The American Journal of Sports

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Long-term Outcomes After First-Generation Autologous Chondrocyte Implantation for Cartilage

Defects of the Knee
Philipp Niemeyer, Stella Porichis, Matthias Steinwachs, Christoph Erggelet, Peter C. Kreuz, Hagen Schmal, Markus
Uhl, Nadir Ghanem, Norbert P. Sdkamp and Gian Salzmann
Am J Sports Med 2014 42: 150 originally published online October 21, 2013
DOI: 10.1177/0363546513506593

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Long-term Outcomes After
First-Generation Autologous
Chondrocyte Implantation for
Cartilage Defects of the Knee
Philipp Niemeyer,*y MD, PhD, Stella Porichis,y MS, Matthias Steinwachs,z MD, PhD,
Christoph Erggelet, MD, PhD, Peter C. Kreuz,|| MD, Hagen Schmal,y MD, PhD,
Markus Uhl,{ MD, PhD, Nadir Ghanem,# MD, Norbert P. Sudkamp,y MD, PhD,
and Gian Salzmann,y MD
Investigation performed at Freiburg University Hospital, Freiburg, Germany

Background: Autologous chondrocyte implantation (ACI) represents an established surgical therapy for large cartilage defects of
the knee joint. Although various studies report satisfying midterm results, little is known about long-term outcomes.
Purpose: To evaluate long-term clinical and magnetic resonance imaging (MRI) outcomes after ACI.
Study Design: Case series; Level of evidence, 4.
Methods: Between January 1997 and June 2001, a total of 86 patients were treated with ACI for isolated cartilage defects of the
knee. The mean patient age at the time of surgery was 33.3 6 10.2 years, and the mean defect size was 6.5 6 4.0 cm2. Thirty-four
defects were located on the medial femoral condyle and 13 on the lateral femoral condyle, while 6 patients were treated for cartilage
defects of the trochlear groove and 17 for patellar lesions. At a mean follow-up of 10.9 6 1.1 years, 70 patients (follow-up rate, 82%)
treated for 82 full-thickness cartilage defects of the knee were available for an evaluation of knee function using standard instru-
ments, while 59 of these patients were additionally evaluated by 1.5-T MRI to quantify the magnetic resonance observation of car-
tilage repair tissue (MOCART) score. Clinical function at follow-up was assessed by means of the Lysholm score, the International
Knee Documentation Committee (IKDC) score, and the Knee injury and Osteoarthritis Outcome Score (KOOS). Patient activity was
assessed by the Tegner score. In addition, pain on a visual analog scale (VAS) and patient satisfaction were evaluated separately.
Results: At follow-up, 77% reported being satisfied or very satisfied. The mean IKDC score at follow-up was 74.0 6 17.3.
The mean Lysholm score improved from 42.0 6 22.5 before surgery to 71.0 6 17.4 at follow-up (P \ .01). The mean pain score on
the VAS decreased from 7.2 6 1.9 preoperatively to 2.1 6 2.1 postoperatively. The mean MOCART score was 44.9 6 23.6.
Defect-associated bone marrow edema was found in 78% of the cases. Nevertheless, no correlation between the MOCART score
and clinical outcome (IKDC score) could be found (Pearson coefficient, r = 0.173).
Conclusion: First-generation ACI leads to satisfying clinical results in terms of patient satisfaction, reduction of pain, and
improvement in knee function. Nevertheless, full restoration of knee function cannot be achieved. Although MRI reveals lesions
in the majority of the cases and the overall MOCART score seems moderate, this could not be correlated with long-term clinical
outcomes.
Keywords: cartilage; knee joint; autologous chondrocyte implantation; long-term outcomes

Autologous chondrocyte implantation (ACI) was intro-
duced by the group of Lars Peterson and Matts Brittberg
in 1987 for the treatment of symptomatic full-thickness
cartilage defects of the knee; the first clinical results
were published in 1994.10 Although many modifications
of this technique have been reported29 since then, the
aim of ACI remains to restore joint function and to actually
The American Journal of Sports Medicine, Vol. 42, No. 1
DOI: 10.1177/0363546513506593
2013 The Author(s)
heal the damaged joint surface, which represents a poten-
tial risk factor for consecutive osteoarthritis.12
The initial hope, to generate hyaline cartilage similar to
natural articular cartilage, has not been fulfilled to its full
extent yet. Repair tissue induced by ACI seems superior to
that induced by other cartilage repair techniques such as
bone marrow stimulation42 but is inferior to the natural car-
tilage transplanted, that is, during osteochondral autograft-
ing. Nevertheless, the histologic quality of ACI tissue seems
better compared with any other regenerative cartilage tech-
nique. Additionally, with regard to the fact that bone marrow
stimulation techniques show a deterioration of clinical results

