Correlation of Arthroscopic Grading and Optical Coherence Tomography as Markers of Early Repair and Predictors of Later Healing Evident on MRI and Histomorphometric Assessment of Cartilage Defects Implanted with Chondrocytes Overexpressing IGF-I.

OBJECTIVE: Injury of articular cartilage is common, and due to the poor intrinsic capabilities of chondrocytes, it can precipitate joint degradation and osteoarthritis (OA). Implantation of autologous chondrocytes into cartilaginous defects has been used to bolster repair. Accurate assessment of the quality of repair tissue remains challenging. This study aimed to investigate the utility of noninvasive imaging modalities, including arthroscopic grading and optical coherence tomography (OCT) for assessment of early cartilage repair (8 weeks), and MRI to determine long-term healing (8 months). DESIGN: Large (15 mm diameter), full-thickness chondral defects were created on both lateral trochlear ridges of the femur in 24 horses. Defects were implanted with autologous chondrocytes transduced with rAAV5-IGF-I, autologous chondrocytes transduced with rAAV5-GFP, naïve autologous chondrocytes, or autologous fibrin. Healing was evaluated at 8 weeks post-implantation using arthroscopy and OCT, and at 8 months post-implantation using MRI, gross pathology, and histopathology. RESULTS: OCT and arthroscopic scoring of short-term repair tissue were significantly correlated. Arthroscopy was also correlated with later gross pathology and histopathology of repair tissue at 8 months post-implantation, while OCT was not correlated. MRI was not correlated with any other assessment variable. CONCLUSIONS: This study indicated that arthroscopic inspection and manual probing to develop an early repair score may be a better predictor of long-term cartilage repair quality following autologous chondrocyte implantation. Furthermore, qualitative MRI may not provide additional discriminatory information when assessing mature repair tissue, at least in this equine model of cartilage repair.

Epidemiology of pediatric cartilage restoration procedures in the United States: insurance and geography play a role.

OBJECTIVES: The purpose of this study is to analyze the epidemiology of children and adolescents undergoing osteochondral autograft transplantation (OAT), osteochondral allograft transplantation (OCA), and autologous chondrocyte implantation (ACI) in the United States. METHODS: The Pediatric Health Information System, a national database consisting of 49 children's hospitals, was queried for all patients undergoing OAT, OCA, and ACI between 2012 and 2018. Demographic information was collected for each subject. United States Census guidelines were used to categorize hospitals geographically. Univariate analysis was followed by purposeful entry multivariate regression to adjust for confounding factors. RESULTS: A total of 809 subjects with a mean age of 15.4 ± 2.4 years were included in the analysis. Of these, 48.6% underwent OCA, 41.9% underwent OAT, and 9.5% underwent ACI. After adjusting for confounders in a multivariate model, ACI was 3.6 times more likely to be performed in patients with private insurance than those that were publicly insured (95% CI 1.6-8.0, p = 0.002). Furthermore, a patient in the Northeast was 33.1 times more likely to undergo ACI than in the West (95% CI 4.5-246.1, p = 0.001). OAT was performed most frequently in the West and Midwest (52.4% and 51.8% of the time, respectively; p < 0.001). CONCLUSION: In the United States, there is substantial variation in the procedures performed for cartilage restoration in children and adolescents. Though ACI is the least commonly selected operation overall, it is significantly more likely to be performed on patients with private insurance and those in the Northeast.

Editorial Commentary: No Clear Winner When Comparing Cost-Effectiveness of Particulated Juvenile Articular Cartilage With Matrix-Induced Autologous Chondrocyte Implantation: Too Many Assumptions.

Various treatment options exist for patellar chondral lesions, including nonoperative management, marrow stimulation, cell-based strategies, and osteochondral transplantation, yet there is insufficient evidence to recommend one treatment over another. One frequently discussed downside of cell-based strategies, including particulated juvenile allograft cartilage and matrix-induced autologous chondrocyte implantation, is the associated cost. Markov modeling is a tool used for economic modeling of different treatments and may be a viable option to compare cell-based strategies for patellar chondral defects. Too many assumptions carry great risk of drawing a strong conclusion. Further high-quality studies and comparative outcome studies are needed before any definitive cost-effectiveness conclusion is made.

