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Systematic Review

Evidence-Based Status of Second- and Third-Generation


Autologous Chondrocyte Implantation Over First Generation:
A Systematic Review of Level I and II Studies
Deepak Goyal, M.B.B.S., M.S.(Orthop), D.N.B.(Orthop), M.N.A.M.S.,
Anjali Goyal, M.B.B.S., M.D., D.I.C.P., Sohrab Keyhani, M.D.(Orthop),
Eng Hin Lee, M.D., F.R.C.S.(C), F.R.C.S.(Ed), F.R.C.S.(Glas), F.A.M.S., and
James H. P. Hui, M.D., F.R.C.S.(Ed)

Purpose: The purpose of this study was to examine the Level I and II evidence for newer generations of autologous
chondrocyte implantation (ACI) versus rst-generation ACI and to establish whether the newer generations have
overcome the limitations associated with rst-generation ACI. Methods: A literature search was carried out for Level I
and II evidence studies on cartilage repair using the PubMed database. All the studies that dealt with ACI were identied.
Only Level I and II studies that compared newer generations against earlier generations were selected, whereas studies
that compared ACI against other methods of cartilage repair were excluded. Results: A total of 7 studies matched the
selection criteria. Two studies compared periosteum-based autologous chondrocyte implantation (P-ACI) against collagen
membraneebased autologous chondrocyte implantation (C-ACI), whereas one study each compared membrane-
associated autologous chondrocyte implantation (MACI) against P-ACI and C-ACI. One study on C-ACI compared
results related to age, whereas 2 studies evaluated postoperative rehabilitation after MACI. There was weak evidence
showing that C-ACI is better than P-ACI and that MACI is comparable with both P-ACI and C-ACI. The weak evidence is
because of studies with short durations of follow-up, small numbers of patients, medium-sized defects, and younger age
groups. There is good evidence favoring an accelerated weight-bearing regimen after MACI. There is currently no
evidence that supports scaffold-based ACI or arthroscopic implantation over rst-generation ACI. Conclusions: The
hypothesis is thus partly proved in favor of C-ACI/MACI against P-ACI with weak evidence, in favor of accelerated weight
bearing after MACI with strong evidence, and not in favor of arthroscopic and scaffold-based implantations because of
unavailable evidence. Level of Evidence: Level II, systematic review of Level I and II studies.

T he technique of autologous chondrocyte implan-


tation (ACI) was rst introduced by Brittberg et al.1
in 1994. This technique was based on implantation of
the ACI technique is also known as periosteum-based
autologous chondrocyte implantation (P-ACI).2,3 How-
ever, rst-generation ACI had many inherent limitations
cultured cells on the prepared defect and covering the related to the periosteum, cost, age, surgical load, lesion,
defect with a periosteal patch. This rst generation of cells, and rehabilitation2,4-11 (Table 1).
With the evolution of the technique, new modica-
tions have been made to the rst-generation technique
From Saumya Orthocare: Centre for Advanced Surgeries of the Knee Joint
(D.G.), Ahmedabad, India; the Department of Pathology, Smt NHL Munic-
such as the use of a membrane instead of perios-
ipal Medical College (A.G.), Ahmedabad, India; Akhtar Hospital, Shahid teum,12,13 use of scaffolds,14 arthroscopic implantation,
Beheshti University of Medical Science (S.K.), Tehran, Iran; and the and so on.5,6,15 ACI that uses suspended cultured
Department of Orthopaedic Surgery, National University of Singapore chondrocytes with a covering of collagen type I/III
(E.H.L., J.H.P.H.), Singapore. membrane is considered second-generation ACI.3 Third-
The authors report that they have no conicts of interest in the authorship
and publication of this article.
generation ACI comprises those procedures that deliver
Received July 11, 2013; accepted July 17, 2013. autologous cultured chondrocytes using cell carriers or
Address correspondence to Deepak Goyal, M.B.B.S., M.S.(Orthop), cell-seeded scaffolds.3 These second- and third-
D.N.B.(Orthop), M.N.A.M.S., Saumya Orthocare: Centre for Advanced generation modications are also known as autologous
Surgeries of the Knee Joint, 210, Baronet, Sabarmati, Ahmedabad, GU chondrocyte implantation using collagen membrane
380005, India. E-mail: deepak@knee.in
2013 by the Arthroscopy Association of North America
(C-ACI),4,12,13,16 membrane-associated autologous
0749-8063/13473/$36.00 chondrocyte implantation (MACI),4,17,18 and scaffold-
http://dx.doi.org/10.1016/j.arthro.2013.07.271 based ACI.8,19

