Development of a tool to predict outcome of Autologous Chondrocyte Implantation

Objective. The study had 2 objectives: first, to evaluate the success of autologous chondrocyte implantation (ACI) in terms of incidence of surgical re-intervention, including arthroplasty, and investigate predictors of successful treatment outcome. The second objective was to derive a tool predicting a patient’s arthroplasty risk following ACI. Design. In this Level II, prognostic study, 170 ACI-treated patients (110 males [aged 36.8 ± 9.4 years]; 60 females [aged 38.1 ± 10.2 years]) completed a questionnaire about further surgery on their knee treated with ACI 10.9 ± 3.5 years previously. Factors commonly assessed preoperatively (age, gender, defect location and number, previous surgery at this site, and the preoperative Lysholm score) were used as independent factors in regression analyses. Results. At final follow-up (maximum of 19 years post-ACI), 40 patients (23.5%) had undergone surgical re-intervention following ACI. Twenty-six patients (15.3%) underwent arthroplasty, more commonly females (25%) than males (10%; P = 0.001). Cox regression analyses identified 4 factors associated with re-intervention: age at ACI, multiple operations before ACI, patellar defects, and lower pretreatment Lysholm scores (Nagelkerke’s R2 = 0.20). Six predictive items associated with risk of arthroplasty following ACI (Nagelkerke’s R2 = 0.34) were used to develop the Oswestry Risk of Knee Arthroplasty index with internal crossvalidation. Conclusion. In a single-center study, we have identified 6 factors (age, gender, location and number of defects, number of previous operations, and Lysholm score before ACI) that appear to influence the likelihood of ACI patients progressing to arthroplasty. We have used this information to propose a formula or “tool” that could aid treatment decisions and improve patient selection for ACI

Magnetic Resonance Imaging Parameters at 1 Year Correlate With Clinical Outcomes Up to 17 Years After Autologous Chondrocyte Implantation

Background: The ability to predict the long-term success of surgical treatment in orthopaedics is invaluable, particularly in clinical trials. The quality of repair tissue formed 1 year after autologous chondrocyte implantation (ACI) in the knee was analyzed and compared with clinical outcomes over time. Hypothesis: Better quality repair tissue and a better appearance on magnetic resonance imaging (MRI) 1 year after ACI lead to improved longer-term clinical outcomes. Study Design: Cohort study; Level of evidence, 3. Methods: Repair tissue quality was assessed using either MRI (11.5 ± 1.4 [n = 91] or 39.2 ± 18.5 [n = 76] months after ACI) or histology (16.3 ± 11.0 months [n = 102] after ACI). MRI scans were scored using the whole-organ magnetic resonance imaging score (WORMS) and the magnetic resonance observation of cartilage repair tissue (MOCART) score, with additional assessments of subchondral bone marrow and cysts. Histology of repair tissue was performed using the Oswestry cartilage score (OsScore) and the International Cartilage Repair Society (ICRS) II score. Clinical outcomes were assessed using the modified Lysholm score preoperatively, at the time of MRI or biopsy, and at a mean 8.4 ± 3.7 years (maximum, 17.8 years) after ACI. Results: At 12 months, the total MOCART score and some of its individual parameters correlated significantly with clinical outcomes. The degree of defect fill, overall signal intensity, and surface of repair tissue at 12 months also significantly correlated with longer-term outcomes. The presence of cysts or effusion (WORMS) significantly correlated with clinical outcomes at 12 months, while the presence of synovial cysts/bursae preoperatively or the absence of loose bodies at 12 months correlated significantly with long-term clinical outcomes. Thirty percent of repair tissue biopsies contained hyaline cartilage, 65% contained fibrocartilage, and 5% contained fibrous tissue. Despite no correlation between the histological scores and clinical outcomes at the time of biopsy, a lack of hyaline cartilage or poor basal integration was associated with increased pain; adhesions visible on MRI also correlated with significantly better histological scores. Conclusion: These results demonstrate that MRI at 12 months can predict longer-term clinical outcomes after ACI. Further investigation regarding the presence of cysts, effusion, and adhesions and their relationship with histological and clinical outcomes may yield new insights into the mechanisms of cartilage repair and potential sources of pain

