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Purpose: To compare short-term patient-reported outcomes (PRO) of two contemporary matrix-associated autologous chondrocyte implantation (M-ACI) products for the treatment of large articular cartilage defects of the knee., Methods: A retrospective, registry-based, matched-pair analysis was performed, comparing PRO of patients undergoing isolated M-ACI with either Spherox™, a spheroid-based ACI (Sb-ACI), or NOVOCART™ Inject, a hydrogel-based ACI product (Hb-ACI), for a focal full-thickness cartilage defect of the knee ≥4 cm 2 . Matching parameters included age, sex, body mass index, defect size, defect localization, symptom duration and previous surgeries. The Knee Injury and Osteoarthritis Outcome Score (KOOS) and the International Knee Documentation Committee (IKDC) score were obtained up to the 24-month follow-up. The total KOOS response rate and percentage of patients attaining a substantial clinical benefit (SCB) in KOOS subscores were calculated., Results: A total of 45 patients per group were matched. The response rate after 24 months was not significantly different between the groups (Sb-ACI 64.4% vs. Hb-ACI 82.2%, p = 0.057). The number of patients with a SCB at 24 months was not significantly different in any KOOS subscore, despite significantly higher improvement of the total KOOS (14.8 ± 16.2 vs. 21.5 ± 15.4, p = 0.047) and KOOS pain in the Hb-ACI group (12.2 ± 18.6 vs. 20.6 ± 19.1, p = 0.037). The IKDC score in the Hb-ACI group was significantly higher at the 12- and 24-month follow-up (60.7 ± 20.2 vs. 70.9 ± 18.0, p = 0.013)., Conclusion: The response rate and number of patients achieving an SCB were not significantly different between patients treated with Sb-ACI or Hb-ACI. Both procedures can achieve favourable 2-year PRO. Hb-ACI was associated with better PRO between 1 and 2 years postoperatively; however, the clinical relevance of this benefit is yet to be proven., Level of Evidence: III, Retrospective comparative study., (© 2024 The Authors. Knee Surgery, Sports Traumatology, Arthroscopy published by John Wiley & Sons Ltd on behalf of European Society of Sports Traumatology, Knee Surgery and Arthroscopy.)

Articular cartilage is crucial for joint function but its avascularity limits intrinsic repair, leading to conditions like osteoarthritis (OA). Chondromodulin-I (Cnmd) has emerged as a key molecule in cartilage biology, with potential implications for OA therapy. Cnmd is primarily expressed in cartilage and plays an important role in chondrocyte proliferation, cartilage homeostasis, and the blocking of angiogenesis. In vivo and in vitro studies on Cnmd, also suggest an involvement in bone repair and in delaying OA progression. Its downregulation correlates with OA severity, indicating its potential as a therapeutic target. Further research is needed to fully understand the mode of action of Cnmd and its beneficial implications for managing OA. This comprehensive review aims to elucidate the molecular characteristics of Cnmd, from its expression pattern, role in cartilage maintenance, callus formation during bone repair and association with OA.

Purpose: To determine whether bipolar lesions (BL) are associated with inferior clinical outcome following articular cartilage regeneration (CR) compared to unipolar lesions (UL)., Methods: A registry-based study, including patients undergoing isolated CR for focal knee cartilage lesions was performed. Lesions were considered UL or BL depending on the opposing cartilage. Propensity score matching was applied to eliminate potential confounders. Two groups comprising 119 patients with similar baseline characteristics were matched. The Knee Injury and Osteoarthritis Outcome Score (KOOS) at baseline, 6, 12, 24, and 36 months following CR served as primary outcome measure. KOOS improvement, reaching the minimal clinically important difference (MCID), KOOS subcomponents, and failure rates were calculated., Results: Autologous chondrocyte implantation (ACI) was the most frequently performed procedure in both groups with 63.0% (BL) and 46.6% (UL). There was a significant difference regarding KOOS at 24 months between UL (76.39 ± 14.96) and BL (69.83 ± 18.83; P = .028), which did not exceed the threshold of MCID. No significant difference was detected at any other follow-up. KOOS improvement from baseline was lower in the BL group at all follow-ups and peaked at 36 months in both groups (UL [26.00 ± 16.12] vs. BL [16.63 ± 17.29]; P = .024). The failure rate in the BL group was higher at 8.2% (9/110) compared to the UL group at 3.9% (4/98) (P = .256)., Conclusions: BL were associated with worse clinical outcome 2 years following CR compared to UL. However, both groups showed an ongoing clinical improvement up to 3 years postoperatively and a low failure rate. While inferior clinical improvement and a lower clinical response rate may be expected in BL patients, the observed differences do not justify excluding these patients from CR., Level of Evidence: Level III, retrospective comparative prognostic trial., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: The treatment of underlying comorbidities is a field of rising interest in cartilage repair surgery. The aim of this study was to analyze the current practice of concomitant surgeries in cartilage repair of the knee especially in the medial or lateral femorotibial compartment. Type, frequency and distribution of additional surgeries for correction of malalignment, knee instability and meniscus deficiency should be evaluated., Methods: Baseline data of 4968 patients of the German Cartilage Registry (KnorpelRegister DGOU) were analyzed regarding the distribution of concomitant surgeries in addition to regenerative cartilage treatment., Results: Beyond 4968 patients 2445 patients with cartilage defects in the femorotibial compartment of the knee could be identified. Of these patients 1230 (50.3%) received additional surgeries for correction of malalignment, instability and meniscus deficiency. Predominant procedures were leg axis corrections (31.3%), partial meniscectomy (20.9%) and ACL reconstruction (13.4%). The distribution of the concomitant surgeries varied between cartilage defects according to the different defect genesis. Patients with traumatic defects were younger (36y) and received predominantly ACL reconstructions (29.2%) (degenerative: 6.7%), whereas patients with degenerative defects were older (43y) and underwent predominantly leg axis corrections (38.0%; traumatic: 11.0%)., Conclusions: This study shows the high frequency and distinct distribution of the concomitant surgeries in addition to regenerative cartilage treatment procedures. Understanding of the underlying cause of the cartilage defect and addressing the comorbidities as a whole joint therapy are of utmost importance for a successful regenerative cartilage treatment. These data provide a baseline for further follow up evaluations and long-term outcome analysis., Level of Evidence: II., (© 2021. The Author(s).)