1872 Arthroscopy: The Journal of Arthroscopic and Related Surgery, Vol 29, No 11 (November), 2013: pp 1872-1878
AUTOLOGOUS CHONDROCYTE IMPLANTATION: EVIDENCE 1873

Table 1. Limitations Associated With First-Generation ACI using membrane, untreated cartilage lesions, stem cells,
(Periosteum-Based ACI) mesenchymal stem cells, and membrane seeded autol-
Periosteum related Another surgery to harvest periosteum4 ogous chondrocyte implantation. The lters used
Periosteal hypertrophy2,4,10 during the search were as follows: published in the past
Suturing to surrounding cartilage8
10 years, humans, clinical trial phase I, clinical trial
Calcication4
Intra-articular adhesions2,10
phase II, randomized controlled trials, prospective
Delamination2,4,10 cohort studies, meta-analyses, systematic reviews, and
Age related Limited to young persons36,53 English language. A total of 34 studies related to carti-
Surgery related Two surgeries1,8,19 lage repair with Level I and II evidence were identi-
Open surgery and longer duration of ed,2,4,8,9,13,16,19,20,22-47 as declared by the journals in
surgery6,8,15,54
Large arthrotomy4,5,8
which the articles were published. The search was
Cost related High cost4 further rened to select only those studies that
Lesion related Approaching inaccessible lesions4 compared newer methods of ACI. This search for Level
Treating irregular lesions8 I and II studies related to ACI resulted in selection of 7
Lesions at osteochondral junctions4 studies.4,16,20,23,36,37,46 The inclusion criterion was any
Delamination of surrounding cartilage during
lesion preparation and suturing4
method of ACI comparing with another method of ACI.
Making water tight chamber8 Exclusion criteria were case series, personal opinions,
Cell related Cell differentiation during culture51 systematic reviews involving studies with Level III, IV,
Cell handling during implantation8 and V evidence, and any method of ACI comparing
Unequal distribution of cells at implanted site11 with another method of cartilage repair. A owchart
Cell leakage11
Cell migration in scaffolds55
describing the selection process for the studies is shown
Rehabilitation Long rehabilitation and slow postoperative in Fig 1.
related recovery4,6,8,9
Late weight bearing6,9 Results
Return to sports52
This systematic review is based on 7 stu-
dies4,16,20,23,36,37,46 (Table 2). Two studies compared P-
The evolution of the second- and third-generation ACI against C-ACI,16,37 whereas one study each
ACI techniques has been quite rapid in the past compared MACI against P-ACI4 and C-ACI.20 One study
decade with the aim of addressing some of the limita- on C-ACI compared results related to age.36 None of the
tions associated with rst-generation ACI.4,8,20 Hence it studies compared the arthroscopic implantation of
is important to examine the evidence in support of the newer-generation techniques with rst-generation
newer modications to ACI while looking for consis- techniques. In addition, none of the studies evaluated
tent, favorable, and reproducible clinical results of the results of second- or third-generation ACI performed
ACI technique in toto. Clinical results provided by ACI because of failed previous cartilage surgery. Two studies
would only be useful when they are long-lasting with evaluated postoperative rehabilitation after MACI.23,46
minimal or no problems associated with rst- There was no study that evaluated return to sports
generation ACI. The balance of the strength and among the different generations of ACI. There has not
weakness of ACI must be in its favor over the simple, been any previous systematic review of the literature that
inexpensive marrow stimulation techniques.2,21 compared the results of the newer generations of ACI
On the basis of Level I and II studies, a comprehensive with those of rst-generation ACI.
analysis of the literature was carried out. The purpose of
this study was to examine the Level I and II evidence
Discussion
for newer generations of ACI versus the rst generation
This systematic review is based on 7 Level I and II
of ACI. The hypothesis was that the newer generations
studies of the different generations of ACI.4,16,20,23,36,37,46
of ACI have overcome the limitations of the rst
Because there has not been any previous study of this
generation with comparable or better results.
nature, there is no existing literature that can be used for
comparison with our ndings. In addition, the great
Methods heterogeneity in patient selection, indications, scoring of
A literature search was carried out in November the defects, scoring of the results, period of follow-up,
2012 using the PubMed database with the following and technique of surgery led to some difculties in
keywords: microfracture, cartilage repair, mosaicplasty, comparing the results of the various studies.
osteochondral autograft, osteochondral plugs, osteo-
articular transfer system, autologous matrix induced ACI Using Collagen Membrane (C-ACI)
chondrogenesis, autologous chondrocyte implantat- First-generation ACI used periosteum (P-ACI) to
ion, periosteum covered autologous chondrocyte create a cartilage chamber over the cartilage defect.
implantation, autologous chondrocyte implantation Although midterm and long-term results from the
1874 D. GOYAL ET AL.