Mood Disorders Are Associated with Increased Perioperative Opioid Usage and Health Care Costs in Patients Undergoing Knee Cartilage Restoration Procedure.

OBJECTIVE: To identify the prevalence of mood disorder diagnoses in patients undergoing cartilage transplantation procedures and determine the relationship between mood disorders, opioid usage, and postoperative health care costs. DESIGN: Patients with current procedural terminology (CPT) codes for osteochondral autograft transplantation (OAT), osteochondral allograft transplantation (OCA), and autologous chondrocyte implantation (ACI) were identified in the Truven Health Marketscan database (January 2009-September 2014). Patients were grouped based on having a preoperative mood disorder diagnosis (preMDD). Preoperative opioids, postoperative opioids ≥90 days, and health care costs within the year postoperative were compared for those with and without mood disorders. Costs were analyzed, adjusting for preoperative cost, sex, age, and opioid usage, for those with and without mood disorders. RESULTS: A total of 3,682 patients were analyzed (ACI: 690, OAT: 1,294, OCA: 1,698). A quarter of patients had preMDD (ACI: 25.4%, OAT: 20.6%, OCA: 22.7%). Postoperative opioid use was more prevalent in preMDD patients (OAT: 37.1% vs. 24.1%, P < 0.001; OCA: 30.4% vs. 24.8%, P = 0.032; ACI: 33.7% vs. 26.2%, P = 0.070) (odds ratio [OR] ranged from 1.29 to 1.86). First-year postoperative log-transformed costs were significantly greater for preMDD patients (ACI: $7,733 vs. $5,689*, P = 0.012; OAT: $5,221 vs. $3,823*, P < 0.001; OCA: $6,973 vs. $3,992*, P < 0.001; *medians reported). The estimated adjusted first postoperative year cost increase for preMDD OCA patients was 41.7% (P < 0.001) and 28.0% for OAT patients (P = 0.034). There was no statistical difference for ACI patients (P = 0.654). CONCLUSION: Cartilage transplantation patients have a high prevalence of preoperative mood disorders. Opioid use and health care costs were significantly greater for patients with preoperative mood disorder diagnoses. LEVEL OF EVIDENCE: Level III, retrospective therapeutic study.

Particulated Juvenile Articular Cartilage and Matrix-Induced Autologous Chondrocyte Implantation Are Cost-Effective for Patellar Chondral Lesions.

PURPOSE: To compare the cost-effectiveness of nonoperative management, particulated juvenile allograft cartilage (PJAC), and matrix-induced autologous chondrocyte implantation (MACI) in the management of patellar chondral lesions. METHODS: A Markov model was used to evaluate the cost-effectiveness of three strategies for symptomatic patellar chondral lesions: 1) nonoperative management, 2) PJAC, and 3) MACI. Model inputs (transition probabilities, utilities, and costs) were derived from literature review and an institutional cohort of 67 patients treated with PJAC for patellar chondral defects (mean age 26 years, mean lesion size 2.7 cm2). Societal and payer perspectives over a 15-year time horizon were evaluated. The principal outcome measure was the incremental cost-effectiveness ratio (ICER) using a $100,000/quality-adjusted life year (QALY) willingness-to-pay threshold. Sensitivity analyses were performed to assess the robustness of the model and the relative effects of variable estimates on base case conclusions. RESULTS: From a societal perspective, nonoperative management, PJAC, and MACI cost $4,140, $52,683, and $83,073 and were associated with 5.28, 7.22, and 6.92 QALYs gained, respectively. PJAC and MACI were cost-effective relative to nonoperative management (ICERs $25,010/QALY and $48,344/QALY, respectively). PJAC dominated MACI in the base case analysis by being cheaper and more effective, but this was sensitive to the estimated effectiveness of both strategies. PJAC remained cost-effective if PJAC and MACI were considered equally effective. CONCLUSIONS: In the management of symptomatic patellar cartilage defects, PJAC and MACI were both cost-effective compared to nonoperative management. Because of the need for one surgery instead of two, and less costly graft material, PJAC was cheaper than MACI. Consequently, when PJAC and MACI were considered equally effective, PJAC was more cost-effective than MACI. Sensitivity analyses accounting for the lack of robust long-term data for PJAC or MACI demonstrated that the cost-effectiveness of PJAC versus MACI depended heavily on the relative probabilities of yielding similar clinical results. LEVEL OF EVIDENCE: III, economic and decision analysis.

