Abstract
Background: New methods have been used, with promising results, to
treat full-thickness cartilage defects. The objective of the present study was
to compare autologous chondrocyte implantation with microfracture in a
randomized trial. We are not aware of any previous randomized studies
comparing these methods.
Methods: Eighty patients without general osteoarthritis who had a
single symptomatic cartilage defect on the femoral condyle in a stable knee
were treated with autologous chondrocyte implantation or microfracture (forty
in each group). We used the International Cartilage Repair Society, Lysholm,
Short Form-36 (SF-36), and Tegner forms to collect data. An independent
observer performed a follow-up examination at twelve and twenty-four months.
Two years postoperatively, arthroscopy with biopsy for histological evaluation
was carried out. The histological evaluation was done by a pathologist and a
clinical scientist, both of whom were blinded to each patient's treatment.
Results: In general, there were small differences between the two
treatment groups. At two years, both groups had significant clinical
improvement. According to the SF-36 physical component score at two years
postoperatively, the improvement in the microfracture group was significantly
better than that in the autologous chondrocyte implantation group (p = 0.004).
Younger and more active patients did better in both groups. There were two
failures in the autologous chondrocyte implantation group and one in the
microfracture group. No serious complications were reported. Biopsy specimens
were obtained from 84% of the patients, and histological evaluation of repair
tissues showed no significant differences between the two groups. We did not
find any association between the histological quality of the tissue and the
clinical outcome according to the scores on the Lysholm or SF-36 form or the
visual analog scale.
Conclusions: Both methods had acceptable short-term clinical
results. There was no significant difference in macroscopic or histological
results between the two treatment groups and no association between the
histological findings and the clinical outcome at the two-year time-point.
Level of Evidence: Therapeutic study, Level I-1a
(randomized controlled trial [significant difference]). See Instructions to
Authors for a complete description of levels of evidence.
Articular cartilage injuries have a limited potential to heal, which over
time may lead to
osteoarthritis1,2.
Cartilage defects in the knee may cause pain, swelling, and catching. There
are several different surgical procedures available to treat cartilage
injuries, but no method has been judged superior. The ultimate aim of
treatment is restoration of normal knee function by regenerating hyaline
cartilage in the defect and complete integration of the regenerated cartilage
with the surrounding cartilage and underlying bone. Arthroscopic
débridement and lavage may provide symptomatic relief for a limited
time3,4,
although a controlled trial of débridement in patients with
osteoarthritis of the knee showed the outcomes to be no better than those of
treatment with a
placebo5. However,
it is important to distinguish between local cartilage defects and
osteoarthritis.
Several marrow-stimulating procedures directed at the recruitment of
bone-marrow cells have been widely used to treat local cartilage defects. With
these methods, the subchondral bone is penetrated to allow fibrin clot
formation within the defect and then the creation of a repair tissue.
Drilling, as described by
Pridie6, has been
used for decades. More recently, marrow-stimulating procedures such as
abrasion7 and
microfracture8-13
have been advocated. Other approaches to the treatment of full-thickness
cartilage defects include methods of resurfacing with
periosteum14,15,
perichondrium16,
osteochondral plugs
(mosaicplasty)17-20,
and
allografts21,22.
Autologous chondrocyte implantation was first described in
199423. Encouraging
primary results were reported, and further research was promoted. The
technique has been widely used in many centers in the United States and
Europe23-36.
In a study in Sweden, use of the procedure on the femoral condyles led to a
good or excellent long-term result in 89% of patients, and eight of twelve
biopsy specimens showed findings consistent with hyaline
tissue34. Some
authors have been skeptical, however, pointing out that the results of
autologous chondrocyte implantation have not been proven to be better than
those of other
methods2,37,38.
Horas et al. found that, after two years of follow-up, the improvement
provided by autologous chondrocyte implantation lagged behind that provided by
osteochondral cylinder
transplantation37.
