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Objective Focal cartilage injuries are debilitating and difficult to treat. Biological cartilage repair procedures are used for patients younger than 40 years, and knee arthroplasties are generally reserved for patients older than 60 years. Resurfacing implants are well suited for patients in this treatment gap. The objective was to investigate the 10-year survival of resurfacing implants in the Danish Knee Arthroplasty Registry. Design In this retrospective cohort study, patients treated with resurfacing implants were followed longitudinally in the Danish Knee Arthroplasty Registry from 1997 to 2020. The primary endpoint was revision surgery. The survival of the resurfacing implants was analyzed by Kaplan-Meier method. Results A total of 379 resurfacing implant procedures were retrieved from the Danish Knee Arthroplasty Registry. The mean age and weight of patients were 50 years (SD = 11) and 84 kg (SD = 17), respectively. The indications for surgery were as follows: secondary osteoarthritis (42%), primary osteoarthritis (32%), and osteochondral lesions (20%). Within the follow-up period, 70 (19%) of the implants were revised to arthroplasties. The 1-, 5-, and 10-year revision-free survival estimation was 0.95 (95% CI 0.93-0.97), 0.84 (95% CI 0.80-0.88), and 0.80 (95% CI 0.75-0.84), respectively. The median time to revision was 2 years. Conclusion The 10-year revision-free survival rate for resurfacing implants was 80%. Based on the revision rates, this treatment offers a viable alternative to biological cartilage repair methods in patients aged 40 to 60 years with focal cartilage pathology. Improved patient selection could further improve the implant survival rate. Further studies are needed to investigate this treatment method.

Objective We sought to report on the demographics and epidemiology of knee cartilage injuries and preferred management in soccer players, across FIFA Medical Centers of Excellence (FMCE). Design A descriptive questionnaire focusing on characteristics of knee cartilage injuries and their management in soccer players during the 10-year period prior to the distribution of the questionnaire was sent to all FMCE around the world in September 2019 via an online platform. Voluntary responses from centers were processed and analyzed. Descriptive characteristics were reported using median and interquartile ranges (IQR) for continuous variables and frequencies and percentages (%) for discrete variables. Results A total of 15 centers from 5 continents responded to the questionnaire and reported on a total of 4526 soccer players. Among centers, the median age was 27 years (IQR: 23-38), the median rate of male players was 75% (IQR: 68-90), and the median rate of professional players was 10% (IQR: 5-23). The most common reported etiology for cartilage injury was traumatic (median 40%, IQR: 13-73). The most common nonoperative treatment utilized was physical therapy (median 90%, IQR: 51%-100%) and the most common operative treatment utilized was bone marrow stimulation/micro-fracture (median 40%, IQR: 19-54%). The utilization of other cartilage restoration procedures varied across centers. Conclusions Our findings highlight different tendencies in the management of these injuries across FMCE and emphasize the need for collaborative efforts focusing on establishing consensus guidelines for the optimal management of these challenging injuries in soccer players.

Objective The purpose of this study was to utilize fragility analysis to assess the robustness of randomized controlled trials (RCTs) evaluating the management of articular cartilage defects of the knee. We hypothesize that the cartilage restorative literature will be fragile with the reversal of only a few outcome events required to change statistical significance. Design RCTs from 11 orthopedic journals indexed on PubMed from 2000 to 2020 reporting dichotomous outcome measures relating to the management of articular cartilage defects of the knee were included. The Fragility Index (FI) for each outcome was calculated through the iterative reversal of a single outcome event until significance was reversed. The Fragility Quotient (FQ) was calculated by dividing each FI by study sample size. Additional statistical analysis was performed to provide median FI and FQ across subgroups. Results Nineteen RCTs containing 60 dichotomous outcomes were included for analysis. The FI and FQ of all outcomes was 4 (IQR 2-7) and 0.067 (IQR 0.034-0.096), respectively. The average number of patients lost to follow-up (LTF) was 3.9 patients with 15.8% of the included studies reporting LTF greater than or equal to 4, the FI of all included outcomes. Conclusions The orthopedic literature evaluating articular cartilage defects of the knee is fragile as the reversal of relatively few outcome events may alter the significance of statistical findings. We therefore recommend comprehensive fragility analysis and triple reporting of the P value, FI, and FQ to aid in the interpretation and contextualization of clinical findings reported in the cartilage restoration literature.

Objective Joint injuries may lead to degeneration of cartilage tissue and initiate development of posttraumatic osteoarthritis. Arthroscopic surgeries can be used to treat joint injuries, but arthroscopic evaluation of articular cartilage quality is subjective. Fourier transform infrared spectroscopy combined with fiber optics and attenuated total reflectance crystal could be used for the assessment of tissue quality during arthroscopy. We hypothesize that fiber-optic mid-infrared spectroscopy can detect enzymatically and mechanically induced damage similar to changes occurring during progression of osteoarthritis. Design Bovine patellar cartilage plugs were extracted and degraded enzymatically and mechanically. Adjacent untreated samples were utilized as controls. Enzymatic degradation was done using collagenase and trypsin enzymes. Mechanical damage was induced by (1) dropping a weight impactor on the cartilage plugs and (2) abrading the cartilage surface with a rotating sandpaper. Fiber-optic mid-infrared spectroscopic measurements were conducted before and after treatments, and spectral changes were assessed with random forest, partial least squares discriminant analysis, and support vector machine classifiers. Results All models had excellent classification performance for detecting the different enzymatic and mechanical damage on cartilage matrix. Random forest models achieved accuracies between 90.3% and 77.8%, while partial least squares model accuracies ranged from 95.8% to 84.7%, and support vector machine accuracies from 91.7% to 80.6%. Conclusions The results suggest that fiber-optic Fourier transform infrared spectroscopy attenuated total reflectance spectroscopy is a viable way to detect minor and major degeneration of articular cartilage. Objective measures provided by fiber-optic spectroscopic methods could improve arthroscopic evaluation of cartilage damage.

Objective In order to appreciate the roles articular cartilage of sesamoid bones and sesamoid fibrocartilage play in anatomy and pathology, the articular cartilage of the patella ( n = 4) and suprapatella ( n = 4) (a sesamoid fibrocartilage) of 12 to 14 weeks old New Zealand rabbits were studied qualitatively and quantitatively. Design/Method The intact knee joints and block specimens from the joints were imaged using microscopic magnetic resonance imaging (µMRI) at a 97.6-µm pixel resolution for the former and 19.5-µm resolution for the latter. Histological sections were made out of the µMRI-imaged specimens, which were imaged using polarized light microscopy (PLM) at 0.25-, 1-, and 4-µm pixel resolutions. Results The patella cartilage varied in thickness across the medial to lateral ends of the sesamoid bone with the central medial aspect slightly thicker than the lateral aspect. The suprapatella fibrocartilage decreased proximally away from the knee joint. Quantitative results of patellar cartilage showed strong dependence of fiber orientation with the tissue depth. Three histological zones can be clearly observed, which are similar to articular cartilage from other large animals. The sesamoid fibrocartilage has one thin surface layer (10 µm thick) of parallel-arranged structured fibers followed immediately by the majority of random fibers in bulk tissue. T2 relaxation time anisotropy was observed in the patellar cartilage but not in the bulk fibrocartilage. Conclusion Given the different functions of these 2 different types of cartilages in joint motion, these quantitative results will be beneficial to future studies of joint diseases using rabbits as the animal model.

Objective The study aim was to evaluate the histological relationship between osteoarthritis (OA) and articular cartilage in disuse atrophy induced by hindlimb unloading in a post-traumatic OA rat model. Design Forty male rats were divided into the 4 following experimental groups: control, hindlimb suspension (HS), OA induced by destabilization of the medial meniscus (OA), and OA induction after hindlimb suspension (HS-OA). Histological changes in the articular cartilage of the tibia were evaluated by the Osteoarthritis Research Society International (OARSI) scores and histomorphometrical analyses at 2, 4, and 8 weeks after OA induction. Results We confirmed that disuse atrophy of the articular cartilage was caused by thinning of the articular cartilage and the decrease in matrix staining for the nonloading period of 4 weeks. The OARSI scores and histomorphological analyses revealed that OA progressed significantly wider and deeper in the HS-OA group than in the OA group over time. In the sham group, disuse atrophy of the articular cartilage recovered at 2 weeks after reloading. Conclusions This study revealed that OA progressed faster in cartilage atrophy than in normal articular cartilage. Further studies are required for investigating the mechanisms of disuse atrophy of cartilage and its association with OA using the biochemical and immunohistochemical analysis.