The Working Group of the German Orthopedic and Trauma Society (DGOU) on Tissue Regeneration has published recommendations on the indication of different surgical approaches for treatment of full-thickness cartilage defects in the knee joint in 2004, 2013 and 2016. Based upon new scientific knowledge and new developments, this recommendation is an update based upon the best clinical evidence available. In addition to prospective randomised controlled clinical trials, this also includes studies with a lower level of evidence. In the absence of evidence, the decision is based on a consensus process within the members of the working group.The principle of making decision dependent on defect size has not been changed in the new recommendation either. The indication for arthroscopic microfracturing has been reduced up to a defect size of 2 cm 2 maximum, while autologous chondrocyte implantation is the method of choice for larger cartilage defects. Additionally, matrix-augmented bone marrow stimulation (mBMS) has been included in the recommendation for defects ranging from 1 to 4.5 cm 2 . For the treatment of smaller osteochondral defects, in addition to osteochondral transplantation (OCT), mBMS is also recommended. For larger defects, matrix-augmented autologous chondrocyte implantation (mACI/mACT) in combination with augmentation of the subchondral bone is recommended., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

Objective: The objective of this study was to evaluate the best available mid- to long-term evidence of surgical procedures for the treatment of localized full-thickness cartilage defects of the knee., Design: Systematic review using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines of Level 1 randomized clinical trials (RCTs), meta-analyses of RCTs and systematic reviews with a minimum follow-up of 5 years. Data extracted included patient demographics, defect characteristics, clinical and radiological outcomes, as well as treatment failures., Results: Six RCTs and 3 Level 1 systematic reviews were included. Two RCTs compared microfracture (MFx) to periosteum-covered autologous chondrocyte implantation (ACI-P), 1 to matrix-associated ACI (M-ACI) and 2 to osteochondral autograft transplantation (OAT). One study compared OAT to collagen membrane covered ACI (ACI-C). The 3 Level 1 systematic reviews/meta-analyses assessed the outcome of MFx, OAT, and various ACI methods in RCTs. OAT showed significantly better outcomes compared with MFx. In the 2 RCTs comparing ACI-P and MFx, no significant differences in clinical outcomes were seen, whereas significantly better outcomes were reported for M-ACI versus MFx in 1 study including patients with larger defects (5 cm 2 ), and for ACI-C versus OAT in terms of Cincinnati Score. Higher failure rates were reported for MFx compared with OAT and for OAT compared with ACI-C, while no significant differences in failure rates were observed for ACI-P compared to MFx., Conclusion: Restorative cartilage procedures (ACI-C or M-ACI and OAT) are associated with better long-term clinical outcomes including lower complication and failure rates when compared with reparative techniques (MFx). Among the restorative procedures, OAT seems to be inferior to ACI especially in larger defects after longer follow-up periods., Level of Evidence: Level I: Systematic review of Level I studies.

Objective: To evaluate whether a sandwich technique procedure for large osteochondral lesions (OCL) of the medial femur condyle reduces clinical symptoms and improves activity level as well as to assess repair tissue integration on MRI over 2 years., Design: Twenty-one patients (median age: 29 years, 18-44 years) who received matrix-associated autologous chondrocyte transplantation (MACT) combined with cancellous bone grafting at the medial femur condyle in a 1-step procedure were prospectively included. Patients were evaluated before surgery (baseline) as well as 3, 6, 12, and 24 months postoperatively, including clinical evaluation, Lysholm score, Tegner Activity Rating Scale, and MRI with Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) score and a modified Whole-Organ Magnetic Resonance Imaging Score (WORMS)., Results: Seventeen patients were available for the 24-month (final) follow-up (4 dropouts). Lysholm significantly improved from 48 preoperatively stepwise to 95 at final follow-up ( P < 0.05). Tegner improvement from 2.5 at baseline to 4.0 at final follow-up was not significant ( P = 1.0). MOCART score improved significantly and stepwise from 65 at 3 months to 90 at 24 months ( P < 0.05). Total WORMS improved from 14.5 at surgery to 7.0 after 24 months ( P < 0.05). Body mass index and defect size at surgery correlated with total WORMS at final follow-up ( P < 0.05) but did not correlate with clinical scores or defect filling., Conclusion: MACT combined with cancellous bone grafting at the medial femoral condyle reduces symptoms continuously over 2 years. A 1-step procedure may reduce perioperative morbidity. However, despite improvements, patients' activity levels remain low, even 2 years after surgery.

Purpose: This article provides an update on the current therapeutic options for cell-based regenerative treatment of the knee with a critical review of the present literature including a future perspective on the use of regenerative cell-based approaches. Special emphasis has been given on the requirement of a whole joint approach with treatment of comorbidities with aim of knee cartilage restoration, particularly in demanding conditions like early osteoarthritis., Methods: This narrative review evaluates recent clinical data and published research articles on cell-based regenerative treatment options for cartilage and other structures around the knee RESULTS: Cell-based regenerative therapies for cartilage repair have become standard practice for the treatment of focal, traumatic chondral defects of the knee. Specifically, matrix-assisted autologous chondrocyte transplantation (MACT) shows satisfactory long-term results regarding radiological, histological and clinical outcome for treatment of large cartilage defects. Data show that regenerative treatment of the knee requires a whole joint approach by addressing all comorbidities including axis deviation, instability or meniscus pathologies. Further development of novel biomaterials and the discovery of alternative cell sources may facilitate the process of cell-based regenerative therapies for all knee structures becoming the gold standard in the future., Conclusion: Overall, cell-based regenerative cartilage therapy of the knee has shown tremendous development over the last years and has become the standard of care for large and isolated chondral defects. It has shown success in the treatment of traumatic, osteochondral defects but also for degenerative cartilage lesions in the demanding condition of early OA. Future developments and alternative cell sources may help to facilitate cell-based regenerative treatment for all different structures around the knee by a whole joint approach., Level of Evidence: IV., (© 2021. The Author(s).)

Subjective patient satisfaction is the most relevant parameter for assessing the success of treatment after orthopaedic surgery. The aim of the present study was to correlate patient-reported outcome parameters (i.e., absolute KOOS, KOOS increase) and revision-free survival with patient's satisfaction. Furthermore, the study aimed on the identification of pre-operative factors that are associated with patient's satisfaction after the surgery.For the present study, 6305 consecutive patients from the German Cartilage Registry (KnorpelRegister DGOU) were analyzed. Patient characteristics and outcome were correlated with patients' satisfaction after a follow-up of three years by Spearman correlation. P values < 0.05 were considered statistically significant.Mean age was 37 ± 12.5 years, 59.7% patients were male, and 40.3% female. Most patients (46.7%) were treated with an autologous chondrocyte implantation (ACI). The strongest correlation of subjective satisfaction and the subscore quality of life (r = 0.682; p < 0.001) was found, whereas the post-operative increase in KOOS from the pre-operative value showed only a moderate correlation (r = 0.520; p < 0.001). There was also a significant correlation with the absolute KOOS value (r = 0.678; p < 0.001), the subscores pain (r = 0.652; p < 0.001), quality of life (r = 0.682; p < 0.001), and sports (r = 0.633; p < 0.001), whereas symptoms (r = 0.504, p < 0.001) and activities of daily life (r = 0.601; p < 0.001) showed a weaker correlation. Pain also correlated highly significant with the patient satisfaction 24 months after surgery (r =  - 0.651, p < 0.001). The correlation between satisfaction after the 2nd and 3rd year (r = 0.727; p < 0.001) is stronger than correlation after six months and three years (r = 0.422, p < 0.001). All pre-operative parameters show a very weak correlation (r < 0.1).The use of standardized measuring instruments (KOOS and Pain) is a relevant outcome parameter in science and clinical practice, whereas absolute values represent satisfaction better than the individual increase. The subscores "pain," "quality of life," and "sports" represent satisfaction better than the subscores "symptoms" and "activity of daily life." Early satisfaction has only a moderate predictive value for satisfaction after 3 years, which is of great practical relevance in particular for the assessment of potential treatment failures. It is remarkable to note that a revision surgery is only very mildly associated with increased dissatisfaction. Pre-operative factors are not reliable prediction factors for post-operative patient satisfaction., (© 2021. The Author(s).)