Comparison of Autologous Chondrocyte Implantation and Osteochondral Allograft Transplantation of the Knee in a Large Insurance Database: Reoperation Rate, Complications, and Cost Analysis.

OBJECTIVE: To compare (1) the reoperation rates, (2) risk factors for reoperation, (3) 30-day complication rates, and (4) cost differences between autologous chondrocyte implantation (ACI) and osteochondral allograft transplantation (OCA) of the knee in a large insurance database. DESIGN: Subjects who underwent knee ACI (Current Procedural Terminology [CPT] code 27412) or OCA (CPT code 27415) with minimum 2-year follow-up were queried from a national insurance database. Reoperation was defined by ipsilateral knee procedure after index surgery. Multivariate logistic regression models were built to determine the effect of independent variables (age, sex, tobacco use, obesity, diabetes, and concomitant osteotomy) on reoperation rates. The 30-day complication rates were assessed using ICD-9-CM codes. The cost of the procedures per patient was calculated. Statistical comparisons were made. All P values were reported with significance set at P < 0.05. RESULTS: A total of 909 subjects (315 ACI and 594 OCA) were included (mean follow-up 39.2 months). There was a significantly higher reoperation rate after index ACI compared with OCA (67.6% vs. 40.4%, P < 0.0001). Concomitant osteotomy at the time of index procedure significantly reduced the risk for reoperation in both groups (odds ratio [OR] 0.2, P < 0.0001 and OR 0.2, P = 0.009). The complication rates were similar between ACI (1.6%) and OCA (1.2%) groups (P = 0.24). Day of surgery payments were significantly higher after ACI compared with OCA (P = 0.013). CONCLUSIONS: Autologous chondrocyte implantation had significantly higher reoperation rates and cost with similar complication rates compared with OCA. Concomitant osteotomy significantly reduced the risk for reoperation in both groups.

Return to Work After Autologous Chondrocyte Implantation of the Knee in Patients with Workers Compensation Insurance.

OBJECTIVE: This retrospective analysis aimed to evaluate patient and defect characteristics on return to work after autologous chondrocyte implantation (ACI) for all patients with workers compensation insurance in our clinic. METHODS: Retrospective analysis of medical records of patients with workers compensation treated with ACI in our clinic over 10 years (August 2004 to November 2014). Data were collected on demographics, lesion size and location, number of defects, duration of symptoms, and outcomes. RESULTS: A total of 28 patients with 30 ACI procedures were included in this analysis. Patients had a mean age of 40.0 years, were mostly male, and tended to be overweight (mean body mass index = 31.5 kg/m2). Most patients were employed in occupations with high physical demand (85.7%) compared with lower physical demand jobs (14.3%). The mean number of lesions per knee = 1.73. Overall, the mean total surface area of the defect was large (12.6 cm2), with large mean individual lesion size of 7.39 cm2. All 28 patients returned to work in some capacity, with a total of 22 (79%) returning to full work, and 6 (21%) returning to modified work. There were no significant differences in the comparison of patients who returned to full versus modified work, in mean age, body mass index, high versus low physical demand occupation, or lesion characteristics (size, chronicity, or location). CONCLUSIONS: Our results demonstrate that in a challenging workers compensation cohort, in patients with multiple large defects, treatment with ACI allows a high percentage of patients to return to their normal vigorous work activities within 9 months to 1 year following cartilage restoration. This study is a level IV retrospective case series.

Morphological Assessment of MACI Grafts in Patients with Revision Surgery and Total Joint Arthroplasty.

