Autologous chondrocyte implantation for the treatment of chondral and osteochondral defects of the talus: a meta-analysis of available evidence

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1 Knee Surg Sports Traumatol Arthrosc (2012) 20: DOI /s KNEE Autologous chondrocyte implantation for the treatment of chondral and osteochondral defects of the talus: a meta-analysis of available evidence Philipp Niemeyer Gian Salzmann Hagen Schmal Hermann Mayr Norbert P. Südkamp Received: 5 June 2011 / Accepted: 13 October 2011 / Published online: 30 October 2011 Ó Springer-Verlag 2011 Abstract Purpose While autologous chondrocyte implantation (ACI) has become an established surgical treatment for cartilage defects of the knee, only little is known about the clinical outcome following ACI for chondral or osteochondral lesion of the ankle. To evaluate efficiency and effectiveness of ACI for talar lesions was aim of the present meta-analysis. Methods An OVID-based literature search was performed to identify any published clinical studies on autologous chondrocyte implantation (ACI) for the treatment of pathologies of the ankle including the following databases: MEDLINE, MEDLINE preprints, EMBASE, CINAHL, Life Science Citations, British National Library of Health, and Cochrane Central Register of Controlled Trials (CENTRAL). Literature search period was from the beginning of 1994 to February Of 54 studies that were identified, a total of 16 studies met the inclusion criteria of the present meta-analysis. Those studies were systematically evaluated. Results All studies identified represented case series (EBM Leven IV). 213 cases with various treatment for osteochondral and chondral defects with a mean size of 2.3 cm 2 (±0.6) have been reported. A total of 9 different scores have been used as outcome parameters. Mean study size was 13 patients (SD 10; range 2 46) with a mean follow-up of 32 ± 27 months (range 6 120). Mean Coleman P. Niemeyer (&) G. Salzmann H. Schmal H. Mayr N. P. Südkamp Department for Orthopedic Surgery and Traumatology, Freiburg University Hospital, Hugstetter Str. 55, Freiburg, Germany philipp.niemeyer@uniklinik-freiburg.de Methodology Score was 65 (SD 11) points. Overall clinical success rate was 89.9%. Conclusions Evidence concerning the use of ACI for osteochondral and chondral defects of the talus is still elusive. Although clinical outcome as described in the studies available seems promising with regard to a lack of controlled studies a superiority or inferiority to other techniques such as osteochondral transplantation or microfracturing cannot be estimated. Keywords Cartilage defect Autologous chondrocyte Ankle joint Meta-analysis Cell transplantation Chondrocyte Introduction Since the introduction of autologous chondrocyte implantation (ACI) by the group of Lars Peterson and Mats Brittberg in 1994 [7], the major focus of this new and innovative therapeutical approach for cartilage repair has always been the treatment of isolated cartilage defects of the knee [8, 15]. For the knee joint, scientific evidence has increased significantly in recent years; there are several prospective randomized trials (RCT) available which proof the efficiency of this surgical method. Those are summarized in some recent reviews [5, 49, 50] including three sequential systematic reviews from the Cochrane library [48, 51, 52]. Although some authors still complain about weaknesses of the individual RCTs [6], the methodology of recent ACI studies has significantly increased as indicated by the Coleman Methodology Score [5, 48, 49] compared to earlier analysis of the quality of cartilage repair studies [19]. Additionally, various authors presented long-term

2 Knee Surg Sports Traumatol Arthrosc (2012) 20: results that seem to demonstrate long-term durability [34, 38, 47]. Therefore, different authors and societies in various countries have recommended ACI as the standard and recommended therapy for the treatment of large fullthickness cartilage defects of the knee exceeding a size of approximately 3 4 cm 2 [4, 5, 9]. Interestingly, although chondral lesions and osteochondritis dissecans seem to be of high clinical relevance in the ankle, the evidence for the use of ACI for the treatment of cartilage lesions of the talus is limited. Although there are some early reports that demonstrated feasibility and proofof-principle [37], only a very limited number of following studies picked up the idea to transfer this technology for the treatment of chondral or osteochondral lesions from the knee to the ankle. To systematically analyze the scientific