Tommy S. de Windt

Is Magnetic Resonance Imaging Reliable in Predicting Clinical Outcome After Articular Cartilage Repair of the Knee? A Systematic Review and Meta-analysis

Background: While MRI can provide a detailed morphological evaluation after articular cartilage repair, its additional value in determining clinical outcome has yet to be determined. Purpose: To evaluate the correlation between MRI and clinical outcome after cartilage repair and to identify parameters that are most important in determining clinical outcome. Study Design: Systematic review and meta-analysis. Methods: A systematic search was performed in Embase, MEDLINE, and the Cochrane Collaboration. Articles were screened for relevance and appraised for quality. Guidelines in the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) Statement were used. Chi-square tests were performed to find variables that could determine correlation between clinical and radiological parameters. Results: A total of 32 articles (total number of patients, 1019) were included. A majority (81%) were case series or cohort studies that used similar standardized MRI techniques. The mean Coleman score was 63 (range, 42-96). For the majority of MRI parameters, limited or no correlation was found. Nine studies (28%) found a correlation between clinical outcome and the composite magnetic resonance observation of cartilage repair tissue (MOCART) or Henderson score and 7 (22%) with defect fill. In 5 studies, a weak to moderate correlation was found between clinical outcome and the T2 index (mean Pearson coefficient r = .53). Conclusion: Strong evidence to determine whether morphological MRI is reliable in predicting clinical outcome after cartilage repair is lacking. Future research aiming specifically at clinical sensitivity of advanced morphological and biochemical MRI techniques after articular cartilage repair could be of great importance to the field.

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.

Allogeneic Mesenchymal Stem Cells Stimulate Cartilage Regeneration and Are Safe for Single‐Stage Cartilage Repair in Humans upon Mixture with Recycled Autologous Chondrons

Traditionally, mesenchymal stem cells (MSCs) isolated from adult bone marrow were described as being capable of differentiating to various lineages including cartilage. Despite increasing interest in these MSCs, concerns regarding their safety, in vivo behavior and clinical effectiveness have restrained their clinical application. We hypothesized that MSCs have trophic effects that stimulate recycled chondrons (chondrocytes with their native pericellular matrix) to regenerate cartilage. Searching for a proof of principle, this phase I (first‐in‐man) clinical trial applied allogeneic MSCs mixed with either 10% or 20% recycled autologous cartilage‐derived cells (chondrons) for treatment of cartilage defects in the knee in symptomatic cartilage defect patients. This unique first in man series demonstrated no treatment‐related adverse events up to one year postoperatively. At 12 months, all patients showed statistically significant improvement in clinical outcome compared to baseline. Magnetic resonance imaging and second‐look arthroscopies showed completely filled defects with regenerative cartilage tissue. Histological analysis on biopsies of the grafts indicated hyaline‐like regeneration with a high concentration of proteoglycans and type II collagen. Short tandem repeat analysis showed the regenerative tissue only contained patient‐own DNA. These findings support the novel insight that the use of allogeneic MSCs is safe and opens opportunities for other applications. Stem cell‐induced paracrine mechanisms may play an important role in the chondrogenesis and successful tissue regeneration found. Stem Cells 2017;35:256–264

Concise Review: Unraveling Stem Cell Cocultures in Regenerative Medicine: Which Cell Interactions Steer Cartilage Regeneration and How?

Cartilage damage and osteoarthritis (OA) impose an important burden on society, leaving both young, active patients and older patients disabled and affecting quality of life. In particular, cartilage injury not only imparts acute loss of function but also predisposes to OA. The increase in knowledge of the consequences of these diseases and the exponential growth in research of regenerative medicine have given rise to different treatment types. Of these, cell‐based treatments are increasingly applied because they have the potential to regenerate cartilage, treat symptoms, and ultimately prevent or delay OA. Although these approaches give promising results, they require a costly in vitro cell culture procedure. The answer may lie in single‐stage procedures that, by using cell combinations, render in vitro expansion redundant. In the last two decades, cocultures of cartilage cells and a variety of (mesenchymal) stem cells have shown promising results as different studies report cartilage regeneration in vitro and in vivo. However, there is considerable debate regarding the mechanisms and cellular interactions that lead to chondrogenesis in these models. This review, which included 52 papers, provides a systematic overview of the data presented in the literature and tries to elucidate the mechanisms that lead to chondrogenesis in stem cell cocultures with cartilage cells. It could serve as a basis for research groups and clinicians aiming at designing and implementing combined cellular technologies for single‐stage cartilage repair and treatment or prevention of OA.

