Autologous chondrocyte implantation for the treatment of retropatellar cartilage defects: clinical results referred to defect localisation

Introduction  Although autologous chondrocyte implantation (ACI) has become well established for the treatment of full-thickness cartilage defects of the knee joint, nevertheless clinical results of retropatellar lesions are still inferior compared to those of defects located on femoral condyles. We report the clinical results obtained in 70 patients treated with ACI for full-thickness defects of the patella, with special reference to defect location and size, age, body mass index and sports activity. Methods  At a follow-up of 38.4 months (range 14–64, follow-up rate 83.3%), patients’ subjective functional knee scores (IKDC, Lysholm) were analysed, as were the results of objective examination (according to ICRS). Results  Mean patient age at the time of surgery was 34.3 years (±10.1). The mean Lysholm score at the time of follow-up was 73.0 (±22.4) and the subjective IKDC score was 61.6 (±21.5); normal and nearly normal clinical results according to the objective criteria of the International Cartilage Research Society (ICRS) were achieved in 67.1% of the patients, while abnormal results were achieved in 20.0% of the patients and severely abnormal results, in 12.9%. While different surgical techniques did not seem to have any significant influence on the treatment results, both defect size and defect location within the patella were found to be significantly associated with clinical outcome. The corollaries to this are that larger cartilage lesions of the patella are associated with an inferior outcome (p = 0.007) and that cartilage defects located on the lateral patellar facet are correlated with a better clinical outcome than those located on the medial facet or those involving both facets (p = 0.017). Conclusion  This study demonstrates that within a group of patients treated with ACI for retropatellar cartilage lesion there are significant differences in clinical outcome, which are important and should be taken into account of when a decision has to be made on whether or not ACI is indicated.     

Long-term follow-up evaluation of autologous chondrocyte implantation for symptomatic cartilage lesions of the knee: A single-centre prospective study

IntroductionAutologous Chondrocyte Implantation (ACI) has been the first technique in reconstruction of a valid articular surface. The aim of this study was to evaluate clinical results of this technique at an average follow up of 162 ± 27 months (range 88–208) in a group of patients who underwent ACI.Materials and methods32 patients were operated between 1997 and 2007 for chondral lesions or osteochondritis dissecans of the knee. Mean size of the defect was 5.48 cm² ± 1.53 (range 2–9). Nine patients were treated with I generation technique and 23 with II generation. All patients were evaluated with Subjective IKDC and Tegner Activity Scales for clinical outcomes and with EQ-VAS for a quantitative measure of health after intervention, starting from pre-operative period and at regular follow up (minimum 88 months-maximum 208 months).ResultsA significant increment of all scores was noticed comparing preoperative and postoperative results. In particular medium IKDC score increased from 40.3 ± 9.6 in preoperative evaluation to 74.2 ± 11.6 at one year (p < 0.00001) and to 83.9 ± 10.4 at 5 years follow up (p < 0.001). Mean IKDC values at the last follow-up were 80.3 ± 14.2, showing no statistical differences with those obtained at five-year follow-up. Tegner Activity Scale values increased from 2.8 ± 1.1 preoperatively to 4.1 ± 1.1 (p < 0.0001) after one year and to 6 ± 1.1 at five years (p < 0.0001). Mean Tegner Activity Scale values decreased to 4.8 ± 1.4 at the last follow-up. EQ-VAS evaluation showed superposable results comparing the 5 years evaluation with the ones at a medium follow up of 162 ± 27 months.DiscussionThe most important finding is the reliability at long-term of ACI technique, which in our series gave excellent clinical results. No statistical differences were observed between first- and second-generation. Clinical outcomes were significantly better for defects in the femoral condyles, influenced by age (worse results over 30 years old).ConclusionsACI represents a valid technique for chondral and osteochondral lesions of the knee in a population heterogeneous for age, sex and activity level with good results even at a long term follow up.     