literature available on ACI of the ankle joint was purpose of the present study. Materials and methods For this systematic review, an OVID-based literature search was performed to identify any published clinical studies on autologous chondrocyte implantation (ACI) for the treatment of pathologies of the ankle including the following databases: MEDLINE, MEDLINE preprints, EMBASE, CINAHL, Life Science Citations, British National Library of Health, and Cochrane Central Register of Controlled Trials (CENTRAL). Literature search period was from the beginning of 1994 to February Search was performed on February 15, 2011, using the following strategy (Database: Ovid MED- LINE(R)\1948 to January Week [; 1 Chondrocytes/tr [Transplantation] (1010); 2 Transplantation, Autologous/ (38538); 31 and 2 (420), 4 autologous chondrocyte transplantation.mp. (214); 5 autologous chondrocyte implantation.mp. (304); 6 4 or 5 (502); 7 3 or 6 (649); 8 (chondrocytes adj5 transplantation).tw. (141); 9 chondrocytes/and transplantation/(4); 10 7 or 8 or 9 (756); 11 Ankle/(5656); 12 Ankle Joint/(8339); 13 Ankle injuries/(6430); 14 Talus/(2765); 15 (talus or talar).tw. (3242); 16 ankle*.tw. (27237); or 12 or 13 or 14 or 15 or 16 (34908); and 17 (54); 19 limit 18 to yr = 1994 Current (54). Only articles in English and German language were included. In accordance with the search strategy, a total of 54 articles related to autologous chondrocyte implantation of the talus were identified. 1 out of 54 articles was excluded because it was published in Spanish language and another was excluded since published in Czech language. Therefore, 52 articles were scanned for appropriateness for the present meta-analysis. Of all 52 articles, full text were obtained and screened by 2 independent reviewers. 24 articles were excluded since the articles represented review articles without original data; 9 articles were excluded because a different surgical technique was focus of clinical evaluation (osteochondral transplantation, bone marrow stimulation, and others). 3 articles were excluded for other reasons (1 case report with an unusual indication, 1 MRI feasibility study, and 1 experimental animal study). All studies reporting on clinical results of autologous chondrocyte implantation (ACI) of the ankle were included independent of population size, methodology, follow-up time and rate and indication (n = 16, see Table 1). Of every article included in the present systematic review, data on study characteristics and design, level of evidence, demographical parameters, diagnosis, defect characteristics, surgical technique and rehabilitation protocol, associated surgical procedures, clinical follow-up, and treatment outcomes were extracted. Specific focus was placed on extracting data describing clinical efficacy of ACI, including clinical ankle function scores. In case of additional reporting of MRI or histological data, these have been evaluated separately. Level of evidence was categorized according to the definition given by Oxford Centre for Evidence-based Medicine and published by Hanzlik et al. [17]. To further assess for the methodological quality of the collected data, the modified Coleman Methodology Scores and subscales were determined for each included study [10, 19]. The Coleman Methodology Score assesses the methodology of clinical studies by use of subscores assigned 10 specific criteria (study size, mean duration of follow-up, number of surgical procedures, type of study, diagnostic certainty, description of surgical procedure, postoperative rehabilitation, outcome measures, outcome assessment, and selection process). Grading studies was performing by assigning a score for each criterion, with a score between 0 and 100. A score of 100 indicates the highest possible study quality. The modified Coleman Methodology Score has been previously used for the analysis of methodological quality of cartilage repair studies [19, 32]. Since various outcome parameters have been used in the studies included in this systematic review, in each individual score, a good or excellent was identified according the recommendations given by the authors of the individual score. For the purpose of this analysis, the percentage of good and excellent results was considered success rate (Fig. 1). Results Characteristics of included patients Out of 54 studies that have been identified using the search algorithm given in Table 1, a total of 16 studies that reported on clinical outcome following ACI at the ankle were included, describing the clinical follow-up of 213