Objective Regulatory guidelines for preclinical cartilage repair studies suggest large animal models (e.g., sheep, goat, [mini]-pig, or horse) to obtain results representative for humans. However, information about the 3-dimensional thickness of articular cartilage at different implantation sites in these models is limited. Design To identify the most suitable site for experimental surgery, cartilage thickness at the medial femoral condyle (MFC), lateral femoral condyle (LFC), and trochlea in ovine, caprine, and porcine cadaver stifle joints was systematically measured using hematoxylin-eosin staining of 6 µm paraffin sections and software-based image analysis. Results Regarding all ventral-dorsal regions of the MFC, goat showed the thickest articular cartilage (maximal mean thickness: 1299 µm), followed by sheep (1096 µm) and mini-pig (604 µm), with the highest values in the most ventral and dorsal regions. Also for the LFC, the most ventral regions showed the thickest cartilage in goat (maximal mean thickness: 1118 µm), followed by sheep (678 µm) and mini-pig (607 µm). Except for the mini-pig, however, the cartilage thickness on the LFC was consistently lower than that on the MFC. The 3 species also differed along the transversal measuring points on the MFC and LFC. In contrast, there were no consistent differences for the regional cartilage thickness of the trochlea among goat and sheep (≥780 µm) and mini-pig (≤500 µm). Conclusions Based on their cartilage thickness, experimental defects on goat and sheep MFC may be viable options for preclinical cartilage repair studies, in addition to well-established horse models.

Background Full-depth cartilage lesions do not heal spontaneously and may progress to osteoarthritis (OA). Treatment for these lesions is warranted when symptomatic. At younger age, biological treatment remains the gold standard, but treatment in the middle-aged patient remains a clinical challenge and focal metal implants have been proposed. We aim to present the subjective outcome at 2 years and the risk of reoperation for any reason at midterm after surgery with a novel customized implant for focal femoral chondral lesions in the knee. Methods In a prospective cohort study, 30 patients were included between January 2013 and December 2017 at 9 different clinics in Sweden. The primary outcome was subjective outcome measurements (Visual Analogue Scale [VAS], EuroQoL [EQ5D], Knee injury and Osteoarthritis Outcome Score [KOOS]) at a minimum of 2 years. The secondary outcome was reoperations for any reason during the follow-up period until December 2019 (mean of 55 months) studied retrospectively by analyzing medical records. Results The VAS, EQ5D, and all the KOOS subscales showed significant improvements from preoperatively to the 2-year follow-up. The VAS showed the greatest improvement at the early (3 months) postoperative stage ( P < 0.001). Five (7%) patients underwent reoperations and one of these was revised to hemiarthroplasty due to OA progression. No implant loosening was detected in any of the cases. Conclusions This customized resurfacing metal implant showed good safety and patient satisfaction. The risk of OA progression and implant loosening is low. Subjective function and pain improved significantly.

Objective The aim of this study was to investigate the roles of SMURF1 and SMURF2 in progenitor cells from the human knee in late-stage osteoarthritis (OA). Design We applied immunohistochemistry, immunocytochemistry, RNAi, lentiviral transfection, and Western blot analysis. We obtained chondrogenic progenitor cells (CPCs) from the articular cartilage and meniscus progenitor cells (MPCs) from the nonvascularized part of the meniscus. Results SMURF1 and SMURF2 appeared in both osteoarthritic tissues. CPCs and MPCs exhibited comparable amounts of these proteins, which influence the balance between RUNX2 and SOX9. The overexpression of SMURF1 reduced the levels of RUNX2, SOX9, and TGFBR1. The overexpression of SMURF2 also reduced the levels of RUNX2 and TGFBR1, while SOX9 levels were not affected. The knockdown of SMURF1 had no effect on RUNX2, SOX9, or TGFBR1. The knockdown of SMURF2 enhanced RUNX2 and SOX9 levels in CPCs. The respective protein levels in MPCs were not affected. Conclusions This study shows that SMURF1 and SMURF2 are regulatory players for the expression of the major regulator transcription factors RUNX2 and SOX9 in CPCs and MPCs. Our novel findings may help elucidate new treatment strategies for cartilage regeneration.

Objective Successful preservation of articular cartilage will increase the availability of osteochondral allografts to treat articular cartilage defects. We compared the effects of 2 methods for storing cartilage tissues using 10-mm diameter osteochondral dowels or femoral condyles at −196°C: (a) storage with a surrounding vitrification solution versus (b) storage without a surrounding vitrification solution. We investigated the effects of 2 additives (chondroitin sulfate and ascorbic acid) for vitrification of articular cartilage. Design Healthy porcine stifle joints ( n = 11) from sexually mature pigs were collected from a slaughterhouse within 6 hours after slaughtering. Dimethyl sulfoxide, ethylene glycol, and propylene glycol were permeated into porcine articular cartilage using an optimized 7-hour 3-step cryoprotectant permeation protocol. Chondrocyte viability was assessed by a cell membrane integrity stain and chondrocyte metabolic function was assessed by alamarBlue assay. Femoral condyles after vitrification were assessed by gross morphology for cartilage fractures. Results There were no differences in the chondrocyte viability (~70%) of 10-mm osteochondral dowels after vitrification with or without the surrounding vitrification solution. Chondrocyte viability in porcine femoral condyles was significantly higher after vitrification without the surrounding vitrification solution (~70%) compared to those with the surrounding vitrification solution (8% to 36%). Moreover, articular cartilage fractures were not seen in femoral condyles vitrified without surrounding vitrification solution compared to fractures seen in condyles with surrounding vitrification solution. Conclusions Vitrification of femoral condyle allografts can be achieved by our optimized approach. Removing the surrounding vitrification solution is advantageous for vitrification outcomes of large size osteochondral allografts.

Objective The main purpose of the present study was to assess the risk for major revision surgery after perichondrium transplantation (PT) at a minimum of 22 years postoperatively and to evaluate the influence of patient characteristics. Design Primary outcome was treatment success or failure. Failure of PT was defined as revision surgery in which the transplant was removed, such as (unicondylar) knee arthroplasty or patellectomy. The functioning of nonfailed patients was evaluated using the International Knee Documentation Committee (IKDC) score. In addition, the influence of patient characteristics was evaluated. Results Ninety knees in 88 patients, aged 16 to 55 years with symptomatic cartilage defects, were treated by PT. Eighty knees in 78 patients were eligible for analysis and 10 patients were lost to follow-up. Twenty-eight knees in 26 patients had undergone major revision surgery. Previous surgery and a longer time of symptoms prior to PT were significantly associated with an increased risk for failure of cartilage repair. Functioning of the remaining 52 patients and influence of patient characteristics was analyzed using their IKDC score. Their median IKDC score was 39.08, but a relatively young age at transplantation was associated with a higher IKDC score. Conclusions This 22-year follow-up study of PT, with objective outcome parameters next to patient-reported outcome measurements in a unique group of patients, shows that overall 66% was without major revision surgery and patient characteristics also influence long-term outcome of cartilage repair surgery.

