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The Treatment of Adult Osteochondritis Dissecans with Autologous Cartilage Implantation: A Systematic Review
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Davidson A. Sacolick, BS James C. Kirven, BS Moneer M. Abouljoud, BS Joshua S. Everhart, MD, MPH David C. Flanigan, MD
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David C. Flanigan, MD, Department of Orthopaedic Surgery, Jameson Crane Sports Medicine Institute, The Ohio State University Wexner Medical Center, 2835 Fred Taylor Dr, Columbus, OH 43202
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Original Article
1
The Treatment of Adult Osteochondritis Dissecans with Autologous Cartilage Implantation: A Systematic Review Davidson A. SacolickQ2, BS1 James C. Kirven, BS1 Moneer M. Abouljoud, BS1 Joshua S. Everhart, MD, MPH1 David C. Flanigan, MD1
Q2
1 Department of Orthopaedic Surgery, Jameson Crane Sports
Q3
Medicine Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio
Address for correspondence Q3David C. Flanigan, MD, Department of Orthopaedic Surgery, Jameson Crane Sports Medicine Institute, The Ohio State University Wexner Medical Center, 2835 Fred Taylor Dr, Columbus, OH 43202 (e-mail: David.fl
[email protected]).
J Knee Surg 2018;00:1–9.
Abstract
Keywords
► autologous chondrocyte implantation ► osteochondritis dissecans ► microfracture ► matrix-induced autologous chondrocyte implantation
We sought to evaluate the effectiveness of autologous chondrocyte implantation (ACI) for the treatment of adult osteochondritis dissecans (OCD) lesions according to patient-reported outcomes, complication rates, and failure rates. A search of MEDLINE, Scopus, and Cochrane Library was performed to identify clinical studies (levels I–IV) reporting outcomes after ACI treatment for OCD in adult knees. Our inclusion criteria included the following: (1) published between January 2000 and April 2017, (2) stable and unstable OCD lesions of the knee, (3) use of ACI in at least one group, (4) subjects 18 years old or skeletally mature, (5) inclusion of at least one patient-reported clinical outcome measure, and (6) written in English. A total of nine studies (179 patients), mean age of 27.6 years (range: 18–49 years), were included. There were 227 OCD lesions with an average size of 4.1 cm2 (range: 1.2–9.4 cm2). The average follow-up was 61.3 months (range: 6.5–120 months). In general, there was significant improvement in symptoms, but better results occurred among active male patients with smaller lesions as well as younger patients. Statistically significant improvement in patientreported outcomes was reported in all studies. There were 23 complications reported (15.6%), including 12 failures (8.2%). Significant improvement in clinical outcome measures demonstrates clinical efficacy of autologous cartilage therapies for the treatment of OCD in adult patients. Better outcomes are often observed with males, active patients, smaller lesion sizes, and younger age at the time of surgery.
Osteochondritis dissecans (OCD) is a focal, idiopathic disruption of the subchondral bone. OCD is rare, affecting between 18 and 28 patients per 100,000, with an increased risk for men and individuals between 10 and 20 years of age,1 particularly during periods of rapid growth.2 In cases of familial OCD, it is proposed that this condition may represent a type of chondrocyte dysplasia. The most common site of an OCD lesion is the lateral aspect of the medial femoral condyle. The exact pathophysiology is unknown. It has been theorized that OCD is caused by an ischemic event to the subchondral bone with resulting avascular necrosis,3 though histopathological analysis of excised specimens has not shown evidence of avascular
necrosis.4 Ribbing has suggested that juvenile OCD lesions may represent a secondary ossification center that later sustains a vascular or mechanical insult,5 but the most widely accepted theory is that OCD is due to occult or repetitive microtrauma.6 This theorized process of disease correlates well with the association of OCD and athletics, as multiple studies have shown up to 60% of patients with OCD report involvement in sporting activities.1,7,8 Full-thickness cartilage defects are both painful and a significant risk factor for the future development of osteoarthritis (OA).9 In skeletally mature patients, OCD lesions at the time of presentation tend to be higher-grade OCD, and their
received May 8, 2018 accepted after revision September 29, 2018
Copyright © 2018 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
DOI https://doi.org/ 10.1055/s-0038-1675568. ISSN 1538-8506.
