Anterior Cruciate Ligament Reconstruction Plus Lateral Extra-articular Tenodesis Has a Similar Return-to-Sport Rate to Anterior Cruciate Ligament Reconstruction Alone but a Lower Failure Rate.

PURPOSE: To determine whether the addition of lateral extra-articular tenodesis (LET) to anterior cruciate ligament reconstruction (ACLR) would improve return-to-sport (RTS) rates in young, active patients who play high-risk sports. METHODS: This multicenter randomized controlled trial compared standard hamstring tendon ACLR with combined ACLR and LET using a strip of the iliotibial band (modified Lemaire technique). Patients aged 25 years or younger with an anterior cruciate ligament-deficient knee were included. Patients also had to meet 2 of the following criteria: (1) pivot-shift grade 2 or greater, (2) participation in a high-risk or pivoting sport, and (3) generalized ligamentous laxity. Time to return and level of RTS were determined via administration of a questionnaire at 24 months postoperatively. RESULTS: We randomized 618 patients in this study, 553 of whom played high-risk sports preoperatively. The proportion of patients who did not RTS was similar between the ACLR (11%) and ACLR-LET (14%) groups; however, the graft rupture rate was significantly different (11.2% in ACLR group vs 4.1% in ACLR-LET group, P = .004). The most cited reason for no RTS was lack of confidence and/or fear of reinjury. A stable knee was associated with nearly 2 times greater odds of returning to a high-level high-risk sport postoperatively (odds ratio, 1.92; 95% confidence interval, 1.11-3.35; P = .02). There were no significant differences in patient-reported functional outcomes or hop test results between groups (P > .05). Patients who returned to high-risk sports had better hamstring symmetry than those who did not RTS (P = .001). CONCLUSIONS: At 24 months postoperatively, patients who underwent ACLR plus LET had a similar RTS rate to those who underwent ACLR alone. Although the subgroup analysis did not show a statistically significant increase in RTS with the addition of LET, on returning, the addition of LET kept subjects playing longer by reducing graft failure rates. LEVEL OF EVIDENCE: Level I, randomized controlled trial.

Exposure to oxLDL impairs TGF-ß activity in human tendon cells.

BACKGROUND: Previous studies have shown that patients with hypercholesterolemia experience elevated levels of oxidized LDL (oxLDL), a molecule which triggers inflammation and collagenase activity. In this study we discovered novel mechanistic effects of oxLDL on tendon cells and the mediators regulating matrix remodeling by analyzing the expression and activity of related proteins and enzymes. These effects may contribute to tendon damage in patients with high cholesterol. METHODS: Isolated human tendon cells (male and female donors age 28 ± 1.4 age 37 ± 5.7, respectively) were incubated in the presence or absence of oxLDL. The influence of oxLDL on the expression level of key mRNA and proteins was examined using real time quantitative PCR, ELISA and Western blots. The activities of enzymes relevant to collagen synthesis and breakdown (lysyl oxidase and matrix metalloproteinases) were quantified using fluorometry. Finally, the isolated human tendon cells in a 3D construct were exposed to combinations of oxLDL and TGF-ß to examine their interacting effects on collagen matrix remodeling. RESULTS: The one-way ANOVA of gene expression indicates that key mRNAs including TGFB, COL1A1, DCN, and LOX were significantly reduced in human tendon cells by oxLDL while MMPs were increased. The oxLDL reduced the activity of LOX at 50 µg/ml, whereas conversely MMP activities were induced at 25 µg/ml (P ≤ 0.01). COL1A1 synthesis and TGF-ß secretion were also inhibited (P ≤ 0.05). Adding recombinant TGF-ß reversed the effects of oxLDL on the expression of collagens and LOX. OxLDL also impaired collagen matrix remodeling (P ≤ 0.01), and adding TGF-ß restored the native phenotype. CONCLUSION: Exposure to oxLDL in patients with hypercholesterolemia may adversely affect the mechanical and structural properties of tendon tissue through a direct action of oxLDL on tendon cells, including impairment of TGF-ß expression. This impairment leads to disturbed matrix remodeling and synthesis, thereby potentially leading to increased risk of acute or chronic tendon injury. Our discovery may provide an opportunity for developing effective treatments for tendon injury in hypercholesterolemia patients by targeting the TGF-ß pathway.

Performance of 5-Strand Hamstring Autograft Anterior Cruciate Ligament Reconstruction in the STABILITY Study: A Subgroup Analysis.

