J.E.J. Bekkers

Treatment Selection in Articular Cartilage Lesions of the Knee A Systematic Review

Background Several treatment options are available to repair articular cartilage lesions of the knee; however, evidence-based parameters for treatment selection are lacking. Purpose To identify parameters for valid treatment selection in the repair of articular cartilage lesions of the knee. Study Design Systematic review. Methods A systematic search was conducted in the databases EMBASE, MEDLINE, and the Cochrane collaboration. The retrieved articles were screened for relevance on title and abstract followed by a full-text study quality appraisal of the remaining articles. Eventually, a total of 4 randomized controlled trials were included. Results Lesion size, activity level, and age were the influencing parameters for the outcome of articular cartilage repair surgery. Lesions greater than 2.5 cm2 should be treated with sophisticated techniques, such as autologous chondrocyte implantation or osteochondral autologous transplantation, while microfracture is a good first-line treatment option for smaller (<2.5 cm2) lesions. Patients who are active show better results after autologous chondrocyte implantation or osteochondral autologous transplantation when compared with microfracture. Younger patients (<30 years) seem to benefit more from any form of cartilage repair surgery compared with those over 30 years of age. Conclusion Lesion size, activity level, and patient age are factors that should be considered in selecting treatment of articular cartilage lesions of the knee. In addition, these factors are a step toward evidence-based, instead of surgeon-preferred, treatment of articular cartilage lesions of the knee.

Validation of the Knee Injury and Osteoarthritis Outcome Score (KOOS) for the treatment of focal cartilage lesions.

OBJECTIVE To validate the Knee Injury and Osteoarthritis Outcome Score (KOOS) for the treatment of focal cartilage lesions. METHODS A total of 40 patients (mean age 35+/-12 years), treated for a focal cartilage lesion in the knee were included in this study. Test-retest data were collected with an intermediate period of 2 days. Patients were asked to complete the Dutch KOOS and complementary questionnaires [short form-36 (SF-36), Lysholm, EuroQol-5D (EQ-5D)] to evaluate the clinimetric properties of the KOOS in terms of internal consistency (Cronbachs alpha), reliability [intra-class-correlation (ICC) and Bland and Altman plots], construct validity (Spearmans rank correlation), floor and ceiling effects and responsiveness. RESULTS The Cronbachs alpha of the KOOS subdomains and total score ranged from 0.74 to 0.96. The overall ICC of the KOOS was 0.97 while the subscales ranged from 0.87 to 0.95. The Bland and Altman plots showed a small individual variance between the two assessments in time. Spearmans rank correlations between the subscales of the KOOS and representative subscales of the SF-36, Lysholm and EQ-5D were high to moderate ranging from 0.43 to 0.70. We observed no floor effect while the largest observed ceiling effect was 10.3%. The responsiveness was moderate to large with the effect size ranging from 0.70 to 1.32 and the standardized response mean 0.61 to 0.87. CONCLUSION This study illustrates the validity and reliability of the KOOS in measuring the clinical condition of patients after treatment of focal cartilage lesions. This study provides a basis for the use of the KOOS for future clinical research in cartilage repair.

Patient Profiling in Cartilage Regeneration Prognostic Factors Determining Success of Treatment for Cartilage Defects

