Cellular senescence in aging and osteoarthritis.

- It is well accepted that age is an important contributing factor to poor cartilage repair following injury, and to the development of osteoarthritis. Cellular senescence, the loss of the ability of cells to divide, has been noted as the major factor contributing to age-related changes in cartilage homeostasis, function, and response to injury. The underlying mechanisms of cellular senescence, while not fully understood, have been associated with telomere erosion, DNA damage, oxidative stress, and inflammation. In this review, we discuss the causes and consequences of cellular senescence, and the associated biological challenges in cartilage repair. In addition, we present novel strategies for modulation of cellular senescence that may help to improve cartilage regeneration in an aging population.

Aarhus Regenerative Orthopaedics Symposium (AROS).

The combination of modern interventional and preventive medicine has led to an epidemic of ageing. While this phenomenon is a positive consequence of an improved lifestyle and achievements in a society, the longer life expectancy is often accompanied by decline in quality of life due to musculoskeletal pain and disability. The Aarhus Regenerative Orthopaedics Symposium (AROS) 2015 was motivated by the need to address regenerative challenges in an ageing population by engaging clinicians, basic scientists, and engineers. In this position paper, we review our contemporary understanding of societal, patient-related, and basic science-related challenges in order to provide a reasoned roadmap for the future to deal with this compelling and urgent healthcare problem.

Efficacy of hip resurfacing arthroplasty: 6 year results from an international multisurgeon prospective cohort study.

Metal-on-metal hip resurfacing is undertaken worldwide. This procedure helps preserve femoral bone stock and allows patients to return to high activity sports. Most outcome studies are individual surgeon case series from single centers where the results and outcomes are evaluated by the same surgeon. One method of increasing the external validity of a follow-up study is to have a multi-centre study design with independent assessment of the outcomes. We present an independent assessment of eleven year follow-up of hip resurfacing outcomes from an international hip resurfacing register. The purpose of this study was to assess: Implant survival at maximum follow-up for revision due to any reason, implant survival at maximum follow-up for revision due to major causes of failure, hip function following hip resurfacing and factors affecting hip function, effect of gender and age on hip function and implant survival, effect of femoral component size on hip function and implant survival. 4535 patients (5000 hips) entered into the registry during 1997-2002 were studied. In summary, at a maximum follow-up of 11 years hip resurfacing has a good implant survival of 96.2% and excellent post-operative function. This is excellent given the international and multisurgeon nature of this cohort where majority of the surgeons were in their learning curve.

Histological and Radiological Assessment of Endogenously Generated Repair Tissue In Vivo Following a Chondral Harvest.

OBJECTIVE: To examine repair tissue formed approximately 15 months after a chondral harvest in the human knee. DESIGN: Sixteen individuals (12 males, 4 females, mean age 36 ± 9 years) underwent a chondral harvest in the trochlea as a pre-requisite for autologous chondrocyte implantation (ACI) treatment. The harvest site was assessed via MRI at 14.3 ± 3.2 months and arthroscopy at 15 ± 3.5 months (using the Oswestry Arthroscopy Score [O-AS] and the International Cartilage Repair Society Arthroscopy Score [ICRS-AS]). Core biopsies (1.8 mm diameter, n = 16) of repair tissue obtained at arthroscopy were assessed histologically (using the ICRS II and OsScore histology scores) and examined via immunohistochemistry for the presence of collagen types I and II. RESULTS: The mean O-AS and ICRS-AS of the repaired harvest sites were 7.2 ± 3.2 and 10.1 ± 3.5, respectively, with 80.3% ± 26% repair fill depth on MRI. The histological quality of the repair tissue formed was variable, with some hyaline cartilage present in 50% of the biopsies; where this occurred, it was associated with a significantly higher ICRS-AS than those with no hyaline cartilage present (median 11 vs. 7.5, P = 0.049). Collagen types I and II were detected in 12/14 and 10/13 biopsies, respectively. CONCLUSIONS: We demonstrate good-quality structural repair tissue formed following cartilage harvest in ACI, suggesting this site can be useful to study endogenous cartilage repair in humans. The trochlea is less commonly affected by osteoarthritis; therefore, location may be critical for spontaneous repair. Understanding the mechanisms and factors influencing this could improve future treatments for cartilage defects.

Spectroscopic measurement of cartilage thickness in arthroscopy: ex vivo validation in human knee condyles.

