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Surgical management of large talar osteochondral defects using autologous chondrocyte implantation
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Surgical management of large talar osteochondral defects using autologous chondrocyte implantation Brandon Erickson, MDa , Yale Fillingham, MDa , Michael Hellman, MDa , Selene G. Parekh, MDb,c, Christopher E. Gross, MDd,* a
Rush University Medical Center, Chicago, IL 60622, United States Department of Orthopaedic Surgery, Duke University Medical Center, Durham, NC 27707, United States Duke Fuqua School of Business, Durham, NC 27707, United States d Medical University of South Carolina, Charleston, SC 29403, United States b c
A R T I C L E I N F O
A B S T R A C T
Article history: Received 26 October 2016 Received in revised form 11 December 2016 Accepted 5 January 2017 Available online xxx
Background: Talar osteochondral lesions (OLT) occur frequently in ankle sprains and fractures. We hypothesize that matrix-induced autologous chondrocyte implantation (MACI) will have a low reoperation rate and high patient satisfaction rate in treating OLT less than 2.5 cm2. Methods: A systematic review was registered with PROSPERO and performed with PRISMA guidelines using three publicly available free databases. Clinical outcome investigations reporting OLT outcomes with levels of evidence I–IV were eligible for inclusion. All study, subject, and surgical technique demographics were analyzed and compared. Statistics were calculated using Student’s t-tests, one-way ANOVA, chi-squared, and two-proportion Z-tests. Results: Nineteen articles met our inclusion criteria, which resulted in a total of 343 patients. Six studies pertained to arthroscopic MACI, 8 to open MACI, and 5 studies to open periosteal ACI (PACI). All studies were Level IV evidence. Due to study quality, imprecise and sparse data, and potential for reporting bias, the quality of evidence is low. In comparison of open and arthroscopic MACI, we found both advantages favoring open MACI. However, open MACI had higher complication rates. Conclusions: No procedure demonstrates superiority or inferiority between the combination of open or arthroscopic MACI and PACI in the management of OLT less than 2.5 cm2. Ultimately, well-designed randomized trials are needed to address the limitation of the available literature and further our understanding of the optimal treatment options. © 2017 European Foot and Ankle Society. Published by Elsevier Ltd. All rights reserved.
Keywords: Talus Osteochondral lesion Autologous chondrocyte implantation
1. Introduction Studies have shown that osteochondral lesion of the talus (OLT) are frequent occurrences when patients sustain both traumatic and atraumatic ankle injuries [1] with a report rate of up to 70% OLT in patients who sustain an ankle sprain or fracture [2]. When a patient is found to have an OLT, studies have shown the a medial OLT has a traumatic etiology 70% of the time, while lateral lesions have a traumatic etiology in 98% of cases [1]. These lesions are seldom treated non-operatively as results of non-operative treatment have shown a success rate of less than 50% [3]. Surgical treatment options for OLT can be broken down into reparative (marrow stimulation) and replacement (transplant of tissue) options, and are frequently dictated by characteristics of the
* Corresponding author. E-mail address: [email protected] (C.E. Gross).
lesion, including size and presence or absence of cysts [4,5]. Patient preference also plays an important role in treatment options, as some techniques can be done arthroscopically while other require a more extensive surgical approach. Reparative options include microfracture while replacement options include osteochondral autograft or allograft transplantation (OAT), autologous chondrocyte implantation (ACI), matrix induced autologous chondrocyte implantation (MACI), periosteal autologous chondrocyte implantation (PACI), and metallic implantation. In these techniques, a patient’s cartilage cells are cultured in the initial procedure. In PACI, a periosteal flap harvested from the patients distal tibia is sutured over the transplanted cells in a second stage procedure. In MACI, a chondrocyte-loaded scaffold is implanted. While microfracture has been classically used for defects less than 1.5 cm2, the optimal treatment for larger lesions has yet to be identified [5]. The purpose of this study was to perform a systematic review [6] of the literature to determine which surgical treatment option for OLT less than 2.5 cm2 excluding microfracture provided the
http://dx.doi.org/10.1016/j.fas.2017.01.002 1268-7731/© 2017 European Foot and Ankle Society. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: B. Erickson, et al., Surgical management of large talar osteochondral defects using autologous chondrocyte implantation, Foot Ankle Surg (2017), http://dx.doi.org/10.1016/j.fas.2017.01.002
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lowest complication rate, best clinic outcomes, and highest patients satisfaction rate. A secondary goal was to determine which treatment provided the best functional outcomes scores in patients for treatment of OLT. The authors’ hypothesis was that MACI would have the lowest complications rate and the highest patient satisfaction rate of the treatments examined.
and Finsen scores. Time to return to sport, patient satisfaction, complications, and reoperations were recorded. When applicable, radiographic follow up with plain radiographs or magnetic resonance imaging (MRI) was recorded. Study methodological quality was evaluated using the MCMS (Modified Coleman Methodology Score) [10].