Objective: To develop patient-focused consensus guidelines on the indications for the use of scaffolds to address chondral and osteochondral femoral condyle lesions., Design: The RAND/UCLA Appropriateness Method (RAM) was used to develop patient-specific recommendations by combining the best available scientific evidence with the collective judgement of a panel of experts guided by a core panel and multidisciplinary discussers. A list of specific clinical scenarios was produced regarding adult patients with symptomatic lesions without instability, malalignment, or meniscal deficiency. Each scenario underwent discussion and a 2-round vote on a 9-point Likert-type scale (range 1-3 "inappropriate," 4-6 "uncertain," 7-9 "appropriate"). Scores were pooled to generate expert recommendations., Results: Scaffold (chondral vs. osteochondral), patient characteristics (age and sport activity level), and lesion characteristics (etiology, size, and the presence of osteoarthritis [OA]) were considered to define 144 scenarios. The use of scaffold-based procedures was considered appropriate in all cases of chondral or osteochondral lesions when joints are not affected by OA, while OA joints presented more controversial results. The analysis of the evaluated factors showed a different weight in influencing treatment appropriateness: the presence of OA influenced 58.3% of the indications, while etiology, size, and age were discriminating factors in 54.2%, 29.2%, and 16.7% of recommendations, respectively., Conclusions: The consensus identified indications still requiring investigation, but also the convergence of the experts in several scenarios defined appropriate or inappropriate, which could support decision making in the daily clinical practice, guiding the use of scaffold-based procedures for the treatment of chondral and osteochondral knee defects.

Objective: The aim of this study was to investigate texture features from T 2 maps as a marker for distinguishing the maturation of repair tissue after 2 different cartilage repair procedures., Design: Seventy-nine patients, after either microfracture (MFX) or matrix-associated chondrocyte transplantation (MACT), were examined on a 3-T magnetic resonance (MR) scanner with morphological and quantitative (T 2 mapping) MR sequences 2 years after surgery. Twenty-one texture features from a gray-level co-occurrence matrix (GLCM) were extracted. The texture feature difference between 2 repair types was assessed individually for the femoral condyle and trochlea/anterior condyle using linear regression models. The stability and reproducibility of texture features for focal cartilage were calculated using intra-observer variability and area under curve from receiver operating characteristics., Results: There was no statistical significance found between MFX and MACT for T 2 values ( P = 0.96). There was, however, found a statistical significance between MFX and MACT in femoral condyle in GLCM features autocorrelation ( P < 0.001), sum of squares ( P = 0.023), sum average ( P = 0.005), sum variance ( P = 0.0048), and sum entropy ( P = 0.05); and in anterior condyle/trochlea homogeneity ( P = 0.02) and dissimilarity ( P < 0.001)., Conclusion: Texture analysis using GLCM provides a useful extension to T 2 mapping for the characterization of cartilage repair tissue by increasing its sensitivity to tissue structure. Some texture features were able to distinguish between repair tissue after different cartilage repair procedures, as repair tissue texture (and hence, probably collagen organization) 24 months after MACT more closely resembled healthy cartilage than did MFX repair tissue.

The goal was to examine gender differences of patient characteristics and outcome after cartilage repair based on a collective of nearly 5,000 patients. Patient characteristics, accompanying therapies, and outcome (Knee Injury and Osteoarthritis Outcome Score [KOOS], reoperations, patient satisfaction) of 4,986 patients of the German cartilage register DGOU were assessed by t test for possible gender differences. P values <0.05 were considered statistically significant. Women were older than men (38.07 ± 12.54 vs. 26.94 ± 12.394 years, P = 0.002), more often preoperated (0.30 ± 0.63 vs. 0.24 ± 0.55, P = 0.001), and had a longer symptom duration (25.22 ± 41.20 vs. 20.67 ± 35.32 months, P < 0.001). Men had greater mean leg axis malalignment than women (3.24° ± 3.26° vs. 2.67° ± 3.06°, P < 0.001), less favorable meniscal status ( P = 0.001), worse defect stage ( P = 0.006), and a more severely damaged corresponding articular surface ( P = 0.042). At baseline (59.84 ± 17.49 vs. 52.10 ± 17.77, P < 0.001), after 6 months (72.83 ± 15.56 vs. 66.56 ± 17.66, P < 0.001), after 12 months (77.88 ± 15.95 vs. 73.07 ± 18.12, P < 0.001), and after 24 months (79.311 ± 15.94 vs. 74.39 ± 18.81, P < 0.001), men had better absolute KOOS values, but women had better relative KOOS increases 6 months (14.59 ± 17.31 vs. 12.49 ± 16.3, P = 0.005) as well as 12 months postoperatively (20.27 ± 18.6 vs. 17.34 ± 17.79, P = 0.001) compared with preoperatively, although 12 and 24 months postoperatively they were subjectively less satisfied with the outcome ( P < 0.001) and had a higher reintervention rate at 24 months (0.17 ± 0.38 vs. 0.12 ± 0.33, P = 0.008). In summary, the present work shows specific gender differences in terms of patient characteristics, defect etiology, defect localization, concomitant therapy, and the choice of cartilage repair procedure. Unexpectedly, contrary to the established scientific opinion, it could be demonstrated that women show relatively better postoperative KOOS increases, despite a higher revision rate and higher subjective dissatisfaction.