Background Cartilage therapy for focal articular lesions has been implemented for more than a decade, and it is becoming increasingly available. What is still lacking, however, is analysis of patient characteristics to help improve outcome or select patients for specific treatment. Purpose To analyze the prognostic value of patient age and defect size, age, and location on clinical outcome 3 years after cartilage therapy. Study Design Cohort study; Level of evidence, 3. Methods Fifty-five patients (age, 35 ± 9 years) were randomly selected from a prospective database. Each had a traumatic knee injury, each was treated for a focal cartilage lesion, and each was assessed with the Knee injury and Osteoarthritis Outcome Score (KOOS) 3 years after surgery. Patient characteristics (ie, patient age and defect size, age, and location) were tested for valid inclusion in the regression model. Multiple linear regression was used to determine which variables influenced clinical improvement. Binary KOOS scores were generated on the basis of age-matched healthy patients and assessed in a logistic regression analysis. Results Normality tests confirmed normal distribution for each variable (P < .05). Defect size did not influence clinical improvement (P > .05). Clinical outcome regarding the treatment of medial defects was better than that of the lateral defects (10.38-25.26 points for the different KOOS subscales; P < .05). The KOOS improvement from baseline was better for patients <30 years compared with patients >30 years (7.31-29.24 points for the different KOOS subscales; P <.05). Patients with defects <24 months were more likely to report the age-matched healthy reference KOOS (odds ratio, 1.8-4.0; P <.05). Conclusion This study illustrates the influence of patient age and defect location and age on clinical outcome 3 years after treatment of a focal cartilage lesion in patients with a traumatic knee injury.

Single-Stage Cell-Based Cartilage Regeneration Using a Combination of Chondrons and Mesenchymal Stromal Cells Comparison With Microfracture

Background: Autologous chondrocyte implantation (ACI) is traditionally a 2-step procedure used to repair focal articular cartilage lesions. With use of a combination of chondrons (chondrocytes in their own territorial matrix) and mesenchymal stromal cells (MSCs), ACI could be innovated and performed in a single step, as sufficient cells would be available to fill the defect within a 1-step surgical procedure. Chondrons have been shown to have higher regenerative capacities than chondrocytes without such a pericellular matrix. Purpose: To evaluate cartilage formation by a combination of chondrons and MSCs in vitro and in both small and large animal models. Study Design: Controlled laboratory study. Methods: Chondrons and MSCs were cultured at different ratios in vitro containing 0%, 5%, 10%, 20%, 50%, or 100% chondrons (n = 3); embedded in injectable fibrin glue (Beriplast); and implanted subcutaneously in nude mice (n = 10; ratios of 0%, 5%, 10%, and 20% chondrons). Also, in a 1-step procedure, a combination of chondrons and MSCs was implanted in a freshly created focal articular cartilage lesion (10% chondrons) in goats (n = 8) and compared with microfracture. The effect of both treatments, after 6-month follow-up, was evaluated using biochemical glycosaminoglycan (GAG) and GAG/DNA analysis and scored using validated scoring systems for macroscopic and microscopic defect repairs. Results: The addition of MSCs to chondron cultures enhanced cartilage-specific matrix production as reflected by a higher GAG production (P < .03), both in absolute levels and normalized to DNA content, compared with chondrocyte and 100% chondron cultures. Similar results were observed after 4 weeks of subcutaneous implantation in nude mice. Treatment of freshly created cartilage defects in goats using a combination of chondrons and MSCs in Beriplast resulted in better microscopic, macroscopic, and biochemical cartilage regeneration (P ≤ .02) compared with microfracture treatment. Conclusion: The combination of chondrons and MSCs increased cartilage matrix formation, and this combination of cells was safely applied in a goat model for focal cartilage lesions, outperforming microfracture. Clinical Relevance: This study describes the bench-to-preclinical development of a new cell-based regenerative treatment for focal articular cartilage defects that outperforms microfracture in goats. In addition, it is a single-step procedure, thereby making the expensive cell expansion and reimplantation of dedifferentiated cells, as in ACI, redundant.