2. Methods
2.1. Statistical analysis
A systematic review was conducted according to PRISMA guidelines (Preferred Reporting Items for Systematic reviews and Meta-Analyses) using a PRISMA checklist [7]. Systematic review registration was performed using the PROSPERO International prospective register of systematic reviews (registration number CRD42015016494) [8]. Two reviewers independently conducted the search on May 1, 2016 using the following databases: Medline, Cochrane Central Register of Controlled Trials, SportDiscus, and CINAHL. The electronic search citation algorithm utilized was: (talus OR talar) AND (osteochondral OR cartilage OR lesions) AND (chondrocyte OR autologous OR implantation OR chondrogenesis). English language Level I–IV evidence (2011 update by the Oxford Centre for Evidence-Based Medicine [9]) clinical studies were eligible. Medical conference abstracts were ineligible for inclusion. All references within included studies were cross-referenced for inclusion if missed by the initial search. If duplicate subject populations were encountered, the study with the longer followup was included. Level V evidence, reviews, letters to the editor, basic science, biomechanical studies, imaging, surgical technique, and classification studies were excluded. A total of 218 studies were located, and, after implementation of the inclusion criteria, 19 studies were included in the final analysis (Table 1). Study subjects of interest in this systematic review underwent either matrix induced autologous chondrocyte implantation (MACI) or periosteal autologous chondrocyte implantation (PACI) for treatment of osteochondral lesions of the talus less than 2.5 cm2. No minimum requirement was set for follow-up. Study and subject demographic parameters analyzed included year of publication, years of subject enrollment, level of evidence, number of subjects, gender, age, body mass index (BMI), diagnoses treated, lesion size, and surgical technique. Clinical outcome scores sought were the VAS (visual analog scale), AOFAS (American orthopaedic foot and ankle society) Hindfoot Score, Hanover, Lower Limb Outcome Assessment, AAOS (American Academy of Orthopaedic Surgeons), FFI (Foot Function Index), Mazur, Tegner,
Study data was aggregated based on each treatment method (open MACI, arthroscopic MACI, open PACI), and weighted outcomes and complication rates were calculated. A heterogeneity and publication bias analysis was performed on all included studies. Due to significant heterogeneity between studies, a random effects model was used for all statistical methods. An Inverse Variance statistical method was used to compare all continuous data outcomes, and was reported using means and standard mean differences. A Mantel–Haenzel statistical method was used to compare all dichotomous data outcomes and complications, and was reported using odds ratios and 95% confidence intervals. The reported p values refer to a one-sided (likelihood ratio) test for difference in outcomes and complication rates between each group. Probability values of <0.05 were considered significant. All statistical tests were performed using Review Manager (RevMan, Version 5.3; Copenhagen, Denmark: The Nordic Cochrane Centre, The Cochrane Collaboration; 2011). 3. Results A total of 219 articles were identified on the initial literature search. Among the initial studies, 196 of 219 were excluded in the primary screening leaving at total of 25 for review of the abstract or full article. After the 25 were reviewed for eligibility based on the inclusion and exclusion criteria, a total of 19 were included in the systematic review [11–29]. Four of the 25 studies represented an analysis of patients at earlier times points [30–33]. Of the 19 studies, none of the studies included randomized or prospective studies. All studies were retrospective case series published between 2003 and 2014. Within the 19 studies, the treatment options presented were 6 studies of arthroscopic MACI, 8 studies of open MACI, and 5 studies of open PACI. The average number of subjects in each study was 18 patients (range, 6–45) with mean ages between 24 and 42 years and mean follow-up between 12 and 119.5 months. Of the collective 343 study subjects, 117 subjects
Table 1 Demographics. Author
Year
# pts enrolled/time period
Mean age
ACI or MACI
Open (O)/arthroscopic (A)
Mean defect surface area (cm2)
Anders Apprich Aurich Battaglia Caumo Dixon Giannini Giannini Giza Lee Magnan Quirbach Ronga Schneider Baums Giannini Kwak Petersen Whittaker
2012 2012 2011 2011 2007 2011 2005 2014 2010 2011 2012 2009 2005 2009 2006 2009 2014 2003 2005
22 10 16 20 14 28 16 46 10 21 30 12 6 20 12 10 32 14 10
23.9 32.4 29.2 35 35.2 41 30.5 31.4 40.2 39 28.9 32.8 28.6 36 29.7 25.8 34 28 42
MACI MACI MACI MACI MACI MACI MACI MACI MACI MACI MACI MACI MACI MACI PACI PACI PACI PACI PACI
O O A A n/a O A A A O A O O O O O O O O
1.94 1.21 1.5 2.7 n/a 1.31 n/a 1.6 1.3 n/a 2.4 n/a 3.4 2.33 2.3 3.1 1.98 1.7 1.95
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(34%) had prior procedure and 56 subjects (16%) had a concomitant procedure at the time of MACI or PACI. Overall a high amount of bias was present among the subgroups within the studies. The location of 203 lesions were noted and included: 102 medial OLTs (50.2%), 38 lateral (18.7%), six central (3.0%), two medial/ lateral (1.0%), and one kissing lesion. The mean surface area of the defect treated with 1.96 cm2 (range: 1.21–3.4).
average MOCART score of 76.99 (SD 10.59) and arthroscopic MACI included a single study of ten subjects with an average MOCART score of 62.40 (SD 15.8). Comparison of open vs. arthroscopic techniques demonstrated a mean difference of 14.59 (SMD 1.2) and overall effect of Z = 2.73 (p = 0.006). Similar to post-operative AOFAS scores, open MACI was favored over arthroscopic MACI with statistically higher MOCART scores.
3.1. AOFAS scores
3.3. Return to level of sport
Nine studies were analyzed for differences between the preoperative and postoperative AOFAS scores. The studies included in the analysis were six studies of arthroscopic MACI, two studies of open MACI, and one study of open PACI. All nine MACI studies had a total of 130 subjects with an average AOFAS score improvement of 32.92 (SMD 2.49) and overall effect of Z = 5.2 (p < 0.0001). Arthroscopic MACI had 32 subjects with an average AOFAS score improvement of 27.58 (SMD 2.82) and overall effect of Z = 4.01 (p < 0.0001). Open MACI had 98 subjects with an average AOFAS score improvement of 34.48 (SMD 2.34) and overall effect of Z = 3.65 (p < 0.0003). Open PACI had 12 subjects with an average AOFAS score improvement of 44.90 (SMD 4.88) and overall effect of Z = 5.60 (p < 0.00001). Regardless of the treatment option all studies included in the analysis demonstrated a statistically significant improvement between pre-operative and post-operative AOFAS scores. Comparison of the percentage of subjects achieving an AOFAS score classification of “excellent” or “good” were compared between MACI vs. PACI as well as arthroscopic MACI vs. open MACI. The overall rate of excellent or good AOFAS outcomes among the eight studies included in the analysis was 79.55%. Among the six studies of MACI with 110 subjects and two studies of PACI with 22 subjects included in the analysis, 77.27% achieved excellent or good AOFAS scores with MACI while 90.91% had the same outcome with PACI. The calculated odds ratio (OR) was 0.34 (0.07, 1.56) with no statistical significance at p = 0.16. Arthroscopic MACI included four studies with 90 subjects and open MACI included one study with six subjects, which demonstrated 83.33% and 74.44% excellent or good AOFAS outcomes. The calculated OR was 1.72 (0.19, 15.47) with a non-statistically significant p-value of 0.63. In terms of percentage of patients achieving an excellent or good AOFAS outcome, no statistical significant was noted between MACI vs. PACI and open vs. arthroscopic MACI. Of the studies, nine studies with 236 subjects were included in the analysis of post-operative AOFAS scores. Among the MACI studies, eight studies including 170 subjects had an average postoperative AOFAS score of 87.29 (SD 12.90) while one study of 12 subjects were included for PACI with an average score of 88.40 (SD 11.1). Analysis comparing MACI vs. PACI demonstrated a mean difference of 1.11 (SMD 0.09) with an overall effect of Z = 0.33 (p = 0.74). Comparison of open vs. arthroscopic MACI respectively included two studies of 32 subjections and one study of 12 subjects. The results demonstrated a mean difference of 5.37 (SMD 0.40) with an overall effect of Z = 3.12 (p = 0.002). Evaluation of postoperative AOFAS scores demonstrate no statistical difference between all MACI and PACI, but open MACI has a greater postoperative AOFAS score compared to arthroscopic MACI.