In contrast, Bentley et al. recently found, in a randomized study, that the
short-term clinical results were better after autologous chondrocyte
implantation than they were after
mosaicplasty24.
Both mosaicplasty and autologous chondrocyte implantation are relatively major
surgical procedures, and the cartilage cell expansion necessary for autologous
chondrocyte implantation is a demanding and expensive additional step.
Microfracture, on the other hand, is a simple one-stage arthroscopic technique
that has had better results than the Pridie drilling technique, with
improvement achieved in up to 75% of patients after five years of
follow-up8-13,39.
However, the repair tissue seen after this procedure has been reported to be
fibrocartilage or, at best, a hybrid of fibrocartilage and hyaline
cartilage8-13,39.
Mosaicplasty techniques can be used only for smaller lesions because of the
limited availability of donor plugs, whereas microfracture and autologous
chondrocyte implantation are suitable for defects of up to at least 10
cm2. We are not aware of any previous randomized controlled studies
comparing these two methods. The objective of the present trial was to compare
autologous chondrocyte implantation with microfracture in a randomized
trial.
Eighty patients with a single symptomatic cartilage defect in a stable knee
were enrolled in the study between January 1999 and February 2000. Experienced
senior knee surgeons at each center selected the patients according to the
inclusion and exclusion criteria in Table
I. It was required that the symptoms (pain, catching, locking, or
swelling with reduction in activities) were most likely related to the
cartilage defect. All of the patients had a localized defect on the femoral
condyle, and none had generalized osteoarthritis.
Forty patients were treated with autologous chondrocyte implantation and
forty, with microfracture. Four university hospitals in Norway participated,
with ten autologous chondrocyte implantation procedures and ten microfracture
operations performed at each center by surgeons who were well trained in both
techniques. Informed consent was obtained from all patients, and the study
protocol was approved by the National Review Board. Financial support was
granted by the Norwegian Ministry of Health. The International Cartilage
Repair Society (ICRS)
form40 was used to
collect demographic data and to record the history, symptoms, functional
score, pain as indicated on a visual analog scale, characteristics of the
cartilage defect, and findings of the baseline clinical examination. In
addition, the Lysholm
score41, the Tegner
score42, and the
Short Form-36
(SF-36)43 were
used. Weight-bearing standing radiographs of the knees were made for all
patients. Patients were excluded if there was narrowing of the joint space or
there were other radiographic signs of osteoarthritis. Patients who had
multiple lesions in the knee or arthroscopically verified general
osteoarthritis were excluded as well. Some patients were excluded because
these findings were observed during arthroscopy.
With use of sealed envelopes, patients who fulfilled the inclusion criteria
were randomized during the arthroscopy to be treated with either autologous
chondrocyte implantation or microfracture. The microfracture procedures were
done during the arthroscopy, whereas the patients randomized to be treated
with autologous chondrocyte implantation had cartilage samples harvested, for
cell extraction, during the arthroscopy; those patients then returned for cell
implantation through an arthrotomy after approximately four weeks. Patients in
both groups were hospitalized for four days after their final operative
procedure and then were treated with an identical rehabilitation protocol.
Continuous passive motion and partial weight-bearing with crutches were
started on the first postoperative day after both procedures. The patients
then remained partially weight-bearing (20 kg) with crutches for eight weeks.
Full weight-bearing was introduced between eight and twelve weeks
postoperatively, depending on the patient's clinical status and function.
Stationary bicycling was started as soon as possible.
An independent observer performed a follow-up clinical examination at
twelve and twenty-four months using the same evaluation forms as had been used
preoperatively. Two years after the cartilage repair, second-look arthroscopy
with biopsy for histological evaluation was carried out. The ICRS cartilage
repair assessment for macroscopic evaluation during arthroscopy was used. The
operation was considered to have failed if the patient needed a reoperation
because of symptoms due to a lack of healing of the primary treated defect.
The need for shaving or trimming a lesion was not defined as a failure.
