You are on page 1of 9

The American Journal of Sports

Medicine http://ajs.sagepub.com/

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

The online version of this article can be found at:


http://ajs.sagepub.com/content/42/1/150

Published by:

http://www.sagepublications.com

On behalf of:
American Orthopaedic Society for Sports Medicine

Additional services and information for The American Journal of Sports Medicine can be found at:

Email Alerts: http://ajs.sagepub.com/cgi/alerts

Subscriptions: http://ajs.sagepub.com/subscriptions

Reprints: http://www.sagepub.com/journalsReprints.nav

Permissions: http://www.sagepub.com/journalsPermissions.nav

>> Version of Record - Jan 2, 2014

OnlineFirst Version of Record - Oct 21, 2013

What is This?

Downloaded from ajs.sagepub.com by guest on April 8, 2016


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

150
Downloaded from ajs.sagepub.com by guest on April 8, 2016
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.

Downloaded from ajs.sagepub.com by guest on April 8, 2016


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

Downloaded from ajs.sagepub.com by guest on April 8, 2016


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

Downloaded from ajs.sagepub.com by guest on April 8, 2016


154 Niemeyer et al The American Journal of Sports Medicine

reduction of pain as well as a return to sports activity have approximately 4 cm2 randomized to either treatment
been published, long-term outcomes and long-term results, with mosaicplasty or ACI for cartilage defects of the knee
which prove the durability of the implants, are still with a minimum follow-up of 10 years. In this study, con-
limited.30,33,46 cerning the failure rate, a significant superiority of ACI
Recently, various studies with long-term results have versus mosaicplasty could be demonstrated. While a failure
been published; nevertheless, the majority of these studies rate of 51% was observed in the mosaicplasty group, the
report clinical and MRI-tomographic outcomes at approxi- failure rate of ACI in this long-term follow-up was 17%.
mately 5 to 10 years after surgery. Moseley et al34 report Functional outcomes, as assessed by the Cincinnati knee
clinical outcomes of a multicenter observational study in score and the Stanmore-Bentley Functional Rating Sys-
72 patients with a mean follow-up of 9.2 years, describing tem, were also better in those patients treated with ACI.4
a failure rate of 17% over time and a deterioration of symp- The present article presents long-term outcomes of 70
toms in 15% of the patients, which seem lower than what patients treated with ACI using cell suspension in combina-
has been reported for arthroscopic microfracturing.24,32 tion with autologous periosteum, which has subsequently
Loken and coauthors26 demonstrate a further improvement been described as first-generation ACI,29 with a mean
in pain when comparing 1-year outcomes of 21 patients with follow-up of 10.9 years. The technique is analogous to the
a longer mean follow-up of 7.4 years. The failure rate was 3 above-mentioned study by Peterson et al40 and is partially
of 21 patients (14%). Recently, Genovese et al18 also identical to the Bentley et al4 study, which used both first-
described the outcomes of 13 patients at 60 months after generation periosteum-covered ACI and second-generation
ACI for cartilage defects of the knee including MRI evalua- Chondro-Gide (Geistlich, Wolhusen, Switzerland).
tion by means of the MOCART score. This group also In direct comparison to those studies, the KOOS value
described satisfying clinical outcomes and a MOCART score in our patient population was slightly better compared
of 65 at 60 months, which was comparable and stable to that with that in the Peterson et al40 study but within the range
found in an earlier evaluation of the identical patients at 30 of those results. A mean score of 81.4 on the pain subscale
months. A generally high satisfaction rate of 98% has been was observed, while the value for KOOS symptoms was