Autologous, allogeneic, induced pluripotent stem cell or a combination stem cell therapy? Where are we headed in cartilage repair and why: a concise review

The evolution of articular cartilage repair procedures has resulted in a variety of cell-based therapies that use both autologous and allogeneic mesenchymal stromal cells (MSCs). As these cells are increasingly available and show promising results both in vitro and in vivo, cell-based strategies, which aim to improve ease of use and cost-effectiveness, are progressively explored. The use of MSCs in cartilage repair makes it possible to develop single-stage cell-based therapies. However, true single-stage procedures rely on one intervention, which will limit cell sources to fraction concentrates containing autologous MSCs or culture-expanded allogeneic MSCs. So far, it seems both autologous and allogeneic cells can safely be applied, but clinical studies are still ongoing and little information on clinical outcome is available. Further development of cell-based therapies may lead to clinical-grade, standardized, off-the-shelf products with easy handling for orthopedic surgeons. Although as of yet no preclinical or clinical studies are ongoing which explore the use of induced pluripotent stem cells for cartilage repair, a good manufacturing practice-grade induced pluripotent stem cell line might become the basis for such a product in the future, providing that cell fate can be controlled. The use of stem cells in clinical trials brings along new ethical issues, such as proper controls and selecting primary outcome measures. More clinical trials are needed to estimate detailed risk-benefit ratios and trials must be carefully designed to minimize risks and burdens for patients while choosing outcome measures that allow for adequate comparison with results from similar trials. In this review, we discuss the different aspects of new stem cell-based treatments, including safety and ethical issues, as well as provide an overview of current clinical trials exploring these approaches and future perspectives.

Treatment and Prevention of (Early) Osteoarthritis Using Articular Cartilage Repair-Fact or Fiction? A Systematic Review.

Early osteoarthritis (OA) is increasingly being recognized in patients who wish to remain active while not accepting the limitations of conservative treatment or joint replacement. The aim of this systematic review was to evaluate the existing evidence for treatment of patients with early OA using articular cartilage repair techniques. A systematic search was performed in EMBASE, MEDLINE, and the Cochrane collaboration. Articles were screened for relevance and appraised for quality. Nine articles of generally low methodological quality (mean Coleman score 58) including a total of 502 patients (mean age range = 36-57 years) could be included. In the reports, both radiological and clinical criteria for early OA were applied. Of all patients included in this review, 75% were treated with autologous chondrocyte implantation. Good short-term clinical outcome up to 9 years was shown. Failure rates varied from 8% to 27.3%. The conversion to total knee arthroplasty rate was 2.5% to 6.5%. Although a (randomized controlled) trial in this patient category with long-term follow-up is needed, the literature suggests autologous chondrocyte implantation could provide good short- to mid-term clinical outcome and delay the need for total knee arthroplasty. The use of standardized criteria for early OA and implementation of (randomized) trials with long-term follow-up may allow for further expansion of the research field in articular cartilage repair to the challenging population with (early) OA.

Allogeneic MSCs and Recycled Autologous Chondrons Mixed in a One-Stage Cartilage Cell Transplantion : A First-in-Man Trial in 35 Patients

MSCs are known as multipotent mesenchymal stem cells that have been found capable of differentiating into various lineages including cartilage. However, recent studies suggest MSCs are pericytes that stimulate tissue repair through trophic signaling. Aimed at articular cartilage repair in a one‐stage cell transplantation, this study provides first clinical evidence that MSCs stimulate autologous cartilage repair in the knee without engrafting in the host tissue. A phase I (first‐in‐man) clinical trial studied the one‐stage application of allogeneic MSCs mixed with 10% or 20% recycled defect derived autologous chondrons for the treatment of cartilage defects in 35 patients. No treatment‐related serious adverse events were found and statistically significant improvement in clinical outcome shown. Magnetic resonance imaging and second‐look arthroscopies showed consistent newly formed cartilage tissue. A biopsy taken from the center of the repair tissue was found to have hyaline‐like features with a high concentration of proteoglycans and type II collagen. DNA short tandem repeat analysis delivered unique proof that the regenerated tissue contained patient‐DNA only. These findings support the hypothesis that allogeneic MSCs stimulate a regenerative host response. This first‐in‐man trial supports a paradigm shift in which MSCs are applied as augmentations or “signaling cells” rather than differentiating stem cells and opens doors for other applications. Stem Cells 2017;35:1984–1993