BACKGROUND: Anterior cruciate ligament (ACL) reconstructions (ACLRs) with graft diameters <8mm have been shown to have higher revision rates. The 5-strand (5S) hamstring autograft configuration is a proposed option to increase graft diameter. PURPOSE: To investigate the differences in clinical outcomes between 4-strand (4S) and 5S hamstring autografts for ACLR in patients who underwent ACLR alone or concomitantly with a lateral extra-articular tenodesis (LET) procedure. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: Data from the STABILITY study were analyzed to compare a subgroup of patients undergoing ACLR alone or with a concomitant LET procedure (ACLR + LET) with a minimum graft diameter of 8mm that had either a 4S or 5S hamstring autograft configuration. The primary outcome was clinical failure, a composite of rotatory laxity and/or graft failure. The secondary outcome measures consisted of 2 patient-reported outcome scores (PROs)-namely, the ACL Quality of Life Questionnaire (ACL-QoL) and the International Knee Documentation Committee (IKDC) score at 24 months postoperatively. RESULTS: Of the 618 patients randomized in the STABILITY study, 399 (228 male; 57%) fit the inclusion criteria for this study. Of these, 191 and 208 patients underwent 4S and 5S configurations of hamstring ACLR, respectively, with a minimum graft diameter of 8mm. Both groups had similar characteristics other than differences in anthropometric factors-namely, sex, height, and weight, and Beighton scores. The primary outcomes revealed no difference between the 2 groups in rotatory stability (odds ratio [OR], 1.19; 95% CI, 0.77-1.84; P = .42) or graft failure (OR, 1.13; 95% CI, 0.51-2.50; P = .76). There was no significant difference between the groups in Lachman (P = .46) and pivot-shift (P = .53) test results at 24 months postoperatively. The secondary outcomes revealed no differences in the ACL-QoL (P = .67) and IKDC (P = .83) scores between the 2 subgroups. CONCLUSION: At the 24-month follow-up, there were no significant differences in clinical failure rates and PROs in an analysis of patients with 4S and 5S hamstring autografts of ≥8mm diameter for ACLR or ACLR + LET. The 5S hamstring graft configuration is a viable option to produce larger-diameter ACL grafts.

Predictors of Graft Failure in Young Active Patients Undergoing Hamstring Autograft Anterior Cruciate Ligament Reconstruction With or Without a Lateral Extra-articular Tenodesis: The Stability Experience.

BACKGROUND: Anterior cruciate ligament (ACL) reconstruction (ACLR) has higher failure rates in young active patients returning to sports as compared with older, less active individuals. Augmentation of ACLR with an anterolateral procedure has been shown to reduce failure rates; however, indications for this procedure have yet to be clearly defined. PURPOSE/HYPOTHESIS: The purpose of this study was to identify predictors of ACL graft failure in high-risk patients and determine key indications for when hamstring ACLR should be augmented by a lateral extra-articular tenodesis (LET). We hypothesized that different preoperative characteristics and surgical variables may be associated with graft failure characterized by asymmetric pivot shift and graft rupture. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: Data were obtained from the Stability 1 Study, a multicenter randomized controlled trial of young active patients undergoing autologous hamstring ACLR with or without a LET. We performed 2 multivariable logistic regression analyses, with asymmetric pivot shift and graft rupture as the dependent variables. The following were included as predictors: LET, age, sex, graft diameter, tear chronicity, preoperative high-grade knee laxity, preoperative hyperextension on the contralateral side, medial meniscal repair/excision, lateral meniscal repair/excision, posterior tibial slope angle, and return-to-sports exposure time and level. RESULTS: Of the 618 patients in the Stability 1 Study, 568 with a mean age of 18.8 years (292 female; 51.4%) were included in this analysis. Asymmetric pivot shift occurred in 152 (26.8%) and graft rupture in 43 (7.6%). The addition of a LET (odds ratio [OR], 0.56; 95% CI, 0.37-0.83) and increased graft diameter (OR, 0.62; 95% CI, 0.44-0.87) were significantly associated with lower odds of asymmetric pivot shift. The addition of a LET (OR, 0.40; 95% CI, 0.18-0.91) and older age (OR, 0.83; 95% CI, 0.72-0.96) significantly reduced the odds of graft rupture, while greater tibial slope (OR, 1.15; 95% CI, 1.01-1.32), preoperative high-grade knee laxity (OR, 3.27; 95% CI, 1.45-7.41), and greater exposure time to sport (ie, earlier return to sport) (OR, 1.18; 95% CI, 1.08-1.29) were significantly associated with greater odds of rupture. CONCLUSION: The addition of a LET and larger graft diameter were significantly associated with reduced odds of asymmetric pivot shift. Adding a LET was protective of graft rupture, while younger age, greater posterior tibial slope, high-grade knee laxity, and earlier return to sport were associated with increased odds of graft rupture. Orthopaedic surgeons should consider supplementing hamstring autograft ACLR with a LET in young active patients with morphological characteristics that make them at high risk of reinjury.