The present state of treatments for articular cartilage defects in the knee

INTRODUCTION

Chondral and osteochondral lesions of the knee are notoriously difficult to treat due to the poor healing capacity of articular cartilage and the hostile environment of moving joints, ultimately causing disabling pain and early osteoarthritis. There are many different reconstructive techniques used currently but few are proven to be of value. However, some have been shown to produce a better repair with hyaline-like cartilage rather than fibrocartilage.

METHODS

A systematic search of all available online databases including PubMed, MEDLINE® and Embase™ was undertaken using several keywords. All the multiple treatment options and methods available were considered. These were summarised and the evidence for and against them was scrutinised.

RESULTS

A total of 460 articles were identified after cross-referencing the database searches using the keywords. These revealed that autologous and matrix assisted chondrocyte implantation demonstrated both ‘good to excellent’ histological results and significant improvement in clinical outcomes.

CONCLUSIONS

Autologous and matrix assisted chondrocyte implantation have been shown to treat symptomatic lesions successfully with significant histological and clinical improvement. There is, however, still a need for further randomised clinical trials, perfecting the type of scaffold and the use of adjuncts such as growth factors. A list of recommendations for treatment and the potential future trends of managing these lesions are given.     

Classification of graft hypertrophy after autologous chondrocyte implantation of full-thickness chondral defects in the knee

OBJECTIVE: Graft hypertrophy is a major complication seen in autologous chondrocyte implantation (ACI) with a periosteal flap. We present the first magnetic resonance imaging (MRI) classification for periosteal hypertrophy including a grading of clinical symptoms and the surgical consequences. METHODS: One hundred and two patients with isolated chondral defects underwent an ACI covered with periosteum and were evaluated preoperatively, 6, 18 and 36 months after surgery. Exclusion criteria were meniscal pathologies, axial malpositioning and ligament instabilities. Baseline clinical scores were compared with follow-up data by paired Wilcoxon-tests for the modified Cincinnati knee, the ICRS (International Cartilage Repair Society) and a new MRI score including the parameters defect filling, subchondral edema, effusion, cartilage signal and graft hypertrophy. Hypertrophic changes were graded from 1 (minimal) to 4 (severe). RESULTS: All scores showed significant improvement (P<0.001) over the entire study period. Patients with femoral lesions had significantly better results than patients with patella lesions after 18 and 36 months postoperative (P<0.03). Periosteal hypertrophy occurred in 28% of all patients. Fifty percent of all patella implants developed hypertrophic changes. No patient with grade 1, and all patients with grade 4 hypertrophy had to undergo revision surgery. The Pearson correlation between graft hypertrophy and ICRS score was 0.78 after 6 months, and 0.69 after 36 months (P<0.01). Inclusion of graft hypertrophy in the MRI score improves the correlation to clinical scores from 0.6 to 0.69. CONCLUSIONS: Grading graft hypertrophy helps to identify patients needing an early shaving of the graft. Its integration into an MRI score improves correlation with clinical scores. Re-operation depends on the grade of hypertrophy and clinical symptoms.     

Autologous implantation of chondrocytes on a solid collagen scaffold: clinical and histological outcomes after two years of follow-up

Abstract From our overall experience in 56 patients, we here report the treatment with matrix-induced autologous chondrocyte implantation (MACI) of 35 patients suffering from knee cartilage defects measuring about 4 cm², and followed for a minimum of 6 months. A total of 36 knees were treated (1 patient on both knees) and clinically observed for 22 months (in some cases for over 39 months), in accordance with a standardised protocol. Subjective parameters (pain, well-being, functional state, symptoms during specific activity) and objective outcomes (IKDC score and Lysholm and Tegner scores) were recorded. One or 2 years after implantation, some biopsies of the regenerated cartilage were histologically evaluated. The subjective parameters (VAS pain score, 2.80±1.49, p<0.0001; change vs. basal score, 2.72) promptly normalized after 1 month, as did the objective ones (IKDC score after 6 months, 1.53±0.59, p<0.0001; change vs. basal score, 1.78). Similar results were observed after the treatment of a femoropatellar kissing lesion. The three cartilage biopsies that were analysed from different patients showed a tissue positivity to immunohistochemical markers of hyaline cartilage. The conclusions of this preliminary analysis are that the clinical outcome and histological evaluation suggest that MACI is able to relieve pain and restore the functionality of the knee, and that the treatment appears capable of regenerating hyaline cartilage.     