2
Autologous Cartilage Implantation
Sacolick et alQ1.
long-term outcomes are often worse than in skeletally immature patients. It is thought that the healing potential of adult lesions is inferior as compared with juvenile OCD.10–12 Cahill reported that in an athletic population, approximately half of skeletally immature patients with OCD of the knee go on to heal using conservative management.13 In contrast, retrospective studies have shown that adult OCD (AOCD) patients follow a degenerative course in up to 50% of cases with a 30year follow-up.11,14 Therefore, for OCD lesions in adults that are either unstable or displaced, surgery is frequently recommended at the time of presentation.7,13,15–19 Autologous chondrocyte implantation (ACI) was first described by Brittberg et al in 199420 and has demonstrated good clinical results with improved durability as compared with alternatives such as microfracture.21 ACI is a two-stage surgical procedure, in which cartilage is first harvested from a nonweight-bearing portion of the joint and then the live chondrocytes are isolated and cultured in a controlled laboratory environment. The second stage involves placement of these chondrocytes over the articular defect. Use of ACI leads to the formation of fibrocartilage at the site of repair, which is advantageous when compared with bone marrow stimulating techniques such as abrasion, drilling, and microfracture, which create fibrocartilage primarily.22 Additionally, ACI leads to the regeneration of autologous tissue, which produces better histological results, particularly for larger osteochondral defects.23 Matrix-induced ACI (MACI) is a similar process to ACI in that chondrocytes are harvested from a nonweight-bearing surface. These are then cultured and embedded in a matrix or scaffold to be implanted in the second stage of the procedure. The use of ACI or MACI is a unique application for the treatment of AOCD lesions, as the depth of the lesion can be variable. Bone grafting of deep lesions (>6 mm) may be necessary, employing a “sandwich” technique for treatment; one layer of periosteum/membrane is used to cover the bone graft, and the other layer of periosteum/membrane is used for the chondrocyte delivery. Currently, there is no clear consensus on the effectiveness of ACI or MACI for this indication, and early studies often focused on short-term radiographic or histological outcomes without long-term follow-up.24 The purpose of this study is to evaluate the effectiveness of ACI for the treatment of AOCD lesions according to patientreported outcomes, complication rates, and failure rates.
cross-referenced for potentially relevant studies that may have been missed from the original search. The review was verified by three independent evaluators. Our inclusion criteria included the following: (1) published between January 2000 and April 2017, (2) stable and unstable OCD lesions of the human knee, (3) use of ACI in at least one study group, (4) subjects 18 years old or skeletally mature, (5) inclusion of at least one patient-reported clinical outcome measure, and (6) written in English. There was no specified follow-up time required for study inclusion. Exclusion criteria included (1) nonclinical studies, (2) nonhuman studies, (3) review papers, and (4) studies without OCD stratified data. If a study included treatment of both adult and juvenile OCD, it was included and the outcomes were analyzed and reported separately for each age groupQ4. A similar method was used to determine if studies that compared ACI to other treatment modalities would be included. The distinction between adult and juvenile OCD is based on Cahill’s definitions of OCD and physeal status.13 Additionally, in our definition of adult, we included patients older than 18 years based on the known gender-based typical age for physeal closure: 14 to 16 for females and 16 to 18 for males.26 Because OCD is an uncommon pathology, and ACI is a relatively new treatment modality, many studies investigated the use of ACI for osteochondral defects in general. In these cases, it was essential that authors reported outcomes for OCD patients separately for inclusion in this review. For the purpose of this study, OCD lesion severity was defined according to the International Cartilage Repair Society (ICRS) scale. This scale relies on the evaluation of OCD lesions arthroscopically. Type I and II lesions are both stable, with the differentiating feature being that type II lesions possess partial articular cartilage discontinuity. A type III lesion, as classified by the ICRS OCD scale, is the one with complete cartilage discontinuity but without dislocation. Type IV lesions are either empty defects or those with a dislocated or a loose fragment within the defect bed.27 The initial application of the search criteria yielded 609 studies (►Fig. 1). After the removal of duplicate studies and those that did not meet inclusion and exclusion criteria, 30 remained for full-text review. Of these, only nine met full criteria for inclusion in this review. Three independent reviewers performed the search, which individually yielded the same nine articles for inclusion.