150
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Vol. 42, No. 1, 2014 Long-term Outcomes After ACI 151

between 2 and 3 years after surgery,31,32 ACI seems a promis- TABLE 1

ing technique to achieve good and excellent long-term out- Characteristics of Patients (N = 70)a
comes. To date, the number of studies that report long-term
outcomes after ACI is still limited.4,5,34,40 Although these Characteristics Value
studies add significant and important information to the Sex
existing knowledge about ACI, these case series reporting Male 45 (35.7)
long-term outcomes after ACI either suffer from a low fol- Female 25 (64.3)
low-up rate,40 the weakness of not using standardized scores Age, y 33.3 6 10.2
systematically for patient evaluations at the time of follow- Body mass index, kg/m2 26.3 6 5.2
up,34 or having a wide range of follow-ups including those Affected knee
between 5 and 12 years after ACI.5 Therefore, additional Right 40 (57.1)
data are needed to learn more about long-term outcomes of Left 30 (42.9)
Defect size, cm2 6.5 6 4.0
patients treated with ACI for full-thickness cartilage defects
No. of defects
of the knee. The present study was set up to present long- 1 lesion 58
term clinical and magnetic resonance imaging (MRI) out- 2 lesions 12
comes of patients treated with cell suspension in combination Defect location
with autologous periosteum. Medial femoral condyle 29 (41.1)
Lateral femoral condyle 13 (18.6)
Trochlea 2 (20.0)
Patella 14 (2.9)
MATERIALS AND METHODS Multiple 12 (17.1)
Concomitant surgeries (n = 20 patients)
The current study was approved by the ethical committee ACL reconstruction 5
of Freiburg University (EK 8-10) and registered in the Ger- High tibial osteotomy 2
man Clinical Trials Register (DRKS00003353). Between Other (eg, partial meniscectomy) 13
January 1997 and June 2001, a total of 86 patients were Previous surgeries (n = 44 patients)
treated for 82 full-thickness cartilage defects of the knee Defect associated 24
joint; of these, 70 were included in the study (16 were Osteochondral transplant 1
lost to follow-up). The mean defect size was 6.5 6 Bone marrow stimulation 5
Abrasion 2
4.0 cm2. In the majority of the patients, a single full-
Chondroplasty 16
thickness cartilage lesion was found (n = 58), while in 12 Nondefect associated 20
patients, 2 defects were treated with ACI independently. ACL reconstruction 10
Defect locations are given in Table 1. Partial meniscectomy 8
All defects were graded III or IV according to the Inter- High tibial osteotomy 2
national Cartilage Repair Society (ICRS) classification,9
a
and all patients underwent autologous periosteum-covered Values are expressed as n (%) or mean 6 standard deviation.
first-generation ACI according to the technique described ACL, anterior cruciate ligament.
by Brittberg and coauthors.10 In all patients, indications
for ACI were determined during routine arthroscopic sur-
gery of the affected knee joint. Generally, ACI was per- During arthroscopic surgery, chondrocytes were har-
formed in defects exceeding a size of 3 cm2, while in vested using a standardized cartilage biopsy tool (Storz, Tut-
smaller defects, arthroscopic microfracturing was pre- tlingen, Germany) from the intercondylar notch. Between 1
ferred. Significant corresponding cartilage lesions, uncon- and 2 million chondrocytes/cm2 (chondrocytes provided by
tained defects, and defects of the subchondral bone plate Genzyme, Cambridge, Massachusetts and Metreon Bioprod-
exceeding a depth of 3 to 4 mm were considered as exclu- ucts GmbH, Freiburg, Germany) were applied as a cell sus-
sion criteria for ACI in this study. Inclusion and exclusion pension injected beneath an autologous periosteum patch,
criteria were identical in those 12 patients who underwent which was fixed with single stitches using 6.0 PDS sutures
previous cartilage repairs in this study. In these 12 (Ethicon, Norderstedt, Germany) to achieve solid fixation in
patients, cartilage repair failed before ACI, and at the the surrounding tissue. In addition, fibrin glue (TissueCol,
time of ACI, there was a persistent cartilage defect that Baxter, Unterschleissheim, Germany) was used for addi-
was graded III or IV according to the ICRS classification. tional fixation and to seal the defect.

*Address correspondence to Philipp Niemeyer, MD, PhD, Department of Orthopedic Surgery and Traumatology, Freiburg University Hospital, Hugstet-
ter Strasse 55, D-79095 Freiburg, Germany (e-mail: philipp.niemeyer@uniklinik-freiburg.de).
y
Department of Orthopedic Surgery and Traumatology, Freiburg University Hospital, Freiburg, Germany.
z
Department for Orthobiology and Cartilage Regeneration, Schulthess Klinik, Zurich, Switzerland.

Center for Biological Joint Surgery, Zurich, Switzerland.
||
Orthopedic Department, Rostock University Hospital, Rostock, Germany.
{
Institute of Diagnostic Radiology, St Josefskrankenhaus, Freiburg, Germany.
#
Diagnostic Imaging Center, Singen, Germany.
One or more of the authors has declared the following potential conflict of interest or source of funding: The study was supported by a grant of the
Deutsche Arthrose-Hilfe e.v.

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152 Niemeyer et al The American Journal of Sports Medicine