Objective To establish a method for investigating the permeability of calcified cartilage zone (CCZ) and to observe solute transport between articular cartilage (AC) and subchondral bone (SB) through intact CCZ in vivo. Design We developed a novel fixing device combined with un-decalcified fluorescence observation method to address the permeability of CCZ in live mice. Twenty-four Balb/c female mice aged 1 to 8 months were used to observe the development of CCZ. Eighty-four Balb/c female mice (aged 1 or 6 months) with mature or immature CCZ of distal femur were used to investigate the permeability of intact CCZ in vivo. Diffusivity of rhodamine B (476 Da) and tetramethyl-rhodamine isothicyanate-dextran (TRITC-Dextran, 20 kDa) was tested from AC to SB in 0 minutes, 1 minute, 15 minutes, 30 minutes, 1 hour, and 2 hours. None diffused knee joints (0 minutes) served as blank control, while in vitro immersion of distal femurs in rhodamine B or TRITC-Dextran for 72 hours served as positive control. Results CCZ was well developed in 6-month mice. Both tracers penetrated immature CCZ down to SB in less than 1 hour in live mice, while the diffusion of both tracers decreased rapidly at tidemark in all testing time points. Conclusion Current study provided direct evidence of blocking effect of CCZ in solute transportation during short diffusion period in live animal, indicating the important role of CCZ in joint development and microenvironment maintenance.

Objective Chondroprogenitors have recently gained prominence due to promising results seen in in vitro and animal studies as a potential contender in cell-based therapy for cartilage repair. Lack of consensus regarding nomenclature, isolation techniques, and expansion protocols create substantial limitations for translational research, especially given the absence of distinct markers of identification. The objective of this systematic review was to identify and collate information pertaining to hyaline cartilage–derived chondroprogenitors, with regard to their isolation, culture, and outcome measures. Design As per Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, a web-based search of Scopus and PubMed databases was performed from January 2000 to May 2020, which yielded 509 studies. A total of 65 studies were identified that met the standardized inclusion criteria which comprised of, but was not limited to, progenitors derived from fibronectin adhesion, migrated subpopulation from explant cultures, and single-cell sorting. Result Literature search revealed that progenitors demonstrated inherent chondrogenesis and minimal tendency for hypertrophy. Multiple sources also demonstrated significantly better outcomes that bone marrow–derived mesenchymal stem cells and comparable results to chondrocytes. With regard to progenitor subgroups, collated evidence points to better and consistent outcomes with the use of migratory progenitors when compared to fibronectin adhesion assay–derived progenitors, although a direct comparison between the two cell populations is warranted. Conclusion Since chondroprogenitors exhibit favorable properties for cartilage repair, efficient characterization of progenitors is imperative, to complete their phenotypic profile, so as to optimize their use in translational research for neocartilage formation.

Objective Osteoarthritis (OA) commonly affects weight-bearing joints and is characterized by articular cartilage breakdown combined with osteophyte formation at the joint margins and chronic nonspecific inflammation of synovium. Understanding the profile of inflammation in a patient population is an essential starting point to predict or prevent OA progression. The aim of this study was to identify the profile of selected biomolecules in synovial fluid (SF) and investigate the correlation according to gender, age, and severity of the disease within patients from among the general knee OA population. Design In our study SF samples were aspirated from the knees of 65 OA patients (46 patients with early knee OA and 19 patients with end-stage knee OA according to the Kellgren-Lawrence grading scale). The concentration of interleukins (IL-6, IL-8), matrix metalloproteinases (MMP-1, MMP-3, MMP-13), MMPs inhibitors (TIMP-1, TIMP-2), cartilage oligomeric matrix protein (COMP), and adiponectin was analyzed using a multiplex ELISA-based approach. Conclusions Our results indicate significant linear correlation of MMP-13 and COMP concentration with age ( P < 0.05), but not with OA severity. In fact, 3 of the examined biomolecules, MMP-3 ( P < 0.01), TIMP-1 ( P < 0.01), and COMP ( P < 0.05) significantly correlate with the grade of knee OA and might be associated with OA severity.

Cartilage defects in the knee are being diagnosed with increased frequency and are treated with a variety of techniques. The aim of any cartilage repair procedure is to generate the highest tissue quality, which might correlate with improved clinical outcomes, return-to-sport, and long-term durability. Minced cartilage implantation (MCI) is a relatively simple and cost-effective technique to transplant autologous cartilage fragments in a single-step procedure. Minced cartilage has a strong biologic potential since autologous, activated non-dedifferentiated chondrocytes are utilized. It can be used both for small and large cartilage lesions, as well as for osteochondral lesions. As it is purely an autologous and homologous approach, it lacks a significant regulatory oversight process and can be clinically adopted without such limitations. The aim of this narrative review is to provide an overview of the current evidence supporting autologous minced cartilage implantation.

Objective To compare the efficacy and safety of costal chondrocyte–derived pellet-type autologous chondrocyte implantation (CCP-ACI) with microfracture (MFx) for repair of articular cartilage defects of the knee. Design Thirty subjects with an International Cartilage Repair Society (ICRS) grade 3 to 4 chondral defect (2-10 cm2 in area; ≤4 cm3 in volume) were randomized at a ratio of 2:1 (CCP-ACI:MFx). Twenty patients were allocated in the CCP-ACI group and 10 patients in the MFx group. CCP-ACI was performed by harvesting costal cartilage at least 4 weeks before surgery. Implantation was performed without any marrow stimulation. Efficacy and safety were assessed at weeks 8, 24, and 48 after surgery according to the magnetic resonance observation of cartilage repair tissue (MOCART) score and clinical outcomes. Results MOCART scores improved from baseline to 24 and 48 weeks postoperatively in both treatment groups. The improvement in MOCART scores in the CCP-ACI group was significantly greater than that in the MFx group at 24 and 48 weeks (39.1 vs 21.8 and 43.0 vs 24.8, respectively). The proportions of complete defect repair and complete integration were significantly higher in the CCP-ACI group than the MFx group at 48 weeks. Improvement in Lysholm score and KOOS subscores, including Function (Sports and Recreational Activity) and knee-related quality of life was significantly greater in the CCP-ACI group than the MFx group at 48 weeks (35.4 vs 31.5, 35.7 vs 28.5, and 27.9 vs 11.6, respectively). Conclusion Treatment of cartilage defects with CCP-ACI yielded satisfactory cartilage tissue repair outcomes, with good structural integration with native cartilage tissue shown by magnetic resonance imaging at 24 and 48 weeks after surgery. Level of Evidence Level 1: Randomized controlled study.

Objective To enhance the in vitro integration of self-assembled articular cartilage to native articular cartilage using chondroitinase ABC. Design To examine the hypothesis that chondroitinase ABC (C-ABC) integration treatment (C-ABCint) would enhance integration of neocartilage of different maturity levels, this study was conducted in 2 phases. In phase I, the impact on integration of 2 treatments, TCL (TGF-β1, C-ABC, and lysyl oxidase like 2) and C-ABCint, was examined via a 2-factor, full factorial design. In phase II, construct maturity (2 levels) and C-ABCint concentration (3 levels) were the factors in a full factorial design to determine whether the effective C-ABCint dose was dependent on neocartilage maturity level. Neocartilages formed or treated per the factors above were placed into native cartilage rings, cultured for 2 weeks, and, then, integration was studied histologically and mechanically. Prior to integration, in phase II, a set of treated constructs were also assayed to provide a baseline of properties. Results In phase I, C-ABCint and TCL treatments synergistically enhanced interface Young’s modulus by 6.2-fold ( P = 0.004) and increased interface tensile strength by 3.8-fold ( P = 0.02) compared with control. In phase II, the interaction of the factors C-ABCint and construct maturity was significant ( P = 0.0004), indicating that the effective C-ABCint dose to improve interface Young’s modulus is dependent on construct maturity. Construct mechanical properties were preserved regardless of C-ABCint dose. Conclusions Applying C-ABCint to neocartilage is an effective integration strategy with translational potential, provided its dose is calibrated appropriately based on implant maturity, that also preserves implant biomechanical properties.