Association of Ligamentous Laxity, Male Sex, Chronicity, Meniscal Injury, and Posterior Tibial Slope With a High-Grade Preoperative Pivot Shift: A Post Hoc Analysis of the STABILITY Study.

BACKGROUND: A spectrum of anterolateral rotatory laxity exists in anterior cruciate ligament (ACL)-injured knees. Understanding of the factors contributing to a high-grade pivot shift continues to be refined. PURPOSE: To investigate factors associated with a high-grade preoperative pivot shift and to evaluate the relationship between this condition and baseline patient-reported outcome measures (PROMs). STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: A post hoc analysis was performed of 618 patients with ACL deficiency deemed high risk for reinjury. A binary logistic regression model was developed, with high-grade pivot shift as the dependent variable. Age, sex, Beighton score, chronicity of the ACL injury, posterior third medial or lateral meniscal injury, and tibial slope were selected as independent variables. The importance of knee hyperextension as a component of the Beighton score was assessed using receiver operator characteristic curves. Baseline PROMs were compared between patients with and without a high-grade pivot. RESULTS: Six factors were associated with a high-grade pivot shift: Beighton score (each additional point; odds ratio [OR], 1.17; 95% CI, 1.06-1.30; P = .002), male sex (OR, 2.30; 95% CI, 1.28-4.13; P = .005), presence of a posterior third medial (OR, 2.55; 95% CI, 1.11-5.84; P = .03) or lateral (OR, 1.76; 95% CI, 1.01-3.08; P = .048) meniscal injury, tibial slope >9° (OR, 2.35; 95% CI, 1.09-5.07; P = .03), and chronicity >6 months (OR, 1.70; 95% CI, 1.00-2.88; P = .049). The presence of knee hyperextension improved the diagnostic utility of the Beighton score as a predictor of a high-grade pivot shift. Tibial slope <9° was associated with only a high-grade pivot in the presence of a posterior third medial meniscal injury. Patients with a high-grade pivot shift had higher baseline 4-Item Pain Intensity Measure scores than did those without a high-grade pivot shift (mean ± SD, 11 ± 13 vs 8 ± 14; P = .04); however, there was no difference between groups in baseline International Knee Documentation Committee, ACL Quality of Life, Knee injury and Osteoarthritis Outcome Score, or Knee injury and Osteoarthritis Outcome Score subscale scores. CONCLUSION: Ligamentous laxity, male sex, posterior third medial or lateral meniscal injury, increased posterior tibial slope, and chronicity were associated with a high-grade pivot shift in this population deemed high risk for repeat ACL injury. The effect of tibial slope may be accentuated by the presence of meniscal injury, supporting the need for meniscal preservation. Baseline PROMs were similar between patients with and without a high-grade pivot shift.

ß1 integrin, ILK and mTOR regulate collagen synthesis in mechanically loaded tendon cells.

Tendons are specialized tissues composed primarily of load-responsive fibroblasts (tenocytes) embedded in a collagen-rich extracellular matrix. Habitual mechanical loading or targeted exercise causes tendon cells to increase the stiffness of the extracellular matrix; this adaptation may occur in part through collagen synthesis or remodeling. Integrins are likely to play an important role in transmitting mechanical stimuli from the extracellular matrix to tendon cells, thereby triggering cell signaling pathways which lead to adaptive regulation of mRNA translation and protein synthesis. In this study, we discovered that mechanical stimulation of integrin ß1 leads to the phosphorylation of AKT, an event which required the presence of integrin-linked kinase (ILK). Repetitive stretching of tendon cells activates the AKT and mTOR pathways, which in turn regulates mRNA translation and collagen expression. These results support a model in which integrins are an upstream component of the mechanosensory cellular apparatus, regulating fundamental tendon cell functions relevant to exercise-induced adaptation and mechanotherapy.

Lateral Extra-articular Tenodesis Reduces Failure of Hamstring Tendon Autograft Anterior Cruciate Ligament Reconstruction: 2-Year Outcomes From the STABILITY Study Randomized Clinical Trial.