described at 60 months after ACI by Ebert et al,16 including 75.6, KOOS activities of daily living was 86.0, KOOS sports
a specific satisfaction rate of 73% of the patients concerning was 62.3, and KOOS quality of life was 54.3. The overall
sports activity. These data are also supported by Corpus activity score was slightly lower compared with that in
et al,14 who found at a mean of 8.4 years after ACI that the Peterson et al40 study; the mean Tegner score was
88.9% of the patients would undergo the procedure again. 4.36. Nevertheless, these clinical results confirm what
Peterson et al40 were the first to publish clinical data of was earlier described by Peterson et al,40 in that long-
224 patients with a follow-up of 10 to 20 years. Interest- term stable functional outcomes can be achieved by means
ingly, while a high percentage of satisfied patients were of ACI in patients with focal cartilage defects. In addition,
reported on MRI, subchondral bone marrow edemas were the results are in line with other studies describing out-
found in a significant proportion of patients, but no corre- comes of ACI in different patient populations.1 Compared
lation to long-term clinical outcomes was reported. The with the evaluation of Corpus et al,14 the mean KOOS val-
overall mean Lysholm score was 69. Additionally, the ues are also in the range of results at 8 years with a ten-
KOOS was used for clinical evaluations, demonstrating dency of slightly superior KOOS values in the present
mean values of 74.8 for pain, 63.0 for symptoms, 81.0 for study.
activities of daily living, 41.5 for sports, and 49.3 for qual- Concerning further evaluation scores, we observed
ity of life. The authors demonstrated stable results of those a mean IKDC score of 74.0 and a mean Lysholm score of
patients with good clinical outcomes at 2 years, which 71.0. This is in the range of earlier reported publications
seems to be a sign of durable regenerative tissue induced and comparable with the clinical outcomes found in the
by ACI. This hypothesis of high-quality repair tissue was study of Peterson et al,40 who published a mean Lysholm
confirmed by an MRI study of the identical group of score of 69 in a total of 224 patients between 10 and 20
patients, demonstrating an equal quality of repair tissue years after periosteum ACI. Although outcomes as evalu-
compared with the surrounding cartilage in 31 patients ated by means of the IKDC score cannot be interpreted
by delayed gadolinium-enhanced MRI of cartilage (dGEM- as complete healing of the cartilage defect, we found
RIC) biochemical scans.46 a very high proportion of patients who considered them-
Furthermore, Moradi et al33 recently published a selves satisfied or very satisfied with their clinical out-
case series of 23 subsequent patients who underwent comes more than 10 years after ACI. This contrast in
periosteum-covered ACI for cartilage defects of the knee patient satisfaction and objective functional outcomes
with a mean follow-up of 9.9 years. Although younger could be caused by a high psychological strain, a high
patients with small defects and a short duration of symptoms pain intensity, and a significant decrease in the quality
seemed to be preferable, a total of 73.1% stated that they of life and activity of patients with cartilage defects before
would undergo the identical operation again. The mean ACI, which have been reported by other authors.21 Fur-
IDKC score at follow-up was 69.1; a slight deterioration of thermore, moderate scores at follow-up could also be
symptoms was observed compared with outcomes at 12 caused by the fact that patients involved in this case series
months. Nevertheless, this lacked statistical significance.33 are not characterized by a selection process before ACI; all
In addition to those results, Bentley et al4 published patients treated with ACI for focal cartilage defects were
data of 100 patients with a mean defect size of involved, regardless of any specific inclusion and exclusion