OBJECTIVE: To compare the histological and immunohistochemical characteristics of matrix-assisted chondrocyte implantation (MACI) grafts between patients with revision surgery and patients with total joint arthroplasty. METHODS: Biopsies of MACI grafts from patients with revision and total joint arthroplasty. The graft tissue characteristics and subchondral bone were examined by qualitative histology, ICRS (International Cartilage Repair Society) II scoring and semiquantitative immunohistochemistry using antibodies specific to type I and type II collagen. RESULTS: A total of 31 biopsies were available, 10 undergoing total knee arthroplasty (TKA) and 21 patients undergoing revision surgery. Patients in the clinically failed group were significantly older (46.3 years) than patients in the revision group (36.6 years) (P = 0.007). Histologically, the predominant tissue in both groups was of fibrocartilaginous nature, although a higher percentage of specimens in the revision group contained a hyaline-like repair tissue. The percentages of type I collagen (52.9% and 61.0%) and type II collagen (66.3% and 42.2%) were not significantly different between clinically failed and revised MACI, respectively. The talar dome contained the best and patella the worst repair tissue. Subchondral bone pathology was present in all clinically failed patients and consisted of bone marrow lesions, including edema, necrosis and fibrosis, intralesional osteophyte formation, subchondral bone plate elevation, intralesional osteophyte formation, subchondral bone cyst formation, or combinations thereof. CONCLUSIONS: MACI grafts in patients with revision and total joint arthroplasty were predominantly fibrocartilage in repair type, did not differ in composition and were histologically dissimilar to healthy cartilage. Clinically failed cases showed evidence of osteochondral unit failure, rather than merely cartilage repair tissue failure. The role of the subchondral bone in relation to pain and failure and the pathogenesis warrants further investigation.

Cartilage Injury in the Knee: Assessment and Treatment Options.

Cartilage injuries in the knee are common and can occur in isolation or in combination with limb malalignment, meniscus, ligament, and bone deficiencies. Each of these problems must be addressed to achieve a successful outcome for any cartilage restoration procedure. If nonsurgical management fails, surgical treatment is largely based on the size and location of the cartilage defect. Preservation of the patient's native cartilage is preferred if an osteochondral fragment can be salvaged. Chondroplasty and osteochondral autograft transfer are typically used to treat small (<2 cm) cartilage defects. Microfracture has not been shown to be superior to chondroplasty alone and has potential adverse effects, including cyst and intralesional osteophyte formation. Osteochondral allograft transfer and matrix-induced autologous chondrocyte implantation are often used for larger cartilage defects. Particulated juvenile allograft cartilage is another treatment option for cartilage lesions that has good to excellent short-term results but long-term outcomes are lacking.

Assessment of Cartilage Growth After Biopsy of Osteochondral Loose Bodies in Adolescent Knees for Use in Autologous Chondrocyte Implantation.

BACKGROUND: The goal of this study is to determine whether harvested cartilage from an osteochondral loose body maintains the same viability for implantation as cartilage harvested from the traditional locations within the adolescent knee for autologous chondrocyte implantation (ACI). METHODS: A retrospective study was performed on all ACI procedures performed from 2014 to 2017 at a single institution. Biopsies were derived from 2 groups: osteochondral loose body verses the intercondylar notch. The viability, yield, identity, potency, and density were obtained from each sample in addition to basic demographics and concomitant injuries. A total of 12 patients with osteochondral loose bodies 14.6 (SD=2.9) and 20 patients 13.6 (SD=3.3) with intercondylar notch biopsies were evaluated for the study. RESULTS: In the microscopic and histologic comparison, there was no significant difference in viability: 94% in the loose bodies and 93% in the intercondylar notch groups, identity: 7.4 d5L versus 6.3 d5L, or yield. Minimum yield is presented as different units in Carticel (1.2×10 cells/vial) and matrix-induced ACI (>8500 relative fluorescent units) products; however, there was no difference between groups and all samples were above the acceptable limit. Minimum identity value is recorded as d5L> -2.00 and all samples were above this limit. In addition, no sample had signs of contamination or endotoxin in either group. CONCLUSION: These results demonstrate an alternative method for obtaining cartilage biopsies in ACI procedures that may limit short-term and long-term donor site morbidity. LEVEL OF EVIDENCE: Level III.

Arthroscopic matrix-associated, injectable autologous chondrocyte transplantation of the hip: significant improvement in patient-related outcome and good transplant quality in MRI assessment.