Four case series have been published on the return to previous level of sport with two studies and 42 subjects on arthroscopic MACI and two studies and 29 subjects on open PACI. Comparison of arthroscopic MACI and open PACI demonstrated respective rates of return to previous level of sport at 66.20% and 55.17%. The calculated OR was 2.29 (0.84, 6.25) with no statistical significance at a p-value of 0.11.
3.2. MOCART (magnetic resonance observation of cartilage repair tissue) scores The MOCART score evaluates the subchondral bone following cartilage repair techniques. It is often compared with clinical outcome [34]. Only three studies published MOCART scores, which limited the comparison between only open vs. arthroscopic MACI. Overall, open MACI included two studies of 32 subjects with an
3.4. Failure rate A comparison of failure rates was performed between MACI vs. PACI and open vs. arthroscopic MACI. Overall among the 14 studies and 281 subjects included in the analysis, the collective failure rate was 3.91%. Among the 11 studies of MACI with 223 subjects and three studies of PACI with 58 subjects included in the analysis, the failure rates were respectively 3.59% and 5.17%. The calculated OR was 0.68 (0.68, 2.66) with no statistical significance at p = 0.58. Arthroscopic MACI included five studies with 122 subjects and open MACI included five studies with 87 subjects, which demonstrated 5.75% and 2.46% rates of failure. The calculated OR was 2.42 (0.56, 10.40) with a non-statistically significant pvalue of 0.24. In terms of percentage of patients experiencing failures, no statistical significant was noted between MACI vs. PACI and open vs. arthroscopic MACI. 3.5. Reoperation rate Analysis of reoperation rates was performed between MACI vs. PACI and open vs. arthroscopic MACI. Of the reviewed studies, 14 studies and 241 subjects included in the analysis, the collective reoperation rate was 21.99%. Among the ten studies of MACI with 172 subjects and four studies of PACI with 69 subjects included in the analysis, the reoperation rates were respectively 23.26% and 18.84%. The calculated OR was 1.31 (0.65, 2.63) with no statistical significance at p = 0.40. Open MACI included four studies with 66 subjects and arthroscopic MACI included five studies with 92 subjects, which demonstrated 16.67% and 31.52% rates of reoperation. The calculated OR was 0.43 (0.20, 0.95) with a statistically significant p-value of 0.04. In terms of percentage of patients experiencing reoperation, no statistical significant was noted between MACI vs. PACI, but open MACI had a significantly lower rate of reoperation compared to arthroscopic MACI. 3.6. Complication rate The rate of complication was examined in regards to all complications, impingement, graft breakdown, wound complications, painful hardware, and non-union. Overall 12 studies with 230 subjects were included in the final analysis with a baseline complication rate of 6.09%. When the complication rates were compared between MACI and PACI, no statistical significant was noted among all complications and individual types of complications (Table 2). Comparison of the associated complications between open and arthroscopic MACI demonstrated a statistically significant increase in overall complications for the open technique with a rate 18.18% compared to 0.78% (p = 0.002; Table 2). In
Please cite this article in press as: B. Erickson, et al., Surgical management of large talar osteochondral defects using autologous chondrocyte implantation, Foot Ankle Surg (2017), http://dx.doi.org/10.1016/j.fas.2017.01.002
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Table 2 Complications of MACI vs. PACI. Procedure
Number of studies
Number of subjects
Complications (%)
Impingement (%)
Graft breakdown (%)
Wound complications (%)
Painful hardware (%)
Non-union (%)
MACI PACI
9 2
194 22
6.70 4.55 OR 1.511
4.12 0.0 OR 2.052
4.12 0.0 OR 0.353
4.12 4.55 OR 0.114
1.03 0.0 OR 0.585
4.12 0.0 OR 0.356
1 2 3 4 5 6
p = 0.70. p = 0.63. p = 0.52. p = 0.12. p = 0.73. p = 0.52.
addition, the rate of impingement was noted to be significantly higher for the open technique of MACI with a rate of 10.61% as opposed to 0.78% for the arthroscopic technique (p = 0.01; Table 3). All other individual types of complications demonstrated no difference between open and arthroscopic MACI. 3.7. Prognostic indicators Many studies [11,12,14,17,18,21,26,27,29] discussed potential correlations with outcomes, however there was no consistent message. Age was the most discussed prognostic factor with three studies [11,17,18] demonstrating improved outcomes with younger patients; however, two studies [12,29] did not show any correlation with age. BMI, gender, and area of lesion were not found to influence outcome [11,12,29]. Battaglia et al. [12] demonstrated that only the depth of the lesion correlated with a negative outcome. The duration was of symptoms was found to be either a predictor of a negative outcome [11] or had no influence [26]. Radiographically, a high signal intensity and absence of edema on T2-weighted MRI images were found to correlate with worse clinical-functional outcomes [14]. 4. Modified Coleman Methodology Score The mean Modified Coleman Methodology Score is 42 3.85 (Table 4). A score of 100 indicates that the study largely avoids various biases, chance, and confounding factors. A score of 42 indicates that the overall quality of the studies is poor. 5. Discussion Osteochondral lesions of the talus primarily affect the medial and lateral edges of the talus, which are commonly associated with sporting activities and trauma [30,35,36]. Historically, lateral edge lesions have been related to a traumatic event in 93–98% of lesions while medial lesions are only accompanied with trauma in 61–67% of patients [1,37]. Non-operative management is available for the OLT; however, patients frequently require operative intervention.