Autologous chondrocyte implantation drives early chondrogenesis and organized repair in extensive full‐ and partial‐thickness cartilage defects in an equine model

Autologous chondrocyte implantation (ACI) has been used clinically for over 15 years and yet definitive evidence of chondrocyte persistence and direct impact on cartilage repair in full‐thickness lesions is scant and no data are available on ACI in partial‐thickness defects in any animal model. This study assessed the effect of chondrocytes secured using periosteal overlay in partial‐ and full‐thickness cartilage defects in the equine model. Paired cartilage defects 15 mm in diameter were made in the patellofemoral joint of 16 horse and repaired with ACI or periosteal flap alone. Response was assessed at 8 weeks by clinical, microradiographic, and histologic appearance, and by collagen type II immunohistochemistry, and proteoglycan and DNA quantification. ACI improved histologic scores in partial‐ and full‐thickness cartilage defects, including defect filling, attachment to the underlying subchondral bone, and presence of residual chondrocyte accumulations. For partial‐thickness defects chondrocyte predominance, collagen type II content, and toluidine stained matrix were enhanced, and attachment to the surrounding cartilage improved. DNA and PG content of grafted partial‐thickness defects was improved by chondrocyte implantation. Periosteal patches alone did not induce cartilage repair. This study indicated implantation of chondrocytes to cartilage defects improved healing with a combination of persisting chondrocyte regions, enhanced collagen type II formation, and better overall cartilage healing scores. Use of ACI in the more challenging partial‐thickness defects also improved histologic indices and biochemical content. The equine model of cartilage healing closely resembles cartilage repair in man, and results of this study confirm cell persistence and improved early cartilage healing events after ACI. © 2011 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 29: 1121–1130, 2011     

Repair of superficial osteochondral defects with an autologous scaffold-free cartilage construct in a caprine model: implantation method and short-term results

OBJECTIVE: To compare four different implantation modalities for the repair of superficial osteochondral defects in a caprine model using autologous, scaffold-free, engineered cartilage constructs, and to describe the short-term outcome of successfully implanted constructs. METHODS: Scaffold-free, autologous cartilage constructs were implanted within superficial osteochondral defects created in the stifle joints of nine adult goats. The implants were distributed between four 6-mm-diameter superficial osteochondral defects created in the trochlea femoris and secured in the defect using a covering periosteal flap (PF) alone or in combination with adhesives (platelet-rich plasma (PRP) or fibrin), or using PRP alone. Eight weeks after implantation surgery, the animals were killed. The defect sites were excised and subjected to macroscopic and histopathologic analyses. RESULTS: At 8 weeks, implants that had been held in place exclusively with a PF were well integrated both laterally and basally. The repair tissue manifested an architecture similar to that of hyaline articular cartilage. However, most of the implants that had been glued in place in the absence of a PF were lost during the initial 4-week phase of restricted joint movement. The use of human fibrin glue (FG) led to massive cell infiltration of the subchondral bone. CONCLUSIONS: The implantation of autologous, scaffold-free, engineered cartilage constructs might best be performed beneath a PF without the use of tissue adhesives. Successfully implanted constructs showed hyaline-like characteristics in adult goats within 2 months. Long-term animal studies and pilot clinical trials are now needed to evaluate the efficacy of this treatment strategy.     