PURPOSE: Acetabular chondral lesions are common in patients with FAI. For large full-thickness cartilage defects, arthroscopic matrix-associated autologous chondrocyte transplantation (MACT) using an injectable in situ crosslinking product is an option. Aim of the study was to evaluate clinical and MRI results 12 months after MACT of acetabular cartilage defects in FAI patients. METHODS: We report data on 21 patients with a focal cartilage defect of the hip [2.97 ± 1.44 cm2 (mean ± SD)] caused by FAI treated with an arthroscopically conducted MACT combined with FAI surgery. The results were assessed with patient-reported outcome measures (iHOT33, EQ-5D) pre- as well as post-operatively and by MRI using MOCART scoring system 6 and 12 months post-operatively. RESULTS: The iHOT33 score improved from 52.9 ± 21.14 (mean ± SD) pre-operative to 81.08 ± 22.04 (mean ± SD; p = 0.0012) 12 months post-operatively. The lower the pre-operative iHOT33 score and the larger the defect size, the greater the observed improvement compared to pre-operative scores at 12 months. Patients showed a significant improvement in EQ-5D-5L index value (p = 0.0015) and EQ-5D VAS (p = 0.0006). MRI analysis after 12 months revealed a complete integration of the transplant in 16 of 20 patients. CONCLUSIONS: Injectable MACT is a promising minimally invasive treatment option for full-thickness cartilage defects of the hip caused by FAI. A significant improvement in symptoms and function associated with an increase in quality of life was detected in patients treated with injectable MACT combined with FAI surgery. This is of considerable clinical relevance, since, in addition to the elimination of the mechanical cause, MACT allows the successful therapy of consequential cartilage damage. LEVEL OF EVIDENCE: Level 4, case series.

Autologous Chondrocyte Implantation with Chondrosphere for Treating Articular Cartilage Defects in the Knee: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

Chondrosphere (Spherox) is a form of autologous chondrocyte implantation (ACI). It is licensed for repair of symptomatic articular cartilage defects of the femoral condyle and the patella of the knee with defect sizes up to 10 cm2 in adults. In a single technology appraisal (STA) [TA508] undertaken by the National Institute of Health and Care Excellence (NICE), Warwick Evidence was the Evidence Review Group (ERG) invited to independently review the evidence submitted by the manufacturer, Co.Don. The clinical effectiveness data came from their COWISI randomised controlled trial (RCT), which compared Chondrosphere with microfracture (MF). The timing of this appraisal was unfortunate given that MF was no longer the most relevant comparator because NICE had contemporaneously published guidance approving ACI in place of MF. Moreover, the COWISI RCT enrolled mostly patients with small defect sizes. Evidence of clinical effectiveness for Chondrosphere used in people with larger defect size came from another RCT, which compared three doses of Chondrosphere and that by design could not provide evidence comparing Chondrosphere to any other forms of ACI. To estimate the relative clinical performance of Chondrosphere versus other ACI, Co.Don conducted an indirect treatment comparison by network meta-analyses (NMA). The NMA was flawed in that the distribution of population characteristics that are effect modifiers greatly differed across the treatment comparisons of the network. The ERG questioned both the appropriateness of the NMA and the validity of the resulting estimates. Co.Don estimated the cost-effectiveness of Chondrosphere using a lifetime Markov model with all patients receiving the first repair during the first cycle of the model then moving into one of three health states: success, no further repair (NFR), or a second repair, if necessary. Subsequent to the first cycle, those who were a success either remained a success or moved to second repair. All those in NFR remained in NFR. The cost-effectiveness of Chondrosphere compared to other ACI forms relied on the clinical effectiveness estimates of success and failure rates obtained from the company's indirect comparisons, the validity of which the ERG questioned. The company revised cost-effectiveness estimates for Chondrosphere versus MF and for Chondrosphere versus matrix-applied characterised autologous cultured chondrocyte implant (MACI) were £4360 and around £18,000 per quality-adjusted life year gained, respectively. NICE recommended ACI using Chondrosphere for treating symptomatic articular cartilage defects of the femoral condyle and patella of the knee in adults only if certain requirements were met.

Microfracture is more cost-effective than autologous chondrocyte implantation: a review of level 1 and level 2 studies with 5 year follow-up.