Despite our limited understanding of the natural history of OLT, we have been able to achieve advances in the surgical options for treating the lesions. Microfracture has been a proven treatment for OLT measuring less than 1.5 cm2 while the optimal treatment for larger lesions measuring up to 2.5 cm2 has not been identified [5]. Interestingly, many patients had lesions less than 1.5 cm2 while only 34% of these cases had prior surgery. This may due to certain surgeons’ patient selection of those with lesions greater than 1.0 cm2. We performed a systematic review of the literature to compare measures of outcome between open or arthroscopic MACI and PACI including (1) AOFAS scores, (2) MOCART scores, (3) return to previous level of sport, (4) failure rates, (5) reoperation rates, and (6) complication rates. The present study has numerous limitations. As with any systematic review, the current review is limited by the lowest level of evidence of the studies included within the analysis [38]. Since the current review relies completely on the examination of level IV evidence, the reported findings will be plagued with the inherent bias of a case series. In the case of comparing open or arthroscopic MACI and PACI, no randomized clinical trials or prospective studies existed to provide more sound evidence. The limitation of retrospective studies raises the possibility of bias in the patient selection by creating stringent inclusion and exclusion criteria to only allow reporting of the patients with the best outcomes. By limiting the literature search to the English language, we have introduced the bias towards the inclusion of studies with statistically significant positive results [39]. Examination of bias within the subgroups of open and arthroscopic treatments present an issue of bias based on the funnel plot. Despite the bias among the subgroups, additional heterogeneity modeling demonstrates the data is relatively homogenous. Most studies have a significant number of patients who underwent a previous, concominant, or later procedure. Therefore it is difficult to isolate the true effect of the MACI or PACI procedures on the outcome measures. In general, all combinations of open vs. arthroscopic MACI and PACI demonstrated significant improvements between the preoperative and postoperative AOFAS scores. Based on the available literature several comparisons were used to evaluate the collective
Table 3 Complications of open vs. arthroscopic MACI. Technique
Number of studies
4 Open Arthroscopic 5
1 2 3 4 5 6
Number of subjects
Complications (%)
Impingement (%)
Graft breakdown (%)
Wound complications (%)
Painful hardware (%)
Non-union (%)
66 128
18.18 0.78 OR 28.221
10.61 0.78 OR 15.072
10.61 0.0 OR 5.893
10.61 0.0 OR 5.894
3.03 0.0 OR 9.965
10.61 0.0 OR 5.896
p = 0.002. p = 0.01. p = 0.28. p = 0.28. p = 0.14. p = 0.28.
Please cite this article in press as: B. Erickson, et al., Surgical management of large talar osteochondral defects using autologous chondrocyte implantation, Foot Ankle Surg (2017), http://dx.doi.org/10.1016/j.fas.2017.01.002
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B. Erickson et al. / Foot and Ankle Surgery xxx (2016) xxx–xxx Table 4 Modified Coleman Methodology Score. Author
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Total
Anders Apprich Aurich Battaglia Baums Caumo Dixon Giannini Giannini Giza Lee Magnan Quirbach Ronga Schneider Giannini Kwak Petersen Whittaker
9 9 9 3 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
3 3 3 3 3 0 0 3 0 3 3 3 3 0 3 3 3 0 0
3 6 0 0 0 6 3 3 0 0 3 3 0 0 3 0 3 3 0
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
8 8 8 8 8 6 8 8 6 6 6 8 8 8 8 8 8 4 8
3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3
0 2 0 0 2 0 0 0 0 0 0 0 0 0 0 0 0 0 0
3 3 3 3 3 3 3 3 3 6 3 3 3 3 3 6 3 3 3
6 3 6 6 6 3 6 6 6 6 6 6 3 6 6 6 6 6 6
3 3 3 3 3 3 3 3 6 6 3 3 3 3 3 3 3 3 3
2 2 2 2 2 2 2 0 2 2 2 2 2 2 2 2 2 2 2
4 2 2 0 4 2 4 0 4 2 0 2 0 4 4 4 4 4 2
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
44 44 39 31 43 37 41 38 39 43 38 42 34 38 44 44 44 37 36
data, which involved comparison of all MACI verses all PACI and open vs. arthroscopic MACI. When evaluating all MACI compared to all PACI, no significance was noted with relationship to any of the following: (1) number of excellent or good AOFAS outcomes, (2) post-operative AOFAS scores, (3) failure rates, (4) reoperation rates, or (5) complication rates regarding all complications, impingement, graft breakdown, wound complications, hardware irritation, or non-union. The only outcomes with statistically significant differences were between open MACI and arthroscopic MACI. Open MACI demonstrated superior results with regards to postoperative AOFAS scores, MOCART scores, reoperation rates. However, open MACI was associated with statistically higher rates of all complications and specifically, impingement, in comparison to arthroscopic MACI. Literature on the treatment of OLT has a growing body of published data; however, it remains to be limited by relatively small case series averaging less than 20 patients. Despite the current review demonstrating no significant difference between MACI and PACI, the studies included in the analysis possess significant limitations that constrain our conclusions. 6. Conclusion Currently the literature would suggest no procedure demonstrates superiority or inferiority between the combination of open or arthroscopic MACI and PACI in the management of OLT less than 2.5 cm2. Although under the comparison of open and arthroscopic MACI, we found both advantages favoring open MACI. However, the measured benefits of open MACI come at the cost of higher complication rates. Ultimately well-designed randomized trials are needed to address the limitation of the available literature and further our understanding of the optimal treatment option. Conflict of interest The authors declare that they have no conflict of interest. References [1] Flick AB, Gould N. Osteochondritis dissecans of the talus (transchondral fractures of the talus): review of the literature and new surgical approach for medial dome lesions. Foot Ankle 1985;5(January–February (4)):165–85. [2] Hannon CP, Smyth NA, Murawski CD, Savage-Elliott I, Deyer TW, Calder JD, et al. Osteochondral lesions of the talus: aspects of current management. Bone Joint J 2014;96-B(February (2)):164–71.
