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
cultured cells on the prepared defect and covering the
defect with a periosteal patch. This rst generation of
From Saumya Orthocare: Centre for Advanced Surgeries of the Knee Joint
(D.G.), Ahmedabad, India; the Department of Pathology, Smt NHL Munic-
ipal Medical College (A.G.), Ahmedabad, India; Akhtar Hospital, Shahid
Beheshti University of Medical Science (S.K.), Tehran, Iran; and the
Department of Orthopaedic Surgery, National University of Singapore
(E.H.L., J.H.P.H.), Singapore.
The authors report that they have no conicts of interest in the authorship
and publication of this article.
Received July 11, 2013; accepted July 17, 2013.
Address correspondence to Deepak Goyal, M.B.B.S., M.S.(Orthop),
D.N.B.(Orthop), M.N.A.M.S., Saumya Orthocare: Centre for Advanced
Surgeries of the Knee Joint, 210, Baronet, Sabarmati, Ahmedabad, GU
380005, India. E-mail: deepak@knee.in
2013 by the Arthroscopy Association of North America
0749-8063/13473/$36.00
http://dx.doi.org/10.1016/j.arthro.2013.07.271
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
related to the periosteum, cost, age, surgical load, lesion,
cells, and rehabilitation2,4-11 (Table 1).
With the evolution of the technique, new modica-
tions have been made to the rst-generation technique
such as the use of a membrane instead of perios-
teum,12,13 use of scaffolds,14 arthroscopic implantation,
and so on.5,6,15 ACI that uses suspended cultured
chondrocytes with a covering of collagen type I/III
membrane is considered second-generation ACI.3 Third-
generation ACI comprises those procedures that deliver
autologous cultured chondrocytes using cell carriers or
cell-seeded scaffolds.3 These second- and third-
generation modications are also known as autologous
chondrocyte implantation using collagen membrane
(C-ACI),4,12,13,16 membrane-associated autologous
chondrocyte implantation (MACI),4,17,18 and scaffold-
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
Table 1. Limitations Associated With First-Generation ACI
(Periosteum-Based ACI)
Periosteum related Another surgery to harvest periosteum4
Periosteal hypertrophy2,4,10
Suturing to surrounding cartilage8
Calcication4
Intra-articular adhesions2,10
Delamination2,4,10
Age related Limited to young persons36,53
Surgery related Two surgeries1,8,19
Open surgery and longer duration of
surgery6,8,15,54
Large arthrotomy4,5,8
Cost related High cost4
Lesion related Approaching inaccessible lesions4
Treating irregular lesions8
Lesions at osteochondral junctions4
Delamination of surrounding cartilage during
lesion preparation and suturing4
Making water tight chamber8
Cell related Cell differentiation during culture51
Cell handling during implantation8
Unequal distribution of cells at implanted site11
Cell leakage11
Cell migration in scaffolds55
Rehabilitation Long rehabilitation and slow postoperative
related recovery4,6,8,9
Late weight bearing6,9
Return to sports52
The evolution of the second- and third-generation
ACI techniques has been quite rapid in the past
decade with the aim of addressing some of the limita-
tions associated with rst-generation ACI.4,8,20 Hence it
is important to examine the evidence in support of the
newer modications to ACI while looking for consis-
tent, favorable, and reproducible clinical results of the
ACI technique in toto. Clinical results provided by ACI
would only be useful when they are long-lasting with
minimal or no problems associated with rst-
generation ACI. The balance of the strength and
weakness of ACI must be in its favor over the simple,
inexpensive marrow stimulation techniques.2,21
On the basis of Level I and II studies, a comprehensive
analysis of the literature was carried out. The purpose of
this study was to examine the Level I and II evidence
for newer generations of ACI versus the rst generation
of ACI. The hypothesis was that the newer generations
of ACI have overcome the limitations of the rst
generation with comparable or better results.
Methods
A literature search was carried out in November
2012 using the PubMed database with the following
keywords: microfracture, cartilage repair, mosaicplasty,
osteochondral autograft, osteochondral plugs, osteo-
articular transfer system, autologous matrix induced
chondrogenesis, autologous chondrocyte implantat-
ion, periosteum covered autologous chondrocyte
implantation, autologous chondrocyte implantation
1873
using membrane, untreated cartilage lesions, stem cells,
mesenchymal stem cells, and membrane seeded autol-
ogous chondrocyte implantation. The lters used
during the search were as follows: published in the past
10 years, humans, clinical trial phase I, clinical trial
phase II, randomized controlled trials, prospective
cohort studies, meta-analyses, systematic reviews, and
English language. A total of 34 studies related to carti-
lage repair with Level I and II evidence were identi-
ed,2,4,8,9,13,16,19,20,22-47 as declared by the journals in
which the articles were published. The search was
further rened to select only those studies that
compared newer methods of ACI. This search for Level
I and II studies related to ACI resulted in selection of 7
studies.4,16,20,23,36,37,46 The inclusion criterion was any
method of ACI comparing with another method of ACI.