BACKGROUND: Persistent anterolateral rotatory laxity after anterior cruciate ligament (ACL) reconstruction (ACLR) has been correlated with poor clinical outcomes and graft failure. HYPOTHESIS: We hypothesized that a single-bundle, hamstring ACLR in combination with a lateral extra-articular tenodesis (LET) would reduce the risk of ACLR failure in young, active individuals. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: This is a multicenter, prospective, randomized clinical trial comparing a single-bundle, hamstring tendon ACLR with or without LET performed using a strip of iliotibial band. Patients 25 years or younger with an ACL-deficient knee were included and also had to meet at least 2 of the following 3 criteria: (1) grade 2 pivot shift or greater, (2) a desire to return to high-risk/pivoting sports, (3) and generalized ligamentous laxity (GLL). The primary outcome was ACLR clinical failure, a composite measure of rotatory laxity or a graft rupture. Secondary outcome measures included the P4 pain scale, Marx Activity Rating Scale, Knee injury Osteoarthritis and Outcome Score (KOOS), International Knee Documentation Committee score, and ACL Quality of Life Questionnaire. Patients were reviewed at 3, 6, 12, and 24 months postoperatively. RESULTS: A total of 618 patients (297 males; 48%) with a mean age of 18.9 years (range, 14-25 years) were randomized. A total of 436 (87.9%) patients presented preoperatively with high-grade rotatory laxity (grade 2 pivot shift or greater), and 215 (42.1%) were diagnosed as having GLL. There were 18 patients lost to follow-up and 11 who withdrew (~5%). In the ACLR group, 120/298 (40%) patients sustained the primary outcome of clinical failure, compared with 72/291 (25%) in the ACLR+LET group (relative risk reduction [RRR], 0.38; 95% CI, 0.21-0.52; P < .0001). A total of 45 patients experienced graft rupture, 34/298 (11%) in the ACLR group compared with 11/291 (4%) in the ACL+LET group (RRR, 0.67; 95% CI, 0.36-0.83; P < .001). The number needed to treat with LET to prevent 1 patient from graft rupture was 14.3 over the first 2 postoperative years. At 3 months, patients in the ACLR group had less pain as measured by the P4 (P = .003) and KOOS (P = .007), with KOOS pain persisting in favor of the ACLR group to 6 months (P = .02). No clinically important differences in patient-reported outcome measures were found between groups at other time points. The level of sports activity was similar between groups at 2 years after surgery, as measured by the Marx Activity Rating Scale (P = .11). CONCLUSION: The addition of LET to a single-bundle hamstring tendon autograft ACLR in young patients at high risk of failure results in a statistically significant, clinically relevant reduction in graft rupture and persistent rotatory laxity at 2 years after surgery. REGISTRATION: NCT02018354 ( ClinicalTrials.gov identifier).

The effect of wedge and tibial slope angles on knee contact pressure and kinematics following medial opening-wedge high tibial osteotomy.

BACKGROUND: High tibial osteotomy is a surgical procedure to treat medial compartment osteoarthritis in varus knees. The reported success rates of the procedure are inconsistent, which may be due to sagittal plane alignment of the osteotomy. The objective of this study was to determine the effect of changing tibial slope, for a range of tibial wedge angles in high tibial osteotomy, on knee joint contact pressure location and kinematics during continuous loaded flexion/extension. METHODS: Seven cadaveric knee specimens were cycled through flexion and extension in an Oxford knee-loading rig. The osteotomy on each specimen was adjusted to seven clinically relevant wedge and slope combinations. We used pressure sensors to determine the position of the centre of pressure in each compartment of the tibial plateau and infrared motion capture markers to determine tibiofemoral and patellofemoral kinematics. FINDINGS: In early knee flexion, a 5° increase in tibial slope shifted the centre of pressure in the medial compartment anteriorly by 4.5mm (P≤0.001), (from the neutral slope/wedge position). Increasing the tibial slope also resulted in the tibia translating anteriorly (P≤0.001). INTERPRETATION: Changes to the tibial slope during high tibial osteotomy for all tested wedge angles shifted the centre of pressure in both the medial and lateral compartments substantially and altered knee kinematics. Tibial slope should be controlled during high tibial osteotomy to prevent unwanted changes in tibial plateau contact loads.

Angiopoietin-like 4 Enhances the Proliferation and Migration of Tendon Fibroblasts.