Fig 1. Flowchart of articles during


selection process.

inventors have shown encouraging results,48,49 the noted that the evidence in favor of C-ACI is based on
issues of periosteal hypertrophy, periosteum suturing, a limited follow-up period of only 2 years. Studies with
calcication, delamination, intra-articular adhesions, longer durations of follow-up, greater number of
and another surgery to harvest the periosteum have patients, and larger lesion sizes are desirable.
been cited as important disadvantages.2,4,8,11,20,50
Gooding et al.16 compared the results of P-ACI Membrane-Seeded Autologous Chondrocyte
(n 33) with those of C-ACI (n 35) in their ran- Implantation (MACI)
domized controlled study (Level II). The mean age of the P-ACI/C-ACI have some inherent problems with the
patients was 30.5 years, and the mean lesion size was techniques. Inaccessible, irregular lesions and lesions at
4.54 cm2. A 2-year follow-up did not show any statistical osteochondral junctions are difcult to manage.4,8 Cell
difference in results between the 2 methods; however, handling and making a watertight chamber are also
a signicant number of patients required periosteal difcult in these areas.8 Unequal distribution of cells
shaving in the P-ACI group. Samuelson and Brown37 in the chamber, delamination, and suturing of the
performed a cost-effective analysis between the 2 tech- membrane to surrounding cartilage also are import-
niques (P-ACI v C-ACI) (Level II). The economic and ant disadvantages.2,4,10,11,20 A large arthrotomy and
decision analysis was based on the literature and costs suturing of either the periosteum or membrane are also
involved at a local hospital. They found both methods to problems.4,5,8,20
be cost-effective. However, their study found C-ACI to The advocates of membrane-seeded chondrocytes
be slightly more cost-effective than P-ACI, mainly believe that MACI can eliminate many of these
because of the high risk of patch hypertrophy. However, problems. Because of its adhesive property, the cell-
this Level II study was based on many assumptions and seeded membrane can be implanted over a less inac-
considered patch hypertrophy as the key variable. The cessible area or at osteochondral junctions. Cells also
studies by Gooding et al. and Samuelson and Brown remain equally distributed, and there is no need to
concluded that C-ACI is as effective as P-ACI as far as make a watertight chamber or perform suturing. The
outcomes and cost are concerned, with C-ACI proving to surgery can also be performed through a mini-
be slightly more economical in the long run. It must be arthrotomy.