PURPOSE: To investigate the magic angle effect in three‐dimensional ultrashort echo time Cones Adiabatic T(1ρ) (3D UTE Cones‐AdiabT(1ρ)) imaging of articular cartilage at 3T. METHODS: The magic angle effect was investigated by repeated 3D UTE Cones‐AdiabT(1ρ) imaging of eight human patellar samples at five angular orientations ranging from 0° to 90° relative to the B(0) field. Cones continuous wave T(1ρ) (Cones‐CW‐T(1ρ)) and Cones‐ [Formula: see text] sequences were also applied for comparison. Cones‐AdiabT(1ρ), Cones‐CW‐T(1ρ) and Cones‐ [Formula: see text] values were measured for four regions of interest (ROIs) (10% superficial layer, 60% transitional layer, 30% radial layer, and a global ROI) for each sample at each orientation to evaluate their angular dependence. RESULTS: 3D UTE Cones‐AdiabT(1ρ) values increased from the radial layer to the superficial layer for all angular orientations. The superficial layer showed the least angular dependence (around 4.4%), while the radial layer showed the strongest angular dependence (around 34.4%). Cones‐AdiabT(1ρ) values showed much reduced magic angle effect compared to Cones‐CW‐T(1ρ) and Cones‐ [Formula: see text] values for all four ROIs. On average over eight patellae, Cones‐AdiabT(1ρ) values increased by 27.2% (4.4% for superficial, 23.8% for transitional, and 34.4% for radial layers), Cones‐CW‐T(1ρ) values increased by 76.9% (11.3% for superficial, 59.1% for transitional, and 117.8% for radial layers), and Cones‐ [Formula: see text] values increased by 237.5% (87.9% for superficial, 262.9% for transitional, and 327.3% for radial layers) near the magic angle. CONCLUSIONS: The 3D UTE Cones‐AdiabT(1ρ) sequence is less sensitive to the magic angle effect in the evaluation of articular cartilage compared to Cones‐ [Formula: see text] and Cones‐CW‐T(1ρ).

Objective TNIIIA2 is a peptide of the extracellular matrix glycoprotein tenascin-C. We evaluated whether intra-articular injection of TNIIIA2 could prevent articular cartilage degeneration without inducing synovitis in an osteoarthritis mice model. Design Ten micrograms per milliliter of TNIIIA2 were injected into the knee joint of mice (group II) to evaluate the induction of synovitis. The control group received an injection of phosphate buffered saline (group I). Synovitis was evaluated using synovitis score 2 and 4 weeks after injection. The ligaments of knee joints of mice were transected to make the osteoarthritis model. After transection, 10 µg/mL of TNIIIA2 was injected into the knee joint (group IV). The control group received an injection of phosphate buffered saline after transection (group III). Histologic examinations were made using hematoxylin and eosin and safranin-O staining at 2, 4, 8, and 12 weeks postoperatively. An in vitro study was also performed to determine the mechanism by which TNIIIA2 prevents cartilage degeneration. Human chondrocytes were isolated, cultured, and treated with TNIIIA2. The expressions of various mRNAs, including inflammatory cytokines, and anabolic and catabolic factors for cartilage were compared using real-time polymerase chain reaction. Results There were no differences between groups in the study of intra-articular injection of mice (group I vs. group II). In the osteoarthritis model, we found development of osteoarthritis was suppressed in group IV at 4 and 8 weeks. TNIIIA2 upregulated the expressions of tumor necrosis factor-α, matrix metalloproteinase 3, and basic fibroblast growth factor. Conclusion We demonstrated that TNIIIA2 could prevent cartilage degeneration without synovitis.

Objective To evaluate the in vivo effect of a single intra-articular injection of local anesthetic (LA) lidocaine on the viability of articular cartilage in the intact or osteoarthritic (OA) human knees, and to measure the synovial postinjection concentration of lidocaine in the knee Design This study includes 3 interconnected experiments: (A) Synovial LA concentration measurement after a 2% lidocaine injection before knee arthroscopy in 10 patients by liquid chromatography–tandem mass spectrometry (LC-MS/MS). (B) Human osteochondral explants ( N = 27) from intact knees procured at autopsies were incubated for different time intervals (30 minutes, 2 hours, 24 hours) with 2% lidocaine, 0.04% lidocaine (measured), or culture medium (control), and later evaluated for cell viability by LIVE/DEAD staining. (C) Ten out of 19 matched patients scheduled for knee replacement received a single intra-articular injection of 2% lidocaine approximately 30 minutes prior to the procedure; 9 patients served as control. Osteochondral samples with OA changes were harvested during surgery and analyzed for chondrocyte viability by LIVE/DEAD staining. Results (A) The synovial LA concentration was significantly lower than the primary concentration injected: average 0.23 mg/mL (0.02%), highest measured 0.37 mg/mL (0.04%). (B) In vitro exposure to a reduced LA concentration had no significant influence on chondrocyte viability in intact cartilage explants (24-hour averages: control, 93%; 0.04% lidocaine, 92%; 2% lidocaine, 79%). (C) Viability of chondrocytes in OA knees was similar between 2% lidocaine injection (85%) and control (80%). Conclusions A single intra-articular knee injection of 2% lidocaine did not influence the chondrocyte viability neither in healthy nor in OA cartilage. A fast postinjection reduction of synovial LA concentration (more than 40 times) is the most likely protective mechanism.

Objective Articular cartilage-derived progenitor cells (ACPCs) are a potential new cell source for cartilage repair. This study aims to characterize endogenous ACPCs from healthy and osteoarthritic (OA) cartilage, evaluate their potential for cartilage regeneration, and compare this to cartilage formation by chondrocytes. Design ACPCs were isolated from full-thickness healthy and OA human cartilage and separated from the total cell population by clonal growth after differential adhesion to fibronectin. ACPCs were characterized by growth kinetics, multilineage differentiation, and surface marker expression. Chondrogenic redifferentiation of ACPCs was compared with chondrocytes in pellet cultures. Pellets were assessed for cartilage-like matrix production by (immuno)histochemistry, quantitative analyses for glycosaminoglycans and DNA content, and expression of chondrogenic and hypertrophic genes. Results Healthy and OA ACPCs were successfully differentiated toward the adipogenic and chondrogenic lineage, but failed to produce calcified matrix when exposed to osteogenic induction media. Both ACPC populations met the criteria for cell surface marker expression of mesenchymal stromal cells (MSCs). Healthy ACPCs cultured in pellets deposited extracellular matrix containing proteoglycans and type II collagen, devoid of type I collagen. Gene expression of hypertrophic marker type X collagen was lower in healthy ACPC pellets compared with OA pellets. Conclusions This study provides further insight into the ACPC population in healthy and OA human articular cartilage. ACPCs show similarities to MSCs, yet do not produce calcified matrix under well-established osteogenic culture conditions. Due to extensive proliferative potential and chondrogenic capacity, ACPCs show potential for cartilage regeneration and possibly for clinical application, as a promising alternative to MSCs or chondrocytes.

Objective This study was undertaken to elucidate the mechanism of improved chondrocyte migration after juvenile articular cartilage fragmentation. Design In vitro organ culture with rabbit cartilage fragments and cell culture with rabbit chondrocytes were performed. In part A, minced juvenile cartilage fragments (~0.5 × 0.5 × 0.5 mm) from rabbits, planted in gelatin sponge and fibrin glue, were cultured for 2, 4, or 6 weeks in vitro and compared with the cartilage chunks (~4 × 4 × 1 mm) and membrane type 1 matrix metalloprotease (MT1-MMP) inhibitor groups. Chondrocyte outgrowth was evaluated on histology and confocal laser scanning microscopy. MT1-MMP expression was compared between the cartilage fragment group and the cartilage chunks group. In part B, articular chondrocytes were harvested from juvenile rabbits, MT1-MMP was transfected into the cells, and cell migration was evaluated using the Transwell and wound healing tests. Results The histology and confocal microscopy results revealed that cell accumulation occurred at the edge of cartilage fragments, and outgrowth was better in the cartilage fragment group than those in the cartilage chunks group. Similar results were observed for MT1-MMP expression. After MT1-MMP inhibition, cells did not accumulate at the edge of the cartilage fragments, and chondrocyte outgrowth did not occur. Furthermore, overexpression of MT1-MMP enhanced the migration of articular chondrocytes. Conclusions Juvenile articular cartilage fragmentation improved chondrocyte migration by upregulating MT1-MMP.

Osteoarthritis (OA) tends to occur in older individuals frequently burdened with comorbidities and diverse pharmacological interactions. As articular cartilage has low regenerative power, potent local tissue engineering approaches are needed to support chondrogenic differentiation. Acellular preparation methods as well as approaches to coax endogenous reparative cells into the joint space appear to have limited success. Supported by our in-vitro and clinical studies, we propose that our novel intra-articular administration of human granulocyte colony stimulating factor (IA-hG-CSF) combined with autologous activated peripheral blood stem cells (AAPBSC) is safe and offers treatment advantages not seen with other cellular interventions in early osteoarthritis.