Long-term clinical results and MRI changes after autologous chondrocyte implantation in the knee of young and active middle aged patients

Background

Autologous chondrocyte implantation (ACI) represents a valid surgical option for symptomatic full-thickness chondral lesions of the knee. Here we report long-term clinical and MRI results of first-generation ACI.

Materials and methods

Fifteen patients (mean age 21.3 years) underwent first-generation ACI for symptomatic chondral defects of the knee between 1997 and 2001. The mean size of the lesions was 5.08 cm² (range 2–9 cm²). Patients were evaluated using the International Knee Documentation Committee (IKDC) Knee Examination Form, the Tegner Activity Scale, and the Knee Injury and Osteoarthritis Outcome Score (KOOS). High-resolution MRI was used to analyze the repair tissue with nine variables (the MOCART scoring system).

Results

The mean follow-up period was 148 months (range 125–177 months). ACI resulted in substantial improvements in all clinical outcome parameters, even as much as 12 years after implantation. A significant decrease in the MOCART score was recorded at final measurement. Reoperation was required in 2 patients; failure was caused by partial detachment of the graft in both cases.

Conclusion

Autologous chondrocyte implantation is an effective and durable solution for the treatment of large, full-thickness cartilage and osteochondral lesions, even in young and active middle-aged patients. High-resolution MRI is a useful and noninvasive method for evaluating the repaired tissue.

Level of evidence

IV.

     

Arthroscopic debridement for focal articular cartilage lesions of the knee: A systematic review

Background and purpose of the studyArthroscopic debridement, the most commonly applied surgical technique for focal cartilage lesions in the knee, is not included in most treatment algorithms because of discouraging results in the management of osteoarthritis of the knee. The present systematic review evaluates the outcome of arthroscopic cartilage debridement as the primary treatment of focal knee chondral lesions in adults, and defines its indications and role as the primary treatment of focal knee chondral lesions.MethodsTwo independent investigators searched PubMed, Cochrane CENTRAL, and Virtual Health Library databases using the terms “knee”, “cartilage”, “chondral”, “lesions”, “injury”, “damage”, “debridement”, “chondroplasty”, “chondrectomy”, alone and in combination. Clinical studies evaluating the effect of mechanical cartilage debridement in adults with symptomatic focal cartilage lesions in the knee joint regardless of the defect size and depth were included. We excluded studies if patients had a concomitant ligament or meniscus injury, and/or had additional debridement with monopolar radiofrequency energy.Main findingsAvailable studies suggest good to excellent short and medium-term functional outcomes (KOOS, LKSS, Tegner scale) for focal cartilage lesions treated with debridement regardless of the defect size and depth. Data are lacking comparing cartilage debridement versus other cartilage repair techniques.ConclusionsArthroscopic debridement of focal articular cartilage lesions of the knee is associated with good to excellent short and medium-term postoperative outcomes, especially in terms of functional improvement. Arthroscopic debridement may be considered in the primary treatment of focal cartilage injuries regardless of the defect size and depth. However, available studies are limited and the level of evidence is low.     

International Cartilage Repair Society (ICRS) and Oswestry macroscopic cartilage evaluation scores validated for use in Autologous Chondrocyte Implantation (ACI) and microfracture

OBJECTIVE: For young patients with cartilage defects, the emergence of clinically applicable cell therapy for biological joint reconstruction is an appealing prospect. Acceptation of this method as a means of standard care requires proof of being reproducible, having long-lasting mechanical integrity, and having a good clinical outcome. This study evaluates the reliability of the International Cartilage Repair Society (ICRS) score and the Oswestry Arthroscopy Score (OAS) in the assessment of regenerative cartilage repair. METHOD: A total of 101 macroscopic images of cartilage repair were made during arthroscopy 12 months post-treatment of either Autologous Chondrocyte Implantation (ACI) or microfracture. These images were examined by seven independent observers with differing levels of experience. The ICRS and OAS scores were randomly presented twice at a 4-week interval. All observers stated their predicted outcome according to actual treatment and defect size. RESULTS: ICRS and OAS scores showed both good inter- and intra observer reliability (0.62 and 0.56 for ICRS; 0.73 and 0.65 for OAS, respectively). Internal consistency (Cronbach's alpha) was satisfactory for research purposes (0.79 and 0.74, respectively). Correlation (equivalence concordance) between both scoring systems was excellent (r=0.94). All observers were inconsistent in predicting actual treatment. Test-re test reliability of estimated defect size and its correlation to true defect size were poor. These results were also applicable to the sub-analyses of the experience of the observer and the quality of imaging. CONCLUSION: The ICRS and OAS are reliable and relevant scores that are now both validated for macroscopic evaluation of cartilage repair as a research tool.     