Quality Assessment
Methods A systematic review was conducted of multiple online databases, including MEDLINE, Scopus, and Cochrane. The search was performed on April 24, 2017, for clinical studies (levels I–IV) that reported outcomes after ACI treatment for OCD in the adult knee (age 18 or skeletally mature). PRISMA (Preferred Reporting Items for Systematic Reviews and MetaAnalyses) guidelines were followed in the preparation of this systematic review.25 Search terms included “osteochondritis dissecans,” “adult,” “knee,” and “surgery.” Abstracts were initially reviewed followed by a review of the entire manuscript of potentially relevant studies. Each bibliography was The Journal of Knee Surgery
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All included studies were evaluated with the Methodological Index for Non-Randomized Studies (MINORS).28 The MINORS scale is a widely accepted and validated assessment tool for nonrandomized clinical outcome studies.28 The MINORS quality assessment was performed independently by two reviewers, and interrater reliability for the MINORS score was assessed by the intraclass correlation coefficient (ICC).
Statistical Analysis For descriptive purposes, summary data for pre- and postoperative patient-reported outcome scores are reported as the average between studies with weighting according to sample
Q4
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3Q1
Fig. 1 Flow chart of study selection process. An initial search revealed 609 hits. After review of the identified studies, nine met all criteria for inclusion in this review.
size. Summary estimates of failure and complication rates were based on raw counts and excluded patients from studies that did not explicitly report complications (or a lack of complications). However, due to intrinsic differences in study design and length of follow-up, we did not provide a pooled measure of effect size or perform a formal meta-analysis. All statements regarding statistical significance refer to results reported within individual studies included this review.
Results Nine studies fulfilled all inclusion and exclusion criteria (►Table 1).29–37 Two studies reported outcomes of both juvenile and adult patients,30,31 and one study compared ACI to other treatment modalities.35 All data incorporated into this review for adult patients treated with ACI were reported separately in these studies. Selected patient and
Table 1 Included studies (n ¼ 9) Author
Year
Country
Follow-up
AOCD patients
Male: female
Average age
Procedure
Surgical technique
MINORS score
Cherubino et al
2003
Italy
6.5 mo
6
4:2
26
MACI
Graft from superomedial trochlea Culture for 3–4 wk and seeded on type I–III collagen bilayer membrane
10.5
Peterson et al
2003
Sweden
5.6 y
23
30:28
26.4
ACI-P
Graft from the upper minor loadbearing area of the medial femoral condyle of the injured knee Sandwich technique for deep lesions
9.5
Krishnan et al
2006
England
4.08 y
9
23:14
40
ACI-C
Graft from articular cartilage from the margin of the trochlea
15.5
Tohyama et al
2009
Japan
24 mo
3
Not reported
>20
Atelocollagenassociated ACI
The tissue-engineered cartilage was implanted 28 d after harvest of the cartilage
10
Ochs et al
2011
Germany
39.8 mo
26
18:8
29.2
MACI þ bone graft
Graft of full-thickness cartilage sample from the edge of the patellofemoral groove 3-dimensional collagen scaffold seeded with autologous chondrocytes Iliac crest bone graft
15.5
Cole et al
2012
United States
4y
40
30:10
30.5
ACI-P
First-generation ACI procedure
12
Kon et al
2012
United States
5.2 y
28
20:8
19.8
Secondgeneration ACI þ bone graft
Healthy cartilage was harvested from the ipsilateral knee Cancellous tibial graft used to fill the osseous defect of the osteochondral lesion was impacted arthroscopically
14
Martinčič et al
2013
Slovenia
10 y
12
Not reported
24.6
ACI-P
First-generation ACI procedure
11.5
Filardo et al
2014
Italy
7y
32
Not specified
29.2
MACI þ bone graft
Autologous chondrocytes seeded onto scaffold Tibial bone graft
12