3 1698 Knee Surg Sports Traumatol Arthrosc (2012) 20: Table 1 Overview of a total of 16 studies that were included in the present meta-analysis (alphabetically sorted by the name of the first author) Author Year Journal Evidence level Technique Indication Size (cm 2 ) Patients Follow-up (months) Success rate (%) Scores Baums 2006 JBJS Am 4 P-ACI CH/OCH AOFAS, HNS-OSG, VAS Caumo 2007 Radiol Med 4 M-ACI CH NA AOFAS Cherubino 2003 J Orthop Surg 4 M-ACI CH NR AOFAS Dorotka 2004 Z Rheumatol 4 P-ACI CH AOFAS Giannini 2009 Am J Sports 4 P-ACI CH AOFAS, MOCART Med Giannini 2001 Foot Ankl Int 4 P-ACI OCH Giannini 2005 Osteoarthritis 4 M-ACI OCH AOFAS Cartilage Giannini 2008 Am J Sports 4 M-ACI OCH AOFAS Med Giza 2010 Foot Ankle 4 M-ACI CH AOFAS, SF-36 Int Koulalis 2002 Clin Orthop 4 M-ACI OCH Finsen Relat Res Lee 2010 Orthopedics 4 M-ACI OCH AOFAS Nam 2009 Am J Sports Med Quirbach 2009 Skeletal Radiol Schneider 2009 Foot Ankle Int 4 P-ACI CH/OCH Tegner, AOFAS; SSE, Finsen 4 M-ACI CH/OCH NR MOCART 4 M-ACI OCH AOFAS Thermann 2008 Orthopade 4 M-ACI CH/OCH HNS-OSG, VAS, CRAS Whittaker 2005 JBJS Br 4 P-ACI OCH Modified Mazur, Schwartz Simon Score OCH osteochondral, CH chondral, P-ACI periosteum-covered ACI, M-ACI matrix-associated ACI, NR not reported Fig. 1 A total of 16 studies could be identified as relevant for the present study that met inclusion and exclusion criteria patients. The average postoperative follow-up was 32 ± 27 months (range 6 120). The mean number of study subjects/study was 13 ± 10 patients (range 2 46). In the majority of studies (6 studies), ACI was used for the treatment of osteochondral defects with or without additional bone graft. In 5 studies, patients were exclusively treated for chondral lesions, while both osteochondral and chondral lesions were treated in the remaining 5 studies. Mean defect size for both indications was 2.3 cm 2 (±0.6). Number of publications in dependence of year published is given in Fig. 2. Characteristics of all included studies are given in Tables 1 and 2. Concerning different techniques of ACI used for cartilage repair, in 6 studies periosteum-covered ACI was applied, while the remaining studies used matrix-associated ACI for surgical treatment including the original MACI TM technique as well as other m-aci techniques (such as Hyalograft C TM, Chondrospheres TM, and Chondron TM ). Outcome parameters and overall success rate For pre- and postoperative assessment of clinical function, a total of 9 different scores have been used. The American Orthopaedic Foot & Ankle Society (AOFAS) score (CITE) was the most common score, which has been used in 10

4 Knee Surg Sports Traumatol Arthrosc (2012) 20: Fig. 2 Publication years of all studies included in the present metaanalysis Table 2 Overall characteristics of all studies (n = 16) included in the present meta-analysis Study characteristics Mean SD (±) Patients per study (n) Defect size (cm 2 ) Follow-up (months) Overall clinical success rate (%) studies, other scores which have been used in more than one study were a Visual Analogue Scale (VAS), the MOCART score, Finsen score, Hannover ankle score, and the modified Mazur score. Overall clinical success rate was 89.9% and varied between 50 and 100% according to the individual scoring system used for the evaluation of clinical outcome. Available evidence No controlled studies could be identified that reported on clinical outcome following ACI of the ankle. All studies, which have been identified, were classified as case series. The majority of the studies included reported on prospective cohort studies. According to the recommendations given by Hanzlik, all studies were therefore classified as evidence level IV. Among those, the majority of the studies were characterized by prospective enrollment of priory treated patients, only a minority of studies reported a retrospective patient enrollment (n = 5). The average Coleman Methodology Score was 65 ± 11 points (range 42 78). With regard to the subscores, highest values were found for surgical technique, diagnostic certainty, patient selection process, follow-up, and concomitant surgical procedures. It was lower for study size and study design (Fig. 2). Discussion The aim of the present study was to evaluate scientific evidence for the treatment of chondral/osteochondral defects of the talus by autologous chondrocyte implantation. The most important finding was that there is a significant lack of evidence concerning the use of ACI on the talus. Although there are promising results that generally demonstrate the efficiency of this treatment, no controlled studies are available. Since