Downloaded from ajs.sagepub.com by guest on April 8, 2016


Vol. 42, No. 1, 2014 Long-term Outcomes After ACI 155

criteria. This might explain the slightly inferior IKDC edema and knee function as evaluated by the IKDC score
scores compared with those in other interventional studies or KOOS. The failed correlation of MRI results and clinical
with a detailed selection process before inclusion.23,43 The outcomes has also been described by other authors before,6
phenomenon that patients included in prospective random- and this circumstance makes monitoring patients after ACI
ized trials are not representative has also been described by the use of MRI difficult. Nevertheless, because we only
earlier.17 Nevertheless, mean functional scores of the pres- evaluated patients once during the clinical course after
ent publication also confirm that no restitutio ad integ- ACI, the present data do not allow us to draw any conclu-
rum is achieved in the majority of the patients. The sion about a possible relationship between an increase or
percentage of patients with persistent moderate symptoms decrease of single factors such as subchondral edemas in
and complaints seems high, although most patients have sequential MRI scans, which might indeed be helpful for
improved and achieved good clinical results in the long postoperative monitoring of ACI patients. Yet, still with
term. regard to other studies evaluating patients by MRI and
Independent of any absolute score values, the present standardized scores, there seems to be a trend for inferior
data demonstrate the long-term efficiency of ACI in the MRI results compared with functional outcomes. Moradi
treatment of focal cartilage defects. We found a very high et al33 found complete filling in only 53.1% of their patients,
rate of patient satisfaction even 10 years after ACI. A bone edema in 47.6%, and effusion of the affected joint in
proportion of 77% of the patients were satisfied with the 47.6%. Only defect filling and repairs correlated with clini-
ACI procedure, which is a remarkable high proportion cal outcomes (IKDC score).33 These observations go along
and once more underlines high patient satisfaction. This with those of Marlovits et al,28 who evaluated the variability
corresponds to what has been reported earlier and con- of the MOCART score and correlations to clinical outcomes
firms previous published studies, which also describe earlier except for the observation that, in this study, against
very high patient satisfaction even with moderate objective the results of the present study and the long-term outcome
functional scores at the time of follow-up.16,33,40 This phe- study of Peterson et al,40 a correlation of subchondral edema
nomenon might be explained by the high preoperative psy- and clinical outcomes has also been postulated. Interest-
chological and physical strains of patients affected by full- ingly, there is a huge range of MOCART scores reported
thickness cartilage defects of the knee.21 in the postoperative clinical course after ACI. Some recent
The overall rate of patients who required subsequent studies evaluating patients after ACI by the MOCART score
surgery during the follow-up period was almost 30%. In describe better MRI findings; Anders et al1 reported a mean
comparison, this is slightly higher than what has been MOCART score of over 80 at 5 years in 22 patients, and
reported earlier20,22,36 but includes all surgeries of the Marlovits et al,27 who used the MOCART score, also
affected knee in the clinical course after ACI and therefore reported a mean score of 75.8 at 5 years in 21 patients.
does not correspond to a treatment or graft failure. Some of Because all these studies have a limited follow-up of
the procedures performed during follow-up were not 5 years, the limited MOCART score of the present
related to the transplant. Although no specific complica- study and the high incidence of pathologic MRI findings
tions related to the implantation of autologous chondro- (including intralesional osteophytes, subchondral edemas,
cytes nor caused by the implantation of autologous etc) in the Swedish studies of Petersons group40,46 might
periosteum were observed, the high revision rate needs be interpreted as potential evidence that MRI findings dete-
to be interpreted against the background that revision riorate over time while clinical outcomes remain stable.
was defined as any secondary surgery during the follow- Referring to the outcome analysis of the present study,
up period. Compared with today, follow-up arthroscopic patients were enrolled as early as 1997 to 2001, which also
surgery was probably indicated more liberally during the explains why the IKDC scores and KOOS values, which
early phase of ACI because little was known about possible had not been assessed at that time, were not available
problems and specific findings during follow-up, and before enrollment. In addition, at this time, only a few pub-
knowledge about typical MRI findings was also limited. lications were available.8,10,39 Limitations, risk factors for
Additionally, concerning the revision rate of this study, it failure, and positive prognostic factors were described
also needs to be considered that first-generation ACI was later.15,22,25 No controlled studies and even no guidelines
used, which is associated with a higher incidence of graft by orthopaedic societies describing the optimal indications
hypertrophy and a significantly higher revision rate com- for ACI were available but were published later on.3,13
pared with second- and third-generation ACI. Against this background, a critical retrospective analysis
In addition to clinical evaluations, we performed MRI of the patients treated with ACI at this early stage has to
analysis of the repair tissue after ACI, which was evaluated be considered. This case series reveals some relevant fac-
by use of the MOCART score. The overall MOCART score tors that make failure more likely compared with the ideal
was 44.9, which is moderate and cannot be considered indications for ACI, which have been evaluated in many
a good result based upon MRI outcomes. Analogous to subsequent publications.25,38 Additionally, no treated
Peterson et al,40 we observed subchondral edemas in the patients were excluded from the present study, and the
vast majority of the cases (85.9%). Although subchondral patient cohort represents a realistic cohort. This also
edemas could be identified as a prognostic factor in the early seems to differ from prospective controlled clinical trials
clinical course after ACI,37 we did not find any correlation and might not be representative to its full extent as demon-
either with the overall MOCART score and clinical out- strated by Engen et al.17 A vast majority of the patients
comes nor with the incidence or size of the subchondral included in the present study underwent multiple