PURPOSE: Angiopoietin-like 4 (ANGPTL4) is known to play a variety of roles in the response to exercise, and more recently has been shown to enhance the healing of tendon, a fibrous load-bearing tissue required for efficient movement. The objective of the current study was to further explore the mechanisms of ANGPTL4's effect on tendon cells using a gene array approach. METHODS: Human tendon fibroblasts were treated with recANGPTL4 and their global transcriptome response analyzed after 4 and 24 h. We also conducted functional studies using tendon fibroblasts derived from human subjects, cultured in the presence or absence of applied cyclic stretch and/or siRNA for ANGPTL4, and as confirmation we also used tendon cells from wild type (ANGPTL4 +/+) or knockout (ANGPTL4-/-) mice. RESULTS: The leading functions of ANGPTL4 predicted by the resulting pathway analysis were cell movement and proliferation. The experiments demonstrated that ANGPTL4 significantly enhanced tendon cell proliferation and the cell cycle progression, as well as adhesion and migration. CONCLUSION: Taken together, these findings provide novel molecular insights into the effect of ANGPTL4, a multifunctional protein that regulates the physiological response to exercise, on fundamental tendon cell functions.

Angiopoietin-like 4 promotes angiogenesis in the tendon and is increased in cyclically loaded tendon fibroblasts.

KEY POINTS: Angiopoietin-like 4 (ANGPTL4) modulates tendon neovascularization. Cyclic loading stimulates the activity of transforming growth factor-ß and hypoxia-inducible factor 1α and thereby increases the expression and release of ANGPTL4 from human tendon cells. Targeting ANGPTL4 and its regulatory pathways is a potential avenue for regulating tendon vascularization to improve tendon healing or adaptation. ABSTRACT: The mechanisms that regulate angiogenic activity in injured or mechanically loaded tendons are poorly understood. The present study examined the potential role of angiopoietin-like 4 (ANGPTL4) in the angiogenic response of tendons subjected to repetitive mechanical loading or injury. Cyclic stretching of human tendon fibroblasts stimulated the expression and release of ANGPTL4 protein via transforming growth factor-ß (TGF-ß) and hypoxia-inducible factor 1α (HIF-1α) signalling, and the released ANGPTL4 was pro-angiogenic. Angiogenic activity was increased following ANGPTL4 injection into mouse patellar tendons, whereas the patellar tendons of ANGPTL4 knockout mice displayed reduced angiogenesis following injury. In human rotator cuff tendons, the expression of ANGPTL4 was correlated with the density of tendon endothelial cells. To our knowledge, this is the first study characterizing a role of ANGPTL4 in the tendon. ANGPTL4 may assist in the regulation of vascularity in the injured or mechanically loaded tendon. TGF-ß and HIF-1α comprise two signalling pathways that modulate the expression of ANGPTL4 by mechanically stimulated tendon fibroblasts and, in the future, these could be manipulated to influence tendon healing or adaptation.

Chondroinduction Is the Main Cartilage Repair Response to Microfracture and Microfracture With BST-CarGel: Results as Shown by ICRS-II Histological Scoring and a Novel Zonal Collagen Type Scoring Method of Human Clinical Biopsy Specimens.

BACKGROUND: Current cartilage repair histological scoring systems are unable to explain the relationship between collagen type II deposition and overall repair quality. PURPOSE/HYPOTHESIS: The purpose of this study was to develop a novel zonal collagen type (ZCT) 5-point scoring system to measure chondroinduction in human clinical biopsy specimens collected after marrow stimulation. The hypothesis was that the ZCT scores would correlate with the International Cartilage Repair Society-II (ICRS-II) overall histological repair assessment score and glycosaminoglycan (GAG) content. STUDY DESIGN: Descriptive laboratory study. METHODS: After optimizing safranin O staining for GAG and immunostaining for human collagen type II and type I (Col2 and Col1, respectively), serial sections from clinical osteochondral repair biopsy specimens (13 months after microfracture or microfracture with BST-CarGel; n = 39 patients) were stained and 3 blinded readers performed histomorphometry for percentage of staining, ICRS-II histological scoring, polarized light microscopy (PLM) scoring, and 5-point ZCT scoring based on tidemark morphology, zonal distribution of Col2 and Col1, and Col1 percentage stain. Because 1 biopsy specimen was missing bone, 38 biopsy specimens were evaluated for ICRS-II, PLM, and ZCT scores. RESULTS: Chondroinduction was identified in 21 biopsy specimens as a Col2 matrix fused to bone that spanned the deep-middle-superficial zones ("full-thickness hyaline repair"), deep-middle zones, or deep zone ("stalled hyaline") that was covered with a variable-thickness Col1-positive matrix, and was scored, respectively, as ZCT = 1 (n = 4 biopsy specimens), ZCT = 2 (n = 6) and ZCT = 3 (n = 11). Other biopsy specimens (n = 17) were fibrocartilage (n = 9; ZCT = 4), fibrous tissue (n = 4, ZCT = 5), or non-marrow derived (n = 4; ZCT = 0). Non-marrow derived tissue had a mean mature tidemark score of 84 out of 100 versus a regenerating tidemark score of 24 for all other biopsy specimens (P = .005). Both "stalled hyaline" repair and fibrocartilage had the same mean Col2 percentage stain; however, fibrocartilage was distinguished by heavy Col1 deposits in the deep zone, a 2-fold higher mean Col1 percentage stain (P = .001), and lower surface integrity (P = .03). ZCT scores correlated with GAG content and the ICRS-II overall assessment score, especially when combined with the PLM score for collagen organization (R = 0.82). Histological scores of the deep zone strongly predicted the ICRS-II overall assessment score (R = 0.99). CONCLUSION: The ICRS-II overall repair assessment score and GAG content correlated with the extent of Col2 deposition free of fibrosis in the deep/middle zone rather than bulk accumulation of Col2. CLINICAL RELEVANCE: Biopsy tissue from the BST-CarGel randomized clinical trial (microfracture without and with BST-CarGel, as treatment groups were not unblinded) showed regenerated tissue consistent with a chondroinduction mechanism in at least half of the treated lesions.