Trauma was the most common etiology of the defects (65% of the cases),
followed by osteochondritis dissecans (28%). Most (89%) of the defects were
located on the medial femoral condyle, with the remaining located on the
lateral femoral condyle. None of the patients had a defect in the trochlea.
All of the patients had had chronic knee problems, with a median duration of
symptoms of thirty-six months, and 94% had had previous knee surgery before
inclusion in the study. These operations included anterior cruciate ligament
reconstruction (fifteen patients), meniscal surgery (fourteen), arthroscopic
lavage and débridements (twenty-nine), Pridie drilling (three), and
operations for osteochondritis dissecans such as drilling or fixation of a
fragment (thirteen). The patients treated with autologous chondrocyte
implantation had undergone an average of 1.6 previous surgical procedures to
treat the cartilage defect, and those in the microfracture group had undergone
an average of 1.4. Preoperatively, no significant differences were found
between the autologous chondrocyte implantation and the microfracture group
with regard to age (mean, 33.3 and 31.1 years, respectively), sex (60% male),
defect size (mean, 5.1 and 4.5 cm2, respectively), body weight, or
baseline clinical data. Most of the patients had an
Outerbridge44
grade-3 or 4 defect; only three patients had a grade-2 defect.
Statistical Methods
A sample-size estimation showed that forty patients in each group would be
required to demonstrate a difference between the Lysholm and SF-36 scores of
the two groups of at least 0.75 standard deviation from the mean, with an
alpha level of 0.05 and a beta level of 90%.
The data were analyzed with the SPSS statistical package (SPSS, Chicago,
Illinois). T tests, the Pearson chi-square and Mann-Whitney U tests, analysis
of covariance, and multiple analysis of variance were used. The level of
significance was p < 0.05.
Autologous Chondrocyte Implantation
The surgical technique described by Brittberg et
al.23 was used.
Cartilage was harvested arthroscopically from a low-load-bearing area on the
proximal part of the medial femoral condyle of the affected knee. The biopsy
specimen was then placed in a sterile transport medium provided by Genzyme
(Boston, Massachusetts) and was sent by express air transport for commercial
cell culturing in their laboratory in Boston. Approximately four weeks later,
the cells were returned for implantation. An arthrotomy was performed, and the
defect was débrided to healthy surrounding cartilage. Periosteum was
taken from the proximal part of the tibia or distal part of the femur and was
sutured to the rim of the débrided defect; fibrin glue was used to form
a watertight chamber. The cultured chondrocytes were then injected beneath the
patch, and a final suture and fibrin sealant were placed at the injection
site.
Microfracture
The technique introduced by Steadman et
al.12 twenty years
ago was used. The procedure consists of accurate débridement of all
unstable and damaged cartilage in the lesion, including the calcified layer
down to the subchondral bone plate. All loose or marginally attached cartilage
was also débrided from the surrounding rim of the defect, to form a
stable perpendicular edge of healthy cartilage. An arthroscopic awl was then
used to make multiple holes in the defect, 3 to 4 mm apart. In order to
preserve the subchondral bone plate, care was taken not to make the holes so
close to each other that they could break into one another.
Histological Analysis
Two-millimeter-diameter core-biopsy specimens were obtained during the
follow-up arthroscopy. The specimens were taken from the central part of the
treated defects and included both repair cartilage tissue and subchondral
bone. The specimens were fixed in 4% formaldehyde and sent to the pathologist
at the University Hospital in Tromsø, where they were embedded in
paraffin, sectioned at a 5-µm thickness, and then stained with hematoxylin
and eosin. The histological evaluation was performed by a pathologist in
Tromsø (V.I.) and a clinical scientist (S.R.) who specializes in
histological analysis of cartilage. Both were blinded to the type of treatment
that the patient had received. Concentrating particularly on the lower region
of the biopsy specimen, they arbitrarily ranked the repair cartilage as
hyaline (Group 1), fibrocartilage-hyaline mixture (Group 2), or fibrocartilage
(Group 3), or they recorded that there was no repair tissue (Group 4).