PURPOSE: Focal cartilage defects in the knee may have devastating effect on the knee joint, where two of the main surgical treatment options are microfracture and autologous chondrocyte implantation. Comparative studies have failed to establish which method yields the best clinical results. A cost-effectiveness analysis of microfracture and autologous chondrocyte implantation would contribute to the clinical decision process. METHODS: A PubMed search identifying level I and level II studies with 5 year follow-up was performed. With the data from these studies, decision trees with associated service provision and costs connected to the two different techniques were designed. In addition to hospital costs, we included costs connected to physiotherapy following surgery. To paint a broader cost picture, we also included indirect costs to the society due to productivity loss caused by work absence. RESULTS: Four high-quality studies, with a follow-up of 5 years, met the inclusion criteria. A total of 319 patients were included, 170 undergoing microfracture and 149 autologous chondrocyte implantation. The re-operation rate was 23 (13.5%) following microfracture, and 18 (12.1%) for autologous chondrocyte implantation. Both groups achieved substantially better clinical scores at 5 years compared to baseline. Microfracture was more cost-effective when comparing all clinical scores. CONCLUSION: Microfracture is associated with both lower costs and lower cost per point increase in patient reported outcome measures. There is a need of well-designed, high-quality randomized controlled trials before reliable conclusions regarding cost-effectiveness in the long run is possible. LEVEL OF EVIDENCE: III.

Structural effects of intra-articular TGF-ß1 in moderate to advanced knee osteoarthritis: MRI-based assessment in a randomized controlled trial.

BACKGROUND: To determine effects of allogeneic human chondrocytes expressing TGF-ß1 (TG-C) on structural progression of MRI features of knee osteoarthritis over a 1 year period. METHODS: This phase II randomized controlled trial of TG-C included patients with moderate to advanced osteoarthritis. Patients were randomized to receive an intraarticular 3:1 mixture of non-transduced allogeneic human chondrocytes and TG-C or placebo. 3 T MRI was acquired for all patients at baseline and follow-up (3, 6 and 12 months). MRIs were assessed using the WORMS system including cartilage damage, bone marrow lesions (BMLs), meniscal damage/extrusion, Hoffa-, effusion-synovitis, and osteophytes. Analyses were performed on a whole knee level, compartmental level, and subregional level. Binary logistic regression with Generalized Estimating Equation was used to compare risks of progression, adjusting for baseline age and gender. Mann - Whitney - Wilcoxon tests were used to assess differences for continuous variables. RESULTS: Fifty-seven Patients were included in the TG-C group and 29 in the placebo group. At 12 months, knees in the TG-C group showed less progression of cartilage damage compared to placebo on a whole knee level (34.6% vs. 47.9%; adjusted RR 0.7, 95%CI [0.5-1.1], p = 0.077). Less progression of Hoffa-synovitis and effusion-synovitis was observed in the TG-C group compared to placebo (9.6% vs. 21.1%, adjusted RR 0.5, 95%CI [0.2,1.2], p = 0.115). No statistically significant differences were seen for BMLs, meniscal damage and osteophytes. CONCLUSIONS: Intraarticular treatment with TG-C showed fewer patients in the treated group with progression in structural OA features and other MRI-defined inflammatory markers such as Hoffa-synovitis and effusion-synovitis. However, no differences were observed in regard to progression of BMLs and meniscal damage, or hypertrophic osteophyte formation. TRIAL REGISTRATION: NCT01221441 .Registered 13th October, 2010.

Cost Effectiveness of Characterised Chondrocyte Implantation for Treatment of Cartilage Defects of the Knee in the UK.

INTRODUCTION: Until recently, treatment options for damage to cartilage in the knee were limited to the use of microfracture or, occasionally, mosaicplasty. The developments of autologous and characterised chondrocyte implantation have provided new treatment options but have large upfront costs. The objective of this study was to estimate the cost effectiveness of characterised chondrocyte implantation in the UK National Health Service. METHODS: An economic model was constructed in Microsoft Excel®, with patients undergoing either microfracture or chondrocyte implantation. Following treatment failure, patients can undergo a series of interventions, ultimately ending in knee replacement. Effectiveness and utility were modelled using clinical trial data, which were supplemented with synthesised registry data, and costs were taken from published sources. Results were expressed in clinical events, quality-adjusted life-years (QALYs) and British pounds. Both costs and outcomes were discounted at 3.5 % per year. RESULTS: Chondrocyte implantation is estimated to reduce the lifetime probability of knee replacement by 50 % in comparison with microfracture, and to increase QALYs by 0.72 (16.57 vs. 15.85). Costs were estimated to be £23,307 for chondrocyte implantation, and £8008 for microfracture, with the incremental cost of £15,299 for chondrocyte implantation reflecting reduced resource use offsetting some of the procedure cost. These values gave a cost per QALY gained of £21,245. CONCLUSION: Chondrocyte implantation is estimated to provide substantial patient benefits over a lifetime horizon, with a considerable increase in QALYs. Despite the increase in costs, the procedure is cost effective at standard thresholds used in the UK.