Cartilage health in high tibial osteotomy using dGEMRIC: Relationships with joint kinematics.

PURPOSE: The aims of this study are to determine how opening-wedge high tibial osteotomy (HTO) affects cartilage health in the tibiofemoral (TF) joint and patella, and to explore relationships between TF and patellofemoral (PF) joint kinematics and cartilage health in HTO. METHODS: 14 knees (13 subjects) with medial TF osteoarthritis (OA) were examined before HTO and 6 and 12 months after HTO using delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) to evaluate cartilage health at the TF joint and patella. They were also examined using a validated 3D MR knee kinematics measurement to obtain 11 rotations and translations at both TF and PF joints. RESULTS: No statistically significant differences in overall TF or patellar dGEMRIC score were found at 6 or 12 months after HTO. However three subjects had large decreases (mean 105 ms) in TF dGEMRIC at 6 months that recovered at 12 months. Kinematics for these subjects were compared to subjects who did not have decreases in TF dGEMRIC at 6 months (n=5). Differences were observed between groups with HTO in anterior and proximal tibial translation (mean differences 3.05 mm and 1.35 mm), and patellar flexion (mean difference 3.65°). These changes were consistent between 6 and 12 months, despite recovery of TF dGEMRIC values. CONCLUSIONS: We did not find significant differences in TF or patellar dGEMRIC before and after HTO with all subjects, however there were differences in kinematics between subjects who had a decrease in TF dGEMRIC at 6 months and those who did not. This suggests a link between joint kinematics and cartilage health in HTO. CLINICAL RELEVANCE: The effect of opening-wedge high tibial osteotomy on cartilage GAG concentration may be linked to specific changes in knee kinematics following surgery.

Dexamethasone decreases substance P expression in human tendon cells: an in vitro study.

OBJECTIVE: Glucocorticoid injections are used by rheumatologists to treat chronic tendinopathy. Surprisingly, the mechanisms by which corticosteroids induce pain relief in this condition have not been investigated. Previous studies have shown local substance P (SP) levels to be correlated with tendon pain and tissue pathology. The objective of this study was to determine whether SP production in human tenocytes is modulated by exposure to dexamethasone. METHODS: Human tendon fibroblasts were cultured in the presence or absence of dexamethasone (1-400 nM), an inhibitor of the glucocorticoid receptor, RU486, recombinant TGF-ß (2.5 or 5.0 ng/ml) or an inhibitor of the TGF-ß receptor (A83.01), recombinant human IL-1ß and IL-6. Expression levels of the genes encoding for SP (TAC1) and its preferred receptor (NK1R), IL-1α, IL-1ß and IL-6 were determined with quantitative PCR and protein levels of SP were examined by EIA and western blot. RESULTS: Exposure of human tendon cells to dexamethasone resulted in a time-dependent reduction of mRNA for SP in both hamstrings and Achilles tenocytes, whereas NK1R was unaffected. The reduction of SP mRNA was dependent on signalling through the glucocorticoid receptor. SP protein was substantially decreased by dexamethasone. Dexamethasone also prevented induction of SP by IL-1ß and by cyclic mechanical loading. CONCLUSION: This study demonstrates that dexamethasone treatment of human tendon fibroblasts reduces the expression of SP through a glucocorticoid receptor-dependent pathway. Drugs interfering with SP signalling could be a future target in the treatment of tendinopathy.