Background: High tibial osteotomy (HTO) for varus deformities is a common concomitant treatment in cartilage surgery. Aim of the present study was to analyze factors influencing the decision towards accompanying HTO in patients with cartilage defects of the medial femoral condyle, such as the amount of varus deformity., Methods: Data from 4986 patients treated for cartilage defects of the knee from the German Cartilage Registry (KnorpelRegister DGOU) were used for the current analysis. Seven hundred and thirty-six patients fulfilled the inclusion criteria. Their data were analyzed for factors influencing the decision towards performing a concomitant HTO using t test, univariate and multivariate binary logistic regression models., Results: The break point at which the majority of patients receive a concomitant HTO is 3° of varus deformity. Several factors apart from the amount of varus deformity (5.61 ± 2.73° vs. 1.72 ± 2.38°, p < 0.00) differed significantly between the group of patients with HTO and those without. These included defect size (441.6 ± 225.3 mm 2 vs. 386.5 ± 204.2 mm 2 , p = 0.001), symptom duration (29.53 ± 44.58 months vs. 21.85 ± 34.17 months, p = 0.021), defect grade (62.5% IVa/IVb vs. 57.3% IVa/IVb, p = 0.014), integrity of corresponding joint surface (10.8% grade III-IV vs. 0.2% grade III-IV, p < 0.001), meniscus status (15.5% > 1/3 resected vs. 4.4% > 1/3 resected, p < 0.001) and number of previous surgeries (1.01 ± 1.06 vs. 0.75 ± 1.00, p = 0.001). In the stepwise multivariate binary logistic regression test, only the amount of varus deformity, symptom duration and quality of the corresponding joint surface remained significant predictors associated with performing a concomitant HTO., Conclusion: Based upon data from a nationwide cohort, additional HTO in context with cartilage repair procedures of the medial femoral condyle is frequently performed even in mild varus deformities less than 5°. Other factors also seem to influence decision for HTO.

Purpose: This study was aimed to determine the impact of bioregenerative operations in case of degenerative cartilage lesions within the media knee compartment., Material and Methods: The CartilageRegistry DGOU was founded in 2013. At the deadline August 2016 a total of 1847 patients were included. A total of 23.3% (n = 432) was suffering from a degenerative cartilage lesion in the medial compartment. Follow-up was performed after 6, 12, and 24 months (online evaluation). The patients were asked for their subject feeling as well as the KOOS (Knee injury and Osteoarthritis Outcome Score) was determined., Results: Most of the patients (n = 358) suffered from a single femoral lesion. In 25 cases single tibial and in 49 cases combined defects ("kissing lesions") were addressed by different treatment options: 39.9% autologous chondrocyte transplantation, in 8.1% in combination with a spongiosa plasty. Other treatments were drilling, microfracturing with or without matrix. In 17.9% the surgeons had chosen combined methods. The bioregenerative treatment was combined with a concomitant operation in 39.7% in patients with medial, in 56.0% in patients with a tibial, and in 67.9% in patients with combined defects. The mostly performed additional operations were osteotomies. There were no gender differences at baseline or during follow-up. The history of patients with femoral defects was shorter than in the other groups. The patients with medial defects judged the subjective outcome significant more frequently better after 6, 12, or 24 months compared with the other groups. The KOOS raised from baseline (median 52 points) to a median of 75 after 6, to 78 points after 12, and to 80 points after 24 months. Patients with femoral defects had a better KOOS-outcome in tendency. Revision operations were required in 7.1%., Conclusions: The treatment of degenerative cartilage lesions (respective early OA) by bioregenerative procedures are well-established measures. These treatments are sufficient to produce high patients' satisfaction and acceptable short/midterm results., Competing Interests: The authors declare that they have no conflict of interest./Die Autoren geben an, dass kein Interessenkonflikt besteht., (Georg Thieme Verlag KG Stuttgart · New York.)

Osteoarthritis (OA) is a degenerative condition that involves the production of inflammatory cytokines (e.g., interleukin-1β (IL-1β), tumour necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6)) that stimulate degradative enzymes, matrix metalloproteinases (MMPs) and aggrecanases (ADAMTS) resulting in articular cartilage breakdown. The presence of interleukin-1β (IL-1β) is one reason for poor clinical outcomes in current cell-based tissue engineering strategies for treating focal early osteoarthritic defects. Mesenchymal stem cells (MSCs) are a potential cell source for articular cartilage regeneration, although IL-1β has been shown to inhibit in vitro chondrogenesis. In vivo, articular chondrocytes reside under a low oxygen environment between 2-5% oxygen (physioxia) and have been shown to enhance in vitro MSC chondrogenic matrix content with reduced hypertrophic marker expression under these conditions. The present investigation sought to understand the effect of physioxia on IL-1β inhibited MSC chondrogenesis. MSCs expanded under physioxic (2% oxygen) and hyperoxic (20%) conditions, then chondrogenically differentiated as pellets in the presence of TGF-β1 and either 0.1 or 0.5 ng/mL IL-1β. Results showed that there were donor variations in response to physioxic culture based on intrinsic GAG content under hyperoxia. In physioxia responsive donors, MSC chondrogenesis significantly increased GAG and collagen II content, whilst hypertrophic markers were reduced compared with hyperoxia. In the presence of IL-1β, these donors showed a significant increase in cartilage matrix gene expression and GAG content relative to hyperoxic conditions. In contrast, a set of MSC donors were unresponsive to physioxia and showed no significant increase in matrix production independent of IL-1β presence. Thus, physioxia has a beneficial effect on MSC cartilage matrix production in responsive donors with or without IL-1β application. The mechanisms controlling the MSC chondrogenic response in both physioxia responsive and unresponsive donors are to be elucidated in future investigations.

