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Original Research |
1 Department of Radiology, MR Centre of Excellence, Medical University Vienna,
Lazarettg. 14, 1090. Vienna, Austria.
2 Department of Imaging Methods, Institute of Measurement Science, Slovak
Academy of Sciences, Bratislava, Slovak Republic.
3 Orthopedic Surgery Department, Inselspital, Bern, Switzerland.
4 Department of Traumatology, Centre for Joints and Cartilage, Medical
University Vienna, Vienna, Austria.
5 Department of Radiology, Landesklinikum St. Poelten, St. Poelten,
Austria.
Received March 1, 2008;
accepted after revision May 30, 2008.
Funding provided by the Austrian Science Fund (FWF) P-18110-B15.
Abstract
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SUBJECTS AND METHODS. Fifteen patients who underwent
matrix-associated autologous chondrocyte transplantation in the knee joint
underwent MRI at baseline and 3-T follow-up MRI 1 year later. Total and zonal
changes in longitudinal relaxivity (
R1) and relative R1 were
calculated for repair tissue and normal hyaline cartilage and compared by use
of analysis of variance.
RESULTS. There was a significant difference between the mean
R1 of repair tissue and that of reference cartilage at baseline and
follow-up (p < 0.001). There was a significant increase in
R1 value and a decrease in GAG content from the deep layer to the
superficial layer in the reference cartilage and almost no variation and
significantly higher values for the repair tissue at both examinations. At
1-year follow-up imaging, there was a 22.7% decrease in R1 value in the
deep zone of the transplant.
CONCLUSION. T1 mapping with dGEMRIC at 3 T shows the zonal structure of normal hyaline cartilage, highly reduced zonal variations in repair tissue, and a tendency toward an increase in global and zonal GAG content 1 year after transplantation.
Keywords: 3 T • articular cartilage • autologous chondrocyte transplantation • dGEMRIC • high field strength • MRI
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GAGs are the main source of fixed-charge density in cartilage. Because GAGs are responsible for the biomechanical protection of cartilage and repair tissue, GAG concentration is an indicator of cartilage graft maturation. Gadolinium diethylene triamine pentaacetate anion (gadopentetate dimeglumine2–) equilibrates in inverse relation to fixed-charge density, which is directly related to GAG concentration. Therefore, T1, which is determined by gadopentetate dimeglumine2– concentration, becomes a specific measure of tissue GAG concentration and distribution [17, 20, 21]. GAG concentration in articular cartilage, however, is not uniform but has a zonal distribution that has been depicted in anatomic microscopic cross-sectional studies [5, 8, 9].
To our knowledge, no in vivo 3-T imaging study has been conducted to evaluate the zonal distribution of GAGs in both normal articular cartilage and cartilage repair tissue after matrix-associated autologous chondrocyte transplantation. Nor has such a study been conducted to track the development of GAGs within a graft over time. GAG development would reflect not only biochemical status but also maturation of a graft and thus might be used in a biomarker technique for assess ment of graft quality. The aims of our study were, first, to evaluate the zonal distribution of GAGs in normal hyaline cartilage and repair tissue in the knee joint by use of quantitative T1 mapping with the 3-T dGEMRIC technique and, second, to monitor, with normal hyaline cartilage as a reference, the development of relative GAG content of grafts 1 year after matrix-associated autologous chondrocyte transplantation.
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The mean defect size was assessed with arthroscopy and was approximately 5.8 cm2 (range, 2.6–12.4 cm2). The same trauma surgeon using the same surgical technique in all operations performed the surgical procedure on all patients. In 14 patients trauma was the cause of the chondral defect of the knee; the other patient had no known history of trauma.
Image Acquisition
All patients were examined on a 3-T MRI unit (Magnetom Trio, Siemens
Medical Solutions) with an eight-channel phased-array knee coil. Quantitative
T1 mapping was performed with a sagittal 3D gradient-recalled echo sequence
with the dual flip-angle excitation pulses introduced by Trattnig et al.
[22]. The following sequence
parameters were used: TR/TE, 50/3.67; field of view, 183 x 200 mm;
matrix size, 317 x 384; in-plane resolution, 0.6 x 0.5 mm; slice
thickness, 1 mm; one slab of 36 slices covering the compart ment of interest;
bandwidth, 130 Hz/pixel; imaging time, 6 minutes 53 seconds. The sequence was
performed with two flip angles, first 35° and then 10°, before and
after IV administration of anionic gadopentetate
dimeglumine2– (Magnevist, Bayer Schering Pharma). For
contrast-enhanced MRI, the protocol introduced by Burstein et al.
[1] was used, that is,
administration of a bolus of 0.2 mmol of contrast agent per kilogram of body
weight. After injection, the patient moderately exercised the knee by walking
up and down stairs for approximately 20 minutes
[23]. Ninety minutes after
contrast administration, the contrast-enhanced MR images were obtained. To
allow the contrast agent to penetrate the articular cartilage and the
cartilage transplant, the physical activity and delay of contrast-enhanced
image acquisition are crucial. The same slab orientation was used for
unenhanced and contrast-enhanced images. At the baseline and follow-up
examinations, the orientation was achieved by identical positioning of the
coil and the knee joint and use of an isotropic 3D sequence to define the
identical sagittal planes before and after contrast administration.