Mechanism of mast cell adhesion to human tenocytes in vitro.

Mast cells and fibroblasts are two key players involved in many fibrotic and degenerative disorders. In the present study we examined the nature of binding interactions between human mast cells and tendon fibroblasts (tenocytes). In the mast cell-fibroblast co-culture model, mast cells were shown to spontaneously bind to tenocytes, in a process that was partially mediated by α5ß1 integrin receptors. The same receptors on mast cells significantly mediated binding of these cells to tissue culture plates in the presence of tenocyte-conditioned media; the tenocyte-derived fibronectin in the media was shown to also play a major role in these binding activities. Upon binding to tenocytes or tissue culture plates, mast cells acquired an elongated phenotype, which was dependent on α5ß1 integrin and tenocyte fibronectin. Additionally, tenocyte-derived fibronectin significantly enhanced mRNA expression of the adhesion molecule, THY1, by mast cells. Our data suggests that α5ß1 integrin mediates binding of mast cells to human tenocyte and to tenocyte-derived ECM proteins, in particular fibronectin.

Enhanced collagen type I synthesis by human tenocytes subjected to periodic in vitro mechanical stimulation.

BACKGROUND: Mechanical stimulation (e.g. slow heavy loading) has proven beneficial in the rehabilitation of chronic tendinopathy, however the optimal parameters of stimulation have not been experimentally determined. In this study of mechanically stimulated human tenocytes, the influence of rest insertion and cycle number on (1) the protein and mRNA levels of type I and III collagen; (2) the mRNA levels of transforming growth factor beta (TGFB1) and scleraxis (SCXA); and (3) tenocyte morphology, were assessed. METHODS: Human hamstring tenocytes were mechanically stimulated using a Flexcell® system. The stimulation regimens were 1) continuous and 2) rest-inserted cyclic equiaxial strain at a frequency of 0.1 Hz for 100 or 1000 cycles. Data were normalized to unstimulated (non-stretched) control groups for every experimental condition. qPCR was performed to determine relative mRNA levels and quantitative immunocytochemistry image analysis was used to assess protein levels and cell morphology. RESULTS: Collagen type I mRNA level and pro-collagen protein levels were higher in tenocytes that were subjected to rest-inserted mechanical stimulation, compared to continuous stretching (p<0.05). Rest insertion and increased cycle number also had significant positive effects on the levels of mRNA for TGFB1 and SCXA (p<0.05). There was no direct relation between cell morphology and gene expression, however mechanical stimulation, overall, induced a metabolically active tenocyte phenotype as evidenced by cells that on average demonstrated a decreased major-minor axis ratio (p<0.05) with greater branching (p<0.01). CONCLUSIONS: The incorporation of rest periods in a mechanical stretching regimen results in greater collagen type I synthesis. This knowledge may be beneficial in refining rehabilitation protocols for tendon injury.

Reoperation following open reduction and plate fixation of displaced mid-shaft clavicle fractures.

BACKGROUND: Operative fixation of displaced, mid-shaft clavicle fractures has become an increasingly common practice. With this emerging trend, data describing patient outcomes with longer follow-up are necessary. PATIENTS AND METHODS: We retrospectively reviewed the medical records of subjects treated with plate fixation for displaced mid-shaft clavicle fractures from 2003 to 2009 at a Level I trauma hospital. All subjects were greater than 12 months post-index surgery. Treatment involved ORIF with either a low-contact dynamic compression plate (LCDC) or a contoured plate (pre-contoured or pelvic reconstruction plate). Our primary outcome was reoperation for any indication. RESULTS: 143 subjects were included. The mean age was 36 ± 14 years and the mean time to reoperation or chart review was 33 months. Contoured plates were used in 64% of cases and LCDC plates were used in the remaining subjects. Twenty-nine subjects (20%) underwent reoperation: 23.5% of subjects treated with LCDC plates and 18.5% of subjects treated with contoured plates (p=0.52). Indications for reoperation included implant irritation (n=25), implant failure (n=2), and non-union (n=2). There was near statistically significant association with reoperation and female gender (p=0.05) but no association between reoperation and age (p=0.14), fracture class (p=0.53), plate type (p=0.49), or plate location (p=0.93). The mean QuickDASH score for the population surveyed was 8.8 (5.5-12.1; 95% CI) with near statistically significant and clinically relevant difference between those considering reoperation and those not 22.3 (8.6-36.0; 95% CI) versus 6.7 (3.6-9.8; 95% CI). CONCLUSIONS: This study represents a large series of displaced clavicle fractures treated with open reduction and plate fixation. Reoperation following plate fixation is relatively common, but primarily due to implant irritation. No difference in reoperation rates between plate types or location could be detected in our current sample size. Also, excellent functional outcomes continue to be observed several years after clavicle fracture fixation.