Objective: Elucidation of whether miRs are involved in mechanotransduction pathways by which cartilage is maintained or disturbed has a particular importance in our understanding of osteoarthritis (OA) pathophysiology. The aim was to investigate whether mechanical loading influences global miR-expression in human chondrocytes and to identify mechanosensitive miRs responding to beneficial and non-beneficial loading regimes as potential to obtain valuable diagnostic or therapeutic targets to advance OA-treatment., Method: Mature tissue-engineered human cartilage was subjected to two distinct loading regimes either stimulating or suppressing proteoglycan-synthesis, before global miR microarray analysis. Promising candidate miRs were selected, re-evaluated by qRT-PCR and tested for expression in human healthy vs OA cartilage samples., Results: After anabolic loading, miR microarray profiling revealed minor changes in miR-expression while catabolic stimulation produced a significant regulation of 80 miRs with a clear separation of control and compressed samples by hierarchical clustering. Cross-testing of selected miRs revealed that miR-221, miR-6872-3p, miR-6723-5p were upregulated by both loading conditions while others (miR-199b-5p, miR-1229-5p, miR-1275, miR-4459, miR-6891-5p, miR-7150) responded specifically after catabolic loading. Mechanosensitivity of miR-221 correlated with pERK1/2-activation induced by both loading conditions. The miR-response to loading was transient and a constitutive deregulation of mechano-miRs in OA vs healthy articular cartilage was not observed., Conclusions: MiRs with broader vs narrower mechanosensitivity were discovered and the first group of mechanosensitive miRs characteristic for non-beneficial loading was defined that may shape the proteome differentially when cartilage tissue is disturbed. The findings prompt future investigations into miR-relevance for mechano-responsive pathways and the corresponding miR-target molecules., (Copyright © 2019 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Purpose: To evaluate the factors influencing the baseline Knee Injury and Osteoarthritis Outcome Score (KOOS) in patients with knee cartilage defects and planned cartilage repair surgery and to provide baseline KOOS data from a large patient population., Material and Methods: Between October 2013 and April 2017, a total of 2815 patients assigned for cartilage repair surgery were included into the German Cartilage Registry (KnorpelRegister DGOU) and their data were analyzed for the present study. Multivariate regression model and ANOVA were used to detect patient- and defect-specific factors with an influence on baseline KOOS. In addition, KOOS baseline data was calculated and compared according to these parameters., Results: Sex, age, body mass index (BMI), and smoking status were revealed as patient-specific factors, and defect location and the number of previous knee and cartilage operations were revealed as defect-specific factors with a significant influence on baseline KOOS. Most subscores were affected in accordance with the total KOOS. Interestingly, defect ICRS grade, defect size, and symptom duration had no significant influence. The mean baseline KOOS was 56.7 (± 17.9). Men had significantly higher mean overall KOOS (60 ± 17.3 vs. 51.8 ± 17.6, p < 0.001) than women, and patients with a BMI over 30 and smokers scored significantly lower (58.07 ± 17.67 vs. 50.32 ± 17.29, p < 0.001; 57.64 ± 17.86 vs. 53.59 ± 18.06, p < 0.001). Patients with two or more previous knee operations as well as patients with more than one previous cartilage procedure also showed significantly lower overall KOOS (57.19 ± 17.89 vs. 54.56 ± 17.58, p < 0.001; 57.68 ± 18.01 vs. 52.72 ± 17.58, p < 0.001)., Conclusion: Several factors influencing baseline KOOS data in patients with knee cartilage defects assigned for cartilage repair surgery could be detected. Their individual influence in the multivariate linear regression model was not very strong. Baseline data according to these criteria is presented in this paper.

Surgical principles for treatment of full-thickness cartilage defects of the knee include bone marrow stimulation techniques (i.e. arthroscopic microfracturing) and transplantation techniques (i.e. autologous chondrocyte implantation and osteochondral transplantation). On the basis of increasing scientific evidence, indications for these established therapeutical concepts have been specified and clear recommendations for practical use have been given. Within recent years, matrix-augmented bone marrow stimulation has been established as a new treatment concept for chondral lesions. To date, scientific evidence is limited and specific indications are still unclear. The present paper gives an overview of available products as well as preclinical and clinical scientific evidence. On the basis of the present evidence and an expert consensus from the "Working Group on Tissue Regeneration" of the German Orthopaedic and Trauma Society (DGOU), indications are specified and recommendations for the use of matrix-augmented bone marrow stimulation are given. In principle, it can be stated that the various products offered in this field differ considerably in terms of the number and quality of related studies (evidence level). Against the background of the current data situation, their application is currently seen in the border area between cell transplantation and bone marrow stimulation techniques, but also as an improvement on traditional bone marrow stimulation within the indication range of microfracturing. The recommendations of the Working Group have preliminary character and require re-evaluation after improvement of the study situation., Competing Interests: Die Autoren geben an, dass kein Interessenkonflikt besteht., (Georg Thieme Verlag KG Stuttgart · New York.)

Background: In clinical practice, there is still no definite treatment algorithm for focal, partial thickness cartilage lesions (grade II - III). It is well-established that debridement (shaving/lavage) of large degenerative cartilage lesions is not recommended, but there is no such recommendation in the case of focal, partial thickness cartilage defects., Materials and Methods: The scientific rationale of cartilage shaving and joint lavage was investigated and a systematic analysis was performed of the literature on the clinical effect of cartilage debridement. Furthermore, a consensus statement on this issue was developed by the working group on Clinical Tissue Regeneration of the German Society of Orthopaedics and Trauma (DGOU)., Results: The therapeutic approach is different for asymptomatic lesions with biomechanical stable residual cartilage tissue and clinically symptomatic defects with unstable fragments. The benefit of a joint lavage or surface smoothening of focal partial thickness has not been proved. Even more importantly, the mechanical or thermal resection of cartilage tissue even induces a zone of necrosis in adjacent cartilage, and thus leads to additional injury. Therefore, large scale smoothening (shaving) of clinically asymptomatic, fibrillated or irregular cartilage defects should not be performed. However, if there are clinical symptoms, resection of unstable and delaminated cartilage fragments may be reasonable, as it can reduce harmful shear tension in residual tissue. This can help to brake the progression of the damage and avoid formation of free bodies., Conclusion: The decision criteria for debridement of partial thickness focal cartilage lesions are multifactorial and include the clinical symptoms, the size and the degree of the defect, the stability of remaining cartilage, localisation of the defect, and individual patient-specific parameters. Debridement is not recommended for asymptomatic lesions, but may be reasonable for symptomatic cases with unstable tissue., Competing Interests: Die Autoren geben an, dass kein Interessenkonflikt besteht., (Georg Thieme Verlag KG Stuttgart · New York.)