Interleukin-6 is elevated in synovial fluid of patients with focal cartilage defects and stimulates cartilage matrix production in an in vitro regeneration model

IntroductionThis study aimed to determine whether, as in osteoarthritis, increased levels of interleukin-6 (IL-6) are present in the synovial fluid of patients with symptomatic cartilage defects and whether this IL-6 affects cartilage regeneration as well as the cartilage in the degenerated knee.MethodsIL-6 concentrations were determined by ELISA in synovial fluid and in conditioned media of chondrocytes regenerating cartilage. Chondrocytes were obtained from donors with symptomatic cartilage defects, healthy and osteoarthritic donors. The effect of IL-6 on cartilage regeneration and on metabolism of the resident cartilage in the knee was studied by both inhibition of endogenous IL-6 and addition of IL-6, in a regeneration model and in osteoarthritic explants in the presence of synovial fluid, respectively. Readout parameters were DNA and glycosaminoglycan (GAG) content and release. Differences between controls and IL-6 blocked or supplemented samples were determined by univariate analysis of variance using a randomized block design.ResultsSynovial fluid of patients with symptomatic cartilage defects contained more IL-6 than synovial fluid of healthy donors (P = 0.001) and did not differ from osteoarthritic donors. IL-6 production of osteoarthritic chondrocytes during cartilage regeneration was higher than that of healthy and defect chondrocytes (P < 0.001). Adding IL-6 increased GAG production by healthy chondrocytes and decreased GAG release by osteoarthritic chondrocytes (P < 0.05). Inhibition of IL-6 present in osteoarthritic synovial fluid showed a trend towards decreased GAG content of the explants (P = 0.06).ConclusionsOur results support a modest anabolic role for IL-6 in cartilage matrix production. Targeting multiple cytokines, including IL-6, may be effective in improving cartilage repair in symptomatic cartilage defects and osteoarthritis.

Articular Cartilage Evaluation After TruFit Plug Implantation Analyzed by Delayed Gadolinium-Enhanced MRI of Cartilage (dGEMRIC)

Background: Quantitative MRI of articular cartilage has rapidly developed in recent years and provides the clinician with a noninvasive tool to determine the biological consequence of an intervention. Purpose: To evaluate the quality of intra-articular cartilage, using the dGEMRIC scanning technique, 1 year after TruFit implantation. The hypothesis was that implantation of a TruFit plug does not lead to damage at the opposing articular cartilage. Study Design: Case series; Level of evidence, 4. Methods: A total of 13 patients (age, 32 ± 8 years) were evaluated with dGEMRIC at 12 ± 4 months after treatment of an osteochondral lesion by implantation of 1 or multiple TruFit plugs. The dGEMRIC scanning protocol was applied 90 minutes after intravenous Magnevist (0.2 mmol/kg body weight) injection. Different regions of interest (ROIs) were defined: the femur cartilage, cartilage directly surrounding the implanted TruFit plug, the TruFit plug, and the articulating and nonarticulating tibia cartilage. The average dGEMRIC index (T1gd; magnetic resonance imaging relaxation time per ROI) was calculated by a pixel-by-pixel curve fitting using the Levenberg-Marquardt method. Differences between the mean T1gd of the individual ROI for all patients were tested using analysis of variance with post hoc Bonferroni correction. A P value <.05 was considered statistically significant. Results: The average T1gd of the TruFit ROI (385 ± 74 ms) was comparable with those in the femur (409 ± 49 ms) and surrounding (392 ± 64 ms) ROIs (P ≥ .339). The average T1gds for the articulating (578 ± 133 ms) and nonarticulating (516 ± 118 ms) ROIs were higher compared with the femur (409 ± 49 ms), surrounding (392 ± 64 ms), and TruFit (385 ± 74 ms) ROIs (P < .002), while no difference was observed between the tibia ROIs (P = .160). Conclusion: Implantation of the TruFit plug in osteochondral lesions does not damage the opposing or surrounding surface, and newly formed tissue inside the plug has cartilage-like dGEMRIC characteristics 12 months after implantation. The implantation of synthetic TruFit plugs is safe for the opposing cartilage, an item that is frequently discussed when using such materials to treat focal cartilage defects.