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Foot and Ankle Surgery xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Foot and Ankle Surgery journal homepage: www.elsevier.com/locate/fas
Surgical management of large talar osteochondral defects using autologous chondrocyte implantation Brandon Erickson, MDa , Yale Fillingham, MDa , Michael Hellman, MDa , Selene G. Parekh, MDb,c, Christopher E. Gross, MDd,* a
Rush University Medical Center, Chicago, IL 60622, United States Department of Orthopaedic Surgery, Duke University Medical Center, Durham, NC 27707, United States Duke Fuqua School of Business, Durham, NC 27707, United States d Medical University of South Carolina, Charleston, SC 29403, United States b c
A R T I C L E I N F O
A B S T R A C T
Article history: Received 26 October 2016 Received in revised form 11 December 2016 Accepted 5 January 2017 Available online xxx
Background: Talar osteochondral lesions (OLT) occur frequently in ankle sprains and fractures. We hypothesize that matrix-induced autologous chondrocyte implantation (MACI) will have a low reoperation rate and high patient satisfaction rate in treating OLT less than 2.5 cm2. Methods: A systematic review was registered with PROSPERO and performed with PRISMA guidelines using three publicly available free databases. Clinical outcome investigations reporting OLT outcomes with levels of evidence I–IV were eligible for inclusion. All study, subject, and surgical technique demographics were analyzed and compared. Statistics were calculated using Student’s t-tests, one-way ANOVA, chi-squared, and two-proportion Z-tests. Results: Nineteen articles met our inclusion criteria, which resulted in a total of 343 patients. Six studies pertained to arthroscopic MACI, 8 to open MACI, and 5 studies to open periosteal ACI (PACI). All studies were Level IV evidence. Due to study quality, imprecise and sparse data, and potential for reporting bias, the quality of evidence is low. In comparison of open and arthroscopic MACI, we found both advantages favoring open MACI. However, open MACI had higher complication rates. Conclusions: No procedure demonstrates superiority or inferiority between the combination of open or arthroscopic MACI and PACI in the management of OLT less than 2.5 cm2. Ultimately, well-designed randomized trials are needed to address the limitation of the available literature and further our understanding of the optimal treatment options. © 2017 European Foot and Ankle Society. Published by Elsevier Ltd. All rights reserved.
Keywords: Talus Osteochondral lesion Autologous chondrocyte implantation
1. Introduction Studies have shown that osteochondral lesion of the talus (OLT) are frequent occurrences when patients sustain both traumatic and atraumatic ankle injuries [1] with a report rate of up to 70% OLT in patients who sustain an ankle sprain or fracture [2]. When a patient is found to have an OLT, studies have shown the a medial OLT has a traumatic etiology 70% of the time, while lateral lesions have a traumatic etiology in 98% of cases [1]. These lesions are seldom treated non-operatively as results of non-operative treatment have shown a success rate of less than 50% [3]. Surgical treatment options for OLT can be broken down into reparative (marrow stimulation) and replacement (transplant of tissue) options, and are frequently dictated by characteristics of the
* Corresponding author. E-mail address: [email protected] (C.E. Gross).
lesion, including size and presence or absence of cysts [4,5]. Patient preference also plays an important role in treatment options, as some techniques can be done arthroscopically while other require a more extensive surgical approach. Reparative options include microfracture while replacement options include osteochondral autograft or allograft transplantation (OAT), autologous chondrocyte implantation (ACI), matrix induced autologous chondrocyte implantation (MACI), periosteal autologous chondrocyte implantation (PACI), and metallic implantation. In these techniques, a patient’s cartilage cells are cultured in the initial procedure. In PACI, a periosteal flap harvested from the patients distal tibia is sutured over the transplanted cells in a second stage procedure. In MACI, a chondrocyte-loaded scaffold is implanted. While microfracture has been classically used for defects less than 1.5 cm2, the optimal treatment for larger lesions has yet to be identified [5]. The purpose of this study was to perform a systematic review [6] of the literature to determine which surgical treatment option for OLT less than 2.5 cm2 excluding microfracture provided the
http://dx.doi.org/10.1016/j.fas.2017.01.002 1268-7731/© 2017 European Foot and Ankle Society. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: B. Erickson, et al., Surgical management of large talar osteochondral defects using autologous chondrocyte implantation, Foot Ankle Surg (2017), http://dx.doi.org/10.1016/j.fas.2017.01.002
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lowest complication rate, best clinic outcomes, and highest patients satisfaction rate. A secondary goal was to determine which treatment provided the best functional outcomes scores in patients for treatment of OLT. The authors’ hypothesis was that MACI would have the lowest complications rate and the highest patient satisfaction rate of the treatments examined.
and Finsen scores. Time to return to sport, patient satisfaction, complications, and reoperations were recorded. When applicable, radiographic follow up with plain radiographs or magnetic resonance imaging (MRI) was recorded. Study methodological quality was evaluated using the MCMS (Modified Coleman Methodology Score) [10].