Continuous passive motion (CPM) was recommended to

all patients after ACI from day 1 after surgery to 6 weeks
after surgery. Patients were instructed to use CPM devices
for up to 6 hours per day. Limited weightbearing of the
affected extremity was recommended for 6 weeks after
ACI. Afterward, weightbearing was stepwise increased to
full weightbearing by week 9 after surgery. Individual lim-
its of flexion were given depending on the exact defect loca-
tion to avoid early exposure of the regenerative cartilage to
axial compression and shear forces.
For an assessment of the clinical course, patient-
reported scores, such as the Knee injury and Osteoarthritis
Outcome Score (KOOS),41 subjective International Knee
Documentation Committee (IKDC) score,9 and Tegner
score,44 were used according to the general recommenda-
tions. In addition, pain at exposure during everyday activ-
ities was quantified using a visual analog scale (VAS),47 Figure 1. Estimated Kaplan-Meier survival curve.
and patients were additionally asked about their satisfac-
tion concerning clinical outcomes (very satisfied, satisfied,
neutral, not satisfied). Follow-up investigations were per- postoperative IKDC and Lysholm scores dependent on
formed by an independent investigator (S.P.) who was defect location were tested using 1-way analysis of vari-
not involved in the surgical treatment. The mean follow- ance (ANOVA). The significance level was P \ .05 for all
up was 10.9 6 1.1 years. analyses. Correlation between the Lysholm and IKDC
scores was analyzed by using the Spearman correlation
factors. For all statistical analyses, the software SPSS Ver-
Magnetic Resonance Imaging sion 19.0 was used (SPSS, Chicago, Illinois).
According to the ICRS recommendations11 for structural
evaluation of the repair tissue, a 1.5-T MRI scanner (Sie- RESULTS
mens, Erlangen, Germany) with a dedicated 8-channel
knee coil was used with the following sequences: Patient Characteristics
 fast spin echo proton density weighted (repetition time/
A total of 70 patients were included in this study. The
echo time [TR/TE], 2810/31 ms) in the coronal and sagit-
mean patient age at the time of ACI was 33.3 6 10.2 years,
tal planes;
the mean number of treated defects was 1.17 (58 patients
 fast spin echo proton density weighted with spectral fat
with single defects, and 12 patients with 2 defects), and
saturation (TR/TE, 3370/36 ms) in the transverse, coro-
the mean defect size was 6.5 6 4.0 cm2. Detailed character-
nal, and sagittal planes; and
istics are given in Table 1.
 fast spin echo T2-weighted with spectral fat saturation
(TR/TE, 5880/60 ms) in the sagittal plane.
Clinical Outcomes
The spatial resolution in the plane was 320 3 320 to 384 3
384 pixels in a field of view of 100 mm2. The T1 and T2 No complications related to the surgical procedure itself,
relaxation times and apparent diffusion coefficients change that is, postoperative infections, were noticed. All patients
during the cultivation of cartilage implants, which sug- experienced an uneventful perioperative and early postop-
gests that the biochemical properties of a cartilage implant erative clinical course. A total of 28.6% of the patients
change as the graft matures. underwent subsequent surgery of the affected joint during
The MRI evaluation was performed according to the rec- the follow-up period. A Kaplan-Meier curve concerning
ommendations given by Marlovits and coauthors28 by event-free survival after ACI is given in Figure 1. Details
means of the magnetic resonance observation of cartilage of the subsequent surgeries are given in Table 2. Outcome
repair tissue (MOCART) score. For MRI, 59 patients with data are expressed as the mean 6 standard deviation. At
71 cartilage defects were available. The MRI evaluation follow-up, pain at exposure on the VAS decreased from
was performed by an independent radiologist (N.G.) who 7.2 6 1.9 preoperatively to 2.1 6 2.1 postoperatively.
was not involved in the surgical treatment and who was Decrease of pain as evaluated on the VAS was significantly
blinded to the clinical outcomes of the individual patients. lower at follow-up compared with preoperative pain on the
VAS (P \ .01).
Statistical Analysis Clinical outcomes were assessed by different objective
scoring systems such as the Lysholm score, IKDC score,
Significant differences between different time points were and KOOS. While the mean Lysholm score increased
evaluated using a Wilcoxon test (IKDC score, Lysholm from 42.0 6 22.5 preoperatively to 71.0 6 17.4 postopera-
score, and Tegner score). Significant differences in the tively, the mean IKDC score at the time of follow-up was

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Vol. 42, No. 1, 2014 Long-term Outcomes After ACI 153

TABLE 2 TABLE 4
Types of Subsequent Surgeries Performed Patient Subjective Satisfaction With Surgical
During the Follow-up Period Treatment at Follow-up

Subsequent Surgery n (%) Very Not

Satisfied Satisfied Neutral Satisfied Total
Bone marrow stimulation 3 (4.3)
Abrasion arthroplasty 4 (5.7) Medial femoral 8 12 9 0 29
Chondroplasty 4 (5.7) condyle
Ligament reconstruction 2 (2.9) Lateral femoral 6 4 3 0 13
Meniscal surgery 3 (4.3) condyle
Realignment 1 (1.4) Trochlea 2 0 0 0 2
Other arthroscopic intervention 4 (5.7) Patella 8 5 0 1 14
Total 21 (30.0) Multiple 4 5 2 1 12
Total 28 26 14 2 70