Exclusion criteria were case series, personal opinions,
systematic reviews involving studies with Level III, IV,
and V evidence, and any method of ACI comparing
with another method of cartilage repair. A owchart
describing the selection process for the studies is shown
in Fig 1.
Results
This systematic review is based on 7 stu-
dies4,16,20,23,36,37,46 (Table 2). Two studies compared P-
ACI against C-ACI,16,37 whereas one study each
compared MACI against P-ACI4 and C-ACI.20 One study
on C-ACI compared results related to age.36 None of the
studies compared the arthroscopic implantation of
newer-generation techniques with rst-generation
techniques. In addition, none of the studies evaluated
results of second- or third-generation ACI performed
because of failed previous cartilage surgery. Two studies
evaluated postoperative rehabilitation after MACI.23,46
There was no study that evaluated return to sports
among the different generations of ACI. There has not
been any previous systematic review of the literature that
compared the results of the newer generations of ACI
with those of rst-generation ACI.
Discussion
This systematic review is based on 7 Level I and II
studies of the different generations of ACI.4,16,20,23,36,37,46
Because there has not been any previous study of this
nature, there is no existing literature that can be used for
comparison with our ndings. In addition, the great
heterogeneity in patient selection, indications, scoring of
the defects, scoring of the results, period of follow-up,
and technique of surgery led to some difculties in
comparing the results of the various studies.
ACI Using Collagen Membrane (C-ACI)
First-generation ACI used periosteum (P-ACI) to
create a cartilage chamber over the cartilage defect.
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
issues of periosteal hypertrophy, periosteum suturing,
calcication, delamination, intra-articular adhesions,
and another surgery to harvest the periosteum have
been cited as important disadvantages.2,4,8,11,20,50
Gooding et al.16 compared the results of P-ACI
(n 33) with those of C-ACI (n 35) in their ran-
domized controlled study (Level II). The mean age of the
patients was 30.5 years, and the mean lesion size was
4.54 cm2. A 2-year follow-up did not show any statistical
difference in results between the 2 methods; however,
a signicant number of patients required periosteal
shaving in the P-ACI group. Samuelson and Brown37
performed a cost-effective analysis between the 2 tech-
niques (P-ACI v C-ACI) (Level II). The economic and
decision analysis was based on the literature and costs
involved at a local hospital. They found both methods to
be cost-effective. However, their study found C-ACI to
be slightly more cost-effective than P-ACI, mainly
because of the high risk of patch hypertrophy. However,
this Level II study was based on many assumptions and
considered patch hypertrophy as the key variable. The
studies by Gooding et al. and Samuelson and Brown
concluded that C-ACI is as effective as P-ACI as far as
outcomes and cost are concerned, with C-ACI proving to
be slightly more economical in the long run. It must be
noted that the evidence in favor of C-ACI is based on
a limited follow-up period of only 2 years. Studies with
longer durations of follow-up, greater number of
patients, and larger lesion sizes are desirable.
Membrane-Seeded Autologous Chondrocyte
Implantation (MACI)
P-ACI/C-ACI have some inherent problems with the
techniques. Inaccessible, irregular lesions and lesions at
osteochondral junctions are difcult to manage.4,8 Cell
handling and making a watertight chamber are also
difcult in these areas.8 Unequal distribution of cells
in the chamber, delamination, and suturing of the
membrane to surrounding cartilage also are import-
ant disadvantages.2,4,10,11,20 A large arthrotomy and
suturing of either the periosteum or membrane are also
problems.4,5,8,20
The advocates of membrane-seeded chondrocytes
believe that MACI can eliminate many of these
problems. Because of its adhesive property, the cell-
seeded membrane can be implanted over a less inac-
cessible area or at osteochondral junctions. Cells also
remain equally distributed, and there is no need to
make a watertight chamber or perform suturing. The
surgery can also be performed through a mini-
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
Two studies compared the results of P-ACI with
those of MACI4 and the results of C-ACI with those of
MACI.20 Bartlett et al.4 reviewed the results of C-ACI
(n 44; mean age, 33.7 years) and those of MACI
(n 47; mean age, 33.4 years) after a mean follow-up
period of 1 year. The mean lesion size was 6 cm2, and
the study was a Level II, randomized, prospective trial.