Hyaline cartilage was clearly differentiated from fibrocartilage by the
homogeneous appearance of the matrix, particularly when viewed under polarized
light, and the round or oval shape of the cells, which often were surrounded
by lacunae. Fibrocartilage, in contrast, had obvious bundles of collagen
fibers, lying in a random, irregular manner, when viewed under polarized
light. Samples in which =60% of the area of matrix was hyaline cartilage
were categorized as Group 1; those in which >40% but <60% was hyaline
cartilage, as Group 2; and those in which =60% was fibrocartilage, as Group
3. Samples were categorized as Group 4 when they were inadequate or when no
obvious repair tissue was present and the tissue was predominantly bone.
Group-4 specimens may have been that way in vivo or the findings may have been
due to sample handling. Examples of the histological appearance and the
ranking of the repair tissue are shown in
Figure 5. The categorizations
were the result of the final consensus between the two assessors.
At two years, the Lysholm score had improved significantly, compared with
the baseline score, in both the autologous chondrocyte implantation group (p
< 0.003) and the microfracture group (p < 0.0001)
(Fig. 1). Pain, according to
the visual analog scale, was significantly reduced in both groups (p <
0.0001 for both) (Fig. 2), with
78% of the patients treated with autologous chondrocyte implantation and 75%
of those treated with microfracture having less pain at the two-year follow-up
evaluation than they had had at the baseline evaluation. The two groups did
not differ significantly with regard to the improvements in the Lysholm and
pain scores at one and two years. However, the microfracture group had
significantly more improvement in the SF-36 physical component score in the
first two years than did the autologous chondrocyte implantation group (p =
0.004). As seen in Figure 3,
there was an almost significant difference in the preoperative physical
component scores between the groups (p = 0.0506). We performed an analysis of
covariance with the preoperative physical component score as a covariate and
found a high correlation between the preoperative and postoperative physical
component scores (p = 0.000001). With the preoperative physical component
scores taken into account, the microfracture group still had a significantly
better result than did the autologous chondrocyte implantation group (p =
0.01). No difference in the SF-36 mental health subscale score was detected
between the groups.
Regardless of their treatment group, younger patients (less than thirty
years old) had a better clinical outcome than did older patients (p = 0.007).
Also, in both groups, more active patients, as indicated by a Tegner score of
>4 points, had a significantly better clinical result (according to the
Lysholm score, visual analog scale, and SF-36 physical component score) than
did less active patients (p = 0.0005).
In the microfracture group, patients with a lesion smaller than 4
cm2 had significantly better clinical results (according to the
Lysholm score, visual analog scale, and SF-36 physical component score) than
did those with a bigger defect (p < 0.003). We did not find this
association between the size of the defect and the clinical outcome in the
autologous chondrocyte implantation group (p > 0.89). We also did not find
any significant differences in clinical results between the patients who had
and had not had previous surgery involving the anterior cruciate ligament (p
> 0.4) or meniscus (p > 0.28), but the numbers of patients were small
for statistical analysis.
The ICRS macroscopic evaluations during the second-look arthroscopy did not
show any difference between the autologous chondrocyte implantation and
microfracture groups (Fig. 4).
The findings were graded as nearly normal in both groups. Biopsies were
performed in sixty-seven patients: thirty-two treated with autologous
chondrocyte implantation and thirty-five treated with microfracture. Six
patients declined to have the biopsy, three patients could not return for the
second-look arthroscopy and biopsy because of pregnancy at the time of the
two-year evaluation, and the surgeons did not perform suitable biopsies in
four patients. The results of the histological evaluations are shown in
Figures 5 and
6. Thirty-nine percent of the
biopsy specimens had at least some hyaline cartilage present, although few
were composed totally of hyaline cartilage. In contrast, 43% had
fibrocartilage throughout most of their depth (Group 3). There was no
significant difference between the groups with regard to the frequency with
which hyaline and fibrocartilage repair tissue were found (p = 0.08). With the
same power, we would have needed 120 biopsies to find a significant difference
between the two groups. Also, there was no association between clinical
outcome (according to the Lysholm score, visual analog scale, and SF-36
physical component score) and the histological quality (according to the
semiquantitative grading of the specimens as group 1, 2, 3, or 4) (p > 0.3,
two-sided t test).