MR images of the femorotibial compartment were acquired in the sagittal plane. A 3D doubleecho steady-state (DESS) sequence (15.1/5.11; field of view, 150 x 150 mm; matrix size, 250 x 250; in-plane resolution, 0.6 x 0.6 mm; slice thickness, 0.6 mm; flip angle, 25°; sensitivity-encoding factor, 2; imaging time, 5 minutes 39 seconds) was used for morphologic evaluation of the graft and the hyaline cartilage [2].
Data Analysis
All MR images, baseline and follow-up, were analyzed in consensus by a
radiologist with 15 years of experience in musculoskeletal imaging and a
resident with experience in MRI of the cartilage. Both observers were blinded
to patient group. Morphologic MR images acquired with the DESS sequence were
used for identification of the graft. If the graft was not easily identified,
surgical reports and drawings were consulted. In all patients, three
consecutive slices covering the cartilage repair tissue were selected and
subjected to further analyses. For all patients, special care was taken that
the same slices were selected for the baseline and follow-up examinations.
On the basis of results of a study by Trattnig et al. [22], the slab was positioned so that the graft was centered within the slab. Care was taken that the regions of interest (ROIs) for assessment of T1 values were completely within the region of the cartilage transplant. The graft was divided into two equally wide zones, specifically, a deep zone and a superficial zone. In each zone, ROIs with a mean pixel count of 100–150 were manually drawn. For standardization of the procedure, all ROIs were drawn by the musculoskeletal expert. A region of normal-appearing hyaline cartilage in the same knee joint was used as a reference, and an ROI with a mean pixel count of 100–150 was manually drawn. For verification of the normal appearance of the selected reference area, the isotropic DESS sequence was used. Again, these reference sites were divided into deep and superficial zones of equal width, and ROIs were manually drawn for assessment of T1 relaxation times. The mean global and zonal T1 relaxation times from all ROIs within the cartilage transplants were calculated. Values were compared with mean global and zonal values of T1 relaxation times of the ROIs of the reference.
For calculation of T1 maps, the DICOM images of the two measurements with
different excitation pulse flip angles were exported with interactive data
language software (IDL, version 6.0; ITT Corporation). The T1 time constant
was calculated on a pixel-by-pixel basis (j, k) according to the
following equation [11,
24]:
 |
Quantitative measurements of R1 = 1/T1 in 1/s were made for the baseline
and follow-up examinations. In agreement with previously published information
[25,
26], measurements of
longitudinal relaxivity before contrast administration
(R1unenhanced), longitudinal relaxivity after contrast
administration (R1contrast-enhanced), and the difference between
R1unenhanced and R1contrast-enhanced (R1 =
R1contrast-enhanced – R1unenhanced) were acquired
for both the transplant and the reference cartilage in all patients in all
locations described earlier. In addition, the relative ratio of R1 for
repair tissue to R1 for normal cartilage was calculated for both
transplant and reference cartilage in all patients in all locations.
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R1 (in 1/s) of the
cartilage transplant was significantly higher than the mean R1 of
normal hyaline cartilage (Fig.
1A,
1B). At the baseline
examination, the mean global R1 for the cartilage repair transplant was
2.11 ± 0.79 versus 0.98 ± 0.37 at the reference site. At the
1-year follow-up examination, the mean global R1 for the cartilage
transplant was 1.84 ± 0.61 versus 0.97 ± 0.4 at the reference
site. At both baseline and follow-up examinations, the difference in global
R1 values of the cartilage transplant and the control cartilage was
statistically significant (p < 0.001). The mean relative R1
was 2.26 ± 0.67 for the baseline examination and 2.07 ± 0.69 for
the follow-up examination. The difference in relative R1 at both time
points was not statistically significant (p = 0.44). The relative
R1 values of the cartilage transplant for all patients at the baseline
and follow-up examinations are depicted in
Figure 2.
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Zonal Variation
The R1 values for the deep and superficial zones of the reference
cartilage and cartilage transplant in all patients are shown in
Table 1.
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Reference Cartilage
At the baseline examination, the mean R1 values for the zonal
variations of the reference cartilage were 0.85 ± 0.438 for the deep
layer and 1.168 ± 0.435 for the superficial layer. The increase in
R1 from the deep to the superficial zone of the reference cartilage was
statistically significant (p = 0.021). At the 1-year follow-up
examination, the mean R1 for the zonal variations of the reference
cartilage was 0.846 ± 0.542 for the deep layer and 1.147 ± 0.349
for the superficial layer at the reference site. The increase in R1
values from the deep to the superficial zone of the reference cartilage again
was statistically significant (p = 0.023).