PURPOSE: To evaluate the accuracy of articular cartilage thickness measurement when implementing a new technology based on spectroscopic measurement into an arthroscopic camera. METHODS: Cartilage thickness was studied by ex vivo arthroscopy at a number of sites (N = 113) in human knee joint osteoarthritic femoral condyles and tibial plateaus, removed from 7 patients undergoing total knee replacement. The arthroscopic image spectral data at each site were used to estimate cartilage thickness. Arthroscopically derived thickness values were compared with reference cartilage thickness as measured by 3 different methods: needle penetration, spiral computed tomography scanning, and geometric measurement after sample slicing. RESULTS: The lowest mean error (0.28 to 0.30 mm) in the regression between arthroscopic and reference cartilage thickness was seen for reference cartilage thickness less than 1.5 mm. Corresponding values for cartilage thickness less than 2.0 and 2.5 mm were 0.32 to 0.40 mm and 0.37 to 0.47 mm, respectively. Cartilage thickness images--created by pixel-by-pixel regression model calculations applied to the arthroscopic images--were derived to demonstrate the clinical use of a camera implementation. CONCLUSIONS: On the basis of this investigation on osteoarthritic material, when one is implementing the spectroscopic method for estimating cartilage thickness into an arthroscopic camera, errors in the range of 0.28 to 0.30 mm are expected. This implementation does not, however, influence the fact that the spectral method performs less well in the cartilage thickness region from 1.5 to 2.5 mm and cannot assess cartilage thicker than 2.5 mm. CLINICAL RELEVANCE: Imaging cartilage thickness directly in the arthroscopic camera video stream could serve as an interesting image tool for in vivo cartilage quality assessment, in connection with cartilage diagnosis, repair, and follow-up.

Hip resurfacing for rheumatoid arthritis: independent assessment of 11-year results from an international register.

Total hip replacement has shown good outcomes for patients with rheumatoid arthritis. Can hip resurfacing give similar results for patients with rheumatoid arthritis? Using an international hip resurfacing register, 47 patients with rheumatoid arthritis were identified and age and gender matched to a group of 131 randomly selected patients with osteoarthritis of the hip joint. Patients completed a questionnaire to record function and implant revision. Hierarchical regression, Cox regression and Kaplan-Meier method were used for analysis. There was a significant increase in post operative hip score in both groups (p < 0.001) with rheumatoid group scoring higher as compared to the osteoarthritis group (p = 0.23). The post operative score was not significantly influenced by pre-operative score and age (p = 0.15 and 0.84, respectively) but the pre-operative score was a predictor of implant failure (p = 0.02). Patient mobility was affected by age with younger patients scoring high on mobility as compared to older patients (p = 0.01). The Kaplan-Meier analysis showed a survival rate of 96.3% in the rheumatoid group and 97.8% in the osteoarthritis group. This difference was not significant (Log rank test, p = 0.45). Our results from an independent and international register show that hip resurfacing provides good post-operative hip function and excellent implant survival for patients with rheumatoid arthritis of the hip joint. This procedure can be considered as a viable option for management of rheumatoid arthritis of the hip joint.

Hip resurfacing and osteonecrosis: results from an independent hip resurfacing register.

INTRODUCTION: Single surgeon studies from specialized centers have suggested that metal-on-metal hip resurfacing in patients with osteonecrosis of hip joint provides good implant survival and function. METHOD: We tested the hypothesis that multicenter results of hip resurfacing, in terms of function and survival, are similar between patients with osteoarthritis and osteonecrosis. PATIENTS: 192 patients (202 hips) underwent metal-on-metal hip resurfacing at different centers around the world. We compared the revision risks in 95 patients (101 hips) with osteonecrosis and 97 patients (101 hips) with osteoarthritis. RESULTS: The mean age at operation was 42 and 43 years and the preoperative and postoperative Harris hip scores were 62 and 96 and 58 and 95 for osteonecrosis and osteoarthritis groups. Survival with revision for any reason as the end point at last follow-up was 97.7% for osteonecrosis and 95.0% for osteoarthritis. CONCLUSION: We conclude that hip resurfacing can be offered to patients with osteonecrosis.

Birmingham hip arthroplasty: five to eight years of prospective multicenter results.