Abbreviations: ACI, autologous chondrocyte implantation; ACI-C, autologous chondrocyte implantation with collagen cover; ACI-P, autologous chondrocyte implantation with periosteum cover; AOCD, adult osteochondritis dissecans; MACI, matrix-induced autologous chondrocyte implantation; MINORS, Methodological Index for Non-Randomized Studies. a ACI-P: ACI as originally described by Brittberg et al in 1994. The chondrocyte suspension is secured within the defect using a periosteum cover. b ACI-C: ACI with chondrocytes in suspension and secured with a collagen allograft cover. cMACI: autologous chondrocytes seeded directly onto a porcine collagen membrane which is then secured to the lesion with fibrin glue.Q5 The Journal of Knee Surgery
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Table 2 Selected patient characteristics
Q1 Table 3 Combined clinical outcomes
n
n
Number of subjects
179
Subjective outcomes at final follow-up
Male
70.2%
Excellent or good
Female
29.8%
Patient-reported clinical outcome measures
Mean age (range)
27.6 y (18–49 y)
Mean preoperative duration of symptoms
8.3 y (two series reported)
BMI
27.6
Mean follow-up (range)
61.3 mo (6.5–120 mo)
Number of lesions (average per knee)
227 (1.27 per knee)
Medial femoral condyle
98 (74%)
Lateral femoral condyle
31 (23%)
Trochlea
3 (2%)
Mean lesion size (range)
4.1 cm2 (1.2–9.4 cm2)
Prior surgeries
61
Loose body removal
23
Drilling
2
Marrow stimulation
1
Meniscectomy
35
CPM used postoperatively
6 (2.8%)
Abbreviations: BMI, body mass index; CPM, continuous passive motion.
lesion characteristics, including lesion size and follow-up, are described in ►Table 2. The average MINORS methodology score for noncomparative studies was 10.5 (standard deviation [SD]: 0.8) and for comparative studies was 15.3 (SD: 0.9). Agreement between raters for MINORS scores was excellent (ICC ¼ 0.85).
Patient-Reported Outcomes Patients were evaluated with several outcome measures including International Knee Documentation Committee Form (62%), Lysholm Knee Questionnaire (33%), EuroQol Visual Analog Scale (44%), Cincinnati Rating System (11%), and Tegner Activity Scale (48%). Statistically significant improvement in patient-reported outcomes was reported in all nine studies (►Table 3).
Autologous Chondrocyte Implantation with Periosteal Cover Three studies reported outcomes of AOCD patients treated with first-generation ACI, which uses a periosteal cover to secure the liquid chondrocyte media.30,34,36 Peterson et al30 employed the sandwich technique for lesions deeper than 8 to 10 mm. They reported good or excellent subjective outcomes in 91% of patients using the Brittberg clinical rating, as well as significant improvement in the Cincinnati rating and Lysholm score. Imaging evaluation also showed promising results, as 13 of 15 patients with magnetic resonance imaging (MRI) at 3.5 years had findings at the area of repair The Journal of Knee Surgery
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85%
IKDC Preoperative IKDC
45.1
Final follow-up IKDC
82.7
Lysholm score Preoperative Lysholm
49.9
Final follow-up Lysholm
89.2
EQ-VAS Preoperative EQ-VAS
51.7
Final follow-up EQ-VAS
83.5
Cincinnati Preoperative Cincinnati
39.6
Final follow-up Cincinnati
80.4
Tegner Activity Scale Preoperative Tegner
3.47
Final follow-up Tegner
6.44
Abbreviations: EQ-VAS, EuroQol visual analog scale; IKDC, International Knee Documentation Committee.
similar to the surrounding normal cartilage. Despite these positive findings, this long-term study found evidence of progression of OA, including osteophytes (56% of patients), joint space narrowing (30%), sclerotic changes (44%), and cyst formation (11%). It was also noted that good results at 2 years were maintained through follow-up in 98% of patients. This study included both adult and juvenile patients. Cole et al34 reported outcomes of AOCD patients who have failed a prior procedure, including debridement, microfracture, and subchondral drilling. The authors noted statistically significant subjective patient improvement from baseline to follow-up at 48 months. However, 35% of patients required a subsequent surgical procedure, and there was an overall failure rate of 15%. Martinčič et al36 followed patients treated with ACI for 10 years, including OCD patients as well as those with other focal chondral lesions. They noted that OCD patients reported the best outcomes as compared with other groups and that all OCD patients had normal or nearly normal exams at final follow-up.