Correlation Between Magnetic Resonance Imaging and Clinical Outcomes After Knee Cartilage Repair: Letter to the Editor

Dear Editor: It is with great interest that we read the review and meta-analysis by Blackman et al published in the AJSM on April 30, 2013, entitled ‘‘Correlation Between Magnetic Resonance Imaging and Clinical Outcomes After Cartilage Repair Surgery in the Knee: A Systematic Review and Meta-analysis.’’ This is particularly so because a few months earlier, we came, in part, to a similar conclusion in a review and meta-analysis also published in the AJSM. In this study, we raised the question of whether magnetic resonance imaging (MRI) is a reliable means to predict clinical outcomes after cartilage repair of the knee. The increasing availability of articular cartilage repair underlines the need for noninvasive tools to monitor treatment outcomes. Currently, MRI is the most promising of these tools and can provide a detailed evaluation of the articular cartilage, soft tissues, and underlying bone. Therefore, it is not surprising that an increasing number of studies investigate the correlation between clinical and radiological outcomes. It is encouraging that the United States–based group of Blackman et al and our Europeanbased group both concluded that future research is needed to improve the utility of MRI for assessing cartilage repair. However, as there are some differences in the methods and interpretation of the results in the 2 studies, a thorough comparison is highly valuable. Blackman et al performed a systematic literature search and included 15 studies in their final quantitative analysis. Only studies that reported correlation coefficients in the text were included, and retrospective case series were excluded. For their meta-analysis, normalized values were created for studies that reported correlation coefficients. For example, 10 studies were included that reported these coefficients for autologous chondrocyte implantation (ACI) and MRI outcomes. Based on these measurements, the authors concluded that T2 and 3-dimensional fast spin echo signals and defect fill had weak correlations with clinical outcomes, while graft hypertrophy and the Henderson score had moderate to good correlations with clinical outcomes after ACI. For microfracture, 4 studies could be included in their metaanalysis, and these showed the Henderson score, subchondral edema, and repair tissue signal (as defined by the Henderson score) to have good to excellent correlations. The authors concluded that ‘‘MRI is a reliable, noninvasive means of monitoring cartilage repair tissue postoperatively that provides useful diagnostic information in patients with persistent symptoms after these types of procedures.’’ In our study, we chose to include retrospective case series because, in our opinion, these studies can provide valuable information regarding the correlation between the 2 outcomes. For our quantitative analysis, we could therefore include 32 studies. With a mean Coleman score of 63 (range, 42-96), the majority of studies were of low methodological quality with a high rate of reporting bias (56%). Moreover, across the studies, there was heterogeneity in the followup, sample sizes, and outcome scores. Unfortunately, many studies that did not find a correlation between clinical and radiological outcomes only stated so without providing exact coefficients. We therefore explicitly chose not to use forest plots in the meta-analysis, as this could have seriously biased the results. Instead, we provided an overview of all Pearson correlation coefficients that could be retrieved. Similar to Blackman et al, we found a weak to moderate correlation between T2 signals and the International Knee Documentation Committee (IKDC) score or Lysholm score in 5 studies. The composite magnetic resonance observation of cartilage tissue (MOCART) and Henderson scores and the defect fill parameter were found to have a weak to moderate correlation to clinical outcomes in 9 and 7 studies, respectively. For the majority of MRI parameters, limited or no correlation was found. As suggested by Blackman et al, it could be that the correlation differs between treatment types. In fact, based on the meta-analysis of 4 studies with a correlation strength (r) of 0.765 (95% confidence interval, 0.755-0.775), they concluded that subchondral edema has a good correlation to clinical outcomes after microfracture. However, when looking at the 4 studies, only Kreuz et al demonstrated a correlation (r = 0.76) with the Henderson score for subchondral edema and the International Cartilage Repair Society (ICRS) score. This raises the question of whether the subgroup meta-analysis performed by Blackman et al represents the correlation between clinical and radiological outcomes as shown in the literature. This is especially relevant because, overall, the majority of studies used the The American Journal of Sports Medicine, Vol. 41, No. 11 DOI: 10.1177/036354651351014