Pioneering centers report excellent results of Birmingham resurfacing arthroplasty. Results from pioneering surgeons are not usually reproduced when implants are used at other centers. We therefore studied patients' satisfaction, postoperative hip function, and survival of Birmingham hip resurfacing in a group, operated by nonpioneering surgeons. The median first year postoperative Harris hip score was 95, and this score was sustained for a period of 8 years. The cumulative survival at 8 years was 95.7%. Most of the failures were in the first year; commonest cause of the first year failures was fracture of femoral neck. This complication is not seen as a substantial problem in the pioneering surgeons' studies. We therefore conclude that this complication is not related to the prosthesis and that its occurrence can be reduced.

Human Articular Chondrocytes Retain Their Phenotype in Sustained Hypoxia While Normoxia Promotes Their Immunomodulatory Potential.

OBJECTIVE: To assess the phenotype of human articular chondrocytes cultured in normoxia (21% O2) or continuous hypoxia (2% O2). DESIGN: Chondrocytes were extracted from patients undergoing total knee replacement (n = 5) and cultured in ~21% (normoxic chondrocytes, NC) and 2% (hypoxic chondrocytes, HC) oxygen in both monolayer and 3-dimensional (3D) pellet culture and compared with freshly isolated chondrocytes (FC). Cells were assessed by flow cytometry for markers indicative of mesenchymal stromal cells (MSCs), chondrogenic-potency and dedifferentiation. Chondrogenic potency and immunomodulatory gene expression was assessed in NC and HC by reverse transcription quantitative polymerase chain reaction. Immunohistochemistry was used to assess collagen II production following 3D pellet culture. RESULTS: NC were positive (>97%, n = 5) for MSC markers, CD73, CD90, and CD105, while HC demonstrated <90% positivity (n = 4) and FC (n = 5) less again (CD73 and CD90 <20%; CD105 <40%). The markers CD166 and CD151, indicative of chondrogenic de-differentiation, were significantly higher on NC compared with HC and lowest on FC. NC also produced the highest levels of CD106 and showed the greatest levels of IDO expression, following interferon-γ stimulation, indicating immunomodulatory potential. NC produced the highest levels of CD49c (>60%) compared with HC and FC in which production was <2%. Hypoxic conditions upregulated expression of SOX9, frizzled-related protein (FRZB), fibroblast growth factor receptor 3 (FGFR3), and collagen type II (COL2A1) and downregulated activin receptor-like kinase 1 (ALK1) in 3 out of 4 patients compared with normoxic conditions for monolayer cells. CONCLUSIONS: Hypoxic conditions encourage retention of a chondrogenic phenotype with some immunomodulatory potential, whereas normoxia promotes dedifferentiation of chondrocytes toward an MSC phenotype with loss of chondrogenic potency but enhanced immunomodulatory capacity.

Combined Autologous Chondrocyte and Bone Marrow Mesenchymal Stromal Cell Implantation in the Knee: An 8-year Follow Up of Two First-In-Man Cases.

Autologous chondrocyte implantation (ACI) has been used to treat cartilage defects for >20 years, with promising clinical outcomes. Here, we report two first-in-man cases (patient A and B) treated with combined autologous chondrocyte and bone marrow mesenchymal stromal cell implantation (CACAMI), with 8-year follow up. Two patients with International Cartilage Repair Society (ICRS) grade III-IV cartilage lesions underwent a co-implantation of autologous chondrocytes and bone marrow-derived mesenchymal stromal cells (BM-MSCs) between February 2008 and October 2009. In brief, chondrocytes and BM-MSCs were separately isolated and culture-expanded in a good manufacturing practice laboratory for a period of 2-4 weeks. Cells were then implanted in combination into cartilage defects and patients were clinically evaluated preoperatively and postoperatively, using the self-reported Lysholm knee score and magnetic resonance imaging (MRI). Postoperative Lysholm scores were compared with the Oswestry risk of knee arthroplasty (ORKA) scores. Patient A also had a second-look arthroscopy, at which time a biopsy of the repair site was taken. Both patients demonstrated a significant long-term improvement in knee function, with postoperative Lysholm scores being consistently higher than ORKA predictions. The most recent Lysholm scores, 8 years after surgery were 100/100 (Patient A) and 88/100 (Patient B), where 100 represents a fully functioning knee joint. Bone marrow lesion (BML) volume was shown to decrease on postoperative MRIs in both patients. Cartilage defect area increased in patient A, but declined initially for patient B, slightly increasing again 2 years after treatment. The repair site biopsy taken from patient A at 14 months postoperatively, demonstrated a thin layer of fibrocartilage covering the treated defect site. The use of a combination of cultured autologous chondrocytes and BM-MSCs appears to confer long-term benefit in this two-patient case study. Improvements in knee function perhaps relate to the observed reduction in the size of the BML.