ObjectiveTo delineate the response of migrating chondrogenic progenitor cells (CPCs) that arose from the surface of mechanically injured articular cartilage to proinflammatory damage-associated-molecular-patterns (DAMPs).DesignBovine CPCs and non-CPC chondrocytes isolated from either impacted or scratched articular cartilage were studied. Those 2 types of cells were treated with mitochondrial DAMPs (MTDs; 10 nM fMLF and 10 µg/mL CpG DNA), or 10 nM HMGB1, or 10 ng/mL IL-1b for 24 hours. At the end of experiments, conditioned media and cell lysates were collected for analysis of expression levels of matrix metalloproteinases (MMPs), chemokines, and cytokines that are associated with cartilage degeneration with Western blotting and quantitative polymerase chain reaction. The difference of expression levels was compared by Welch’s t-test.ResultsOur data indicated that HMGB1 and MTDs remarkably upregulated pro-MMP-13 expression in CPCs. Compared with non-CPCs, CPCs expressed significantly more baseline mRNAs of MMP-13, CXCL12, and IL-6. MTDs greatly increased the expression of MMP-13 and IL-6 in CPCs by over 100-fold ( P < 0.001). MTDs also significantly increased IL-8 expression in CPCs to a similar extent ( P < 0.001). However, when IL-1b was present, CPCs expressed less MMP-3 and active MMP-13 proteins as well as less CCL2 and IL-6 than did non-CPCs.ConclusionsWe concluded that CPCs were more sensitive than non-CPCs in response to DAMPs, especially MTDs. The proinflammatory nature of CPCs implied their critical role in the early phase of posttraumatic osteoarthritis development.

Objective Fibrin has been used as a standard material for scaffold fixation during cartilage repair surgery. Most of the commercially available fibrin preparations need an additional method for scaffold fixation, most often with sutures, thus damaging the surrounding healthy cartilage. There is therefore a need to find alternatives to this method. In our study, we have investigated the potential possibility to use mussel adhesive protein as such an alternative. Methods In this study, hydrophobic plastic was coated with the mussel adhesive protein Mefp-1 as well as with other cell adhesives (poly-lysine, fibronectin, and collagen). Human keratinocytes and chondrocytes were seeded on these substrates at 37°C in culture medium, followed by analysis of attachment and proliferation by crystal violet staining and metabolic labelling. Performance of Mefp-1 and fibrin as tissue glues were estimated by tensional force resistance measurement of moist porcine dermis (as a correlate to scaffold) glued to dermis, cartilage, or bone at 37°C. Results Mefp-1 supported maximal cell attachment at a coating density of approximately 1 µg/cm2. This was at least as good as the other adhesives tested. In addition, it supported cell proliferation at least as good as regular tissue culture plastic over a 7-day period. Measurement of tensional force resistance showed that Mefp-1 performed equally well as fibrin when porcine dermis was glued to cartilage and bone at the same concentration. Separation of the moist tissues after 15-minute incubation required a force of approximately 1 N/cm2 for both compounds. Conclusions Mefp-1 show properties that qualify it as a compound that potentially could replace fibrin as a tissue glue for scaffold fixation. Given the possibilities to modify this protein by bioengineering, it is likely that the properties can be further improved.

Objective Cartilage tissue engineering has evolved as one of the therapeutic strategies for cartilage defect, which relies on a large number of viable chondrocytes. Because of limited availability of cartilage and low chondrocytes yield from cartilage, the need for an improve isolation protocol for maximum yield of viable cells is a key to achieving successful clinical constructs. This study optimizes and compares different protocols for isolation of chondrocytes from cartilage. Design We employed enzymatic digestion of cartilage using collagenase II and trypsin. The chondrocytes yield, growth kinetics, aggrecan, and collagen type 2 (COL2) expression were evaluated. Collagen type 1 (COL1) mRNA expression was assessed to monitor the possibility of chondrocytes dedifferentiation. Results Chondrocyte yield per gram of cartilage was significantly higher ( P < 0.05) using collagenase II in Hank’s balanced salt solution (HBSS) compared with 0.25% trypsin. The number of chondrocyte yield per gram was higher in cartilage digested with collagenase in HBSS compared with Dulbecco’s modified Eagle medium/F12; however, the difference was not statistically significant. Chondrocytes seeded at lower densities had shorter population doubling time compared to those seeded at higher density. Protein and gene expression of chondrocyte phenotype indicates the expression of aggrecan and COL2. The expression of COL1 was significantly increased ( P < 0.05) in passage 3 compared with primary chondrocytes. The mRNA expression of chondrocyte phenotype was similar in primary and passaged one cells. Conclusions Collagenase in HBSS yield the highest number of viable chondrocytes and the isolated cells expressed chondrocyte phenotype. This protocol can be employed to generate large number of viable chondrocytes, particularly with limited cartilage biopsies.

Objective In native articular cartilage, chondrocytes are surrounded by a thin pericellular matrix (PCM) forming chondrons. The PCM is exclusively rich in type VI collagen. The retention of the PCM has a significant influence on the metabolic activity of the chondrocytes. Design This study investigated the influence of 2 hydrogels (hyaluronic acid [HA] and agarose) and 2 media compositions (basal and chondrogenic) on the preservation/maintenance and acceleration of PCM formation over a 21-day time course. Different combinations of chondrocytes, chondrons, and mesenchymal stem cells (MSCs) were studied. Results Both hydrogels preserved chondrons PCM from day 1 up to 21-day culture regardless of media composition. Type VI collagen immunostaining of the cultured chondrons appeared both dense and homogenous. The presence of MSCs did not influence this outcome. At day 1, type VI collagen was not present around chondrocytes alone or their co-culture with MSCs. In the HA hydrogel, type VI collagen was located within the PCM after 7 days in both mono- and co-cultures. In the agarose hydrogel, collagen VI was located within the PCM at 7 days (co-cultures) and 14 days (monocultures). In both hydrogel systems, chondrogenic media enhanced the production of key extracellular matrix components in both mono- and co-cultures in comparison to basal media (11.5% and 14% more in glycosaminoglycans and type II collagen for chondrocytes samples at day 21 culture samples, respectively). However, the media types did not enhance type VI collagen synthesis. Conclusion Altogether, a 3D chondrogenic hydrogel environment is the primary condition for maintenance and acceleration of PCM formation.

Objective The outcome of arthroscopic treatment for femoroacetabular impingement (FAI) depends on the preoperative status of the hip cartilage. Quantitative T2 can detect early biochemical cartilage changes, but its routine implementation is challenging. Furthermore, intrinsic T2 variability between patients makes it difficult to define a threshold to identify cartilage lesions. To address this, we propose a normalized T2-index as a new method to evaluate cartilage in FAI. Design We retrospectively analyzed magnetic resonance imaging (MRI) data of 18 FAI patients with arthroscopically confirmed cartilage defects. Cartilage T2 maps were reconstructed from multi-spin-echo 3-T data using the echo-modulation-curve (EMC) model-based technique. The central femoral cartilage, assumed healthy in early-stage FAI, was used as the normalization reference to define a T2-index. We investigated the ability of the T2-index to detect surgically confirmed cartilage lesions. Results The average T2-index was 1.14 ± 0.1 and 1.13 ± 0.1 for 2 separated segmentations. Using T2-index >1 as the threshold for damaged cartilage, accuracy was 88% and 100% for the 2 segmentations. We found moderate intraobserver repeatability, although separate segmentations yielded comparable accuracy. Damaged cartilage could not be identified using nonnormalized average T2 values. Conclusions This preliminary study confirms the importance of normalizing T2 values to account for interpatient variability and suggests that the T2-index is a promising biomarker for the detection of cartilage lesions in FAI. Future work is needed to confirm that combining T2-index with morphologic MRI and other quantitative biomarkers could improve cartilage assessment in FAI.