2. Methods
2.1. Statistical analysis
A systematic review was conducted according to PRISMA guidelines (Preferred Reporting Items for Systematic reviews and Meta-Analyses) using a PRISMA checklist [7]. Systematic review registration was performed using the PROSPERO International prospective register of systematic reviews (registration number CRD42015016494) [8]. Two reviewers independently conducted the search on May 1, 2016 using the following databases: Medline, Cochrane Central Register of Controlled Trials, SportDiscus, and CINAHL. The electronic search citation algorithm utilized was: (talus OR talar) AND (osteochondral OR cartilage OR lesions) AND (chondrocyte OR autologous OR implantation OR chondrogenesis). English language Level I–IV evidence (2011 update by the Oxford Centre for Evidence-Based Medicine [9]) clinical studies were eligible. Medical conference abstracts were ineligible for inclusion. All references within included studies were cross-referenced for inclusion if missed by the initial search. If duplicate subject populations were encountered, the study with the longer followup was included. Level V evidence, reviews, letters to the editor, basic science, biomechanical studies, imaging, surgical technique, and classification studies were excluded. A total of 218 studies were located, and, after implementation of the inclusion criteria, 19 studies were included in the final analysis (Table 1). Study subjects of interest in this systematic review underwent either matrix induced autologous chondrocyte implantation (MACI) or periosteal autologous chondrocyte implantation (PACI) for treatment of osteochondral lesions of the talus less than 2.5 cm2. No minimum requirement was set for follow-up. Study and subject demographic parameters analyzed included year of publication, years of subject enrollment, level of evidence, number of subjects, gender, age, body mass index (BMI), diagnoses treated, lesion size, and surgical technique. Clinical outcome scores sought were the VAS (visual analog scale), AOFAS (American orthopaedic foot and ankle society) Hindfoot Score, Hanover, Lower Limb Outcome Assessment, AAOS (American Academy of Orthopaedic Surgeons), FFI (Foot Function Index), Mazur, Tegner,
Study data was aggregated based on each treatment method (open MACI, arthroscopic MACI, open PACI), and weighted outcomes and complication rates were calculated. A heterogeneity and publication bias analysis was performed on all included studies. Due to significant heterogeneity between studies, a random effects model was used for all statistical methods. An Inverse Variance statistical method was used to compare all continuous data outcomes, and was reported using means and standard mean differences. A Mantel–Haenzel statistical method was used to compare all dichotomous data outcomes and complications, and was reported using odds ratios and 95% confidence intervals. The reported p values refer to a one-sided (likelihood ratio) test for difference in outcomes and complication rates between each group. Probability values of <0.05 were considered significant. All statistical tests were performed using Review Manager (RevMan, Version 5.3; Copenhagen, Denmark: The Nordic Cochrane Centre, The Cochrane Collaboration; 2011). 3. Results A total of 219 articles were identified on the initial literature search. Among the initial studies, 196 of 219 were excluded in the primary screening leaving at total of 25 for review of the abstract or full article. After the 25 were reviewed for eligibility based on the inclusion and exclusion criteria, a total of 19 were included in the systematic review [11–29]. Four of the 25 studies represented an analysis of patients at earlier times points [30–33]. Of the 19 studies, none of the studies included randomized or prospective studies. All studies were retrospective case series published between 2003 and 2014. Within the 19 studies, the treatment options presented were 6 studies of arthroscopic MACI, 8 studies of open MACI, and 5 studies of open PACI. The average number of subjects in each study was 18 patients (range, 6–45) with mean ages between 24 and 42 years and mean follow-up between 12 and 119.5 months. Of the collective 343 study subjects, 117 subjects
Table 1 Demographics. Author
Year
# pts enrolled/time period
Mean age
ACI or MACI
Open (O)/arthroscopic (A)
Mean defect surface area (cm2)
Anders Apprich Aurich Battaglia Caumo Dixon Giannini Giannini Giza Lee Magnan Quirbach Ronga Schneider Baums Giannini Kwak Petersen Whittaker
2012 2012 2011 2011 2007 2011 2005 2014 2010 2011 2012 2009 2005 2009 2006 2009 2014 2003 2005
22 10 16 20 14 28 16 46 10 21 30 12 6 20 12 10 32 14 10
23.9 32.4 29.2 35 35.2 41 30.5 31.4 40.2 39 28.9 32.8 28.6 36 29.7 25.8 34 28 42
MACI MACI MACI MACI MACI MACI MACI MACI MACI MACI MACI MACI MACI MACI PACI PACI PACI PACI PACI
O O A A n/a O A A A O A O O O O O O O O
1.94 1.21 1.5 2.7 n/a 1.31 n/a 1.6 1.3 n/a 2.4 n/a 3.4 2.33 2.3 3.1 1.98 1.7 1.95
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(34%) had prior procedure and 56 subjects (16%) had a concomitant procedure at the time of MACI or PACI. Overall a high amount of bias was present among the subgroups within the studies. The location of 203 lesions were noted and included: 102 medial OLTs (50.2%), 38 lateral (18.7%), six central (3.0%), two medial/ lateral (1.0%), and one kissing lesion. The mean surface area of the defect treated with 1.96 cm2 (range: 1.21–3.4).
average MOCART score of 76.99 (SD 10.59) and arthroscopic MACI included a single study of ten subjects with an average MOCART score of 62.40 (SD 15.8). Comparison of open vs. arthroscopic techniques demonstrated a mean difference of 14.59 (SMD 1.2) and overall effect of Z = 2.73 (p = 0.006). Similar to post-operative AOFAS scores, open MACI was favored over arthroscopic MACI with statistically higher MOCART scores.
3.1. AOFAS scores
3.3. Return to level of sport
Nine studies were analyzed for differences between the preoperative and postoperative AOFAS scores. The studies included in the analysis were six studies of arthroscopic MACI, two studies of open MACI, and one study of open PACI. All nine MACI studies had a total of 130 subjects with an average AOFAS score improvement of 32.92 (SMD 2.49) and overall effect of Z = 5.2 (p < 0.0001). Arthroscopic MACI had 32 subjects with an average AOFAS score improvement of 27.58 (SMD 2.82) and overall effect of Z = 4.01 (p < 0.0001). Open MACI had 98 subjects with an average AOFAS score improvement of 34.48 (SMD 2.34) and overall effect of Z = 3.65 (p < 0.0003). Open PACI had 12 subjects with an average AOFAS score improvement of 44.90 (SMD 4.88) and overall effect of Z = 5.60 (p < 0.00001). Regardless of the treatment option all studies included in the analysis demonstrated a statistically significant improvement between pre-operative and post-operative AOFAS scores. Comparison of the percentage of subjects achieving an AOFAS score classification of “excellent” or “good” were compared between MACI vs. PACI as well as arthroscopic MACI vs. open MACI. The overall rate of excellent or good AOFAS outcomes among the eight studies included in the analysis was 79.55%. Among the six studies of MACI with 110 subjects and two studies of PACI with 22 subjects included in the analysis, 77.27% achieved excellent or good AOFAS scores with MACI while 90.91% had the same outcome with PACI. The calculated odds ratio (OR) was 0.34 (0.07, 1.56) with no statistical significance at p = 0.16. Arthroscopic MACI included four studies with 90 subjects and open MACI included one study with six subjects, which demonstrated 83.33% and 74.44% excellent or good AOFAS outcomes. The calculated OR was 1.72 (0.19, 15.47) with a non-statistically significant p-value of 0.63. In terms of percentage of patients achieving an excellent or good AOFAS outcome, no statistical significant was noted between MACI vs. PACI and open vs. arthroscopic MACI. Of the studies, nine studies with 236 subjects were included in the analysis of post-operative AOFAS scores. Among the MACI studies, eight studies including 170 subjects had an average postoperative AOFAS score of 87.29 (SD 12.90) while one study of 12 subjects were included for PACI with an average score of 88.40 (SD 11.1). Analysis comparing MACI vs. PACI demonstrated a mean difference of 1.11 (SMD 0.09) with an overall effect of Z = 0.33 (p = 0.74). Comparison of open vs. arthroscopic MACI respectively included two studies of 32 subjections and one study of 12 subjects. The results demonstrated a mean difference of 5.37 (SMD 0.40) with an overall effect of Z = 3.12 (p = 0.002). Evaluation of postoperative AOFAS scores demonstrate no statistical difference between all MACI and PACI, but open MACI has a greater postoperative AOFAS score compared to arthroscopic MACI.