TABLE 3
Functional Scores of Patients at Follow-upa

No. of Patients Mean 6 SD TABLE 5

Results of Morphologic MRI Evaluationa
IKDC 70 74.0 6 17.3
Lysholm 70 71.0 6 17.4 Item Defects, n (%)
KOOS 4 70 68.4 6 19.9
KOOS pain 70 81.4 6 18.2 Subchondral irregularity and overgrowth
KOOS symptoms 70 75.6 6 17.3 No 44 (62.0)
KOOS activities of daily living 70 86.0 6 16.7 Yes 27 (38.0)
KOOS sports 70 62.3 6 29.0 Subchondral cysts
KOOS quality of life 70 54.3 6 23.9 No 48 (67.6)
Tegner preoperatively 70 5.67 6 2.39 Yes 23 (32.4)
Tegner at follow-up 70 4.36 6 1.63 Subchondral bone marrow edema
MOCART 59 44.9 6 23.6 No 10 (14.1)
Yes 61 (85.9)
a
The mean follow-up was 10.9 6 1.1 years. IKDC, International Medial meniscusb
Knee Documentation Committee; KOOS, Knee injury and Osteo- Normal 33 (46.5)
arthritis Outcome Score; KOOS 4, combined score from 4 sub- Tear 12 (16.9)
scales: pain, symptoms, activities of daily living, and quality of Loss of substance 20 (28.1)
life; MOCART, magnetic resonance observation of cartilage repair Completely lost 8 (8.5)
tissue. Lateral meniscus
Normal 50 (70.4)
Tear 5 (7.0)
74.0 6 17.3. No differences in the IKDC and Lysholm Loss of substance 12 (16.9)
scores by defect location were observed (P . .05). The Completely lost 4 (5.6)
IKDC score as well as the KOOS subscales at the time of Defect filling
follow-up are given in Table 3. Additionally, patients Complete 21 (29.6)
reported being very satisfied with the procedure in 28 Filling 6 (8.5)
Incomplete .50% 25 (35.2)
cases, satisfied in 26 cases, neutral in 14 cases, and
Incomplete \50% 15 (21.1)
not satisfied in 2 cases. Those results, by defect location, Full-thickness defect 4 (5.6)
are given in Table 4.
Sports activity was assessed by the Tegner score before a
From 59 patients with 71 cartilage defects.
surgery and at the time of follow-up. A slight decrease in b
Two patients had both a tear and a loss of substance; therefore,
the Tegner score during the follow-up period was found. there were 73 defects in this category.
The mean Tegner score decreased from 5.67 6 2.39 to
4.36 6 1.63 (P \ .01).
DISCUSSION
MRI Evaluation
Autologous chondrocyte implantation was introduced by
The MRI scans were evaluated by means of the MOCART Brittberg and coworkers10 in 1994 for the treatment of
score. At follow-up, the mean MOCART score was 44.9 6 full-thickness cartilage defects of the knee. Since then, it
23.6. Morphologic MRI evaluation results at the time of has been incorporated into the treatment algorithms of
follow-up are given in Table 5. No correlation of the various international expert groups and represents
MOCART score and postoperative knee function in terms a well-accepted treatment for defects exceeding a size of
of the IKDC score could be found (Spearman coefficient, 3 to 4 cm2.13,35 Although multiple studies demonstrating
r = 0.148; P = .255). the effect of ACI in terms of functional improvement and