Objective To report radiographic and magnetic resonance imaging findings, patient-reported outcomes, and complications and/or reoperations following nonarthroplasty surgical intervention for focal glenohumeral cartilage defects. Design A literature search was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Patients were included if they possessed a chondral defect of the humeral head, glenoid, or both, which had been treated with a joint preserving nonarthroplasty procedure. Risk of bias assessment was performed using the Methodological Index for Non-Randomized Studies scoring system. Study demographics, surgical technique, imaging findings, patient-reported outcomes, complications, failures, and reoperations were collected. Results Fourteen studies with 98 patients (100 shoulders) met the inclusion criteria. Patient ages ranged from 7 to 74 years. The nonarthroplasty surgical techniques utilized included microfracture (67 shoulders), osteochondral transplantation (28 shoulders), chondrocyte transplantation (4 shoulders), and internal fixation (1 shoulder). The rates of radiographic union and progression of osteoarthritis ranged between 90% to 100% and 57% to 100%, respectively. Visual analog scores ranged from 0 to 1.9 at final follow-up. Mean postoperative ASES (American Shoulder and Elbow Surgeons) shoulder scores ranged from 75.8-100. Mean postoperative CSS (Constant Shoulder Score) scores ranged from 83.3-94. Mean postoperative SSV (Subjective Shoulder Value) ranged from 70% to 99%. Failure and reoperation rates ranged between 0% to 35% and 0% to 30%, respectively, with the most common reoperation being conversion to prosthetic arthroplasty. Conclusions In this systematic review, nonarthroplasty surgical techniques demonstrated acceptable rates of radiographic healing, improved patient reported outcomes, minimal complications, and low rates of failure or reoperation. Joint preserving techniques are likely viable options to prolong function of the native shoulder and provide short- to midterm pain relief in young and highly active patients. Level of Evidence Level IV.

Background Complex meniscal lesions often require meniscectomy with favorable results in the short term but a high risk of early osteoarthritis subsequently. Partial meniscectomy treated with meniscal substitutes may delay articular cartilage degeneration. Purpose To evaluate the status of articular cartilage by T2 mapping after meniscal substitution with polyurethane scaffolds enriched with mesenchymal stem cells (MSC) and comparison with acellular scaffolds at 12 months. Methods Seventeen patients (18-50 years) with past meniscectomies were enrolled in 2 groups: (1) acellular polyurethane scaffold (APS) or (2) polyurethane scaffold enriched with MSC (MPS). Patients in the MPS group received filgrastim to stimulate MSC production, and CD90+ cells were obtained and cultured in the polyurethane scaffold. The scaffolds were implanted arthroscopically into partial meniscus defects. Concomitant injuries (articular cartilage lesions or cartilage lesions) were treated during the same procedure. Changes in the quality of articular cartilage were evaluated with T2 mapping in femur and tibia at 12 months. Results In tibial T2 mapping, values for the MPS group increased slightly at 9 months but returned to initial values at 12 months ( P > 0.05). In the APS group, a clear decrease from 3 months to 12 months was observed ( P > 0.05). This difference tended to be significantly lower in the APS group compared with the MPS group at the final time point ( P = 0.18). In the femur, a slight increase in the MPS group (47.8 ± 3.4) compared with the APS group (45.3 ± 4.9) was observed ( P > 0.05). Conclusion Meniscal substitution with polyurethane scaffold maintains normal T2 mapping values in adjacent cartilage at 12 months. The addition of MSC did not show any advantage in the protection of articular cartilage over acellular scaffolds ( P > 0.05).

One of the most pressing issues in osteoarthritis (OA) research is the development of disease-modifying OA drugs (DMOADs), as currently there are no such drugs available. The paucity of suitable DMOADs is mostly due to the lack of approved ideal therapeutic targets necessary for the development of these drugs. However, based on recent discoveries from our laboratory and other independent laboratories, it is indicated that a cell surface receptor tyrosine kinase for collagen type II, discoidin domain receptor 2 (DDR2), may be an ideal therapeutic target for the development of DMOADs. In this article, we review the current status of research in understanding roles of DDR2 in the development of OA.

Objective To describe histological and metabolic characteristics of glenohumeral joint (GHJ) articular cartilage and compare to knee and ankle joints. Design Macroscopically healthy human humeral head, glenoid, knee, and ankle articular cartilage were obtained from tissue donors ( N = 16, 9 males, 7 females; age 45-78 years), within 24 hours of death. Gross morphology of each joint was assessed using Collins grading. Cartilage explants were removed from the entire surface of each joint, cultured for 48 hours with or without interleukin-1β and processed for histology with Safranin O, proteoglycan (PG) synthesis/content, and polymerase chain reaction for collagen II, aggrecan, and SOX9. Results were compared between uncultured and cultured controls and across all 3 joints. Results Structural differences were seen on histology between GHJ cartilage and knee and ankle cartilage of the same Collins grade, specifically, depletion of Safranin O staining in the extracellular matrix. Treatment of glenoid and humerus specimens with IL-1β demonstrated a trend toward decreased PG synthesis in each explant but this decrease did not reach significance. There was no significant difference in PG synthesis between humerus, glenoid, knee, and ankle samples at baseline, day-0 control, 48-hour control, and 48 hours after treatment with 0.1 ng or 10 ng of IL-1β. There were no significant increases in collagen II, SOX9, and aggrecan expression in glenoid and humeral head cartilage samples treated with IL-1β compared to baseline controls. Conclusions GHJ articular cartilage did not significantly differ from ankle or knee cartilage with regard to PG synthesis and gene expression. However, it did differ in its histological appearance in normal state.

Objectives: RNA isolation is necessary for the evaluation of gene expression. Due to the nature of its extracellular matrix, RNA isolation from articular hyaline cartilage is difficult and thus the tissue is commonly enzymatically digested in order to extract RNA from the obtained chondrocytes. We hypothesized that the digestion process affects the expression levels of common cartilage-associated genes. Design: Expression of cartilage-associated genes was compared between intact cartilage and digested chondrocytes from weight bearing and non-weight bearing regions of the equine fetlock joint. Results: The gene expression of SOX9, COL1A2, COL2A1, ACAN, and COLX were analyzed. Digested cartilage showed a significant decrease in the expression of COL1A2, COL2A1, and ACAN compared to intact cartilage in both joint regions, and an increase in COLX expression in non-weight bearing cartilage only. Conclusions: Enzymatic digestion of cartilage significantly impacts gene expression profile. We conclude that while RNA isolation from intact cartilage is more technically difficult, determination of gene expression should be conducted on intact cartilage if true representation of the in vivo processes is sought.

Objective This study evaluated the effects of mesenchymal stem cell-extracellular vesicles (MSC-EVs) on chondrocyte proliferation in vitro and on cartilage repair in vivo following bone marrow stimulation (BMS) of focal chondral defects of the knee. Methods Six adult Göttingen minipigs received 2 chondral defects in each knee. The pigs were randomized to treatment with either BMS combined with MSC-EVs or BMS combined with phosphate-buffered saline (PBS). Intraarticular injections MSC-EVs or PBS were performed immediately after closure of the surgical incisions, and at 2 and 4 weeks postoperatively. Repair was evaluated after 6 months with gross examination, histology, histomorphometry, immunohistochemistry, and micro-computed tomography (µCT) analysis of the trabecular bone beneath the defect. Results Defects treated with MSC-EVs had more bone in the cartilage defect area than the PBS-treated defects (7.9% vs. 1.5%, P = 0.02). Less than 1% of the repair tissue in both groups was hyaline cartilage. International Cartilage and Joint Preservation Society II histological scoring showed that defects treated with MSC-EVs scored lower on “matrix staining” (20.8 vs. 50.0, P = 0.03), “cell morphology” (35.4 vs. 53.8, P = 0.04), and “overall assessment” (30.8 vs. 52.9, P = 0.03). Consistently, defects treated with MSC-EVs had lower collagen II and higher collagen I areal deposition. Defects treated with MSC-EVs had subchondral bone with significantly higher tissue mineral densities than PBS-treated defects (860 mg HA/cm3 vs. 838 mg HA/cm3, P = 0.02). Conclusion Intraarticular injections of MSC-EVs in conjunction with BMS led to osseous ingrowth that impaired optimal cartilage repair, while enhancing subchondral bone healing.