Autologous chondrocyte implantation-derived synovial fluids display distinct responder and non-responder proteomic profiles

Hulme, Charlotte H. & Wilson, Emma L. - Equal contributorsBackground Autologous chondrocyte implantation (ACI) can be used in the treatment of focal cartilage injuries to prevent the onset of osteoarthritis (OA). However, we are yet to understand fully why some individuals do not respond well to this intervention. Identification of a reliable and accurate biomarker panel that can predict which patients are likely to respond well to ACI is needed in order to assign the patient to the most appropriate therapy. This study aimed to compare the baseline and mid-treatment proteomic profiles of synovial fluids (SFs) obtained from responders and non-responders to ACI. Methods SFs were derived from 14 ACI responders (mean Lysholm improvement of 33 (17–54)) and 13 non-responders (mean Lysholm decrease of 14 (4–46)) at the two stages of surgery (cartilage harvest and chondrocyte implantation). Label-free proteome profiling of dynamically compressed SFs was used to identify predictive markers of ACI success or failure and to investigate the biological pathways involved in the clinical response to ACI. Results Only 1 protein displayed a ≥2.0-fold differential abundance in the preclinical SF of ACI responders versus non-responders. However, there is a marked difference between these two groups with regard to their proteome shift in response to cartilage harvest, with 24 and 92 proteins showing ≥2.0-fold differential abundance between Stages I and II in responders and non-responders, respectively. Proteomic data has been uploaded to ProteomeXchange (identifier: PXD005220). We have validated two biologically relevant protein changes associated with this response, demonstrating that matrix metalloproteinase 1 was prominently elevated and S100 calcium binding protein A13 was reduced in response to cartilage harvest in non-responders. Conclusions The differential proteomic response to cartilage harvest noted in responders versus non-responders is completely novel. Our analyses suggest several pathways which appear to be altered in non-responders that are worthy of further investigation to elucidate the mechanisms of ACI failure. These protein changes highlight many putative biomarkers that may have potential for prediction of ACI treatment success

Two independent proteomic approaches provide a comprehensive analysis of the synovial fluid proteome response to Autologous Chondrocyte Implantation

Background: Autologous chondrocyte implantation (ACI) has a failure rate of approximately 20%, but it is yet to be fully understood why. Biomarkers are needed that can pre-operatively predict in which patients it is likely to fail, so that alternative or individualised therapies can be offered. We previously used label-free quantitation (LF) with a dynamic range compression proteomic approach to assess the synovial fluid (SF) of ACI responders and non-responders. However, we were able to identify only a few differentially abundant proteins at baseline. In the present study, we built upon these previous findings by assessing higher-abundance proteins within this SF, providing a more global proteomic analysis on the basis of which more of the biology underlying ACI success or failure can be understood. Methods: Isobaric tagging for relative and absolute quantitation (iTRAQ) proteomic analysis was used to assess SF from ACI responders (mean Lysholm improvement of 33; n = 14) and non-responders (mean Lysholm decrease of 14; n = 13) at the two stages of surgery (cartilage harvest and chondrocyte implantation). Differentially abundant proteins in iTRAQ and combined iTRAQ and LF datasets were investigated using pathway and network analyses. Results: iTRAQ proteomic analysis confirmed our previous finding that there is a marked proteomic shift in response to cartilage harvest (70 and 54 proteins demonstrating ≥ 2.0-fold change and p < 0.05 between stages I and II in responders and non-responders, respectively). Further, it highlighted 28 proteins that were differentially abundant between responders and non-responders to ACI, which were not found in the LF study, 16 of which were altered at baseline. The differential expression of two proteins (complement C1s subcomponent and matrix metalloproteinase 3) was confirmed biochemically. Combination of the iTRAQ and LF proteomic datasets generated in-depth SF proteome information that was used to generate interactome networks representing ACI success or failure. Functional pathways that are dysregulated in ACI non-responders were identified, including acute-phase response signalling. Conclusions: Several candidate biomarkers for baseline prediction of ACI outcome were identified. A holistic overview of the SF proteome in responders and non-responders to ACI  has been profiled, providing a better understanding of the biological pathways underlying clinical outcome, particularly the differential response to cartilage harvest in non-responders