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154 Niemeyer et al
reduction of pain as well as a return to sports activity have
been published, long-term outcomes and long-term results,
which prove the durability of the implants, are still
limited.30,33,46
Recently, various studies with long-term results have
been published; nevertheless, the majority of these studies
report clinical and MRI-tomographic outcomes at approxi-
mately 5 to 10 years after surgery. Moseley et al34 report
clinical outcomes of a multicenter observational study in
72 patients with a mean follow-up of 9.2 years, describing
a failure rate of 17% over time and a deterioration of symp-
toms in 15% of the patients, which seem lower than what
has been reported for arthroscopic microfracturing.24,32
Loken and coauthors26 demonstrate a further improvement
in pain when comparing 1-year outcomes of 21 patients with
a longer mean follow-up of 7.4 years. The failure rate was 3
of 21 patients (14%). Recently, Genovese et al18 also
described the outcomes of 13 patients at 60 months after
ACI for cartilage defects of the knee including MRI evalua-
tion by means of the MOCART score. This group also
described satisfying clinical outcomes and a MOCART score
of 65 at 60 months, which was comparable and stable to that
found in an earlier evaluation of the identical patients at 30
months. A generally high satisfaction rate of 98% has been
described at 60 months after ACI by Ebert et al,16 including
a specific satisfaction rate of 73% of the patients concerning
sports activity. These data are also supported by Corpus
et al,14 who found at a mean of 8.4 years after ACI that
88.9% of the patients would undergo the procedure again.
Peterson et al40 were the first to publish clinical data of
224 patients with a follow-up of 10 to 20 years. Interest-
ingly, while a high percentage of satisfied patients were
reported on MRI, subchondral bone marrow edemas were
found in a significant proportion of patients, but no corre-
lation to long-term clinical outcomes was reported. The
overall mean Lysholm score was 69. Additionally, the
KOOS was used for clinical evaluations, demonstrating
mean values of 74.8 for pain, 63.0 for symptoms, 81.0 for
activities of daily living, 41.5 for sports, and 49.3 for qual-
ity of life. The authors demonstrated stable results of those
patients with good clinical outcomes at 2 years, which
seems to be a sign of durable regenerative tissue induced
by ACI. This hypothesis of high-quality repair tissue was
confirmed by an MRI study of the identical group of
patients, demonstrating an equal quality of repair tissue
compared with the surrounding cartilage in 31 patients
by delayed gadolinium-enhanced MRI of cartilage (dGEM-
RIC) biochemical scans.46
Furthermore, Moradi et al33 recently published a
case series of 23 subsequent patients who underwent
periosteum-covered ACI for cartilage defects of the knee
with a mean follow-up of 9.9 years. Although younger
patients with small defects and a short duration of symptoms
seemed to be preferable, a total of 73.1% stated that they
would undergo the identical operation again. The mean
IDKC score at follow-up was 69.1; a slight deterioration of
symptoms was observed compared with outcomes at 12
months. Nevertheless, this lacked statistical significance.33
In addition to those results, Bentley et al4 published
data of 100 patients with a mean defect size of
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The American Journal of Sports Medicine
approximately 4 cm2 randomized to either treatment
with mosaicplasty or ACI for cartilage defects of the knee
with a minimum follow-up of 10 years. In this study, con-
cerning the failure rate, a significant superiority of ACI
versus mosaicplasty could be demonstrated. While a failure
rate of 51% was observed in the mosaicplasty group, the
failure rate of ACI in this long-term follow-up was 17%.
Functional outcomes, as assessed by the Cincinnati knee
score and the Stanmore-Bentley Functional Rating Sys-
tem, were also better in those patients treated with ACI.4
The present article presents long-term outcomes of 70
patients treated with ACI using cell suspension in combina-
tion with autologous periosteum, which has subsequently
been described as first-generation ACI,29 with a mean
follow-up of 10.9 years. The technique is analogous to the
above-mentioned study by Peterson et al40 and is partially
identical to the Bentley et al4 study, which used both first-
generation periosteum-covered ACI and second-generation
Chondro-Gide (Geistlich, Wolhusen, Switzerland).
In direct comparison to those studies, the KOOS value
in our patient population was slightly better compared
with that in the Peterson et al40 study but within the range
of those results. A mean score of 81.4 on the pain subscale
was observed, while the value for KOOS symptoms was
75.6, KOOS activities of daily living was 86.0, KOOS sports
was 62.3, and KOOS quality of life was 54.3. The overall
activity score was slightly lower compared with that in
the Peterson et al40 study; the mean Tegner score was
4.36. Nevertheless, these clinical results confirm what
was earlier described by Peterson et al,40 in that long-
term stable functional outcomes can be achieved by means
of ACI in patients with focal cartilage defects. In addition,
the results are in line with other studies describing out-
comes of ACI in different patient populations.1 Compared
with the evaluation of Corpus et al,14 the mean KOOS val-
ues are also in the range of results at 8 years with a ten-
dency of slightly superior KOOS values in the present
study.
Concerning further evaluation scores, we observed
a mean IKDC score of 74.0 and a mean Lysholm score of
71.0. This is in the range of earlier reported publications
and comparable with the clinical outcomes found in the
study of Peterson et al,40 who published a mean Lysholm
score of 69 in a total of 224 patients between 10 and 20
years after periosteum ACI. Although outcomes as evalu-
ated by means of the IKDC score cannot be interpreted
as complete healing of the cartilage defect, we found
a very high proportion of patients who considered them-
selves satisfied or very satisfied with their clinical out-
comes more than 10 years after ACI. This contrast in
patient satisfaction and objective functional outcomes
could be caused by a high psychological strain, a high
pain intensity, and a significant decrease in the quality
of life and activity of patients with cartilage defects before