There was improvement in all clinical scores with both
the techniques, and arthroscopic/histologic assess-
ments showed no signicant difference between the
groups. Zeifang et al.20 compared full-thickness carti-
lage lesions treated with either P-ACI or MACI tech-
niques. This Level II study was performed in 21
patients with a mean age of 29.3 years. The mean size
of the defect was 4.1 cm2, and the follow-up period
was 2 years. The International Knee Documentation
Committee (IKDC) score, Tegner activity score, and
Short Form 36 score all yielded similar results in both
the groups; however, the Lysholm and Gillquist scores
(knee functionality) favored the P-ACI technique.
Magnetic resonance imaging (MRI) study showed
a signicantly lower magnetic resonance observation
of cartilage repair tissue (MOCART) score (7.0  2.7
for MACI v 10.3  1.6 for P-ACI, P .0123) at 6
months (n 17) corresponding to more positive (more
normal) MRI diagnostic ndings; however, the differ-
ences between the study groups were not signicant at
12 months (n 17) or 24 months (n 11). Both of
these studies showed comparable results between
MACI and P-ACI or C-ACI. However, it must be
pointed out that these studies have a short follow-up
duration,4,20 a small number of patients,20 medium-
sized defects,20 and a younger age group.20 More
evidence is required from studies with larger numbers
of patients, larger defect sizes, and longer durations of
follow-up.
Scaffold-Based ACI and Arthroscopic Implantation
The problems with the cultivation of chondrocytes are
the slow growth and the dedifferentiation of cells,
including a switch of collagen synthesis from type II to
type I.20,51 It has been shown that if chondrocytes are
grown on a scaffold rather than in a monolayer culture,
the cells do not dedifferentiate. The advocates of
scaffold-based ACI believe that a cartilage defect is
a 3-dimensional defect and, hence, a 3-dimensional
repair method should be an ideal choice. An arthros-
copic approach to cartilage repair also has certain
advantages over open surgery, such as shorter hospital
stay, less requirement for medications such as analge-
sics and antibiotics, and shorter recovery and rehabili-
tation. Arthroscopic implantation of ACI is possible with
scaffold-based ACI techniques. However, to date, no
controlled trial comparing the arthroscopic implanta-
tion of the different generations of ACI and scaffold-
based ACI has been performed.
1875
ACI-C at Older Age
The case series published so far with good results have
been performed in younger patients.49 It is therefore
important to establish whether these better results are
obtained in older patients.
Niemeyer et al.36 studied ACI results in patients aged
40 years or older. This Level II study compared
younger patients (group 1; mean age, 31 years; n
37) with older patients (group 2; mean age, 47.8 years;
n 37). Two years follow-up for isolated cartilage
defects treated with C-ACI showed comparable results
for the subjective IKDC score (72.2  15.8 [mean 
SD] in group 1 v 76.1  14.1 in group 2) and Lysholm
score (80.42  15.37 in group 1 v 80.65  12.01 in
group 2). Patients aged 40 years or older did not
have inferior outcomes up to 2 years after C-ACI
compared with the younger age group. Although both
the groups were matched with respect to defect size
and location, the size of the defects was not
mentioned. A longer duration of follow-up is desirable
for strong evidence. It should be noted, however, that
this study did not look at results in patients aged older
than 50 years.
Rehabilitation
Periosteum-based procedures required a larger arthrot-
omy, a separate periosteum harvesting incision, a longer
duration of surgery, and an extended hospitalizati-
on. Hence, long rehabilitation and slow postoperat-
ive recovery, late weight bearing, and early
return to sports were major areas of concern after
P-ACI.4,6,8,9
Wondrasch et al.46 compared the role of accelerated
weight bearing versus delayed weight bearing after the
MACI procedure. There was no difference in clinical
outcome at 2 years based on the IKDC, Tegner, and the
Knee Injury and Osteoarthritis Outcome Score (KOOS).