Osteoarthritis (OA), the most prevalent joint disease, is a major cause of disability worldwide. Growth hormone (GH) has been suggested to play significant roles in maintaining articular chondrocyte function and ultimately articular cartilage (AC) homeostasis. In humans, the age‐associated decline in GH levels was hypothesized to play a role in the etiology of OA. We studied the impact of adult‐onset isolated GH deficiency (AOiGHD) on the life span and skeletal integrity including the AC, in 23‐ to 30‐month‐old male and female mice on C57/BL6 genetic background. Reductions in GH during adulthood were associated with extended life span and reductions in body temperature in female mice only. However, end‐of‐life pathology revealed high levels of lymphomas in both sexes, independent of GH status. Skeletal characterization revealed increases in OA severity in AOiGHD mice, evidenced by AC degradation in both femur and tibia, and significantly increased osteophyte formation in AOiGHD females. AOiGHD males showed significant increases in the thickness of the synovial lining cell layer that was associated with increased markers of inflammation (IL‐6, iNOS). Furthermore, male AOiGHD showed significant increases in matrix metalloproteinase‐13 (MMP‐13), p16, and β‐galactosidase immunoreactivity in the AC as compared to controls, indicating increased cell senescence. In conclusion, while the life span of AOiGHD females increased, their health span was compromised by high‐grade lymphomas and the development of severe OA. In contrast, AOiGHD males, which did not show extended life span, showed an overall low grade of lymphomas but exhibited significantly decreased health span, evidenced by increased OA severity., In humans, the natural decline in growth hormone (GH) secretion during aging, termed somatopause, associates with reduced health span. We found that age‐induced somatopause in mice increased primary osteoarthritis (OA) of the knee joint. This was evidenced by the loss of articular cartilage, increased osteophyte formation, and thickening of the synovial membrane. At the cellular level, somatopause increased chondrocyte expression of matrix‐degrading enzymes, senescence, and inflammatory markers.

Systemic application of glucocorticoids is an essential anti-inflammatory and immune-modulating therapy for severe inflammatory or autoimmunity conditions. However, its long-term effects on articular cartilage of patients' health need to be further investigated. In this study, we studied the effects of dexamethasone (Dex) on the homeostasis of articular cartilage and the progress of destabilization of medial meniscus (DMM)-induced osteoarthritis (OA) in adult mice. Long-term administration of Dex aggravates the proteoglycan loss of articular cartilage and drastically accelerates cartilage degeneration under surgically induced OA conditions. In addition, Dex increases calcium content in calcified cartilage layer of mice and the samples from OA patients with a history of long-term Dex treatment. Moreover, long term usage of Dex results in decrease subchondral bone mass and bone density. Further studies showed that Dex leads to calcification of extracellular matrix of chondrocytes partially through activation of AKT, as well as promotes apoptosis of chondrocytes in calcified cartilage layer. Besides, Dex weakens the stress-response autophagy with the passage of time. Taken together, our data indicate that long-term application of Dex may predispose patients to OA and or even accelerate the OA disease progression development of OA patients.

Objective: Patients frequently use the internet as a source to obtain health information. The purpose of this study was to evaluate the quality and readability of online resources on the diagnosis and treatment of ankle osteochondral lesions (OCLs). Design: Three search terms (“ankle cartilage defect,” “cartilage injury,” “ankle cartilage damage”) were entered into 3 search engines (Google, Yahoo, and Bing). The first 20 websites from each search was collected excluding websites intended for health care providers. The quality of the websites were evaluated using the DISCERN instrument, JAMA benchmark, and a Quality rating criteria specific to ankle OCL. The readability was assessed using Flesch Reading Ease (FRE) and Flesch-Kincaid Grade Level (FKGL). Statistical analysis was performed using one-way analysis of variance. Results: A total of 41 websites were reviewed. The mean quality ratings were poor across the assessment tools: DISCERN = 38.5 ± 9.0 (range, 23.7-56.7) out of 80; JAMA = 1.0 ± 1.1 (range, 0-3.3) out of 4; and Quality rating criteria = 11.3 ± 4.6 (range, 4-20.7) out of 24. The mean FRE and FKGL were 40.7 ± 32.0 (range, −152.3 to 60.2) and 13.5 ± 10.8 (range, 8.4-80.7), respectively; higher than the recommended reading level for patients (fifth grade). Conclusions: The quality and readability of credible sources for ankle OCL were poor, which could lead to misinformation. This study should guide the improvement of online information on ankle OCL.

Objective Despite new strategies in tissue engineering, cartilage repair remains a major challenge. Our aim is to treat patients with focal lesions of articular cartilage with autologous hyaline cartilage implants using a scaffold-free approach. In this article, we describe experiments to optimize production of scaffold-free cartilage discs. Design Articular chondrocytes were expanded in vitro, seeded in transwell inserts and redifferentiated using established chondrogenic components. Experimental variables included testing 2 different expansion media, adding bone morphogenetic protein 2 (BMP2), insulin-like growth factor 1 (IGF1), growth/differentiation factor 5 (GDF5), or fibroblast growth factor 18 (FGF18) to the differentiation medium and allowing the disc to float freely in large wells. Cartilage discs were analyzed by weight and thickness, real-time RT-qPCR (reverse transcriptase qualitative polymerase chain reaction), fluorescence immunostaining, transmission electron microscopy, second harmonic generation imaging, and measurement of Young’s modulus. Results Addition of BMP2 to the chondrogenic differentiation medium (CDM) was essential for stable disc formation, while IGF1, GDF5, and FGF18 were redundant. Allowing discs to float freely in CDM on a moving platform increased disc thickness compared with discs kept continuously in transwell inserts. Discs cultured for 6 weeks reached a thickness of almost 2 mm and Young’s modulus of >200 kPa. There was abundant type II collagen. Collagen fibrils were 25 nm thick, with a tendency to be organized perpendicular to the disc surface. Conclusion Scaffold-free engineering using BMP2 and providing free movement in CDM produced firm, elastic cartilage discs with abundant type II collagen. This approach may potentially be used in clinical trials.

Objective To compare radius of curvature (RoC) of distal femur osteochondral autograft transfer (OAT) donor sites from the intercondylar notch and trochlear ridge with recipient sites on the distal and posterior condyles and evaluate differences between recipient sites. Design Nineteen cadaveric femurs were scanned with a 3-dimensional high-resolution sensor. Donor regions included the lateral (LTR) and medial trochlear ridges (MTR), and the lateral (LICN) and medial intercondylar notch (MICN). Recipient regions analyzed were the distal medial (DMFC), posterior medial (PMFC), distal lateral (DLFC), and posterior lateral femur condyle (PLFC). Six-millimeter OAT grafts were simulated, and average RoC of all regions was compared using an analysis of variance. Post hoc testing was performed using Fisher’s least significant difference. Results We found no significant differences in RoC of the LICN compared with all 4 recipient sites ( P = 0.19, 0.97, 0.11, and 0.75 for DLFC, PLFC, DMFC, and PMFC, respectively) or the LTR and MTR to the posterior condyles (LTR vs. PLFC and PMFC; P = 0.72, 0.47, MTR vs. PLFC and PMFC P = 0.39, 0.22, respectively). Significant differences were found for RoC of the MICN compared with each recipient site ( P < 0.001) and between distal and posterior femoral condyles (DLFC vs. PLFC, P = 0.016; DMFC vs. PMFC, P = 0.023). Conclusion The LICN is the ideal donor option for all recipient sites on the femoral condyles with respect to RoC of 6-mm OAT plugs. The MTR and LTR were acceptable donor sources for the posterior condyles, while the MICN was a poor match for all recipient sites. Additionally, the distal femur condyle and posterior femur condyle have different RoCs.