There were two failures, at six and eighteen months, in the autologous
chondrocyte implantation group, and one failure, at fifteen months, in the
microfracture group. The patients who had a failure were all symptomatic and
underwent revision with another cartilage treatment; they were then excluded
from the study.
Arthroscopic débridement was performed prior to the second-look
arthroscopy in ten patients (25%) in the autologous chondrocyte implantation
group and in four (10%) in the microfracture group. In the autologous
chondrocyte implantation group, shaving was done mainly because of symptomatic
tissue hypertrophy. In the microfracture group, one patient had
arthrofibrosis, requiring manipulation and operative release, and the other
three had minor débridements. No serious complications, such as deep
infection or a thromboembolic event, were recorded. One of the patients
treated with autologous chondrocyte implantation was diagnosed as having
psoriatic arthritis in the operatively treated knee one year after the
surgery. As was the case prior to the surgery, there was no evidence of
osteoarthritis on standing radiographs at the two-year follow-up
evaluation.
There have been several uncontrolled studies on both autologous chondrocyte
implantation and microfracture in which good and excellent results were
reported8-13,23,25-31,33-36,39,45.
The present study is, to our knowledge, the first to compare autologous
chondrocyte implantation and microfracture in a randomized trial with
independent observers judging the clinical outcome and quality of the repair
tissue. Autologous chondrocyte implantation and osteochondral plugs were
compared in a prospective comparative trial by Horas et al., who did not find
the results of autologous chondrocyte implantation to be as good as had been
previously reported in the
literature37. In
their study, the clinical results of autologous chondrocyte implantation were
inferior to those provided by osteochondral plugs, and defects treated with
autologous chondrocyte implantation were primarily filled with fibrocartilage.
In contrast, Bentley et al. reported that autologous chondrocyte implantation
yielded better results than did osteochondral plugs (mosaicplasty), and they
found hyaline cartilage in seven of nineteen biopsy specimens obtained one
year after autologous chondrocyte
implantation24.
In our trial, we found that autologous chondrocyte implantation and
microfracture yielded similar clinical results. Lysholm scores and pain scores
improved significantly after both operations, with approximately 76% of all
patients having less pain at the two-year follow-up examination than they had
had preoperatively. There was no significant difference between the groups
with regard to these scores at either one or two years. However, the
improvement in the SF-36 physical component score was significantly better in
the microfracture group than it was in the autologous chondrocyte implantation
group. One reason for this could be that microfracture involves less surgery
and therefore the rehabilitation is easier than that following autologous
chondrocyte implantation. However, one could expect a smaller difference
between groups after two years compared with the difference at one year. It is
important to note that our cohort of patients had chronic lesions (median
duration of symptoms, thirty-six months), with a mean of 1.5 previous
operations. This may explain why their final clinical scores were not higher
(e.g., the Lysholm scores were in the 70 to 75-point range).
The arthroscopic evaluation at two years also demonstrated similar results
in the two groups. The macroscopic classifications of the repair tissue did
not differ significantly, with the mean values classified as nearly normal in
both groups, indicating acceptable repair and filling of the treated
defects.
We also did not find any significant differences regarding histological
quality between the two treatment groups. These results are not consistent
with those in the first study by Brittberg et al., in which eleven of fifteen
patients had "hyaline-like cartilage" after autologous chondrocyte
implantation23.