Autologous Chondrocyte Implantation with Collagen Cover One study investigated the use of ACI with a collagen membrane cover rather than a periosteal cover used to secure the liquid chondrocyte media.31 Krishnan et al31 investigated the use of a porcine type I/III collagen membrane. They reported that 44.4% of AOCD patients had excellent or good results. This
Autologous Cartilage Implantation study also compared adult patients to juvenile patients and found patient age to be a more significant predictor for patient outcomes than the state of the physis. This study noted lesions >6 cm2 to be associated with worse outcomes for adults, but lesion size was not a significant factor for juvenile patients. Overall, Krishnan et al reported that 82.1% of juvenile OCD patients had excellent or good outcomes, whereas only 44.4% of AOCD patients had excellent or good outcomes.
Matrix-Induced Autologous Chondrocyte Implantation and ACI with a Collagen Gel Three studies reported clinical outcomes following MACI treatment for AOCD.29,33,37 In this technique, the chondrocytes are seeded directly onto the collagen membrane scaffold that is then implanted. Cherubino et al29 had the shortest follow-up (mean: 6.5 months) and reported no complications. All patients had either abnormal or severely abnormal knees according to preoperative ICRS evaluation. At final followup, they reported that 66.6% of patients achieved normal knees and 33.3% had nearly normal knees. There was also functional improvement noted with the Tegner Activity Scale and Lysholm Score (►Table 2). This study also included an MRI evaluation of participants at 6 and 12 months. There was evidence of fibrocartilage in the defect sites with restoration of the articular surface in all knees studied. Tohyama et al32 report an ACI technique that involved an atelocollagen gel as a scaffold for the cultured chondrocytes. This group noted an increase in Lysholm score of 37.3 11.9 points for AOCD patients following treatment. They found no difference in OCD patients when compared with traumatic and osteoarthritic lesions.
ACI and MACI with Bone Grafting Three studies specifically described techniques that included both bone grafting and the use of autologous chondrocytes. Kon et al described a technique that involved second-generation ACI (ACI with chondrocytes in suspension and sealed with a collagen membrane cover) with bone grafting.38 This technique used cancellous tibial bone grafts to fill the osseous defect of the osteochondral lesion. The authors reported significant subjective improvement with this treatment. Although not found to be statistically significant, there was a trend toward better results with ACI when compared with a bone marrow stimulating technique. Ochs et al33 described a technique that used monocortical cancellous cylinder harvest from the iliac crest to fill the osseous defect. They reported significant subjective improvement and noted that all patients who participated in sport before treatment were able to return to their previous level of activity. Subgroup analysis of body mass index, age at surgery (>30 or 6 cm2
Osteochondral allograft
Single surgery Bone-to-bone healing promotes faster recovery
Expensive Surgery timing dictated by graft availability
ACI
Regeneration of cartilage Arthroscopic procedure Less donor-site morbidity
Two surgeries Expensive
Abbreviations: ACI, autologous chondrocyte implantation; OCD, osteochondritis dissecans.
This is a relatively simple procedure with good short-term results; however, the long-term outcomes tend to be worse.19 Microfracture is a form of marrow stimulation that leads to the formation of fibrocartilage. Microfracture of OCD lesions has high long-term failure rates, even in juvenile patients, when compared with osteochondral autografting.46 Finally, osteochondral grafts are an attractive option for either primary or salvage treatment of AOCD lesions. The rates of osseous consolidation and cartilage survival for allograft or autograft are excellent,35 and bone-to-bone healing promotes faster recovery than procedures relying on graft maturation with proliferation of chondrocytes over time. However, osteochondral autografts are limited by lesion size and location; the donor and recipient size must have a similar surface contour, and larger grafts (particularly over 6 cm2) have worse outcomes as well as increased donor-site morbidity.35 Osteochondral allografts can be used on large defects but are expensive; additionally, surgical scheduling is dictated by the availability of an appropriately size-matched donor allograft.35,47 Though ACI for the treatment of AOCD lesions results in acceptable short- and midterm outcomes and does not have associated donor-site morbidity as is seen with osteochondral autograft, it does have disadvantages. The biggest disadvantage to ACI is that it requires two separate surgeries and potentially has a more significant financial burden for patients. According to Samuelson and Brown, in a study of ACI (regardless of indication), the estimated costs in U.S. dollars of ACI with periosteum cover (ACI-P) was $66,752 and for ACI with collagen cover (ACI-C) was $66,939.50 (including surgery costs, imaging, physical therapy and durable medical equipment).48 Though there are high upfront costs, ACI is considered cost-effective over time, with an estimated cost per quality-adjusted life year of US$9,466 for ACI-P and US$9,243 for ACI-C.48 The cost-efficacy of ACI for the treatment of OCD lesions is potentially better than ACI for chondral lesions due to improved symptom relief and long-