Table 2. Therapeutic Cartilage Studies Comparing Various Generations of ACI (Level of Evidence I and II)

v C-ACI v MACI Age Related Postoperative WB


Level Study Level Study Level Study Level Study
P-ACI I Gooding et al.,16 2006 II Zeifang et al.,20 2010
II Samuelson and Brown,37 2012
C-ACI I Bartlett et al.,4 2005 II Niemeyer et al.,36 2010
MACI I Ebert et al.,23 2012
I Wondrasch et al.,46 2009
WB, weight bearing.
AUTOLOGOUS CHONDROCYTE IMPLANTATION: EVIDENCE 1875

Two studies compared the results of P-ACI with ACI-C at Older Age
those of MACI4 and the results of C-ACI with those of The case series published so far with good results have
MACI.20 Bartlett et al.4 reviewed the results of C-ACI been performed in younger patients.49 It is therefore
(n 44; mean age, 33.7 years) and those of MACI important to establish whether these better results are
(n 47; mean age, 33.4 years) after a mean follow-up obtained in older patients.
period of 1 year. The mean lesion size was 6 cm2, and Niemeyer et al.36 studied ACI results in patients aged
the study was a Level II, randomized, prospective trial. 40 years or older. This Level II study compared
There was improvement in all clinical scores with both younger patients (group 1; mean age, 31 years; n
the techniques, and arthroscopic/histologic assess- 37) with older patients (group 2; mean age, 47.8 years;
ments showed no signicant difference between the n 37). Two years follow-up for isolated cartilage
groups. Zeifang et al.20 compared full-thickness carti- defects treated with C-ACI showed comparable results
lage lesions treated with either P-ACI or MACI tech- for the subjective IKDC score (72.2  15.8 [mean 
niques. This Level II study was performed in 21 SD] in group 1 v 76.1  14.1 in group 2) and Lysholm
patients with a mean age of 29.3 years. The mean size score (80.42  15.37 in group 1 v 80.65  12.01 in
of the defect was 4.1 cm2, and the follow-up period group 2). Patients aged 40 years or older did not
was 2 years. The International Knee Documentation have inferior outcomes up to 2 years after C-ACI
Committee (IKDC) score, Tegner activity score, and compared with the younger age group. Although both
Short Form 36 score all yielded similar results in both the groups were matched with respect to defect size
the groups; however, the Lysholm and Gillquist scores and location, the size of the defects was not
(knee functionality) favored the P-ACI technique. mentioned. A longer duration of follow-up is desirable
Magnetic resonance imaging (MRI) study showed for strong evidence. It should be noted, however, that
a signicantly lower magnetic resonance observation this study did not look at results in patients aged older
of cartilage repair tissue (MOCART) score (7.0  2.7 than 50 years.
for MACI v 10.3  1.6 for P-ACI, P .0123) at 6
months (n 17) corresponding to more positive (more Rehabilitation
normal) MRI diagnostic ndings; however, the differ- Periosteum-based procedures required a larger arthrot-
ences between the study groups were not signicant at omy, a separate periosteum harvesting incision, a longer
12 months (n 17) or 24 months (n 11). Both of duration of surgery, and an extended hospitalizati-
these studies showed comparable results between on. Hence, long rehabilitation and slow postoperat-
MACI and P-ACI or C-ACI. However, it must be ive recovery, late weight bearing, and early
pointed out that these studies have a short follow-up return to sports were major areas of concern after
duration,4,20 a small number of patients,20 medium- P-ACI.4,6,8,9
sized defects,20 and a younger age group.20 More Wondrasch et al.46 compared the role of accelerated
evidence is required from studies with larger numbers weight bearing versus delayed weight bearing after the
of patients, larger defect sizes, and longer durations of MACI procedure. There was no difference in clinical
follow-up. outcome at 2 years based on the IKDC, Tegner, and the
Knee Injury and Osteoarthritis Outcome Score (KOOS).
Scaffold-Based ACI and Arthroscopic Implantation Although there was a high prevalence of bone marrow
The problems with the cultivation of chondrocytes are edema in the accelerated weight-bearing group at 6
the slow growth and the dedifferentiation of cells, months, it was the same at nal follow-up of 104
including a switch of collagen synthesis from type II to weeks. Although, in the nal analysis, this Level I
type I.20,51 It has been shown that if chondrocytes are evidence study does favor early weight bearing after
grown on a scaffold rather than in a monolayer culture, MACI, the sample size was small (N 31) and the
the cells do not dedifferentiate. The advocates of study involved only lesions in femoral condyles. The
scaffold-based ACI believe that a cartilage defect is patients in the accelerated weight-bearing group were
a 3-dimensional defect and, hence, a 3-dimensional much younger (mean age, 28.3 years) than those in the
repair method should be an ideal choice. An arthros- delayed weight-bearing group (mean age, 38 years).
copic approach to cartilage repair also has certain A longer duration of follow-up and a correlation of
advantages over open surgery, such as shorter hospital the size of the lesion with accelerated weight bearing
stay, less requirement for medications such as analge- are required. A study by Ebert et al.23 also compared
sics and antibiotics, and shorter recovery and rehabili- the results of accelerated weight bearing with tradi-
tation. Arthroscopic implantation of ACI is possible with tional weight bearing in MACI patients. The sample size
scaffold-based ACI techniques. However, to date, no of patients (N 63) was good, and cases were followed
controlled trial comparing the arthroscopic implanta- up for 5 years. All 63 patients (31 in the accelerated
tion of the different generations of ACI and scaffold- weight-bearing group and 32 in the traditional weight-
based ACI has been performed. bearing group) were assessed at 3 months, 12 months,
1876 D. GOYAL ET AL.