Cartilage Transplant
At the baseline examination, the mean R1 for the zonal variations of
the cartilage transplant was 2.369 ± 1.25 for the deep layer and 1.972
± 0.648 for the superficial layer. At the 1-year follow-up examination,
the mean R1 of the cartilage transplant was 1.833 ± 0.725 for
the deep layer and 1.912 ± 0.625 for the superficial layer. At both
time points the zonal variations of the cartilage transplant were not
statistically significant. However, there was a 22.7% decrease in R1
for the deep zone of the cartilage transplant from 2.369 at baseline to 1.833
at follow-up. Although these findings were not statistically significant
(p = 0.163), the changes in the deep zone were more pronounced than
those in the superficial zone, where almost no change occurred (1.972 at
baseline, 1.912 at follow-up (p = 0.687).
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R1 to monitor relative GAG content at the repair
site at both baseline and follow-up examinations. In an in vitro study, Wayne et al. [27] found that use of the ratio of T1 after gadolinium enhancement to T1 before contrast administration made it possible to differentiate collagenase- and chondroitase-treated cartilage. The T1 values after gadolinium enhancement alone were significantly different between treated and untreated cartilage. In a study with a small number of patients who had undergone autologous chondrocyte transplantation, Watanabe et al. [26] found a correlation only between absolute GAG content and relative change in relaxation rate.
The finding by Williams et al.
[28] of a mean R1 of
0.61 ± 0.19 (range, 0.08–0.9) in healthy cartilage emphasizes the
importance of calculation of individual ratios, such as relative R1,
between repair tissue and normal hyaline cartilage. In agreement with the
findings by Watanabe et al.
[26], we found significantly
higher R1 values for transplant than for reference site cartilage in
all patients at both baseline and follow-up examinations. These findings and
the findings in previous studies by Trattnig et al.
[22], who investigated the
R1 of cartilage transplants and normal hyaline cartilage at different
postoperative intervals, suggest that, although there is maturation of the
graft with a slight increase in relative GAG content over time, the R1
of a cartilage transplant is always significantly higher than the R1 of
normal cartilage. This finding indicates that relative GAG content probably
never reaches the level of healthy cartilage tissue.
GAG concentration in articular cartilage is not uniform. It has a zonal
organization with a decrease in GAG content from the deep to the superficial
layers of the cartilage, as depicted in anatomic, microscopic, cross-sectional
studies [5,
8,
9]. In our study, this zonal
GAG distribution was confirmed by a corresponding zonal distribution of
R1 values in normal articular cartilage at both the baseline and
follow-up examinations. However, in the cartilage transplant there was almost
no zonal variation of GAGs with R1 values of 2.369 s–1
for the deep to 1.972 s–1 for the superficial zone at
baseline and 1.833 s–1 for the deep to 1.912
s–1 for the superficial zone at follow-up. During graft
maturation, there was a slight increase in GAG content with a 22.7% decrease
in R1 value from 2.369 in the deep zone at baseline to 1.833 at the
1-year follow-up examination of the cartilage transplant, indicating a greater
increase in GAG content in the deep zone. These findings, however, were not
statistically significant. Moreover, at both time points cartilage transplant
had statistically significantly higher global and zonal R1 values in
both zones compared with normal hyaline cartilage. The global R1 was
2.11 for the cartilage transplant and 0.98 for the reference site at baseline
and 1.84 for the cartilage transplant versus 0.97 for the reference site at
follow-up. These findings support the results of studies by Tins et al.
[29], Roberts et al.
[30], and Moriya et al.
[31], who investigated the
histologic features of grafts 1 year after matrix-associated autologous
chondrocyte transplantation for management of femoral condylar defects. Those
authors found varied mixtures of hyaline and fibrocartilage, which seemed to
indicate that the histologic composition of cartilage transplant is different
from that of normal cartilage.
Because minor zonal variations and changes in zonal R1 values of the
cartilage transplant, mainly in the deep zone, were detected, baseline
evaluation and monitoring of the development of zonal R1 values may be
a biomarker technique for assessing the initial quality of a cartilage
transplant and development of the transplant over time. This technique may
complement evaluation of zonal differentiation with T2 mapping and facilitate
definition of the organization of cartilage transplants. These preliminary
findings, however, need to be investigated further and validated in clinical
studies with larger numbers of patients.
A limitation of this study was the relatively small number of patients
included. Another was that histopathologic specimens were not available for
direct comparison. Because, however, most of the patients had a good or
excellent clinical outcome, there was no clinical indication for arthroscopic
biopsy of the cartilage transplant, and the patients refused this procedure.
To overcome this limitation, intraindividual comparison of R1 values
with the values at a remote weight-bearing cartilage site in the same knee
joint was performed. Because of the lack of arthroscopic correlation, the
intactness of this reference site was determined with conventional cartilage
MRI.
The dGEMRIC technique, based on 3D gradient-recalled echo sequences with two flip-angle excitation pulses can be used for zonal T1 mapping of normal hyaline cartilage and cartilage transplants. The dGEMRIC technique shows a zonal GAG content distribution in normal hyaline cartilage and a highly reduced zonal structure in cartilage transplant. Quantitative T1 mapping of cartilage shows a statistically insignificant tendency toward an increase in both global and zonal GAG content mainly in the deep zone over a follow-up period of 1 year in patients who have undergone matrix-associated autologous chondrocyte transplantation in the knee joint.
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