Background Symptomatic pre-arthritic deformities such as femoroacetabular impingement (FAI) or hip dysplasia often lead to localised cartilage defects and subsequently to osteoarthritis. The present review of the working group "Clinical Tissue Regeneration" of the German Society of Orthopaedics and Trauma (DGOU) and the hip committee of the AGA (German speaking Society for Arthroscopy and Joint Surgery) provides an overview of current knowledge of the diagnosis and surgical treatment of cartilage defects, in order to infer appropriate therapy recommendations for the hip. Methods Review of FAI and resultant cartilage damage in the hip as reported in published study findings in the literature and discussion of the advantages and disadvantages of different surgical procedures to preserve the joint. Results Most published studies on the surgical treatment of cartilage damage in the hip report defects caused by cam-type FAI at the acetabulum. Development of these defects can be prevented by timely elimination of the relevant deformities. At present, current full-thickness cartilage defects are mostly treated with bone marrow-stimulating techniques such as microfracture (MFx), with or without a biomaterial, and matrix-assisted autologous chondrocyte transplantation (MACT). Osteochondral autologous transplantation (OAT) is not the treatment of choice for isolated full-thickness chondral defects at the hip, because of the unfavourable risk-benefit profile. Due to the relatively short history of cartilage repair surgery on the hip, the studies available on these procedures have low levels of evidence. However, it is already becoming obvious that the experience gained with the same procedures on the knee can be applied to the hip as well. For example, limited healing and regeneration of chondral defects after MFx can also be observed at the hip joint. Conclusions The cartilage surface of the acetabulum, where FAI-related chondral lesions appear, is considerably smaller than the weight-bearing cartilage surface of the knee joint. However, as in the knee joint, MACT is the therapy of choice for full-thickness cartilage defects of more than 1.5 - 2 cm 2 . Minimally invasive types of MACT (e.g. injectable chondrocyte implants) should be preferred in the hip joint. In cases where a single-stage procedure is indicated or there are other compelling reasons for not performing a MACT, a bone marrow-stimulating technique in combination with a biomaterial covering is preferable to standard MFx. For treatment of lesions smaller than 1.5 - 2 cm 2 the indication for a single-stage procedure is wider. As with defects in the knee, it is not possible to determine a definite upper age limit for joint-preserving surgery or MACT in the hip, as the chronological age of patients does not necessarily correlate with their biological age or the condition of their joints. Advanced osteoarthritis of the hip is a contraindication for any kind of hip-preserving surgery. Long-term observations and prospective randomised studies like those carried out for other joints are necessary., Competing Interests: Interessenkonflikt: Die Autoren geben an, dass kein Interessenkonflikt besteht., (Georg Thieme Verlag KG Stuttgart · New York.)

Background: Large osteochondral defects of the knee are a challenge for regenerative treatment. While matrix-guided autologous chondrocyte transplantation (MACT) represents a successful treatment for chondral defects, the treatment potential in combination with bone grafting by cancellous bone or bone block augmentation for large and deep osteochondral defects has not been evaluated., Purpose: To evaluate 1- to 3-year clinical outcomes and radiological results on magnetic resonance imaging (MRI) after the treatment of large osteochondral defects of the knee with bone augmentation and MACT. Special emphasis is placed on different methods of bone grafting (cancellous bone grafting or bone block augmentation)., Study Design: Case series; Level of evidence, 4., Methods: Fifty-one patients were included. Five patients were lost to follow-up. This left 46 patients (mean age, 28.2 years) with a median follow-up time of 2 years. The 46 patients had 47 deep, large osteochondral defects of the knee joint (1 patient with bilateral defects; mean defect size, 6.7 cm 2 ). The origin of the osteochondral defects was osteochondritis dissecans (n = 34), osteonecrosis (n = 8), or subchondral cysts (n = 5). Depending on the depth, all defects were treated by cancellous bone grafting (defect depth ≤10 mm; n = 16) or bone block augmentation (defect depth >10 mm; n = 31) combined with MACT. Clinical outcomes were followed at 3 months, 6 months, 1 year, 2 years, and 3 years and evaluated using the International Knee Documentation Committee (IKDC) score and Cincinnati score. A magnetic resonance imaging (MRI) evaluation was performed at 1 and 2 years, and the magnetic resonance observation of cartilage repair tissue (MOCART) score with additional specific subchondral bone parameters (bone regeneration, bone signal quality, osteophytes, sclerotic areas, and edema) was analyzed., Results: The clinical outcome scores revealed a significant increase at follow-up (6 months to 3 years) compared with the preclinical results. The median IKDC score increased from 42.6 preoperatively to 75.3 at 1 year, 79.7 at 2 years, and 84.3 at 3 years. The median Cincinnati score significantly increased from 39.8 preoperatively to 72.0 at 1 year, 78.0 at 2 years, and 80.3 at 3 years. The MRI evaluation revealed a MOCART score of 82.6 at 1 year without a deterioration at the later follow-up time point. Especially, the subchondral bone analysis showed successful regeneration. All bone blocks and cancellous bone grafts were integrated in the bony defects, and no chondrocyte transplant failure could be detected throughout the follow-up., Conclusion: Large and deep osteochondral defects of the knee joint can be treated successfully with bone augmentation and MACT. The treatment of shallow bony defects with cancellous bone grafting and deep bony defects with bone block augmentation shows promising results.

Background: Autologous chondrocyte implantation (ACI) is an established and well-accepted procedure for the treatment of localised full-thickness cartilage defects of the knee., Methods: The present review of the working group "Clinical Tissue Regeneration" of the German Society of Orthopaedics and Trauma (DGOU) describes the biology and function of healthy articular cartilage, the present state of knowledge concerning therapeutic consequences of primary cartilage lesions and the suitable indication for ACI., Results: Based on best available scientific evidence, an indication for ACI is given for symptomatic cartilage defects starting from defect sizes of more than three to four square centimetres; in the case of young and active sports patients at 2.5cm(2), while advanced degenerative joint disease needs to be considered as the most important contraindication., Conclusion: The present review gives a concise overview on important scientific background and the results of clinical studies and discusses the advantages and disadvantages of ACI., Level of Evidence: Non-systematic Review., (Copyright © 2016 Elsevier B.V. All rights reserved.)

In recent years treatment of early osteoarthritis came more and more into focus of orthopaedic research. In particular regenerative therapy options seem to have a high potential to fill the existing treatment gap for patients with early osteoarthritic changes. This article focuses on basic science, recent developments and available clinical data in the important field of operative regeneration procedures for treatment of chondral and osteochondral defects in early degenerative joints. It highlights current knowledge and perspectives of treatment options like microfracture, autologous or allogenous osteochondral transplantations and autologous chondrocyte transplantation. Further the role of biomaterials in a degenerative joint environment is illuminated. First clinical data of regenerative therapy in early osteoarthritis are encouraging to intensify research efforts in this important field. Future treatment perspectives for patients who suffer from early degenerative cartilage changes are discussed.

There is an increasing awareness on the importance in identifying early phases of the degenerative processes in knee osteoarthritis (OA), the crucial period of the disease when there might still be the possibility to initiate treatments preventing its progression. Early OA may show a diffuse and ill-defined involvement, but also originate in the cartilage surrounding a focal lesion, thus necessitating a separate assessment of these two entities. Early OA can be considered to include a maximal involvement of 50 % of the cartilage thickness based on the macroscopic ICRS classification, reflecting an OARSI grade 4. The purpose of this paper was to provide an updated review of the current status of the diagnosis and definition of early knee OA, including the clinical, radiographical, histological, MRI, and arthroscopic definitions and biomarkers. Based on current evidence, practical classification criteria are presented. As new insights and technologies become available, they will further evolve to better define and treat early knee OA.