Cyclic strain alters the expression and release of angiogenic factors by human tendon cells.

Angiogenesis is associated with the tissue changes underlying chronic overuse tendinopathy. We hypothesized that repetitive, cyclic loading of human tendon cells would lead to increased expression and activity of angiogenic factors. We subjected isolated human tendon cells to overuse tensile loading using an in vitro model (1 Hz, 10% equibiaxial strain). We found that mechanically stimulated human tendon cells released factors that promoted in vitro proliferation and tube formation by human umbilical vein endothelial cells (HUVEC). In response to cyclic strain, there was a transient increase in the expression of several angiogenic genes including ANGPTL4, FGF-2, COX-2, SPHK1, TGF-alpha, VEGF-A and VEGF-C, with no change in anti-angiogenic genes (BAI1, SERPINF1, THBS1 and 2, TIMP1-3). Cyclic strain also resulted in the extracellular release of ANGPTL4 protein by tendon cells. Our study is the first report demonstrating the induction of ANGPTL4 mRNA and release of ANGPTL4 protein in response to cyclic strain. Tenocytes may contribute to the upregulation of angiogenesis during the development of overuse tendinopathy.

A physiotherapy triage service for orthopaedic surgery: an effective strategy for reducing wait times.

PURPOSE: To investigate the effectiveness of a physiotherapy triage service for orthopaedic surgery referrals from primary-care physicians. METHODS: A prospective, observational design was used with patients referred to an orthopaedic surgeon based out of two small urban centres in British Columbia. The level of agreement between the physiotherapist and surgeon was determined using a weighted kappa statistic (κw) with 95% CI. A patient satisfaction questionnaire was administered, and the surgical conversion rate (SCR) was calculated to assess the level of appropriate referrals. RESULTS: The analysis found substantial agreement (κw=0.77; 95% CI, 0.60-0.94) between surgeon and physiotherapist for surgical management decisions. All patients reported being "satisfied" or "very satisfied" with the overall care they received from the physiotherapist. The SCR of patients referred by the physiotherapist to the surgeon was 91%, versus 22% among patients referred by a general practitioner or emergency physician. CONCLUSION: More than three-fourths of patients referred by primary-care physicians did not need to see a surgeon and were able to be managed by an experienced orthopaedic physiotherapist. This triage model could have considerable impact on orthopaedic wait times in Canada by minimizing unnecessary referrals; the model could also promote timely and conservative management of non-surgical conditions by physiotherapists.

Objectif : Étudier l'efficacité d'un service de triage en physiothérapie pour aiguillages vers la chirurgie orthopédique provenant de médecins de premier recours. Méthodes : On a utilisé un concept d'observation prospective des patients référés à un chirurgien orthopédiste dans deux petites localités urbaines de la Colombie-Britannique. On a déterminé le niveau d'entente entre le physiothérapeute et le chirurgien en établissant une statistique kappa pondérée (weighted kappa, κw) comportant un IC à 95%. On a administré aux patients un questionnaire sur leur satisfaction et calculé un taux de conversion chirurgicale (TCC) afin d'évaluer le niveau des références appropriées. Résultats : L'analyse a révélé une convergence importante (κw=0,77; IC à 95%, 0,60 à 0,94) entre le chirurgien et le physiothérapeute sur le plan des décisions relatives à la prise en charge chirurgicale. Tous les patients se sont dits « satisfaits ¼ ou « très satisfaits ¼ des soins généraux qu'ils ont reçus du physiothérapeute. Le TCC des patients référés par le physiothérapeute au chirurgien s'est établi à 91% contre 22% chez les patients référés par un généraliste ou un urgentiste. Conclusion : Plus de trois quarts des patients référés à un chirurgien orthopédiste par des médecins de premier recours n'ont pas eu à consulter un chirurgien et ont été pris en charge par un physiothérapeute orthopédiste chevronné. Ce modèle de triage pourrait avoir un effet considérable sur les temps d'attente en orthopédie au Canada en réduisant au minimum les aiguillages inutiles. Le modèle pourrait aussi promouvoir une prise en charge rapide et conservatrice de problèmes non chirurgicaux par des physiothérapeutes.