Predictors of fracture healing in patients with recalcitrant nonunions treated with autologous culture expanded bone marrow-derived mesenchymal stromal cells.

The study reports the prospective outcome of treating severe recalcitrant fracture nonunion in patients with autologous bone marrow-derived mesenchymal stromal cells (BMSC) from 2003 to 2010 and analyze predictors of union. Autologous BMSC were culture expanded and inserted at nonunion site with or without carriers in addition to surgical stabilization of the fracture. Radiological union was ascertained by musculoskeletal radiologists on plain radiographs and/or CT scans. A logistic regression analysis was performed with cell-expansion parameters (cell numbers, cell doubling time) and known clinical factors (e.g., smoking and diabetes) as independent variables and fracture union as the dependent variable to identify the factors that influence bony healing. An Eq5D index score assessed the effect of treatment on general quality of health. A total of 35 patients (mean age 51+/-13 years) with established nonunion (median 2.9 years, 1-33) and, at least one failed nonunion surgery (median 4,1-14) received treatment. Fracture union was achieved in 21 patients (60%; 95%CI 44-75) at 2.6 years. Multiple penalized logistic regression revealed faster cell doubling time (p = 0.07), absence of diabetes (p = 0.003), less previous surgeries (p = 0.008), and lower age at cell implantation (p = 0.02) were significant predictors for fracture union. A significant increase in Eq5D index (p = 0.01) was noted with a mean rise of the score by 0.34 units (95%CI 0.11-0.58) at 1 year following the study. In summary, the study revealed cell doubling time as a novel in vitro parameter in conjunction with age, multiple surgeries, and diabetes as being significant predictors of the fracture union. © 2018 The Authors. Journal of Orthopaedic Research® Published by Wiley Periodicals, Inc. J Orthop Res 37:1303-1309, 2019.

Articular cartilage: structure, injuries and review of management.

INTRODUCTION: Chondral and osteochondral injuries are commonly seen in today's clinical practice. Articular cartilage provides an ultimate low-friction gliding surface, which none of the artificial constructs have been able to replace successfully. Retrospective review of the knee arthroscopies has revealed an underestimated incidence of this complex problem. Cartilage injuries in the knee joint if left untreated lead to pre-mature early arthritis and affect the activities of daily living. Various different treatment methods of cartilage regeneration have shown encouraging results, but unfortunately none has proved to be the ultimate solution. SOURCES OF DATA: This article re-visits the intricate structure of articular cartilage and reviews the different methods of regeneration described in the literature, based on evidence-based effectiveness. The methods described by their originators and their results are considered gold standards for those methods, as being the best available evidence. AREAS OF AGREEMENT: Majority of the authors agree that cartilage injuries are complex and difficult to treat. If untreated, cartilage defects lead to early osteoarthritis. Great debate still persists about the best available treatment for symptomatic chondral or osteochondral defect(s). AREAS OF CONTROVERSY: The controversy about the management outplays its aetiological theories. Several authors have reported good results with different techniques; however none has proved to be the solution for the problem. GROWING POINTS: Up until 1990, marrow stimulation techniques were routine form of management for chondral defects. However, ever since autologous chondrocyte implantation was successfully introduced in humans, it has provided a new dimension for the treatment of chondral defects. AREAS TIMELY FOR DEVELOPING RESEARCH: The success of any treatment lies in its longevity. The new minimally invasive techniques are being invented. However, timely research, on the basis of randomized controlled trial comparing different methods of cartilage reconstruction is necessary for decision-making in today's evidence-based medical world.

An arthroscopic hip documentation form.

Hip arthroscopy is becoming increasingly popular. A simple, precise, and practical means of recording arthroscopic findings will be useful for diagnostic, research, and audit purposes. Basic principles of cartography exist to produce two-dimensional paper representations of our spherical planet. We used the same principles to produce a two-dimensional map of the acetabulum and femoral head. The resulting hip diagram shows the acetabulum as viewed from the side and the femoral head as viewed from above. The ligamentum teres is attached to the medial margin of the head. The head-neck junction and part of the femoral neck is shown at the opposite margin of the ligamentum teres. The hip documentation form is simple, precise, and accurate. We use it to record our findings at hip arthroscopy, which we have used to assist us in our practice.