term outcomes; Martinčič et al had the longest follow-up of the included studies (10 years) and found ACI to produce superior results for OCD as compared with focal chondral lesions.36 More generally, they found that patients with OCD had a lower rate of OA at final follow-up compared with patients with traumatic lesions. The authors suggested this to be due to the relatively younger age of their OCD cohort as well as the biomechanical advantage of having intact ligaments and menisci as compared with the trauma patients studied. Finally, there is a potential risk of failure, complication, or need for reoperation following ACI. In this review, 15.7% had a complication (including failures, 8.2%) and 20.5% had an unplanned reoperation. These are comparable to the rates of failure (1.5– 7.7%) or unplanned reoperation (1.4–27%) following ACI for any indication in a systematic review by Harris et al.39
Limitations There are limitations to this systematic review. The studies analyzed were not randomized comparisons of surgical techniques. Similar to other available cartilage restoration studies, this review lacks a natural history control model for comparison to determine the true efficacy of autologous cartilage implantation. The studies analyzed were level IV evidence case series, and therefore carried the inherent limitations and biases associated with this type of study. There was also variability between included studies with regard to mean patient age, previous treatments, lesion stability, defect characteristics, length of nonoperative treatment, classification systems used (arthroscopic, clinical, and radiographic), specific surgical technique, clinical outcome scoring systems, and length of follow-up. These sources of selection, performance, and detection bias influence the conclusions of this review. However, this review is powerful in that it analyzed more than 200 lesions with up to 10 years follow-up. The Journal of Knee Surgery
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Q1 15 Hughston JC, Hergenroeder PT, Courtenay BG. Osteochondritis
Significant improvement in clinical outcome measures demonstrates the clinical efficacy of autologous cartilage therapies for the treatment of OCD in adult patients. Better outcomes are often observed with males, active patients, smaller lesion sizes, and younger age at the time of surgery.
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Ethical Review Statement This systematic review did not require approval by the Biomedical Institutional Review Board of The Ohio State University. Note David Flanigan is a consultant for Smith & Nephew, DePuy Mitek, and Zimmer.
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Funding None. 22
Conflict of Interest None.
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osteochondritis dissecans of the knee: current concepts review. Am J Sports Med 2006;34(07):1181–1191 Peterson L, Minas T, Brittberg M, Nilsson A, Sjögren-Jansson E, Lindahl A. Two- to 9-year outcome after autologous chondrocyte transplantation of the knee. Clin Orthop Relat Res 2000;(374):212–234 Gunton MJ, Carey JL, Shaw CR, Murnaghan ML. Drilling juvenile osteochondritis dissecans: retro- or transarticular? Clin Orthop Relat Res 2013;471(04):1144–1151 Kocher MS, Micheli LJ, Yaniv M, Zurakowski D, Ames A, Adrignolo AA. Functional and radiographic outcome of juvenile osteochondritis dissecans of the knee treated with transarticular arthroscopic drilling. Am J Sports Med 2001;29(05):562–566 Gudas R, Simonaitytė R, Čekanauskas E, Tamosiūnas R. A prospective, randomized clinical study of osteochondral autologous transplantation versus microfracture for the treatment of osteochondritis dissecans in the knee joint in children. J Pediatr Orthop 2009;29(07):741–748 Sherman SL, Garrity J, Bauer K, Cook J, Stannard J, Bugbee W. Fresh osteochondral allograft transplantation for the knee: current concepts. J Am Acad Orthop Surg 2014;22(02):121–133 Samuelson EM, Brown DE. Cost-effectiveness analysis of autologous chondrocyte implantation: a comparison of periosteal patch versus type I/III collagen membrane. Am J Sports Med 2012;40(06):1252–1258
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