Purpose: This study was to investigate the cytotoxic potency of local anesthetics on human mesenchymal stem cells during chondrogenesis., Methods: Aggregates were created from density-gradient centrifugation-separated bone marrow-derived mesenchymal stem cells. After 7, 14, and 21 days, aggregates were analyzed histologically and immunohistochemically and exposed to equipotent concentrations of bupivacaine, ropivacaine, and mepivacaine for 1 h. Cell viability, apoptosis, and necrosis were determined using live-dead and caspase staining. Additionally, following a 1-h exposure on day 7, aggregates were cultured under chondrogenic conditions until day 21 to assess the effects of local anesthetics on differentiation potency of mesenchymal stem cells., Results: In the course of chondrogenesis, mesenchymal stem cells were embedded in varying amount and structure of cartilage-specific extracellular matrix. Contents of sulfated glycosaminoglycan, type I and II collagen increased from day 7 to day 21. Compared to control, death rates of mesenchymal stem cells were significantly elevated 1 day after treatment at 7 and 14 days. Four days after exposure, death rates were 13-15 % at 7 and 11-17 % at 14 days. Mesenchymal stem cell viability in aggregates at 21 days was unchanged to controls. The width of the superficial aggregate zone containing stem cell necrosis decreased with elongated differentiation time. Apoptosis rates were elevated in the edge regions of aggregates, reaching maximum values 4 days after treatment. Local anesthetic exposure on day 7 reduced Collagen II, but not DNA contents in aggregates at 21 days. Bupivacaine, ropivacaine, and mepivacaine did not differ in mesenchymal stem cell cytotoxicity in aggregates., Conclusion: Local anesthetic exposure results in cytotoxicity of mesenchymal stem cells undergoing chondrogenesis, especially in superficial layers. Therefore, induced cell damage should be avoided during chondrogenesis of mesenchymal stem cells, particularly early after cartilage repair.

Objective: Mesenchymal progenitor cell chondrogenesis is the biologic platform for the generation or regeneration of cartilage, but the external influence of the sympathetic nervous system on this process is not yet known. Sympathetic nerve fibers are present in articular tissue, and the sympathetic nervous system influences the musculoskeletal system by, for example, increasing osteoclastogenesis. This study was initiated to explore the role of the sympathetic neurotransmitter norepinephrine (NE) in mesenchymal stem cell (MSC)-dependent and cartilage progenitor cell (CPC)-dependent chondrogenesis., Methods: Using human MSCs or CPCs, chondrogenic differentiation was induced in the presence of NE, the specific β-adrenergic receptor (β-AR) agonist isoproterenol, and the specific β-AR antagonist nadolol. We studied sympathetic nerve fibers, tyrosine hydroxylase (TH) expression, catecholamine biosynthesis, and synovial fluid levels in human joints, as well as cartilage-specific matrix deposition during differentiation., Results: TH+ sympathetic nerve fibers were present in the synovial tissue, meniscus, and subchondral bone marrow. In addition, synovial fluid from patients with knee trauma demonstrated high concentrations of NE. During MSC or CPC chondrogenesis, β-AR were expressed. Chondrogenic aggregates treated with NE or isoproterenol synthesized lower amounts of type II collagen and glycosaminoglycans. NE and isoproterenol treatment dose-dependently increased the levels of cartilage hypertrophy markers (type X collagen and matrix metalloproteinase 13). Nadolol reversed the inhibition of chondrogenesis and the up-regulation of cartilage hypertrophy., Conclusion: Our findings demonstrate NE-dependent inhibition of chondrogenesis and acceleration of hypertrophic differentiation. By inhibiting cartilage repair, these sympathetic influences can be important after joint trauma. These findings may be a basis for novel neurochondrogenic therapeutic options., (Copyright © 2014 by the American College of Rheumatology.)

Background: Matrix-guided autologous chondrocyte transplantation (MACT) has been proposed as an option for treating large full-thickness cartilage defects. However, little is known about the chondrogenic potential of transplants for MACT at the time of implantation, although cell quality and chondrogenic differentiation of the implants are crucial for restoration of function after MACT., Questions/purposes: We therefore asked: (1) Do MACT implants allow deposition of extracellular cartilage matrix in an in vitro culture model? (2) Are these implants associated with improved knee function 1 year after MACT in large cartilage defects?, Methods: We retrospectively reviewed all 125 patients with large localized cartilage defects (mean defect size 5 cm(2)) of the knee who were treated with MACT from 2005 to 2010. The mean age was 31 years (range, 16-53 years). Portions of the cell-matrix constructs (n = 50) that were not implanted in the cartilage defects were further cultured and tested for their potential to form articular cartilage. Knee function of all patients was analyzed preoperatively, 3 months, and 1 year postoperatively with the International Knee Documentation Committee (IKDC) score., Results: In vitro assessment of the cell-matrix implants showed chondrogenic differentiation with positive staining for glycosaminoglycans and collagen II in all cultures. Enzyme-linked immunosorbent assay showed an increase of collagen II production. We observed an improvement in median IKDC score from 41 to 67 points at last followup., Conclusions: Cartilage extracellular matrix deposition shows adequate implant quality for MACT at the time of implantation and justifies the use for treatment of large cartilage defects.

Introduction: The treatment of large full thickness cartilage defects with matrix guided autologous chondrocyte transplantation shows promising results. However, in many cases an arthrotomy is needed to implant the cell seeded scaffolds. Recently techniques have been developed for arthroscopically guided ACT implantation. Correct defect mapping, to assess size and depth of the chondral lesions, and precise scaffold preparation and fixation are crucial for successful chondrocyte transplantation and remain to be not sufficiently optimized., Method: In the present study, the geometries of two cartilage defects in cadaver knees were three times assessed, measured and transferred to biodegradable scaffolds with a navigation system by three different executors. The scaffolds were arthroscopically implanted into the cartilage defects., Results: The cartilage defect assessment was reproducible between all executors for all defect geometries. The implanted scaffolds showed a correct defect filling., Conclusion: The study showed the feasibility of an arthroscopic implantation of scaffolds for autologous chondrocytes transplantation. Navigation was a useful tool to exactly assess the cartilage defect geometry and allowed a precise transfer of navigated cartilage defect geometries for individualized scaffold preparation. Navigation can help to accomplish and optimize arthroscopically guided chondrocyte transplantations.