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.

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.

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 cross-validation. 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.

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

BACKGROUND: 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.

Efficacy and safety of autologous cell therapies for knee cartilage defects (autologous stem cells, chondrocytes or the two): randomized controlled trial design.

AIM: The main aim of this trial is to test the safety and efficacy of autologous stromal/stem cells, chondrocytes or the two combined in the treatment of knee cartilage defects. PATIENTS & METHODS: Patients with symptomatic chondral/osteochondral defects will be randomized to cell therapy treatment with one of three cell populations (1:1:1). The primary efficacy outcome is a functional knee score (Lysholm) at 15 months post-treatment and the primary safety outcome is the incidence of adverse events. Secondary objectives are to analyze repair tissues, quality of life and cost-utility assessments. Exploratory objectives are to identify predictors for success/potency and dose-response relationships. RESULTS & CONCLUSION: This trial has been carefully designed so that valuable scientific and clinical information can be gathered throughout and in the final analysis.

Current in vivo wear of metal-on-metal bearings assessed by exercise-related rise in plasma cobalt level.

Baseline metal ion levels are elevated in patients with metal-on-metal (MOM) hip arthroplasty. Interpretation of baseline levels is difficult as measurements are influenced by wear, corrosion, and metal ion release from stored metal in the body. Schmalzried et al. demonstrated that "wear is the function of use, not time." The specific research question we asked was: Does physiological exercise increase the wear of metal-on-metal articulation which can be measured from the plasma metal ion levels? Patients with three different well functioning MOM bearings [two types of resurfacing (BHR 46.8 mm and Cormet 48 mm) and Metasul 28 mm] were included. Blood samples were taken immediately before, immediately after, and 1 h after exercise to determine cobalt and chromium levels. A significant increase (p<0.005) in serum cobalt and chromium of 13% and 11%, respectively, was noticed after the exercise. Rise of cobalt levels in patients with a resurfacing MOM was 8.5 times (BHR group) or 6.5 times (Cormet group) larger than in those with a Metasul MOM (p=0.021 and p=0.047). Neither rise of metal levels nor baseline levels correlated with any other factor (p>0.27). Exercise-related elevations of plasma cobalt level provides information on current in vivo wear production that cannot be inferred from a baseline measurement of cobalt levels. Chromium levels cannot provide reliable information on the in vivo wear of the devices. Diameter was the important feature of the implant in determining exercise-related elevations of plasma cobalt level. Exercise-related elevations of plasma cobalt level is a potential in vivo tool to understand and improve the tribology of metal-metal bearings.

Evaluating Joint Morbidity after Chondral Harvest for Autologous Chondrocyte Implantation (ACI): A Study of ACI-Treated Ankles and Hips with a Knee Chondral Harvest.

OBJECTIVE: To establish if harvesting cartilage to source chondrocytes for autologous chondrocyte implantation (ACI) results in donor site morbidity. DESIGN: Twenty-three patients underwent ACI for chondral defects of either the ankle or the hip. This involved cartilage harvest from the knee (stage I), chondrocyte expansion in the laboratory and implantation surgery (stage II) into the affected joint. Prior to chondral harvest, no patient had sought treatment for their knee. Lysholm knee scores were completed prior to chondral harvest and annually post-ACI. Histological analyses of the donor site were performed at 12.3 ± 1.5 months for 3 additional patients who had previously had ACI of the knee. RESULTS: The median preoperative Lysholm score was 100, with no significant differences observed at either 13.7±1.7 months or 4.8±1.8 years postharvest (median Lysholm scores 91.7 and 87.5, respectively). Patients whose cartilage was harvested from the central or medial trochlea had a significantly higher median Lysholm score at latest follow-up (97.9 and 93.4, respectively), compared with those taken from the intercondylar notch (median Lysholm score 66.7). The mean International Cartilage Repair Society (ICRS) II histological score for the biopsies taken from the donor site of 3 additional knee ACI patients was 117 ± 10 (maximum score 140). CONCLUSIONS: This study suggests that the chondral harvest site in ACI is not associated with significant joint morbidity, at least up to 5 years postharvest. However, one should carefully consider the location for chondral harvest as this has been shown to affect knee function in the longer term.