Mesenchymal stem cell therapy in the treatment of osteoarthritis: reparative pathways, safety and efficacy - a review.

Osteoarthritis is a leading cause of pain and disability across the world. With an aging population its prevalence is likely to further increase. Current accepted medical treatment strategies are aimed at symptom control rather than disease modification. Surgical options including joint replacement are not without possible significant complications. A growing interest in the area of regenerative medicine, led by an improved understanding of the role of mesenchymal stem cells in tissue homeostasis and repair, has seen recent focused efforts to explore the potential of stem cell therapies in the active management of symptomatic osteoarthritis. Encouragingly, results of pre-clinical and clinical trials have provided initial evidence of efficacy and indicated safety in the therapeutic use of mesenchymal stem cell therapies for the treatment of knee osteoarthritis. This paper explores the pathogenesis of osteoarthritis and how mesenchymal stem cells may play a role in future management strategies of this disabling condition.

Assessment of the Safety of Chondrocyte Sheet Implantation for Cartilage Regeneration.

We have previously studied the effects of chondrocyte sheets on the repair and regeneration of articular cartilage by using temperature-responsive culture inserts. On the basis of this work, we succeeded in rapid fabrication of chondrocyte sheets with the use of a coculture method in which inserts were placed between synoviocytes and chondrocytes. Treatment of cartilage defects using layered chondrocyte sheets promotes repair and regeneration; this method is compatible with in vivo osteoarthritis models that reproduce partial-thickness defects. In human stem cell clinical research guidelines, the Ministry of Health, Labour and Welfare (MHLW) approved several applications related to this technology. Indeed, its translation to a clinical setting is already yielding favorable results. In this study, we evaluated the risk of tumorigenesis associated with this treatment and characterized the dynamics of biological processes associated with the posttransplantation cell sheets in vivo. Furthermore, we also confirmed the safety of the procedure by using array comparative genomic hybridization (array CGH) and G-band staining to screen for deleterious genetic aberrations during prolonged subculture of cells. The safety of chondrocytes that were cultured for longer than normal was confirmed by the array CGH and G-band staining results. In addition, tumorigenicity testing confirmed that culture chondrocyte sheets are not tumorigenic. Furthermore, from the evaluation of bioluminescence imaging following implantation of the cell sheets, it was confirmed that the transplanted chondrocytes and synoviocytes remained in the knee joint and did not transfer elsewhere over time. We believe that the technique used in this study is a highly useful method for evaluating the safety of not only chondrocytes but also extensive subculturing in general.

The comparison between the different generations of autologous chondrocyte implantation with other treatment modalities: a systematic review of clinical trials.

PURPOSE: This paper aims to review the current evidence for autologous chondrocyte implantation (ACI) generations relative to other treatment modalities, different cell delivery methods and different cell source application. METHODS: Literature search was performed to identify all level I and II studies reporting the clinical and structural outcome of any ACI generation in human knees using the following medical electronic databases: PubMed, EMBASE, Cochrane Library, CINAHL, SPORTDiscus and NICE healthcare database. The level of evidence, sample size calculation and risk of bias were determined for all included studies to enable quality assessment. RESULTS: Twenty studies were included in the analysis, reporting on a total of 1094 patients. Of the 20 studies, 13 compared ACI with other treatment modalities, seven compared different ACI cell delivery methods, and one compared different cell source for implantation. Studies included were heterogeneous in baseline design, preventing meta-analysis. Data showed a trend towards similar outcomes when comparing ACI generations with other repair techniques and when comparing different cell delivery methods and cell source selection. Majority of the studies (80 %) were level II evidence, and overall the quality of studies can be rated as average to low, with the absence of power analysis in 65 % studies. CONCLUSION: At present, there are insufficient data to conclude any superiority of ACI techniques. Considering its two-stage operation and cost, it may be appropriate to reserve ACI for patients with larger defects or those who have had inadequate response to other repair procedures until hard evidence enables specific clinical recommendations be made. LEVEL OF EVIDENCE: II.