the introduction in 1994 [7], autologous chondrocyte implantation (ACI) has become an essential part of surgical treatment for cartilage defects of the knee joint. At present, long-term follow-up data [34, 38, 47] on the one hand side and prospective randomized controlled studies, which compare ACI to other surgical techniques for cartilage restoration, are available [2, 20 22, 40, 41], while on the other hand, several meta-analyses on the issue of ACI for cartilage defects of the knee are available [48, 51, 52]. With regard to this, autologous chondrocyte implantation for cartilage defects of the knee can be considered an efficient and safe procedure for the treatment of cartilage defects. Although scientific data on the optimal indication concerning defect size are missing, experts and societies generally recommend ACI for the treatment of larger fullthickness cartilage defects that exceed a size of 3 4 cm 2 [4, 9]. In contrast to the situation of ACI in the knee, data that evaluate efficiency, safety, and usefulness of autologous chondrocyte implantation for chondral (or osteochondral) defects in other joint are rare. Purpose of the present study was to evaluate the scientific evidence available on clinical outcome of ACI in the ankle. This seems to be of high relevance, against the background that there are important differences in defect etiology, biomechanics, and also cartilage biology. Compared to the knee joint, the ankle has a higher congruency and cartilage of the ankle is characterized by a higher content of proteoglycans turnover and synthesis, which results in higher stiffness and reduced permeability [26]. Furthermore, a decreased response to catabolic factors such as interleukin-1 and fibronectin has been described. In addition, subchondral bone seems of higher clinical relevance, since it is involved in the defect more frequently on the one hand side and since an increased flow and pressure of the synovial fluid might be the cause for observed osteolysis or talar cysts [45, 46]. All these factors make it necessary to study outcome and availability of ACI in the ankle separate from the knee. Although all clinical studies independent of study design were included in the present meta-analysis, only 16 studies were identified as relevant reporting clinical outcome of ACI. All studies represented case series (level of evidence IV [36]), partially patients were included prospectively and partially a retrospective analysis of patient treated with ACI in the ankle was performed. In contrast to the little amount of clinical data available, there are a large number of review articles on the topic of ACI in the ankle. Most of them are considered expert

5 1700 Knee Surg Sports Traumatol Arthrosc (2012) 20: opinions in this field and more or less describe either technical aspects or the personal opinion of the authors [1, 14, 18, 24, 28, 31, 37]. Zengerink and co-workers have published a systematic review in Nevertheless, in this analysis, only studies before December 2006 are included and the review is not specific for ACI in the ankle, but it rather aims to compare the outcome of different cartilage repair techniques available for osteochondral lesions of the talus [54]. As major conclusion of this article, the authors state that the evidence available is not sufficient to give any strong recommendations on what kind of treatment should be recommended. Concerning the 16 studies considered relevant for the present analysis, a total of 213 patients were reported with a mean follow-up of approximately 32 months. 50% of the studies included were published within the last 3 years, indicating that there is an increasing interest in this topic (see Fig. 2). In the majority of the cases, ACI was performed for osteochondral lesions rather than for isolated cartilage defects, which probably represents the incidence of pathologies in the ankle joint. Furthermore, a huge variety of technical modifications was used. In 6 studies, periosteum-covered ACI was applied, while some studies report on clinical outcome with the use of biomaterials or other techniques such as the use of Chondrospheres TM (co.don, Teltow, Germany) [23] (2nd and 3rd generation according to Marlovits et al. [29]). The variety of different techniques and low published numbers make conclusions on different techniques of ACI impossible. Interestingly, all studies have been published later than year 2001 (also see Fig. 2) and still periosteum-covered ACI represents the majority of studies, although membranes and biomaterials have been available and already become popular