Four case series have been published on the return to previous level of sport with two studies and 42 subjects on arthroscopic MACI and two studies and 29 subjects on open PACI. Comparison of arthroscopic MACI and open PACI demonstrated respective rates of return to previous level of sport at 66.20% and 55.17%. The calculated OR was 2.29 (0.84, 6.25) with no statistical significance at a p-value of 0.11.
3.2. MOCART (magnetic resonance observation of cartilage repair tissue) scores The MOCART score evaluates the subchondral bone following cartilage repair techniques. It is often compared with clinical outcome [34]. Only three studies published MOCART scores, which limited the comparison between only open vs. arthroscopic MACI. Overall, open MACI included two studies of 32 subjects with an
3.4. Failure rate A comparison of failure rates was performed between MACI vs. PACI and open vs. arthroscopic MACI. Overall among the 14 studies and 281 subjects included in the analysis, the collective failure rate was 3.91%. Among the 11 studies of MACI with 223 subjects and three studies of PACI with 58 subjects included in the analysis, the failure rates were respectively 3.59% and 5.17%. The calculated OR was 0.68 (0.68, 2.66) with no statistical significance at p = 0.58. Arthroscopic MACI included five studies with 122 subjects and open MACI included five studies with 87 subjects, which demonstrated 5.75% and 2.46% rates of failure. The calculated OR was 2.42 (0.56, 10.40) with a non-statistically significant pvalue of 0.24. In terms of percentage of patients experiencing failures, no statistical significant was noted between MACI vs. PACI and open vs. arthroscopic MACI. 3.5. Reoperation rate Analysis of reoperation rates was performed between MACI vs. PACI and open vs. arthroscopic MACI. Of the reviewed studies, 14 studies and 241 subjects included in the analysis, the collective reoperation rate was 21.99%. Among the ten studies of MACI with 172 subjects and four studies of PACI with 69 subjects included in the analysis, the reoperation rates were respectively 23.26% and 18.84%. The calculated OR was 1.31 (0.65, 2.63) with no statistical significance at p = 0.40. Open MACI included four studies with 66 subjects and arthroscopic MACI included five studies with 92 subjects, which demonstrated 16.67% and 31.52% rates of reoperation. The calculated OR was 0.43 (0.20, 0.95) with a statistically significant p-value of 0.04. In terms of percentage of patients experiencing reoperation, no statistical significant was noted between MACI vs. PACI, but open MACI had a significantly lower rate of reoperation compared to arthroscopic MACI. 3.6. Complication rate The rate of complication was examined in regards to all complications, impingement, graft breakdown, wound complications, painful hardware, and non-union. Overall 12 studies with 230 subjects were included in the final analysis with a baseline complication rate of 6.09%. When the complication rates were compared between MACI and PACI, no statistical significant was noted among all complications and individual types of complications (Table 2). Comparison of the associated complications between open and arthroscopic MACI demonstrated a statistically significant increase in overall complications for the open technique with a rate 18.18% compared to 0.78% (p = 0.002; Table 2). In
Please cite this article in press as: B. Erickson, et al., Surgical management of large talar osteochondral defects using autologous chondrocyte implantation, Foot Ankle Surg (2017), http://dx.doi.org/10.1016/j.fas.2017.01.002
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Table 2 Complications of MACI vs. PACI. Procedure
Number of studies
Number of subjects
Complications (%)
Impingement (%)
Graft breakdown (%)
Wound complications (%)
Painful hardware (%)
Non-union (%)
MACI PACI
9 2
194 22
6.70 4.55 OR 1.511
4.12 0.0 OR 2.052
4.12 0.0 OR 0.353
4.12 4.55 OR 0.114
1.03 0.0 OR 0.585
4.12 0.0 OR 0.356
1 2 3 4 5 6
p = 0.70. p = 0.63. p = 0.52. p = 0.12. p = 0.73. p = 0.52.
addition, the rate of impingement was noted to be significantly higher for the open technique of MACI with a rate of 10.61% as opposed to 0.78% for the arthroscopic technique (p = 0.01; Table 3). All other individual types of complications demonstrated no difference between open and arthroscopic MACI. 3.7. Prognostic indicators Many studies [11,12,14,17,18,21,26,27,29] discussed potential correlations with outcomes, however there was no consistent message. Age was the most discussed prognostic factor with three studies [11,17,18] demonstrating improved outcomes with younger patients; however, two studies [12,29] did not show any correlation with age. BMI, gender, and area of lesion were not found to influence outcome [11,12,29]. Battaglia et al. [12] demonstrated that only the depth of the lesion correlated with a negative outcome. The duration was of symptoms was found to be either a predictor of a negative outcome [11] or had no influence [26]. Radiographically, a high signal intensity and absence of edema on T2-weighted MRI images were found to correlate with worse clinical-functional outcomes [14]. 4. Modified Coleman Methodology Score The mean Modified Coleman Methodology Score is 42 3.85 (Table 4). A score of 100 indicates that the study largely avoids various biases, chance, and confounding factors. A score of 42 indicates that the overall quality of the studies is poor. 5. Discussion Osteochondral lesions of the talus primarily affect the medial and lateral edges of the talus, which are commonly associated with sporting activities and trauma [30,35,36]. Historically, lateral edge lesions have been related to a traumatic event in 93–98% of lesions while medial lesions are only accompanied with trauma in 61–67% of patients [1,37]. Non-operative management is available for the OLT; however, patients frequently require operative intervention.