Missed low-grade infection in suspected aseptic loosening has no consequences for the survival of total hip arthroplasty

Background and purpose — Aseptic loosening and infection are 2 of the most common causes of revision of hip implants. Antibiotic prophylaxis reduces not only the rate of revision due to infection but also the rate of revision due to aseptic loosening. This suggests under-diagnosis of infections in patients with presumed aseptic loosening and indicates that current diagnostic tools are suboptimal. In a previous multicenter study on 176 patients undergoing revision of a total hip arthroplasty due to presumed aseptic loosening, optimized diagnostics revealed that 4–13% of the patients had a low-grade infection. These infections were not treated as such, and in the current follow-up study the effect on mid- to long-term implant survival was investigated. Patients and methods — Patients were sent a 2-part questionnaire. Part A requested information about possible re-revisions of their total hip arthroplasty. Part B consisted of 3 patient-related outcome measure questionnaires (EQ5D, Oxford hip score, and visual analog scale for pain). Additional information was retrieved from the medical records. The group of patients found to have a low-grade infection was compared to those with aseptic loosening. Results — 173 of 176 patients from the original study were included. In the follow-up time between the revision surgery and the current study (mean 7.5 years), 31 patients had died. No statistically significant difference in the number of re-revisions was found between the infection group (2 out of 21) and the aseptic loosening group (13 out of 152); nor was there any significant difference in the time to re-revision. Quality of life, function, and pain were similar between the groups, but only 99 (57%) of the patients returned part B. Interpretation — Under-diagnosis of low-grade infection in conjunction with presumed aseptic revision of total hip arthroplasty may not affect implant survival.

Clinical Outcome 3 Years After Autologous Chondrocyte Implantation Does Not Correlate With the Expression of a Predefined Gene Marker Set in Chondrocytes Prior to Implantation but Is Associated With Critical Signaling Pathways

Background: There is a need for tools to predict the chondrogenic potency of autologous cells for cartilage repair. Purpose: To evaluate previously proposed chondrogenic biomarkers and to identify new biomarkers in the chondrocyte transcriptome capable of predicting clinical success or failure after autologous chondrocyte implantation. Study Design: Controlled laboratory study and case-control study; Level of evidence, 3. Methods: Five patients with clinical improvement after autologous chondrocyte implantation and 5 patients with graft failures 3 years after implantation were included. Surplus chondrocytes from the transplantation were frozen for each patient. Each chondrocyte sample was subsequently thawed at the same time point and cultured for 1 cell doubling, prior to RNA purification and global microarray analysis. The expression profiles of a set of predefined marker genes (ie, collagen type II α1 [COL2A1], bone morphogenic protein 2 [BMP2], fibroblast growth factor receptor 3 [FGFR3], aggrecan [ACAN], CD44, and activin receptor–like kinase receptor 1 [ACVRL1]) were also evaluated. Results: No significant difference in expression of the predefined marker set was observed between the success and failure groups. Thirty-nine genes were found to be induced, and 38 genes were found to be repressed between the 2 groups prior to autologous chondrocyte implantation, which have implications for cell-regulating pathways (eg, apoptosis, interleukin signaling, and β-catenin regulation). Conclusion: No expressional differences that predict clinical outcome could be found in the present study, which may have implications for quality control assessments of autologous chondrocyte implantation. The subtle difference in gene expression regulation found between the 2 groups may strengthen the basis for further research, aiming at reliable biomarkers and quality control for tissue engineering in cartilage repair. Clinical Relevance: The present study shows the possible limitations of using gene expression before transplantation to predict the chondrogenic and thus clinical potency of the cells. This result is especially important as the chondrogenic potential of the chondrocytes is currently part of quality control measures according to European and American legislations regarding advanced therapies.