Quality of scaffold fixation in a human cadaver knee model

OBJECTIVE Newly developed regenerative cartilage interventions based on the application of 3D-scaffolds require a further evaluation of the surgical techniques involved. The present study compared four different scaffold fixation techniques [fibrin glue (FG), transosseous (TS) fixation, biodegradable pin (BP) fixation and continuous cartilage sutures (CS)] to implant a custom-printed porous PEOT/PBT1000/70/30 scaffold in a human cadaver knee model. METHODS After implantation, the knees were subjected to a vertically oriented loaded continuous passive motion (CPM) protocol. The fixation techniques were evaluated after 60 and a subsequent 150 motion cycles, focusing on area coverage, outline attachment and scaffold integrity. After the total of 210 cycles, also an endpoint fixation test was performed. RESULTS The fixation techniques revealed marginal differences for area coverage and outline attachment after 60 and 150 cycles. The FG scored higher on scaffold integrity compared to TS (P<0.05) and CS (P=0.01). Endpoint fixation was highest for the CS, whereas FG showed a weak final fixation strength (P=0.01). CONCLUSIONS This study showed that optimal fixation cannot be combined always with high scaffold integrity. Special attention devoted to scaffold properties in relation to the fixation technique may result in an improvement of scaffold fixation, and thus clinical cartilage regenerative approaches involving these scaffolds.

A validated new histological classification for intervertebral disc degeneration

UNLABELLED Histology is an important outcome variable in basic science and pre-clinical studies regarding intervertebral disc degeneration (IVD). Nevertheless, an adequately validated histological classification for IVD degeneration is still lacking and the existing classifications are difficult to use for inexperienced observers. OBJECTIVE Therefore the aim of this study was to develop and to validate a new histological classification for IVD degeneration. Moreover, the new classification was compared to the frequently used non-validated classification. METHODS The new classification was applied to human IVD sections. The sections were scored twice by two independent inexperienced observers, twice by two experienced IVD researchers and once by a pathologist. For comparison, the sections were also scored according to the classification described by Boos et al. by two experienced IVD researchers. Macroscopic grading according Thompson et al., glycosaminoglycan (GAG) content and age were used for validation. RESULTS The new classification had an excellent intra- and a good inter-observer reliability. Intraclass Correlation Coefficients (ICC) were 0.83 and 0.74, respectively. Intra- and inter-observer reliability were comparable for experienced and inexperienced observers. Statistically significant correlations were found between the new classification, macroscopic score, GAG content in the nucleus pulposus (NP) and age; Correlation coefficient (CC) 0.79, -0.62 and 0.68, respectively. The CCs of the Boos classification were all lower compared to the new classification. CONCLUSION the new histological classification for IVD degeneration is a valid instrument for evaluating IVD degeneration in human IVD sections and is suitable for inexperienced and experienced researchers.

Cartilage Repair in Football (Soccer) Athletes What Evidence Leads to Which Treatment? A Critical Review of the Literature

The prevalence of focal articular cartilage lesions among athletes is higher than in the general population. Treatment goals differ considerably between the professional and recreational athlete. High financial stakes and the short duration of a professional career influence the treatment selection for the professional athlete, while such parameters weigh differently in recreational sports. This article describes our investigation of the relation between sports and a high prevalence of focal cartilage lesions. In addition, we provide a critical review of the best available evidence for cartilage surgery and treatment selection, evaluate specific patient profiles for professional and recreational athletes, and propose a treatment algorithm for the treatment of focal cartilage lesions in football (soccer) players.

Diagnostic Modalities for Diseased Articular Cartilage—From Defect to Degeneration A Review

The progression of cartilage matrix damage to generalized degeneration is associated with specific pathophysiological and clinical aspects. Reliable detection of stage-related characteristics of cartilage disease serves both a therapeutic and prognostic goal. Over the past years, several (pre)clinical diagnostic modalities for cartilage pathologies have been advocated. Each modality focuses on different aspects of the disease. Early diagnosis, before irreversible damage has occurred, opens up the possibility for better treatment and improves the patients’ prognosis. This article gives an overview of the diagnostic modalities available for monitoring cartilage pathology and focuses on reliability, clinical value, current status, and possible applications.