However, 50% of the biopsies in the autologous chondrocyte implantation group
in our study showed some hyaline tissue (Groups 1 and 2). There was a tendency
in our study for the autologous chondrocyte implantation procedure to result
in more hyaline repair cartilage than the microfracture procedure, but this
was not a significant finding with the numbers available.
Peterson et al. reported a failure rate of 11% after autologous chondrocyte
implantation of the femoral condyles, with most of the failures occurring less
than two years
postoperatively34.
They concluded that a graft surviving for two years is likely to remain viable
three to eight years later and that autologous chondrocyte implantation
results in a durable repair in the majority of patients. Roberts et al. found
that biopsies showing hyaline morphology had been performed at a longer time
interval after autologous chondrocyte implantation (average, 19.8 months) than
had biopsies showing fibrocartilage (average, 12.0
months)45. This
observation suggests that continuous remodeling of the graft may take place
and that the transplant may become more hyaline with time.
It has been suggested that traditional drilling and débridement lead
to good and excellent results for up to five years and that the results then
decline2.
Histological analysis of repair tissue after such operations was reported to
show mainly
fibrocartilage2.
However, Steadman et al. suggested that microfracture can provide a more
durable repair than can traditional drilling and that the repair tissue may be
a hybrid of hyaline cartilage and
fibrocartilage39.
That observation is in agreement with our findings.
In our study, younger and more active patients in both treatment groups had
a better clinical outcome. This finding is consistent with those of previous
studies of both animals and
humans8,15.
The two-year failure rates in our study were low (5% and 2.5%) and were
comparable with those in previously published
reports24,30,34,37,39.
Ten reoperations were performed in the autologous chondrocyte implantation
group and four, in the microfracture group. Most of these were minor
débridements, but it is remarkable that one of every four patients
treated with autologous chondrocyte implantation needed this procedure before
the planned two-year second-look arthroscopy. Hypertrophy of tissue (probably
periosteum) was the major reason for these reoperations. Using a collagen
membrane instead of periosteum possibly could reduce this problem.
Peterson46
expressed the opinion that a periosteal flap that is too thick (not cleaned
properly of fat and fibrous tissue) may be one reason for hypertrophy. In
addition, autologous chondrocyte implantation is complex surgery, and there is
thus a learning curve for the surgeons. All surgeons participating in this
study were trained in both procedures, but autologous chondrocyte implantation
is a more technically demanding procedure than microfracture; it also requires
two separate surgical procedures. Because microfracture is a relatively simple
one-stage procedure, it may be more suitable for a primary first-line
cartilage repair of a local contained
defect39. In
patients in whom microfracture has failed and in those with bigger,
noncontained defects, autologous chondrocyte implantation may be a better
option.
Randomized controlled trials of surgical procedures are difficult to
perform. Double blinding is difficult, particularly in this study, in which it
was not possible to blind either the patients or the surgeons to which
treatment was being given because of the two-stage nature of the autologous
chondrocyte implantation.
This is one of the largest, most comprehensive studies of biopsy specimens
from cartilage repair sites in patients treated with autologous chondrocyte
implantation available to date, and it should add considerably to the database
of histological results after cartilage resurfacing techniques.
In conclusion, both methods appear to have acceptable short-term results.
Younger and more active patients have better clinical results regardless of
which type of treatment they receive. According to the SF-36 physical
component scores at two years postoperatively, the improvement in the
microfracture group was significantly better than that in the autologous
chondrocyte implantation group, but it remains to be seen if that difference
is maintained into the future. No significant differences were found regarding
the macroscopic appearance or the histological quality of the repair tissue,
and we did not find any association between the histological quality of the
tissue and the clinical outcome. Mid-term and long-term follow-up is needed to
determine if one method is better than the other for generating long-lasting
hyaline cartilage and alleviating symptoms.
Note: The authors thank Tom Wilsgaard and Jan Herman Kuiper for
their statistical assistance.
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