Cellular senescence is a program activated during diverse situations of cell stress. Chondrocytes differ from other somatic cells as articular cartilage is an avascular tissue. The effects of oxidative stress on chondrocytes are still unknown. Our studies were to investigate into the proliferation potential, cytological features and the telomere linked stress response system of human osteoarthritic chondrocytes, subjected to acute or prolonged oxidant challenge with hydrogen peroxide. Telomere length was measured using the telomere restriction fragment assay, gene expression was determined by RT-PCR. Sub-lethal doses of oxidative stress induced cell-cycle arrest, senescent-morphological features and senescence-associated β-galactosidase positivity. Prolonged oxidative treatment had no effects on cell proliferation or morphology. Sub-lethal and prolonged low doses of oxidative stress considerably accelerated telomere attrition. The effects of sub-lethal oxidative stress regarding proliferation and telomere biology were more distinct in senescent cells. Acute oxidant insult caused up-regulation of p21 expression to levels comparable to senescent cells. TRF2 protects telomere ends and showed elevated expression levels. SIRT1 and XRCC5 enable cells to cope with unfavorable growing conditions. Both were up-regulated after oxidant insult, but expression levels decreased in aging cells. Taken together, oxidative stress considerably accelerated telomere shortening and cellular aging in chondrocytes. Senescent cells showed a reduced tolerance to oxidative stress., (Copyright © 2011 Orthopaedic Research Society.)

Decreasing replicative potential and dedifferentiation of articular chondrocytes during expansion in cell culture are essential limitations for tissue engineering and cell therapy approaches. Telomeres and telomerase play a key role in cell development, aging, and tumorigenesis. There is evidence that growth factors are involved in regulating telomerase activity. Therefore, the objective was to evaluate the effect of selected growth factors on telomere biology of serially passaged chondrocytes. Human articular chondrocytes were isolated from cartilage of three patients undergoing total knee arthroplasty. The chondrocytes were cultured in monolayer with the growth factors PDGF-BB, TGF-beta1, and bFGF. Telomere length was measured by telomere restriction fragment length assay, and telomerase activity was determined by quantifying the gene expression of its catalytic subunit hTERT by rtPCR. Chondrocytes cultured with PDGF-BB and TGF-beta1 showed a significantly higher proliferation rate than control cells. None of the growth factor cultures revealed an accelerated rate of telomere shortening. Telomerase was not expressed in significant amounts in any of the chondrocyte cultures. Growth factor treatment of chondrocyte cell cultures for cell therapy purposes can be regarded as safe in terms of telomere biology.

Objective: Repair of focal articular cartilage lesions is usually performed by employing cell-based therapeutic strategies such as autologous chondrocyte implantation (ACI). The aim of this study was to determine whether periosteum exerts pro-chondrogenic effects on the transplanted cells beyond its biomechanical role in ACI., Methods: Micromass pellets of human articular chondrocytes were cocultured for up to 28 days with human periosteal explants either with physical contact or separated by a membrane allowing paracrine interactions only. Quantitative reverse transcription (RT)-PCR, ELISA, immunohistochemistry and collagen isolation were used to analyse the expression and secretion of TGF-beta1, collagens I and II and chondrogenic differentiation markers such as MIA (CD-RAP) and aggrecan., Results: TGF-beta1 gene expression was induced significantly in paracrine cocultures in periosteum, whereas it was repressed in physical contact cocultures. However, a higher TGF-beta1 secretion rate was observed in physical contact cocultures compared with periosteal monocultures. The expression of COL2A1, melanoma inhibitory activity (cartilage-derived retinoic acid-sensitive protein) [MIA (CD-RAP)] and aggrecan was mainly unaffected by culture conditions, whereas COL1A1 gene expression was increased in periosteal paracrine cocultures. Collagen I staining was induced in micromass pellets from paracrine cocultures, whereas it was repressed in chondrocytes from physical contact cocultures., Conclusions: We found evidence for a bidirectional regulating system with paracrine signalling pathways between periosteum and articular chondrocytes. Stimulation of TGF-beta1 and COL1A1 gene expression in periosteal paracrine cocultures and the increased release of TGF-beta1 protein in physical contact conditions indicate an anabolic, and not merely chondrogenic micro-environment in this in vitro model for periosteal-based ACI.

Objective: Posttraumatic integration of articular cartilage at fracture sites is essential for mechanical stability of cartilage, and ruptured cartilage is a prerequisite for early osteoarthritis. This study was undertaken to investigate effects on articular cartilage integration mediated by steroid hormones, interleukin-1beta (IL-1beta), and combinations thereof., Methods: Articular cartilage blocks were cultured in partial apposition for 2 weeks with ascorbic acid, testosterone, 17beta-estradiol, and dehydroepiandrosterone (DHEA), with or without IL-1beta. Mechanical integration was measured as adhesive strength, i.e., the maximum force at rupture of integrated cartilage blocks divided by the overlap area. Glycosaminoglycan content was used to study synthesized extracellular matrix., Results: Culture in medium without supplements did not lead to integration (adhesive strength 0 kPa). With administration of ascorbic acid (100 microg/ml), the median adhesive strength was 49 kPa. In comparison with ascorbic acid alone, all steroid hormones induced a strong, concentration-dependent stimulation of integration (with maximum values observed with DHEA at 3 x 10(-5)M, testosterone at 10(-8)M, and 17beta-estradiol at 10(-11)M). For testosterone and 17beta-estradiol, this was also reflected by an increase of glycosaminoglycan content. Adhesive strength was increased with IL-1beta at 10 pg/ml, but not at 1 pg/ml or 100 pg/ml. In the presence of both IL-1beta and sex hormones, integration of articular cartilage was reduced., Conclusion: This is the first study to demonstrate that steroid hormones such as 17beta-estradiol, DHEA, and testosterone stimulate articular cartilage integration. This effect is abrogated by low concentrations of IL-1beta. In the absence of IL-1beta or after neutralization of IL-1beta, steroid hormones might be favorable adjuvant compounds to optimize cartilage integration.

Cartilage repair with autologous chondrocyte transplantation shows intriguing results. Chondrogenic transplants generally must be inserted into cartilage defects via arthrotomy. The following study showed that arthroscopically-guided navigation could detect and precisely measure the cartilage defect sizes of different geometries. The new cartilage defect-managing module allowed for the precise transfer of navigated cartilage defect geometries for exact size preparation of the tissue engineering scaffolds. Therefore, navigation can help accomplish chondrocyte transplantation arthroscopically.

The development of isolation and culture techniques for mesenchymal progenitor cells from various tissues has promoted interest in the use of these cells for repair and regeneration of musculoskeletal tissues. The chondrogenic differentiation of these pluripotential cells seems to be mediated by numerous cytokines most of which belong to the transforming growth factor-beta superfamily. Strategies to repair articular cartilage have focused on delivery of these cytokines or progenitor cells to the area of damage. More recently, with the development of gene transfer techniques, these cells have become the target of in vivo gene therapy, which involves direct injection of viral and nonviral vectors carrying transgenes. Furthermore, they are viewed as potential carriers of the transgenes for ex vivo gene therapy, in which the gene transfer is done in vitro with culture-expanded cells that then are implanted or injected. In vitro data suggest that the chondrogenic potential of these cells is maintained with virally mediated ex vivo gene transfer. By transducing these cells with chondroinductive factors, the bioactive factors and the target cells are delivered to the repair site.