ACI, which have been reported by other authors.21 Fur-
thermore, moderate scores at follow-up could also be
caused by the fact that patients involved in this case series
are not characterized by a selection process before ACI; all
patients treated with ACI for focal cartilage defects were
involved, regardless of any specific inclusion and exclusion
Vol. 42, No. 1, 2014
criteria. This might explain the slightly inferior IKDC
scores compared with those in other interventional studies
with a detailed selection process before inclusion.23,43 The
phenomenon that patients included in prospective random-
ized trials are not representative has also been described
earlier.17 Nevertheless, mean functional scores of the pres-
ent publication also confirm that no restitutio ad integ-
rum is achieved in the majority of the patients. The
percentage of patients with persistent moderate symptoms
and complaints seems high, although most patients have
improved and achieved good clinical results in the long
term.
Independent of any absolute score values, the present
data demonstrate the long-term efficiency of ACI in the
treatment of focal cartilage defects. We found a very high
rate of patient satisfaction even 10 years after ACI. A
proportion of 77% of the patients were satisfied with the
ACI procedure, which is a remarkable high proportion
and once more underlines high patient satisfaction. This
corresponds to what has been reported earlier and con-
firms previous published studies, which also describe
very high patient satisfaction even with moderate objective
functional scores at the time of follow-up.16,33,40 This phe-
nomenon might be explained by the high preoperative psy-
chological and physical strains of patients affected by full-
thickness cartilage defects of the knee.21
The overall rate of patients who required subsequent
surgery during the follow-up period was almost 30%. In
comparison, this is slightly higher than what has been
reported earlier20,22,36 but includes all surgeries of the
affected knee in the clinical course after ACI and therefore
does not correspond to a treatment or graft failure. Some of
the procedures performed during follow-up were not
related to the transplant. Although no specific complica-
tions related to the implantation of autologous chondro-
cytes nor caused by the implantation of autologous
periosteum were observed, the high revision rate needs
to be interpreted against the background that revision
was defined as any secondary surgery during the follow-
up period. Compared with today, follow-up arthroscopic
surgery was probably indicated more liberally during the
early phase of ACI because little was known about possible
problems and specific findings during follow-up, and
knowledge about typical MRI findings was also limited.
Additionally, concerning the revision rate of this study, it
also needs to be considered that first-generation ACI was
used, which is associated with a higher incidence of graft
hypertrophy and a significantly higher revision rate com-
pared with second- and third-generation ACI.
In addition to clinical evaluations, we performed MRI
analysis of the repair tissue after ACI, which was evaluated
by use of the MOCART score. The overall MOCART score
was 44.9, which is moderate and cannot be considered
a good result based upon MRI outcomes. Analogous to
Peterson et al,40 we observed subchondral edemas in the
vast majority of the cases (85.9%). Although subchondral
edemas could be identified as a prognostic factor in the early
clinical course after ACI,37 we did not find any correlation
either with the overall MOCART score and clinical out-
comes nor with the incidence or size of the subchondral
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Long-term Outcomes After ACI 155
edema and knee function as evaluated by the IKDC score
or KOOS. The failed correlation of MRI results and clinical
outcomes has also been described by other authors before,6
and this circumstance makes monitoring patients after ACI
by the use of MRI difficult. Nevertheless, because we only
evaluated patients once during the clinical course after
ACI, the present data do not allow us to draw any conclu-
sion about a possible relationship between an increase or
decrease of single factors such as subchondral edemas in
sequential MRI scans, which might indeed be helpful for
postoperative monitoring of ACI patients. Yet, still with
regard to other studies evaluating patients by MRI and
standardized scores, there seems to be a trend for inferior
MRI results compared with functional outcomes. Moradi
et al33 found complete filling in only 53.1% of their patients,
bone edema in 47.6%, and effusion of the affected joint in
47.6%. Only defect filling and repairs correlated with clini-
cal outcomes (IKDC score).33 These observations go along
with those of Marlovits et al,28 who evaluated the variability
of the MOCART score and correlations to clinical outcomes
earlier except for the observation that, in this study, against
the results of the present study and the long-term outcome
study of Peterson et al,40 a correlation of subchondral edema
and clinical outcomes has also been postulated. Interest-
ingly, there is a huge range of MOCART scores reported
in the postoperative clinical course after ACI. Some recent
studies evaluating patients after ACI by the MOCART score
describe better MRI findings; Anders et al1 reported a mean
MOCART score of over 80 at 5 years in 22 patients, and
Marlovits et al,27 who used the MOCART score, also
reported a mean score of 75.8 at 5 years in 21 patients.
Because all these studies have a limited follow-up of
5 years, the limited MOCART score of the present
study and the high incidence of pathologic MRI findings
(including intralesional osteophytes, subchondral edemas,
etc) in the Swedish studies of Petersons group40,46 might
be interpreted as potential evidence that MRI findings dete-
riorate over time while clinical outcomes remain stable.
Referring to the outcome analysis of the present study,
patients were enrolled as early as 1997 to 2001, which also
explains why the IKDC scores and KOOS values, which
had not been assessed at that time, were not available
before enrollment. In addition, at this time, only a few pub-
lications were available.8,10,39 Limitations, risk factors for
failure, and positive prognostic factors were described
later.15,22,25 No controlled studies and even no guidelines
by orthopaedic societies describing the optimal indications
for ACI were available but were published later on.3,13