Downloaded from ajs.sagepub.com by guest on April 8, 2016


156 Niemeyer et al The American Journal of Sports Medicine

operations before ACI, and the mean duration of symptoms 11. Choi Y, Potter HG. MR imaging sequences for evaluation of cartilage
was several years. Both parameters have been correlated repair. Radiographics. 2008;28:1043-1059.
12. Cicuttini F, Ding C, Wluka A, Davis S, Ebeling PR, Jones G. Associ-
with inferior prognoses recently,22,45 and the percentage
ation of cartilage defects with loss of knee cartilage in healthy,
of concomitant surgeries (number of concomitant surger- middle-age adults: a prospective study. Arthritis Rheum. 2005;
ies, n = 20; 30%) was lower compared with patients treated 52(7):2033-2039.
in our institution recently, as some new studies demon- 13. Cole BJ, Pascual-Garrido C, Grumet RC. Surgical management of
strate the benefit of addressing discrete deformities, such articular cartilage defects in the knee. J Bone Joint Surg Am.
as a slight malalignment, more aggressively.7 Additionally, 2009;91(7):1778-1790.
MRI at follow-up revealed a substantial loss of the menis- 14. Corpus KT, Bajaj S, Daley EL, et al. Long-term evaluation of autolo-
gous chondrocyte implantation: minimum 7-year follow-up. Carti-
cus of the affected compartment in more than a third of the lage. 2012;3(4):342-350.
patients. Because none of these patients underwent partial 15. de Windt TS, Bekkers JE, Creemers LB, Dhert WJ, Saris DB. Patient
meniscectomy after ACI, this is a pre-existing parameter profiling in cartilage regeneration: prognostic factors determining
that certainly also influences the clinical course after success of treatment for cartilage defects. Am J Sports Med.
ACI negatively. Outcomes in this case series report 2009;37 Suppl 1:58S-62S.
patients who were treated with first-generation ACI. 16. Ebert JR, Robertson WB, Woodhouse J, et al. Clinical and magnetic
resonance imaging-based outcomes to 5 years after matrix-induced
Many studies reveal a higher complication rate and infe-
autologous chondrocyte implantation to address articular cartilage
rior clinical outcomes of this type of ACI in direct compar- defects in the knee. Am J Sports Med. 2011;39(4):753-763.
ison to second- or third-generation ACI.19,22,36 A further 17. Engen CN, Engebretsen L, Aroen A. Knee cartilage defect patients
improvement of outcomes in long-term follow-up studies enrolled in randomized controlled trials are not representative of
seems likely for recently developed autologous cell prod- patients in orthopedic practice. Cartilage. 2010;1(4):312-319.
ucts.2,36 Taking all these parameters together, the overall 18. Genovese E, Ronga M, Angeretti MG, et al. Matrix-induced autolo-
gous chondrocyte implantation of the knee: mid-term and long-
satisfaction of the patients in this long-term follow-up
term follow-up by MR arthrography. Skeletal Radiol. 2011;40(1):47-
study is even more remarkable. 56.
19. Gooding CR, Bartlett W, Bentley G, Skinner JA, Carrington R, Flana-
gan A. A prospective, randomised study comparing two techniques
REFERENCES of autologous chondrocyte implantation for osteochondral defects
in the knee: periosteum covered versus type I/III collagen covered.
1. Anders S, Goetz J, Schubert T, Grifka J, Schaumburger J. Treatment of Knee. 2006;13(3):203-210.
deep articular talus lesions by matrix associated autologous chondrocyte 20. Harris JD, Siston RA, Brophy RH, Lattermann C, Carey JL, Flanigan
implantation: results at five years. Int Orthop. 2012;36(11):2279-2285. DC. Failures, re-operations, and complications after autologous
2. Bartlett W, Skinner JA, Gooding CR, et al. Autologous chondrocyte chondrocyte implantation: a systematic review. Osteoarthritis Carti-
implantation versus matrix-induced autologous chondrocyte implan- lage. 2011;19(7):779-791.
tation for osteochondral defects of the knee: a prospective, rando- 21. Heir S, Nerhus TK, Rotterud JH, et al. Focal cartilage defects in the