Second-look assessment after all-arthroscopic autologous chondrocyte implantation with spheroides at the knee joint.

PURPOSE: To report arthroscopic second look as well as clinical results after arthroscopic autologous chondrocyte implantation (ACI) for articular cartilage repair at the knee joint. METHODS: A second-look assessment after arthroscopic ACI using spheroides was performed in 41 patients with 57 full-size articular cartilage defects of the knee. The median time from ACI to second-look arthroscopy was 10 (6-72) months. The ACI was assessed macroscopically and by probing according to the International Cartilage Repair Score (ICRS)-Cartilage Repair Assessment (CRA) to get information on the amount and quality of regeneration. Clinical follow-up with subjective outcome scores was performed an average of 34.5 ± 19.2 months after ACI. Twenty-seven (65.8 %) of ACI's were combined with additional procedures. RESULTS: The ICRS-CRA was rated "normal" or "nearly normal" in 52 of 57 (91.3 %) and "abnormal" in 5 (8.8 %) of all cartilage defects. At follow-up, evaluation of KOOS was an average of 81.0 ± 12.9 for pain, 76.8 ± 16.6 for symptoms, 85.1 ± 14.9 for activities of daily living, 55.3 ± 27.7 for sport and recreation and 50.6 ± 23.8 for quality of live. IKDC was 63.0 ± 18.8, Lysholm score was 79.0 ± 18.0, and Tegner score was 4 (1-6). Subjective assessment according to the VAS scale was an average of 7.4 ± 2.1 for overall satisfaction and 6.7 ± 2.5 satisfaction for the operated knee. Seven patients (22.6 %) showed low subjective outcome scores at last follow-up-of these, 2 patients showed a CRA 3 and 5 a CRA 1 or 2. CONCLUSION: At second-look arthroscopy, 52 (91.3 %) of all cartilage defects showed a normal or nearly normal macroscopic articular cartilage regeneration after arthroscopic ACI using spheroides. Twenty-four patients (77.4 %) showed good subjective clinical results. The high number of concomitant surgery reflexes the complex aetiology of cartilage lesions and complexity of treatment. Thus, a strict indication and surgical planing is necessary to avoid clinical failures. LEVEL OF EVIDENCE: IV.

Whole joint MRI assessment of surgical cartilage repair of the knee: cartilage repair osteoarthritis knee score (CROAKS).

OBJECTIVE: To develop a magnetic resonance imaging (MRI) scoring system for follow-up of knee cartilage repair procedures integrating assessment of the repair site and the whole joint called Cartilage Repair OsteoArthritis Knee Score (CROAKS), and to assess its reliability. DESIGN: MRI examinations of 20 patients that had undergone matrix-associated autologous chondrocyte transplantation (MACT) of the knee 12 months before were semi-quantitatively assessed for the repair site using features of the magnetic resonance observation of cartilage repair tissue (MOCART) system and for the whole joint based on experiences with the MRI Osteoarthritis Knee Score (MOAKS) instrument. Intra- and inter-observer reliability was calculated using weighted (w) kappa statistics for plates (medial/lateral tibia, medial/lateral femur, trochlea, patella), compartments (medial tibio-femoral, lateral tibio-femoral, patello-femoral) and the whole joint. For certain features with low prevalence the overall percent agreement was calculated in addition. RESULTS: For cartilage, reliability on a plate level ranged between 0.48 (lateral femur) and 1.00 (medial femur). BML assessment showed comparable results ranging on a plate level between 0.46 and 1.00 with overall percent agreement between 83.3% and 100%. Meniscal morphology assessment ranged between 0.62 and 0.94. For repair site assessment reliability ranged from 0.41 (signal intensity inter-observer) to 1.00 (several features). Overall percent agreement was above 80% for 17 of 22 features assessed (intra- and inter-observer results combined). CONCLUSIONS: Combined scoring of the repair site and whole joint assessment for common osteoarthritis features using CROAKS, which is based on experience with two established semi-quantitative scoring tools, is feasible and may be performed with good to excellent reliability.