Against this background, a critical retrospective analysis
of the patients treated with ACI at this early stage has to
be considered. This case series reveals some relevant fac-
tors that make failure more likely compared with the ideal
indications for ACI, which have been evaluated in many
subsequent publications.25,38 Additionally, no treated
patients were excluded from the present study, and the
patient cohort represents a realistic cohort. This also
seems to differ from prospective controlled clinical trials
and might not be representative to its full extent as demon-
strated by Engen et al.17 A vast majority of the patients
included in the present study underwent multiple
156 Niemeyer et al
operations before ACI, and the mean duration of symptoms
was several years. Both parameters have been correlated
with inferior prognoses recently,22,45 and the percentage
of concomitant surgeries (number of concomitant surger-
ies, n = 20; 30%) was lower compared with patients treated
in our institution recently, as some new studies demon-
strate the benefit of addressing discrete deformities, such
as a slight malalignment, more aggressively.7 Additionally,
MRI at follow-up revealed a substantial loss of the menis-
cus of the affected compartment in more than a third of the
patients. Because none of these patients underwent partial
meniscectomy after ACI, this is a pre-existing parameter
that certainly also influences the clinical course after
ACI negatively. Outcomes in this case series report
patients who were treated with first-generation ACI.
Many studies reveal a higher complication rate and infe-
rior clinical outcomes of this type of ACI in direct compar-
ison to second- or third-generation ACI.19,22,36 A further
improvement of outcomes in long-term follow-up studies
seems likely for recently developed autologous cell prod-
ucts.2,36 Taking all these parameters together, the overall
satisfaction of the patients in this long-term follow-up
study is even more remarkable.
REFERENCES
1. Anders S, Goetz J, Schubert T, Grifka J, Schaumburger J. Treatment of
deep articular talus lesions by matrix associated autologous chondrocyte
implantation: results at five years. Int Orthop. 2012;36(11):2279-2285.
2. Bartlett W, Skinner JA, Gooding CR, et al. Autologous chondrocyte
implantation versus matrix-induced autologous chondrocyte implan-
tation for osteochondral defects of the knee: a prospective, rando-
mised study. J Bone Joint Surg Br. 2005;87(5):640-645.
3. Behrens P, Bosch U, Bruns J, et al. [Indications and implementation
of recommendations of the working group Tissue Regeneration and
Tissue Substitutes for autologous chondrocyte transplantation
(ACT)]. Z Orthop Ihre Grenzgeb. 2004;142(5):529-539.
4. Bentley G, Biant LC, Vijayan S, Macmull S, Skinner JA, Carrington
RW. Minimum ten-year results of a prospective randomised study
of autologous chondrocyte implantation versus mosaicplasty for
symptomatic articular cartilage lesions of the knee. J Bone Joint
Surg Br. 2012;94(4):504-509.
5. Beris AE, Lykissas MG, Kostas-Agnantis I, Manoudis GN. Treatment
of full-thickness chondral defects of the knee with autologous chon-
drocyte implantation: a functional evaluation with long-term follow-
up. Am J Sports Med. 2012;40(3):562-567.
6. Blackman AJ, Smith MV, Flanigan DC, Matava MJ, Wright RW, Bro-
phy RH. Correlation between magnetic resonance imaging and clin-
ical outcomes after cartilage repair surgery in the knee: a systematic
review and meta-analysis. Am J Sports Med. 2013;41(6):1426-1434.
7. Bode G, Schmal H, Pestka JM, Ogon P, Sudkamp NP, Niemeyer P. A
non-randomized controlled clinical trial on autologous chondrocyte
implantation (ACI) in cartilage defects of the medial femoral condyle
with or without high tibial osteotomy in patients with varus deformity
of less than 5 degrees. Arch Orthop Trauma Surg. 2013;133(1):43-49.
8. Brittberg M. Autologous chondrocyte transplantation. Clin Orthop
Relat Res. 1999;367 Suppl:S147-S155.
9. Brittberg M. ICRS Clinical Cartilage Injury Evaluation System. Paper
presented at: 3rd ICRS Meeting; April 28, 2000; Goteborg, Sweden.
Available at: www.cartilage.org/_files/contentmanagement/ICRS_
evaluation.pdf. Accessed January 3, 2012.
10. Brittberg M, Lindahl A, Nilsson A, Ohlsson C, Isaksson O, Peterson L.
Treatment of deep cartilage defects in the knee with autologous
chondrocyte transplantation. N Engl J Med. 1994;331(14):889-895.
Downloaded from ajs.sagepub.com by guest on April 8, 2016
The American Journal of Sports Medicine
11. Choi Y, Potter HG. MR imaging sequences for evaluation of cartilage
repair. Radiographics. 2008;28:1043-1059.
12. Cicuttini F, Ding C, Wluka A, Davis S, Ebeling PR, Jones G. Associ-
ation of cartilage defects with loss of knee cartilage in healthy,
middle-age adults: a prospective study. Arthritis Rheum. 2005;
52(7):2033-2039.
13. Cole BJ, Pascual-Garrido C, Grumet RC. Surgical management of
articular cartilage defects in the knee. J Bone Joint Surg Am.
2009;91(7):1778-1790.
14. Corpus KT, Bajaj S, Daley EL, et al. Long-term evaluation of autolo-
gous chondrocyte implantation: minimum 7-year follow-up. Carti-
lage. 2012;3(4):342-350.
15. de Windt TS, Bekkers JE, Creemers LB, Dhert WJ, Saris DB. Patient
profiling in cartilage regeneration: prognostic factors determining
success of treatment for cartilage defects. Am J Sports Med.
2009;37 Suppl 1:58S-62S.
16. Ebert JR, Robertson WB, Woodhouse J, et al. Clinical and magnetic
resonance imaging-based outcomes to 5 years after matrix-induced
autologous chondrocyte implantation to address articular cartilage
defects in the knee. Am J Sports Med. 2011;39(4):753-763.
17. Engen CN, Engebretsen L, Aroen A. Knee cartilage defect patients
enrolled in randomized controlled trials are not representative of
patients in orthopedic practice. Cartilage. 2010;1(4):312-319.
18. Genovese E, Ronga M, Angeretti MG, et al. Matrix-induced autolo-
gous chondrocyte implantation of the knee: mid-term and long-
term follow-up by MR arthrography. Skeletal Radiol. 2011;40(1):47-
56.
19. Gooding CR, Bartlett W, Bentley G, Skinner JA, Carrington R, Flana-
gan A. A prospective, randomised study comparing two techniques
of autologous chondrocyte implantation for osteochondral defects
in the knee: periosteum covered versus type I/III collagen covered.
Knee. 2006;13(3):203-210.
20. Harris JD, Siston RA, Brophy RH, Lattermann C, Carey JL, Flanigan
DC. Failures, re-operations, and complications after autologous
chondrocyte implantation: a systematic review. Osteoarthritis Carti-
