfering with the effects of the corticosteroid in an inflammatory condition.

Regeneration of a full-thickness defect in rotator cuff tendon with umbilical cord-derived mesenchymal stem cells in a rat model.

Although rotator cuff disease is a common cause of shoulder pain, there is still no treatment method that could halt or reveres its development and progression. The purpose of this study was to investigate the efficacy of umbilical cord-derived mesenchymal stem cells (UC MSCs) on the regeneration of a full-thickness rotator cuff defect (FTD) in a rat model. We injected either UC MSCs or saline to the FTD and investigated macroscopic, histological and biomechanical results and cell trafficking. Treatment with UC MSCs improved macroscopic appearance in terms of tendon thickness at two weeks, and inflammation, defect size, swelling/redness and connection surrounding tissue and slidability at four weeks compared to the saline group. Histologically, UC MSCs induced the tendon matrix formation recovering collagen organization, nuclear aspect ratio and orientation angle of fibroblast as well as suppressing cartilage-related glycosaminoglycan compared to saline group at four weeks. The UC MSCs group also improved ultimate failure load by 25.0% and 19.0% and ultimate stress by 27.3% and 26.8% at two and four weeks compared to saline group. UC MSCs labeled with PKH26 exhibited 5.3% survival at four weeks compared to three hours after injection. This study demonstrated that UC MSCs regenerated the FTD with tendon tissue similar properties to the normal tendon in terms of macroscopic, histological and biomechanical characteristics in a rat model.

Allogeneic Platelet-Rich Plasma Versus Corticosteroid Injection for the Treatment of Rotator Cuff Disease: A Randomized Controlled Trial.

BACKGROUND: The use of platelet-rich plasma (PRP) for the treatment of rotator cuff disease is still controversial. The purpose of the present study was to investigate the safety and efficacy of a fully characterized allogeneic pure PRP injection into the subacromial space of patients with rotator cuff disease in comparison with corticosteroid injection. METHODS: A 2-group, parallel, assessor-blinded, randomized controlled trial was conducted. A total of 60 patients with clinically and structurally diagnosed rotator cuff disease were randomly assigned to receive a subacromial injection of either 4 mL of allogeneic pure PRP or a 4-mL mixture of 1 mL of 40-mg/mL triamcinolone acetonide and 3 mL of 2% lidocaine under ultrasonographic guidance. The primary outcomes were safety and the Constant score at 1 month. The secondary outcomes were pain, range of motion, muscle strength, functional scores, and overall satisfaction and function. RESULTS: There were no treatment-related adverse events. The Constant score at 1 month did not significantly differ between the PRP and corticosteroid groups. At 6 months, the DASH (Disabilities of the Arm, Shoulder and Hand) score, overall function, and external rotation were significantly better in the PRP group than in the corticosteroid group, and the other clinical outcomes did not show significant differences. All pain measurements, the strength of the supraspinatus and infraspinatus, and 5 functional scores also improved slowly and steadily after injection, becoming significantly better at 6 months compared with those before the injection, whereas those in the corticosteroid group responded promptly but did not further improve. CONCLUSIONS: Allogeneic PRP injections for the treatment of rotator cuff disease are safe but are not definitely superior to corticosteroid injections with respect to pain relief and functional improvement during 6 months. The DASH score, overall function, and external rotation were significantly better in the PRP group than in the steroid group at 6 months. Generally, PRP slowly but steadily reduced pain and improved function of the shoulder until 6 months, whereas corticosteroid did not. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

Regeneration of a full-thickness defect of rotator cuff tendon with freshly thawed umbilical cord-derived mesenchymal stem cells in a rat model.