Objective To create a treatment algorithm for focal grade 3 or 4 cartilage defects of the knee using both classic and novel cartilage restoration techniques. Design A comprehensive review of the literature was performed highlighting classic as well as novel cartilage restoration techniques supported by clinical and/or basic science research and currently being employed by orthopedic surgeons. Results There is a high level of evidence to support the treatment of small to medium size lesions (2) without subchondral bone involvement with traditional techniques such as marrow stimulation, osteochondral autograft transplant (OAT), or osteochondral allograft transplant (OCA). Newer techniques such as autologous matrix-induced chondrogenesis and bone marrow aspirate concentrate implantation have also been shown to be effective in select studies. If subchondral bone loss is present OAT or OCA should be performed. For large lesions (>4 cm2), OCA or matrix autologous chondrocyte implantation (MACI) may be performed. OCA is preferred over MACI in the setting of subchondral bone involvement while cell-based modalities such as MACI or particulated juvenile allograft cartilage are preferred in the patellofemoral joint. Conclusions Numerous techniques exist for the orthopedic surgeon treating focal cartilage defects of the knee. Treatment strategies should be based on lesion size, lesion location, subchondral bone involvement, and the level of evidence supporting each technique in the literature.

Objective There has been a debate as to the alignment of the collagen fibers. Using a hand lens, Sir William Hunter demonstrated that the collagen fibers ran perpendicular and later aspects were supported by Benninghoff. Despite these 2 historical studies, modern technology has conflicting data on the collagen alignment. Design Ten mature New Zealand rabbits were used to obtain 40 condyle specimens. The specimens were passed through ascending grades of alcohol, subjected to critical point drying (CPD), and viewed in the scanning electron microscope. Specimens revealed splits from the dehydration process. When observing the fibers exposed within the opening of the splits, parallel fibers were observed to run in a radial direction, normal to the surface of the articular cartilage, radiating from the deep zone and arcading as they approach the surface layer. After these observations, the same samples were mechanically fractured and damaged by scalpel. Results The splits in the articular surface created deep fissures, exposing parallel bundles of collagen fibers, radiating from the deep zone and arcading as they approach the surface layer. On higher magnification, individual fibers were observed to run parallel to one another, traversing radially toward the surface of the articular cartilage and arcading. Mechanical fracturing and scalpel damage induced on the same specimens with the splits showed randomly oriented fibers. Conclusion Collagen fiber orientation corroborates aspects of Hunter’s findings and compliments Benninghoff. Investigators must be aware of the limits of their processing and imaging techniques in order to interpret collagen fiber orientation in cartilage.

Purpose To evaluate the effect of imaging plane and experience of observers on the reliability of T2 mapping of native and repair cartilage tissue of the knee. Methods Fifteen consecutive patients from two randomised controlled trials (RCTs) were included in this cross-sectional study. Patients with an isolated knee cartilage lesion were randomised to receive either debridement or microfracture (RCT 1) or debridement or autologous chondrocyte implantation (RCT 2). T2 mapping was performed in coronal and sagittal planes two years postoperatively. A musculoskeletal radiologist, a resident of radiology and two orthopaedic surgeons measured the T2 values independently. Intraclass Correlation Coefficient (ICC) with 95% Confidence Intervals was used to calculate the inter- and intraobserver agreement. Results Mean age for the patients was 36.8 ± 11 years, 8 (53%) were men. The overall interobserver agreement varied from poor to good with ICCs in the range of 0.27– 0.76 for native cartilage and 0.00 – 0.90 for repair tissue. The lowest agreement was achieved for evaluations of repair cartilage tissue. The estimated ICCs suggested higher inter- and intraobserver agreement for radiologists. On medial femoral condyles, T2 values were higher for native cartilage on coronal images (p p Conclusions The reliability of T2 mapping of articular cartilage is influenced by the imaging plane and the experience of the observers. This influence may be more profound for repair cartilage tissue. This is important to consider when using T2 mapping to measure outcomes after cartilage repair surgery. Trial registration ClinicalTrials.gov, NCT02637505 and NCT02636881, registered December 2015. Level of evidence II, based on prospective data from two RCTs.

The osmotic pressure in articular cartilage serves an important mechanical function in healthy tissue. Its magnitude is thought to play a role in advancing osteoarthritis. The aims of this study were to: (1) isolate and quantify the magnitude of cartilage swelling pressure in situ; and (2) identify the effect of salt concentration on material parameters. Confined compression stress-relaxation testing was performed on 18 immature bovine and six mature human cartilage samples in solutions of varying osmolarities. Direct measurements of osmotic pressure revealed nonideal and concentration-dependent osmotic behavior, with magnitudes approximately 1/3 those predicted by ideal Donnan law. A modified Donnan constitutive behavior was able to capture the aggregate behavior of all samples with a single adjustable parameter. Results of curve-fitting transient stress-relaxation data with triphasic theory in febio demonstrated concentration-dependent material properties. The aggregate modulus HA increased threefold as the external concentration decreased from hypertonic 2 M to hypotonic 0.001 M NaCl (bovine: HA=0.420±0.109 MPa to 1.266±0.438 MPa; human: HA=0.499±0.208 MPa to 1.597±0.455 MPa), within a triphasic theory inclusive of osmotic effects. This study provides a novel and simple analytical model for cartilage osmotic pressure which may be used in computational simulations, validated with direct in situ measurements. A key finding is the simultaneous existence of Donnan osmotic and Poisson–Boltzmann electrostatic interactions within cartilage.

Objectives Recapitulating the mechanical properties of articular cartilage (AC) is vital to facilitate the clinical translation of cartilage tissue engineering. Prior to evaluation of tissue-engineered constructs, it is fundamental to investigate the biomechanical properties of native AC under sudden, prolonged, and cyclic loads in a practical manner. However, previous studies have typically reported only the response of native AC to one or other of these loading regimes. We therefore developed a streamlined testing protocol to characterize the elastic and viscoelastic properties of human knee AC, generating values for several important parameters from the same sample. Design Human AC was harvested from macroscopically normal regions of distal femoral condyles of patients ( n = 3) undergoing total knee arthroplasty. Indentation and unconfined compression tests were conducted under physiological conditions (temperature 37 °C and pH 7.4) and testing parameters (strain rates and loading frequency) to assess elastic and viscoelastic parameters. Results The biomechanical properties obtained were as follows: Poisson ratio (0.4 ± 0.1), instantaneous modulus (52.14 ± 9.47 MPa) at a loading rate of 1 mm/s, Young’s modulus (1.03 ± 0.48 MPa), equilibrium modulus (7.48 ± 4.42 MPa), compressive modulus (10.60 ± 3.62 MPa), dynamic modulus (7.71 ± 4.62 MPa) at 1 Hz and loss factor (0.11 ± 0.02). Conclusions The measurements fell within the range of reported values for human knee AC biomechanics. To the authors’ knowledge this study is the first to report such a range of biomechanical properties for human distal femoral AC. This protocol may facilitate the assessment of tissue-engineered composites for their functionality and biomechanical similarity to native AC prior to clinical trials.

Objective During skeletal growth, the articular cartilage expands to maintain its cover of bones in joints, however, it is unclear when and how cartilage grows. We aim to determine the expanding growth pattern and timing across the tibia plateau in human knees. Design Six human tibia plateaus (2 healthy, 2 with osteoarthritis, and 2 with posttraumatic osteoarthritis) were used for full-depth cartilage sampling systematically across the joint surface at 12 medial and 4 lateral sites. Methodologically, we took advantage of the performed nuclear bomb tests in the years 1955 to 1963, which increased the atmospheric 14C that was incorporated into human tissues. Cartilage was treated enzymatically to extract collagen, analyzed for 14C content, and year at formation was determined from historical atmospheric 14C concentrations. Results By age-determination, each tibia condyle had central points of formation surrounded by later-formed cartilage toward the periphery. Furthermore, the tibia plateaus contained collagen with 14C levels corresponding to mean donor age of 11.7 years (±3.8 SD). Finally, the medial condyle had lower 14C levels corresponding to formation 1 year later than the lateral condyle ( P = 0.009). Conclusions Human cartilage on the tibia plateau contains collagen that has experienced little if any turnover since school-age. The cartilage formation develops from 2 condyle centers and radially outward with the medial condyle finishing slightly later than the lateral condyle. This suggests a childhood programmed cartilage formation with a very limited adulthood collagen turnover.