mised study. J Bone Joint Surg Br. 2005;87(5):640-645. knee impair quality of life as much as severe osteoarthritis: a compar-
3. Behrens P, Bosch U, Bruns J, et al. [Indications and implementation ison of Knee Injury and Osteoarthritis Outcome Score in 4 patient
of recommendations of the working group Tissue Regeneration and categories scheduled for knee surgery. Am J Sports Med.
Tissue Substitutes for autologous chondrocyte transplantation 2010;38(2):231-237.
(ACT)]. Z Orthop Ihre Grenzgeb. 2004;142(5):529-539. 22. Jungmann PM, Salzmann GM, Schmal H, Pestka JM, Sudkamp NP,
4. Bentley G, Biant LC, Vijayan S, Macmull S, Skinner JA, Carrington Niemeyer P. Autologous chondrocyte implantation for treatment of
RW. Minimum ten-year results of a prospective randomised study cartilage defects of the knee: what predicts the need for reinterven-
of autologous chondrocyte implantation versus mosaicplasty for tion? Am J Sports Med. 2012;40(1):58-67.
symptomatic articular cartilage lesions of the knee. J Bone Joint 23. Kon E, Filardo G, Berruto M, et al. Articular cartilage treatment in
Surg Br. 2012;94(4):504-509. high-level male soccer players: a prospective comparative study of
5. Beris AE, Lykissas MG, Kostas-Agnantis I, Manoudis GN. Treatment arthroscopic second-generation autologous chondrocyte implanta-
of full-thickness chondral defects of the knee with autologous chon- tion versus microfracture. Am J Sports Med. 2011;39(12):2549-2557.
drocyte implantation: a functional evaluation with long-term follow- 24. Kreuz PC, Erggelet C, Steinwachs MR, et al. Is microfracture of chon-
up. Am J Sports Med. 2012;40(3):562-567. dral defects in the knee associated with different results in patients
6. Blackman AJ, Smith MV, Flanigan DC, Matava MJ, Wright RW, Bro- aged 40 years or younger? Arthroscopy. 2006;22(11):1180-1186.
phy RH. Correlation between magnetic resonance imaging and clin- 25. Krishnan SP, Skinner JA, Bartlett W, et al. Who is the ideal candidate
ical outcomes after cartilage repair surgery in the knee: a systematic for autologous chondrocyte implantation? J Bone Joint Surg Br.
review and meta-analysis. Am J Sports Med. 2013;41(6):1426-1434. 2006;88(1):61-64.
7. Bode G, Schmal H, Pestka JM, Ogon P, Sudkamp NP, Niemeyer P. A 26. Loken S, Ludvigsen TC, Hoysveen T, Holm I, Engebretsen L, Reinholt
non-randomized controlled clinical trial on autologous chondrocyte FP. Autologous chondrocyte implantation to repair knee cartilage
implantation (ACI) in cartilage defects of the medial femoral condyle injury: ultrastructural evaluation at 2 years and long-term follow-up
with or without high tibial osteotomy in patients with varus deformity including muscle strength measurements. Knee Surg Sports Trauma-
of less than 5 degrees. Arch Orthop Trauma Surg. 2013;133(1):43-49. tol Arthrosc. 2009;17(11):1278-1288.
8. Brittberg M. Autologous chondrocyte transplantation. Clin Orthop 27. Marlovits S, Aldrian S, Wondrasch B, et al. Clinical and radiological
Relat Res. 1999;367 Suppl:S147-S155. outcomes 5 years after matrix-induced autologous chondrocyte
9. Brittberg M. ICRS Clinical Cartilage Injury Evaluation System. Paper implantation in patients with symptomatic, traumatic chondral
presented at: 3rd ICRS Meeting; April 28, 2000; Goteborg, Sweden. defects. Am J Sports Med. 2012;40(10):2273-2280.
Available at: www.cartilage.org/_files/contentmanagement/ICRS_ 28. Marlovits S, Singer P, Zeller P, Mandl I, Haller J, Trattnig S. Magnetic
evaluation.pdf. Accessed January 3, 2012. resonance observation of cartilage repair tissue (MOCART) for the
10. Brittberg M, Lindahl A, Nilsson A, Ohlsson C, Isaksson O, Peterson L. evaluation of autologous chondrocyte transplantation: determination
Treatment of deep cartilage defects in the knee with autologous of interobserver variability and correlation to clinical outcome after 2
chondrocyte transplantation. N Engl J Med. 1994;331(14):889-895. years. Eur J Radiol. 2006;57(1):16-23.