BACKGROUND: It is difficult to immediately use mesenchymal stem cells (MSCs) for the patient with rotator cuff disease because isolation and culture time are required. Thus, the MSCs would be prepared in advanced in cryopreserved condition for an "off-the-shelf" usage in clinic. This study investigated the efficacy of freshly thawed MSCs on the regeneration of a full-thickness tendon defect (FTD) of rotator cuff tendon in a rat model. METHODS: We evaluated morphology, viability, and proliferation of cultured umbilical cord-derived MSCs (C-UC MSCs) and freshly thawed umbilical cord-derived MSCs (T-UC MSCs) at passage 10 in vitro. In animal experiments, we created a FTD in the supraspinatus of rats and injected the injured tendon with saline, cryopreserved agent (CPA; control), C-UC MSCs, and T-UC MSCs, respectively. Two and 4 weeks later, macroscopic, histological, biomechanical, and cell trafficking were evaluated. T test and ANOVA were used with SPSS. Differences with p < .05 were considered statistically significant. RESULTS: T-UC MSCs had fibroblast-like morphology and showed greater than 97% viability and stable proliferation comparable to the C-UC MSCs at passage 10. In animal experiments, compared with the control group, the macroscopic appearance of the T-UC MSCs was more recovered at 2 and 4 weeks such as inflammation, defect size, neighboring tendon, swelling/redness, the connecting surrounding tissue and slidability. Histologically, the nuclear aspect ratio, orientation angle of fibroblasts, collagen organization, and fiber coherence were improved by 33.33%, 42.75%, 1.86-fold, and 1.99-fold at 4 weeks, and GAG-rich area decreased by 88.13% and 94.70% at 2 and 4 weeks respectively. Further, the T-UC MSCs showed enhanced ultimate failure load by 1.55- and 1.25-fold compared with the control group at both 2 and 4 weeks. All the improved values of T-UC MSCs were comparable to those of C-UC MSCs. Moreover, T-UC MSCs remained 8.77% at 4 weeks after injury, and there was no significant difference between C-UC MSCs and T-UC MSCs. CONCLUSIONS: The morphology, viability, and proliferation of T-UC MSCs were comparable to those of C-UC MSCs. Treatment with T-UC MSCs could induce tendon regeneration of FTD at the macroscopic, histological, and biomechanical levels comparable to treatment with C-UC MSCs.

Regeneration of the rotator cuff tendon-to-bone interface using umbilical cord-derived mesenchymal stem cells and gradient extracellular matrix scaffolds from adipose tissue in a rat model.

Regeneration of the gradient structure of the tendon-to-bone interface (TBI) is a crucial goal after rotator cuff repair. The purpose of this study was to investigate the efficacy of a biomimetic hydroxyapatite-gradient scaffold (HA-G scaffold) isolated from adipose tissue (AD) with umbilical cord derived mesenchymal stem cells (UC MSCs) on the regeneration of the structure of the TBI by analyzing the histological and biomechanical changes in a rat repair model. As a result, the HA-G scaffold had progressively increased numbers of hydroxyapatite (HA) particles from the tendon to the bone phase. After seeding UC MSCs to the scaffold, specific matrices, such as collagen, glycoaminoglycan, and calcium, were synthesized with respect to the HA density. In a rat repair model, compared to the repair group, the UC MSCs seeded HA-G scaffold group had improved collagen organization and cartilage formation by 52% at 8 weeks and 262.96% at 4 weeks respectively. Moreover, ultimate failure load also increased by 30.71% at 4 weeks in the UC MSCs seeded HA-G scaffold group compared to the repair group. Especially, the improved values were comparable to values in normal tissue. This study demonstrated that HA-G scaffold isolated from AD induced UC MSCs to form tendon, cartilage and bone matrices similar to the TBI structure according to the HA density. Furthermore, UC MSC-seeded HA-G scaffold regenerated the TBI of the rotator cuff in a rat repair model in terms of histological and biomechanical properties similar to the normal TBI. Statement of Significance We found specific extracellular matrix (ECM) formation in the biomimetic-hydroxyapatite-gradient-scaffold (HA-G-scaffold) in vitro as well as improved histological and biomechanical results of repaired rotator cuff after the scaffold implantation in a rat model. This study has four strengths; An ECM scaffold derived from human adipose tissue; only one-layer used for a gradient scaffold not a multilayer used to mimic the unique structure of the gradient tendon-to-bone-interface (TBI) of the rotator cuff; UC-MSCs as a new cell source for TBI regeneration; and the UC-MSCs synthesized specific matrices with respect to the HA density without any other stimuli. This study suggested that the UC-MSC seeded HA-G-scaffold could be used as a promising strategy for the regeneration of rotator cuff tears.

Intratendinous Injection of Mesenchymal Stem Cells for the Treatment of Rotator Cuff Disease: A 2-Year Follow-Up Study.