lage. 2011;19(7):779-791.
21. Heir S, Nerhus TK, Rotterud JH, et al. Focal cartilage defects in the
knee impair quality of life as much as severe osteoarthritis: a compar-
ison of Knee Injury and Osteoarthritis Outcome Score in 4 patient
categories scheduled for knee surgery. Am J Sports Med.
2010;38(2):231-237.
22. Jungmann PM, Salzmann GM, Schmal H, Pestka JM, Sudkamp NP,
Niemeyer P. Autologous chondrocyte implantation for treatment of
cartilage defects of the knee: what predicts the need for reinterven-
tion? Am J Sports Med. 2012;40(1):58-67.
23. Kon E, Filardo G, Berruto M, et al. Articular cartilage treatment in
high-level male soccer players: a prospective comparative study of
arthroscopic second-generation autologous chondrocyte implanta-
tion versus microfracture. Am J Sports Med. 2011;39(12):2549-2557.
24. Kreuz PC, Erggelet C, Steinwachs MR, et al. Is microfracture of chon-
dral defects in the knee associated with different results in patients
aged 40 years or younger? Arthroscopy. 2006;22(11):1180-1186.
25. Krishnan SP, Skinner JA, Bartlett W, et al. Who is the ideal candidate
for autologous chondrocyte implantation? J Bone Joint Surg Br.
2006;88(1):61-64.
26. Loken S, Ludvigsen TC, Hoysveen T, Holm I, Engebretsen L, Reinholt
FP. Autologous chondrocyte implantation to repair knee cartilage
injury: ultrastructural evaluation at 2 years and long-term follow-up
including muscle strength measurements. Knee Surg Sports Trauma-
tol Arthrosc. 2009;17(11):1278-1288.
27. Marlovits S, Aldrian S, Wondrasch B, et al. Clinical and radiological
outcomes 5 years after matrix-induced autologous chondrocyte
implantation in patients with symptomatic, traumatic chondral
defects. Am J Sports Med. 2012;40(10):2273-2280.
28. Marlovits S, Singer P, Zeller P, Mandl I, Haller J, Trattnig S. Magnetic
resonance observation of cartilage repair tissue (MOCART) for the
evaluation of autologous chondrocyte transplantation: determination
of interobserver variability and correlation to clinical outcome after 2
years. Eur J Radiol. 2006;57(1):16-23.
Vol. 42, No. 1, 2014
29. Marlovits S, Zeller P, Singer P, Resinger C, Vecsei V. Cartilage repair:
generations of autologous chondrocyte transplantation. Eur J Radiol.
2006;57(1):24-31.
30. Minas T, Von Keudell A, Bryant T, Gomoll AH. The John Insall Award:
a minimum 10-year outcome study of autologous chondrocyte
implantation [published online August 24, 2013]. Clin Orthop Relat
Res. doi:10.1007/s11999-013-3146-9.
31. Mithoefer K, McAdams T, Williams RJ, Kreuz PC, Mandelbaum BR.
Clinical efficacy of the microfracture technique for articular cartilage
repair in the knee: an evidence-based systematic analysis. Am J
Sports Med. 2009;37(10):2053-2063.
32. Mithoefer K, Williams RJ 3rd, Warren RF, et al. The microfracture
technique for the treatment of articular cartilage lesions in the
knee: a prospective cohort study. J Bone Joint Surg Am.
2005;87(9):1911-1920.
33. Moradi B, Schonit E, Nierhoff C, et al. First-generation autologous
chondrocyte implantation in patients with cartilage defects of the
knee: 7 to 14 years clinical and magnetic resonance imaging fol-
low-up evaluation [published online October 2, 2012]. Arthroscopy.
doi:10.1016/j.arthro.2012.05.883.
34. Moseley JB Jr, Anderson AF, Browne JE, et al. Long-term durability
of autologous chondrocyte implantation: a multicenter, observational
study in US patients. Am J Sports Med. 2010;38(2):238-246.
35. Niemeyer P, Andereya S, Angele P, et al. Autologous chondrocyte
implantation (ACI) for cartilage defects of the knee: a guideline by
the working group Tissue Regeneration of the German Society of
Orthopaedic Surgery and Traumatology (DGOU) [in German]. Z
Orthop Unfall. 2013;151(1):38-47.
36. Niemeyer P, Pestka JM, Kreuz PC, et al. Characteristic complications
after autologous chondrocyte implantation for cartilage defects of the
knee joint. Am J Sports Med. 2008;36(11):2091-2099.
37. Niemeyer P, Salzmann G, Steinwachs M, et al. Presence of subchon-
dral bone marrow edema at the time of treatment represents a nega-
tive prognostic factor for early outcome after autologous
chondrocyte implantation. Arch Orthop Trauma Surg. 2010;
130(8):977-983.
For reprints and permission queries, please visit SAGEs Web site at http://www.sagepub.com/journalsPermissions.nav
Downloaded from ajs.sagepub.com by guest on April 8, 2016
Long-term Outcomes After ACI 157
38. Niemeyer P, Salzmann GM, Hirschmuller A, Sudkamp NP. Factors
that influence clinical outcome following autologous chondrocyte
implantation for cartilage defects of the knee [in German]. Z Orthop
Unfall. 2012;150(1):83-88.
39. Peterson L, Minas T, Brittberg M, Nilsson A, Sjogren-Jansson E, Lin-
dahl A. Two- to 9-year outcome after autologous chondrocyte trans-
plantation of the knee. Clin Orthop Relat Res. 2000;374:212-234.
40. Peterson L, Vasiliadis HS, Brittberg M, Lindahl A. Autologous chon-
drocyte implantation: a long-term follow-up. Am J Sports Med.
2010;38(6):1117-1124.
41. Roos EM, Roos HP, Lohmander LS, Ekdahl C, Beynnon BD. Knee
Injury and Osteoarthritis Outcome Score (KOOS): development of
a self-administered outcome measure. J Orthop Sports Phys Ther.
1998;28(2):88-96.
42. Saris DB, Vanlauwe J, Victor J, et al. Characterized chondrocyte
implantation results in better structural repair when treating symp-
tomatic cartilage defects of the knee in a randomized controlled trial
versus microfracture. Am J Sports Med. 2008;36(2):235-246.
43. Saris DB, Vanlauwe J, Victor J, et al. Treatment of symptomatic car-
tilage defects of the knee: characterized chondrocyte implantation
results in better clinical outcome at 36 months in a randomized trial
compared to microfracture. Am J Sports Med. 2009;37 Suppl
1:10S-19S.
44. Tegner Y, Lysholm J. Rating systems in the evaluation of knee liga-
ment injuries. Clin Orthop Relat Res. 1985;198:43-49.
45. Vanlauwe J, Saris DB, Victor J, Almqvist KF, Bellemans J, Luyten FP.
Five-year outcome of characterized chondrocyte implantation versus
microfracture for symptomatic cartilage defects of the knee: early
treatment matters. Am J Sports Med. 2011;39(12):2566-2574.
46. Vasiliadis HS, Danielson B, Ljungberg M, McKeon B, Lindahl A,
Peterson L. Autologous chondrocyte implantation in cartilage lesions
of the knee: long-term evaluation with magnetic resonance imaging
and delayed gadolinium-enhanced magnetic resonance imaging
technique. Am J Sports Med. 2010;38(5):943-949.
47. Williamson A, Hoggart B. Pain: a review of three commonly used pain
rating scales. J Clin Nurs. 2005;14(7):798-804.