in ACI for cartilage defects of the knee in 2003/04 [16, 43]. In those studies, in which matrix-associated ACI was used, several different products were used. Even the use of biomaterialfree products (Chondrospheres TM, CoDon, Germany) has been reported [23]. Low case numbers and inhomogeneous indications and patients do not allow any conclusion about what kind of ACI might be superior. Even more problematic, concerning a direct comparison between individual studies was that different outcome parameters have been used in order to evaluate patients following ACI. Although the AOFAS score was used in the majority of studies, overall more than 10 different scoring systems were applied, so that the authors decided to describe good and excellent results according to the individual score used in the present study as success. All prospective studies included in the present metaanalysis report an improvement at time of follow-up when compared to preoperative, indicating that the application of autologous chondrocyte seems efficient concerning clinical improvement in patients with chondral or osteochondral defects of the talus. The overall success rate of the present study was 89.9% and therefore considerably high. Additional MRI and histological data were available in 10 studies, while 6 reported second-look arthroscopies. Interestingly, the success rate concerning outcome of MRI as described by the authors was lower compared to clinical success rate (range %) [3, 11, 23, 35, 39, 44], while those rare cases of second-look arthroscopy report sufficient repair tissue during re-look arthroscopy [13, 23]. In the majority of the studies, ACI was used as a treatment for osteochondral defects, and only a few studies were exclusively dealing with isolated chondral lesions. This is probably due to the fact that osteochondral lesions of the talus are much more frequent compared to isolated cartilage defects with intact underlying bone. Nevertheless, this also makes interpretation of the data available more difficult because in some patients ACI was performed in combination with concomitant bone graft (i.e. [13]). Furthermore, since ACI is considered a 2nd treatment after failed initial minimal invasive treatment by some surgeons, patients included in the present meta-analysis differ in terms that in some studies, ACI was generally considered a second-line treatment after failed initial treatment [35, 44, 53], while in others ACI was used as a first-line treatment. For the knee joint clinical relevance, concerning this factor has been demonstrated, since the failure rate of ACI is described to be significantly higher in cases of ACI as second-line treatment following failed prior bone marrow stimulation [30]. Concerning data of the present metaanalysis, patient numbers are too small to draw any similar conclusions and to directly compare those subgroups of patients. The success rate in 2 studies in which all patients were treated with ACI as second-line treatment are described as very good with a success rate of 90% and 100%, respectively [44, 53]. With regard to the limited number of patients available, due to the good results and low failure rates, the effect of prior minimal invasive therapy seems limited. Concerning the mean defect size of patients, which were included in the present meta-analysis, mean size was 2.3 cm 2 and therefore significantly smaller compared to studies of ACI in the knee. Obviously, smaller defects compared to the knee are considered an indication for ACI in the ankle. Evidence-based recommendations concerning this parameter are missing. Nevertheless, it seems reasonable to consider smaller defects of the ankle being an indication for ACI compared to the knee, since the percentage of the joint surface involved in the pathology is certainly larger even the absolute mean value of defect size is only 2.3 cm 2. The overall Coleman Score to address quality of the individual studies in the present meta-analysis was 65 points, which is below the study quality of recent ACI studies in the knee [5, 48, 49]. Nevertheless, some studies