细胞载体作为软骨修复中的下一代细胞疗法

背景自从第一位患者接受培养自体软骨细胞移植 （ACI） 以来已过去20多年,新型的软骨修复细胞疗法已经出现.自体培养软骨细胞是第一代细胞疗法,它使用的是混悬培养的自体软骨细胞结合骨膜修补.胶原膜覆盖ACI （CACI）是第二代细胞疗法,它使用的是接种了混悬培养软骨细胞的Ⅰ/Ⅲ型胶原膜上.现今,因关节镜移植术的需求而开发出了第三代细胞疗法,也即采用细胞载体或接种了细胞的支架来移植培养的自体软骨细胞.目的 本文综述了目前基质诱导的自体软骨细胞移植 （MACI） 的情况,它是迄今为止使用最广泛的载体系统.本文还探讨了Ⅰ/Ⅲ型胶原膜的特点、与胶原膜相关的细胞行为、手术技术、康复、临床结果和组织修复效果.研究设计 系统回顾.方法通过搜索 Medline 数据库从1949 年成立以来到 2007年12月的数据,找出相关文献;确认出关于细胞行为、制作过程、手术技术和康复方案的基础和临床研究同行评审的文献.具有原始数据以及使用Ⅰ/Ⅲ型胶原膜的基础和临床研究也被纳入.结果 这些研究获得的数据证实使用MACI治疗的患者在临床结果方面有总体改善.观察到视觉模拟疼痛量表（VAS）评分降低（范围在 1.7～5.32 分）,而改良Cincinnati（范围在3.8～34.2分）评分、Lysholm-Gillquist（范围在23.09～47.6分）评分、Tegner-Lysholm（范围在1.39～3.9分）评分和国际膝关节文献委员会分类量表评分（P〈0.05）均有改善.通过关节镜（包括国际软骨修复学会评分）、MRI 和组织学评估,患者也显示出质量良好的（透明样）组织修复,并且术后并发症发生率较低.结论本综述的结果提示：第三代细胞疗法MACI 程序在治疗有症状的、全层关节软骨缺损修复方面是一种大有前景的方法.     

Cartilage repair evolution in post-traumatic osteochondral lesions of the talus: from open field autologous chondrocyte to bone-marrow-derived cells transplantation

The aims of this study are to describe evolution in cartilage repair from open field autologous chondrocyte implantation to regeneration by arthroscopic bone-marrow-derived cells (BMDCs) “one step” technique; to present the results of a series of patients consecutively treated and to compare in detail the different techniques used in order to establish the advantages obtained with the evolution in cartilage regenerative methods.81 patients (mean age 30 ± 8 years) were evaluated in this study. Patient assessment included clinical AOFAS score, X-rays and MRI preoperatively and at different established follow-ups. All the lesions were >1.5 cm² and received open autologous chondrocyte implantation (10 cases), arthroscopic autologous chondrocyte implantation (46 cases), and “one step” arthroscopic repair by BMDC transplantation (25 cases). For arthroscopic repair techniques a hyaluronic acid membrane was used to support cells and specifically designed instrumentation was developed. Patients of all the three groups underwent a second arthroscopy with a bioptic cartilage harvest at 1 year follow-up.Mean AOFAS score before surgery was 57.1 ± 17.2 and 92.6 ± 10.5 (P < 0.0005) at mean 59.5 ± 26.5 months. A similar pattern of AOFAS improvement in results was found in the three different techniques. Histological evaluations highlighted collagen type II and proteoglycan expression.The cartilage repair techniques described were able to provide a repair tissue which closely approximates the characteristics of the naive hyaline cartilage. Evolution in surgical technique, new biomaterials and more recently the use of BMDCs permitted a marked reduction in procedure morbidity and costs up to a “one step” technique able to overcome all the drawbacks of previous repair techniques.     