PURPOSE: To assess the mid-term safety and efficacy of an intratendinous injection of autologous adipose tissue-derived mesenchymal stem cells (AD MSCs) for rotator cuff disease at 2-year follow-up. METHODS: The first part of the study consisted of 3 dose-escalation groups, with 3 patients each, for the evaluation of safety: low-dose (1.0 × 107 cells), mid-dose (5.0 × 107), and high-dose (1.0 × 108) groups. For the second part, we planned to include 9 patients receiving the high dose for the evaluation of exploratory efficacy. Clinical outcomes were assessed according to pain, range of motion, muscle strength, functional scores, overall satisfaction and function, and presence of failure. Structural outcomes included changes in volume of tendon defects measured using magnetic resonance imaging. RESULTS: This study enrolled 19 patients (9 for the first part and 10 for the second part) with partial-thickness rotator cuff tears. There were no treatment-related adverse events at minimum 2-year follow-up. Intratendinous injection of AD MSCs reduced shoulder pain by approximately 90% at 1 and 2 years in the mid- and high-dose groups. The strength of the supraspinatus, infraspinatus, and teres minor significantly increased by greater than 50% at 2 years in the high-dose group. Shoulder function measured with 6 commonly used scores improved for up to 2 years in all dose groups. Structural outcomes evaluated with magnetic resonance imaging showed that the volume of bursal-sided defects in the high-dose group nearly disappeared at 1 year and did not recur at up to 2 years. No failures-defined as the performance of any kind of shoulder surgery or return of the Shoulder Pain and Disability Index score to the preinjection level-occurred during follow-up. CONCLUSIONS: This study showed continued safety and efficacy of an intratendinous injection of AD MSCs for the treatment of partial-thickness rotator cuff tears over a 2-year period through regeneration of tendon defects. LEVEL OF EVIDENCE: Level III, retrospective comparative study.

Characterization of Tendon-Specific Markers in Various Human Tissues, Tenocytes and Mesenchymal Stem Cells.

Background: Unlike bone, cartilage, or muscle, tendon-specific markers are not well established. The purpose of the study was to investigate expression pattern and level of 6 well-known tendon-specific markers, in various human musculoskeletal tissues, tenocytes, and mesenchymal stem cells (MSCs). Methods: Musculoskeletal tissue samples of tendon, bone, cartilage, nerve, muscle, and fat were obtained from patients undergoing orthopedic surgery. Tenocytes, MSCs from bone marrow, adipose tissue, and umbilical cord were isolated from each tissue and cultured. Six tendon-specific markers, scleraxis (Scx), tenomodulin (TNMD), thrombospondin-4 (TSP-4), tenascin-C (TNC), type I collagen (Col I), and type III collagen (Col III) were investigated in tendon tissue, tenocytes, and MSCs. Results: mRNA levels of 6 tendon-specific markers were significantly higher in tendon tissue that in other connective tissues levels of Scx, TNMD, TSP-4, and Col III immediately decreased after plating tenocytes in culture dishes whereas those of TNC and Col I did not. In comparison with tendon tissue, mRNA levels pattern of Scx, TNMD, and TSP-4 in tenocytes were significantly higher than that in MSCs, but lower than in tendon tissue whereas expression pattern of TNC, Col I and III showed different pattern with each other. Conclusion: This study demonstrated that 6 commonly used tendon-specific markers were mainly expressed in tendon tissue, but that expression level and pattern of the tendon-specific markers with respect to kinds of tissues, culture duration of tenocytes and sources of MSCs.

Anterior capsular abnormality: another important MRI finding for the diagnosis of adhesive capsulitis of the shoulder.

OBJECTIVE: To evaluate the usefulness of anterior capsular abnormality, thickening, and abnormal signal intensity on MRI for the diagnosis of adhesive capsulitis of the shoulder. MATERIALS AND METHODS: This retrospective study included 29 patients with adhesive capsulitis and 20 controls. Clinical criteria with significant restricted passive motion was used for the diagnosis of adhesive capsulitis. The anterior capsular thickness and signal intensity were evaluated on the thickest portion of anterior glenohumeral joint capsule, located deep to the subscapularis muscle. In addition, the previously known MR findings of adhesive capsulitis, such as humeral and glenoid capsular thickness in axillary recess, maximal axillary capsular thickness, and coracohumeral ligament thickness, were measured. The presence of humeral and glenoid capsular abnormal hyperintensity in axillary recess, abnormal hyperintensity, and obliteration of the subcoracoid fat triangle were also evaluated. RESULTS: All MRI findings significantly differed between adhesive capsulitis and controls. Among MR findings, multivariable analysis showed that anterior capsular thickness, maximal axillary capsular thickness, and anterior capsular abnormal hyperintensity were variables that could differentiate adhesive capsulitis from the control group, with odds ratios of 7.97, 17.75, and 12.41, respectively (p < 0.05). In ROC analysis, the anterior capsular thickness showed high diagnostic performances with an AUC of 0.897. The cut-off value of anterior capsular thickness at 3.5 mm showed excellent diagnostic accuracy, with sensitivity of 68.97% and specificity of 100%. CONCLUSIONS: Anterior capsular abnormality, thickening, and abnormal hyperintensity can be used for the diagnosis of adhesive capsulitis of shoulder, in addition to previously known abnormal MRI findings.