Downloaded from ajs.sagepub.com by guest on April 8, 2016


Vol. 42, No. 1, 2014 Long-term Outcomes After ACI 157

29. Marlovits S, Zeller P, Singer P, Resinger C, Vecsei V. Cartilage repair: 38. Niemeyer P, Salzmann GM, Hirschmuller A, Sudkamp NP. Factors
generations of autologous chondrocyte transplantation. Eur J Radiol. that influence clinical outcome following autologous chondrocyte
2006;57(1):24-31. implantation for cartilage defects of the knee [in German]. Z Orthop
30. Minas T, Von Keudell A, Bryant T, Gomoll AH. The John Insall Award: Unfall. 2012;150(1):83-88.
a minimum 10-year outcome study of autologous chondrocyte 39. Peterson L, Minas T, Brittberg M, Nilsson A, Sjogren-Jansson E, Lin-
implantation [published online August 24, 2013]. Clin Orthop Relat dahl A. Two- to 9-year outcome after autologous chondrocyte trans-
Res. doi:10.1007/s11999-013-3146-9. plantation of the knee. Clin Orthop Relat Res. 2000;374:212-234.
31. Mithoefer K, McAdams T, Williams RJ, Kreuz PC, Mandelbaum BR. 40. Peterson L, Vasiliadis HS, Brittberg M, Lindahl A. Autologous chon-
Clinical efficacy of the microfracture technique for articular cartilage drocyte implantation: a long-term follow-up. Am J Sports Med.
repair in the knee: an evidence-based systematic analysis. Am J 2010;38(6):1117-1124.
Sports Med. 2009;37(10):2053-2063. 41. Roos EM, Roos HP, Lohmander LS, Ekdahl C, Beynnon BD. Knee
32. Mithoefer K, Williams RJ 3rd, Warren RF, et al. The microfracture Injury and Osteoarthritis Outcome Score (KOOS): development of
technique for the treatment of articular cartilage lesions in the a self-administered outcome measure. J Orthop Sports Phys Ther.
knee: a prospective cohort study. J Bone Joint Surg Am. 1998;28(2):88-96.
2005;87(9):1911-1920. 42. Saris DB, Vanlauwe J, Victor J, et al. Characterized chondrocyte
33. Moradi B, Schonit E, Nierhoff C, et al. First-generation autologous implantation results in better structural repair when treating symp-
chondrocyte implantation in patients with cartilage defects of the tomatic cartilage defects of the knee in a randomized controlled trial
knee: 7 to 14 years clinical and magnetic resonance imaging fol- versus microfracture. Am J Sports Med. 2008;36(2):235-246.
low-up evaluation [published online October 2, 2012]. Arthroscopy. 43. Saris DB, Vanlauwe J, Victor J, et al. Treatment of symptomatic car-
doi:10.1016/j.arthro.2012.05.883. tilage defects of the knee: characterized chondrocyte implantation
34. Moseley JB Jr, Anderson AF, Browne JE, et al. Long-term durability results in better clinical outcome at 36 months in a randomized trial
of autologous chondrocyte implantation: a multicenter, observational compared to microfracture. Am J Sports Med. 2009;37 Suppl
study in US patients. Am J Sports Med. 2010;38(2):238-246. 1:10S-19S.
35. Niemeyer P, Andereya S, Angele P, et al. Autologous chondrocyte 44. Tegner Y, Lysholm J. Rating systems in the evaluation of knee liga-
implantation (ACI) for cartilage defects of the knee: a guideline by ment injuries. Clin Orthop Relat Res. 1985;198:43-49.
the working group Tissue Regeneration of the German Society of 45. Vanlauwe J, Saris DB, Victor J, Almqvist KF, Bellemans J, Luyten FP.
Orthopaedic Surgery and Traumatology (DGOU) [in German]. Z Five-year outcome of characterized chondrocyte implantation versus
Orthop Unfall. 2013;151(1):38-47. microfracture for symptomatic cartilage defects of the knee: early
36. Niemeyer P, Pestka JM, Kreuz PC, et al. Characteristic complications treatment matters. Am J Sports Med. 2011;39(12):2566-2574.
after autologous chondrocyte implantation for cartilage defects of the 46. Vasiliadis HS, Danielson B, Ljungberg M, McKeon B, Lindahl A,
knee joint. Am J Sports Med. 2008;36(11):2091-2099. Peterson L. Autologous chondrocyte implantation in cartilage lesions
37. Niemeyer P, Salzmann G, Steinwachs M, et al. Presence of subchon- of the knee: long-term evaluation with magnetic resonance imaging
dral bone marrow edema at the time of treatment represents a nega- and delayed gadolinium-enhanced magnetic resonance imaging
tive prognostic factor for early outcome after autologous technique. Am J Sports Med. 2010;38(5):943-949.
chondrocyte implantation. Arch Orthop Trauma Surg. 2010; 47. Williamson A, Hoggart B. Pain: a review of three commonly used pain
130(8):977-983. rating scales. J Clin Nurs. 2005;14(7):798-804.

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