2 years, and 5 years with KOOS, Short-Form Health carried out for a minimum period of 10 years to
Survey (SF-36), visual analog scale, 6-minute walk test, specically check for correlation of repair tissue with
and knee range-of-motion assessment. MRI evaluation the possible inuence of factors such as age, lesion size,
was also performed after a similar duration in 29 cases and onset of osteoarthritis. Such long-term cohort
in each group. Both groups showed comparable studies would enable a more comprehensive and
improvement at 2 years and at 5 years on all clinical balanced assessment of the inferiority or superiority of
scales except the visual analog scale, which showed newer-generation ACI techniques over rst-generation
a signicantly lower frequency of pain at 5 years in the ACI.
accelerated weight-bearing group. MRI-based scores
also did not show any signicant difference in both Limitations
groups at 2 years and 5 years. Patient age and defect The limitation of this study was that there were very
size exhibited signicant negative correlations (P > .5) few available studies that could match the selection
with several MRI-based parameters at 5 years. There criteria. The absence of any previous study of a similar
was no signicant correlation (P > .5) between clinical nature made it difcult for comparisons to be made in
and MRI-based outcomes as well. Both the study by this study.
Wondrasch et al.46 and the study by Ebert et al. were in
favor of the accelerated weight-bearing regimen after Conclusions
MACI, with the study of Ebert et al. having a larger C-ACI is a marginally better alternative to P-ACI, with
number of patients, longer duration of follow-up, and evidence limited to a follow-up period of only 2 years.
greater number of clinical and MRI parameters to create MACI gives comparable results to P-ACI or C-ACI
signicant evidence. methods; however, the available evidence is from
studies with a short duration of follow-up with small
Return to Sports numbers of patients having medium-sized defects in
Chondral injuries are common in sports participants. a younger age group. The results of C-ACI performed in
Hence, it is important to have good data on the results the group aged 40 to 50 years are comparable with the
of ACI in high-demand patients, as well as to determine results in those aged younger than 40 years, with
when such patients can return to sports after ACI. evidence limited to 2 years follow-up and an unspec-
However, none of the studies compared the results of ied defect size. An accelerated weight-bearing regimen
newer-generation ACI with rst-generation ACI by is favored after MACI with signicant evidence from
evaluating results in high-demand patients or return to a larger number of patients with a longer duration of
sports. follow-up and greater numbers of clinical and MRI
In summary, there is some evidence based on Level I parameters. There is no evidence at present that
and II studies that C-ACI has marginally better supports scaffold-based ACI or arthroscopic implanta-
outcomes than P-ACI and that MACI has comparable tion over rst-generation ACI. The hypothesis is thus
outcomes to P-ACI and C-ACI. However, the evidence partly proved in favor of C-ACI/MACI against P-ACI
thus far is limited to studies with a short duration of with weak evidence, in favor of accelerated weight
follow-up, small number of patients, small lesion size, bearing after MACI with strong evidence, and not in
and younger patients. There is also evidence in support favor of arthroscopic and scaffold-based implantations
of comparable results of C-ACI between patients aged because of unavailable evidence.
40 to 50 years and patients aged younger than 40 years,
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