Although there was a high prevalence of bone marrow
edema in the accelerated weight-bearing group at 6
months, it was the same at nal follow-up of 104
weeks. Although, in the nal analysis, this Level I
evidence study does favor early weight bearing after
MACI, the sample size was small (N 31) and the
study involved only lesions in femoral condyles. The
patients in the accelerated weight-bearing group were
much younger (mean age, 28.3 years) than those in the
delayed weight-bearing group (mean age, 38 years).
A longer duration of follow-up and a correlation of
the size of the lesion with accelerated weight bearing
are required. A study by Ebert et al.23 also compared
the results of accelerated weight bearing with tradi-
tional weight bearing in MACI patients. The sample size
of patients (N 63) was good, and cases were followed
up for 5 years. All 63 patients (31 in the accelerated
weight-bearing group and 32 in the traditional weight-
bearing group) were assessed at 3 months, 12 months,
1876 D. GOYAL ET AL.
2 years, and 5 years with KOOS, Short-Form Health
Survey (SF-36), visual analog scale, 6-minute walk test,
and knee range-of-motion assessment. MRI evaluation
was also performed after a similar duration in 29 cases
in each group. Both groups showed comparable
improvement at 2 years and at 5 years on all clinical
scales except the visual analog scale, which showed
a signicantly lower frequency of pain at 5 years in the
accelerated weight-bearing group. MRI-based scores
also did not show any signicant difference in both
groups at 2 years and 5 years. Patient age and defect
size exhibited signicant negative correlations (P > .5)
with several MRI-based parameters at 5 years. There
was no signicant correlation (P > .5) between clinical
and MRI-based outcomes as well. Both the study by
Wondrasch et al.46 and the study by Ebert et al. were in
favor of the accelerated weight-bearing regimen after
MACI, with the study of Ebert et al. having a larger
number of patients, longer duration of follow-up, and
greater number of clinical and MRI parameters to create
signicant evidence.
Return to Sports
Chondral injuries are common in sports participants.
Hence, it is important to have good data on the results
of ACI in high-demand patients, as well as to determine
when such patients can return to sports after ACI.
However, none of the studies compared the results of
newer-generation ACI with rst-generation ACI by
evaluating results in high-demand patients or return to
sports.
In summary, there is some evidence based on Level I
and II studies that C-ACI has marginally better
outcomes than P-ACI and that MACI has comparable
outcomes to P-ACI and C-ACI. However, the evidence
thus far is limited to studies with a short duration of
follow-up, small number of patients, small lesion size,
and younger patients. There is also evidence in support
of comparable results of C-ACI between patients aged
40 to 50 years and patients aged younger than 40 years,
but again, the evidence is for a small group of patients
with a shorter duration of follow-up and not for
patients aged older than a mean of 50 years. Evidence is
in favor of an accelerated weight-bearing regimen after
MACI with support of a larger number of patients,
longer duration of follow-up, and greater numbers of
clinical and MRI parameters. We could not nd any
evidence in favor of arthroscopic implantation or
scaffold-based ACI.
Multicenter prospective trials should be conducted
with signicant numbers of patients matched for char-
acteristics such as age, lesion size, cartilage history,
activity level, and common outcomes score, and these
patients should be randomized into second- and third-
generation ACI versus rst-generation ACI. Ideally,
quantitative and qualitative assessments should be
carried out for a minimum period of 10 years to
specically check for correlation of repair tissue with
the possible inuence of factors such as age, lesion size,
and onset of osteoarthritis. Such long-term cohort
studies would enable a more comprehensive and
balanced assessment of the inferiority or superiority of
newer-generation ACI techniques over rst-generation
ACI.
Limitations
The limitation of this study was that there were very
few available studies that could match the selection
criteria. The absence of any previous study of a similar
nature made it difcult for comparisons to be made in
this study.
Conclusions
C-ACI is a marginally better alternative to P-ACI, with
evidence limited to a follow-up period of only 2 years.
MACI gives comparable results to P-ACI or C-ACI
methods; however, the available evidence is from
studies with a short duration of follow-up with small
numbers of patients having medium-sized defects in
a younger age group. The results of C-ACI performed in
the group aged 40 to 50 years are comparable with the
results in those aged younger than 40 years, with
evidence limited to 2 years follow-up and an unspec-
ied defect size. An accelerated weight-bearing regimen
is favored after MACI with signicant evidence from
a larger number of patients with a longer duration of
follow-up and greater numbers of clinical and MRI
parameters. There is no evidence at present that
supports scaffold-based ACI or arthroscopic implanta-
tion over rst-generation ACI. 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.
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