6 Knee Surg Sports Traumatol Arthrosc (2012) 20: reach a satisfying Coleman Score of more than 70 points [3, 12, 27, 35, 42]. With regard to the fact that only level IV studies were identified (representing case series), the average Coleman Score was higher than initially expected by the authors of this meta-analysis, which is probably caused by the fact that a homogenous and well-described surgical treatment as well as a detailed description of the rehabilitation is considered really important in the Coleman Methodology Score and leads to a significant increase in the overall score. Most studies were analogous concerning study design and mainly differed by the parameters follow-up and case number. Since all studies involved are reporting a very recent surgical technique, most authors emphasize surgical technique and really describe this in details (Coleman subscales given in Fig. 3). The publication of Qiurbach and co-workers represents an exemption concerning this observation, since it focuses on MRI evaluation [39]. Nevertheless, detailed reporting of surgical technique and postoperative rehabilitation helps to increase the overall Coleman Score and makes it important to focus on subscales. Concerning the subscales of the Coleman Score for the evaluation of study quality, highest values could be achieved in the subscale diagnostic certainty, since in all patients the diagnosis of a chondral or osteochondral lesion was checked via arthroscopy, which seems a consequence of the two-step character of autologous chondrocyte implantation that makes an arthroscopy prior to transplantation necessary for cell harvesting. Additionally, satisfying quality was found in the subscale description of surgery. In contrast to these subscales, in all other subscales, relevant deficits have been identified including probably the most relevant subscales study size (which probably represents the most relevant deficit at all), follow-up, and type of study. Against the background that only one study could Fig. 3 Mean Coleman Score with regard to the subscales of all studies included in the present meta-analysis (Coleman Score items (in percent of max. available points per item) describe the following: A1 study size, A2 follow-up, A3 number of surgical procedures, A4 study type, A5 diagnostic certainty, A6 description of surgical procedure, A7 description of postoperative rehabilitation, B1 outcome criteria, B2 outcome assessment, B3 description of the selection process) be identified reporting long-term outcome, average follow-up was approximately 32 months. Therefore, in the vast majority of the studies analyzed here, only short- and mid-term outcome was reported. This is of great relevance with regard to the observation when ACI is compared to other techniques such as microfracturing. Differences in functional outcome between treatment groups show a tendency to increase over time [40] probably in bone marrow stimulation (such as microfracturing), there is a trend toward inferior results after 24 months following surgery [25, 33]. Nevertheless, when Coleman Score data are evaluated, one might consider that mid-term and long-term follow-up is not fully considered when applying the score. All studies reporting on a follow-up longer than 24 months automatically are estimated by the subscale maximum. Per contra, a minimum of 60 study subjects are required to score maximum points in this particular subscale. We consider these estimates out of proportion, since on the one hand in selected cases, it may require longer than 24 months to result in a potential endpoint situation following ACI, while on the other hand, it may turn out very difficult to report on 60 consecutive patients all receiving ACI at the ankle. Conclusion Data available suggest that an improvement in ankle function and good clinical outcome can be achieved with the use of autologous chondrocyte implantation in patients with chondral and osteochondral lesions of the talus. Due to inhomogeneous outcome parameters, different indications, different technical modifications of ACI used, it seems difficult to quantify this effect. The limited number of patients reported does also not allow identifying prognostic factors for clinical outcome as it has been reported for the knee joint. Influence of previous surgery, duration of symptoms, influence of transarthroscopic surgery, and others remain unclear. Furthermore, since no controlled studies are available, a superiority or inferiority to other techniques such as osteochondral transplantation or microfracturing cannot be estimated. At least, the number of reported patients suggests that no specific complication concerning the use of ACI in the ankle is observed. Therefore, further clinical trials are clearly necessary. Controlled clinical trials are encouraged by the authors in order to evaluate efficiency and safety of this method. References 1. Aurich M, Venbrocks RA, Fuhrmann RA (2008) Autologous chondrocyte transplantation in the ankle joint. Rational or irrational? Orthopade 37(3):188 ( )

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