Despite our limited understanding of the natural history of OLT, we have been able to achieve advances in the surgical options for treating the lesions. Microfracture has been a proven treatment for OLT measuring less than 1.5 cm2 while the optimal treatment for larger lesions measuring up to 2.5 cm2 has not been identified [5]. Interestingly, many patients had lesions less than 1.5 cm2 while only 34% of these cases had prior surgery. This may due to certain surgeons’ patient selection of those with lesions greater than 1.0 cm2. We performed a systematic review of the literature to compare measures of outcome between open or arthroscopic MACI and PACI including (1) AOFAS scores, (2) MOCART scores, (3) return to previous level of sport, (4) failure rates, (5) reoperation rates, and (6) complication rates. The present study has numerous limitations. As with any systematic review, the current review is limited by the lowest level of evidence of the studies included within the analysis [38]. Since the current review relies completely on the examination of level IV evidence, the reported findings will be plagued with the inherent bias of a case series. In the case of comparing open or arthroscopic MACI and PACI, no randomized clinical trials or prospective studies existed to provide more sound evidence. The limitation of retrospective studies raises the possibility of bias in the patient selection by creating stringent inclusion and exclusion criteria to only allow reporting of the patients with the best outcomes. By limiting the literature search to the English language, we have introduced the bias towards the inclusion of studies with statistically significant positive results [39]. Examination of bias within the subgroups of open and arthroscopic treatments present an issue of bias based on the funnel plot. Despite the bias among the subgroups, additional heterogeneity modeling demonstrates the data is relatively homogenous. Most studies have a significant number of patients who underwent a previous, concominant, or later procedure. Therefore it is difficult to isolate the true effect of the MACI or PACI procedures on the outcome measures. In general, all combinations of open vs. arthroscopic MACI and PACI demonstrated significant improvements between the preoperative and postoperative AOFAS scores. Based on the available literature several comparisons were used to evaluate the collective
Table 3 Complications of open vs. arthroscopic MACI. Technique
Number of studies
4 Open Arthroscopic 5
1 2 3 4 5 6
Number of subjects
Complications (%)
Impingement (%)
Graft breakdown (%)
Wound complications (%)
Painful hardware (%)
Non-union (%)
66 128
18.18 0.78 OR 28.221
10.61 0.78 OR 15.072
10.61 0.0 OR 5.893
10.61 0.0 OR 5.894
3.03 0.0 OR 9.965
10.61 0.0 OR 5.896
p = 0.002. p = 0.01. p = 0.28. p = 0.28. p = 0.14. p = 0.28.
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B. Erickson et al. / Foot and Ankle Surgery xxx (2016) xxx–xxx Table 4 Modified Coleman Methodology Score. Author
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Total
Anders Apprich Aurich Battaglia Baums Caumo Dixon Giannini Giannini Giza Lee Magnan Quirbach Ronga Schneider Giannini Kwak Petersen Whittaker
9 9 9 3 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
3 3 3 3 3 0 0 3 0 3 3 3 3 0 3 3 3 0 0
3 6 0 0 0 6 3 3 0 0 3 3 0 0 3 0 3 3 0
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
8 8 8 8 8 6 8 8 6 6 6 8 8 8 8 8 8 4 8
3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3
0 2 0 0 2 0 0 0 0 0 0 0 0 0 0 0 0 0 0
3 3 3 3 3 3 3 3 3 6 3 3 3 3 3 6 3 3 3
6 3 6 6 6 3 6 6 6 6 6 6 3 6 6 6 6 6 6
3 3 3 3 3 3 3 3 6 6 3 3 3 3 3 3 3 3 3
2 2 2 2 2 2 2 0 2 2 2 2 2 2 2 2 2 2 2
4 2 2 0 4 2 4 0 4 2 0 2 0 4 4 4 4 4 2
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
44 44 39 31 43 37 41 38 39 43 38 42 34 38 44 44 44 37 36
data, which involved comparison of all MACI verses all PACI and open vs. arthroscopic MACI. When evaluating all MACI compared to all PACI, no significance was noted with relationship to any of the following: (1) number of excellent or good AOFAS outcomes, (2) post-operative AOFAS scores, (3) failure rates, (4) reoperation rates, or (5) complication rates regarding all complications, impingement, graft breakdown, wound complications, hardware irritation, or non-union. The only outcomes with statistically significant differences were between open MACI and arthroscopic MACI. Open MACI demonstrated superior results with regards to postoperative AOFAS scores, MOCART scores, reoperation rates. However, open MACI was associated with statistically higher rates of all complications and specifically, impingement, in comparison to arthroscopic MACI. Literature on the treatment of OLT has a growing body of published data; however, it remains to be limited by relatively small case series averaging less than 20 patients. Despite the current review demonstrating no significant difference between MACI and PACI, the studies included in the analysis possess significant limitations that constrain our conclusions. 6. Conclusion Currently the literature would suggest no procedure demonstrates superiority or inferiority between the combination of open or arthroscopic MACI and PACI in the management of OLT less than 2.5 cm2. Although under the comparison of open and arthroscopic MACI, we found both advantages favoring open MACI. However, the measured benefits of open MACI come at the cost of higher complication rates. Ultimately well-designed randomized trials are needed to address the limitation of the available literature and further our understanding of the optimal treatment option. Conflict of interest The authors declare that they have no conflict of interest. References [1] Flick AB, Gould N. Osteochondritis dissecans of the talus (transchondral fractures of the talus): review of the literature and new surgical approach for medial dome lesions. Foot Ankle 1985;5(January–February (4)):165–85. [2] Hannon CP, Smyth NA, Murawski CD, Savage-Elliott I, Deyer TW, Calder JD, et al. Osteochondral lesions of the talus: aspects of current management. Bone Joint J 2014;96-B(February (2)):164–71.
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