Microfracture for the treatment of cartilage defects in the knee joint – A golden standard?

The evidence for the effectiveness of the microfracture procedure is largely derived from case series and few randomized trials. Clinical outcomes improve with microfracture for the most part, but in some studies these effects are not sustained. The quality of cartilage repair following microfracture is variable and inconsistent due to unknown reasons. Younger patients have better clinical outcomes and quality of cartilage repair than older patients. When lesion location was shown to affect microfracture outcome, patients with lesions of the femoral condyle have the best clinical improvements and quality of cartilage repair compared with patients who had lesions in other areas. Patients with smaller lesions have better clinical improvement than patients with larger lesions. The necessity of long postoperative CPM and restricted weight bearing is widely accepted but not completely supported by solid data. Maybe new developments like the scaffold augmented microfracture⁶ will show even more consistent clinical and biological results as well as faster rehabilitation for the treatment of small to medium sized cartilage defects in younger individuals.All in all there is limited evidence that micro fracture should be accepted as gold standard for the treatment of cartilage lesions in the knee joint. There is no study available which compares empty controls or non-surgical treatment/physiotherapy with microfracture. According to the literature there is even evidence for self regeneration of cartilage lesions. The natural history of damaged cartilage seems to be written e.g. by inflammatory processes, genetic predisposition and other factors. Possibly that explains the large variety of the clinical outcome after micro fracture and possibly the standard tools for evaluation of new technologies (randomized controlled trials, case series, etc.) are not sufficient (anymore).Future technologies will be evaluated by big data from international registries for earlier detection of safety issues, for detection of subtle but crucial co-factors for failure and osteoarthritis as well as for lower financial burdens affecting industry and healthcare systems likewise.     

Matrix‐induced autologous chondrocyte implantation in sheep: objective assessments including confocal arthroscopy

The assessment of cartilage repair has largely been limited to macroscopic observation, magnetic resonance imaging (MRI), or destructive biopsy. The aims of this study were to establish an ovine model of articular cartilage injury repair and to examine the efficacy of nondestructive techniques for assessing cartilage regeneration by matrix‐induced autologous chondrocyte implantation (MACI). The development of nondestructive assessment techniques facilitates the monitoring of repair treatments in both experimental animal models and human clinical subjects. Defects (Ø 6 mm) were created on the trochlea and medial femoral condyle of 21 sheep randomized into untreated controls or one of two treatment arms: MACI or collagen‐only membrane. Each group was divided into 8‐, 10‐, and 12‐week time points. Repair outcomes were examined using laser scanning confocal arthroscopy (LSCA), MRI, histology, macroscopic ICRS grading, and biomechanical compression analysis. Interobserver analysis of the randomized blinded scoring of LSCA images validated our scoring protocol. Pearson correlation analysis demonstrated the correlation between LSCA, MRI, and ICRS grading. Testing of overall treatment effect independent of time point revealed significant differences between MACI and control groups for all sites and assessment modalities (Asym Sig < 0.05), except condyle histology. Biomechanical analysis suggests that while MACI tissue may resemble native tissue histologically in the early stages of remodeling, the biomechanical properties remain inferior at least in the short term. This study demonstrates the potential of a multisite sheep model of articular cartilage defect repair and its assessment via nondestructive methods. © 2007 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 26:292–303, 2008