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Published online before print February 16, 2006, 10.1148/radiol.2383050173
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(Radiology 2006;239:201-208.)
© RSNA, 2006

Musculoskeletal Imaging

Delayed Gadolinium-enhanced MR to Determine Glycosaminoglycan Concentration in Reparative Cartilage after Autologous Chondrocyte Implantation: Preliminary Results1

Atsuya Watanabe, MD, Yuichi Wada, MD, Takayuki Obata, MD, Takuya Ueda, MD, Mitsuru Tamura, PE, Hiroo Ikehira, MD and Hideshige Moriya, MD

1 From the Departments of Orthopaedic Surgery (A.W., Y.W., H.M.) and Radiology (T.U.), Graduate School of Medicine, Chiba University, Chiba, Japan; and Department of Medical Imaging, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-Ku, Chiba-Shi, Chiba 263-8555, Japan (A.W., T.O., M.T., H.I.). Received February 5, 2005; revision requested April 4; revision received May 2; final version accepted June 3. Supported by Health Science Research grants from the Ministry of Health and Welfare of Japan and by grants-in-aid from the Ministry of Education, Culture, Sports, Science and Technology. Address correspondence to T.O. (e-mail: t_obata{at}nirs.go.jp).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Purpose: To prospectively evaluate delayed gadolinium-enhanced magnetic resonance (MR) imaging of cartilage for assessment of glycosaminoglycan (GAG) concentration in reparative cartilage after autologous chondrocyte implantation (ACI).

Materials and Methods: The study was approved by the ethics review committee of the National Institute of Radiological Sciences, and informed consent was obtained from all patients. The study group comprised nine knees of nine patients (six male, three female; mean age at ACI, 21.2 years ± 7.5 [standard deviation]; age range, 13–35 years) who had undergone ACI and second-look arthroscopy with biopsy. MR imaging was performed at 1.5 T before and after intravenous injection of anionic gadopentetate dimeglumine. The precontrast R1 (R1pre), postcontrast R1 (R1post), and difference between R1pre and R1post ({Delta}R1) were measured in reparative cartilage and normal cartilage. GAG concentrations in cartilage biopsy specimens were measured by using high-performance liquid chromatography. To evaluate delayed gadolinium-enhanced MR imaging of cartilage for assessment of GAG concentration, the authors defined the relative R1pre, relative R1post, and relative {Delta}R1 (ie, R1pre, R1post, or {Delta}R1, respectively, in reparative cartilage divided by that in normal cartilage) and the relative GAG concentration (ie, GAG concentration in reparative cartilage divided by that in normal cartilage). They then examined the relationships between relative R1pre, relative R1post, relative {Delta}R1, and relative GAG by using correlation analysis.

Results: A significant correlation between relative {Delta}R1 and relative GAG concentration (r = 0.818, P < .05) was observed. However, no significant correlation between relative R1pre and relative GAG concentration (r = 0.010, P = .983) or between relative R1post and relative GAG concentration (r = 0.660, P = .106) was observed.

Conclusion: Study results indicate that pre- and postcontrast imaging is necessary for delayed gadolinium-enhanced MR imaging evaluation of reparative cartilage after ACI.

© RSNA, 2006


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Articular cartilage is a type of hyaline cartilage characterized by an extracellular matrix that contains a fine network of collagen and abundant proteoglycan that is tolerant to dynamic load. However, articular cartilage, which lacks blood vessels and has low cell density, is known to have limited healing potential (1,2). Thus, the development of a full-thickness articular cartilage defect, especially in weight-bearing areas, can cause severe pain and joint dysfunction, which may eventually develop into osteoarthritis (3,4). Attempts to repair articular cartilage defects have involved the use of various marrow-stimulation techniques, including subchondral drilling (5,6), abrasion chondroplasty (7,8), and microfracture (9,10). The goal of these techniques is to recruit pluripotent mesenchymal cells from the bone marrow to synthesize new fibrocartilage that will cover the defect (11,12). However, fibrocartilage repair tissue tends to have weak mechanical strength and is prone to degeneration over time, which leads to the return of the clinically important symptoms (13).

Autologous chondrocyte implantation (ACI) was introduced by Brittberg et al (14) in 1994 as a treatment for full-thickness defects of the articular cartilage in the knee. Repairing a hyaline cartilage defect by using ACI could improve the long-term durability of the reparative cartilage and prevent the onset of late osteoarthritis. Various groups in clinical follow-up studies have reported good to excellent results (15,16). However, several authors who have conducted histologic examinations and/or biochemical analyses of ACI repair sites have reported that the reparative cartilage was not always identical to the hyaline cartilage found in normal cartilage tissue (17–19). In some patients, the tissue filling the defect was identified as fibrocartilage or a mixture of fibrocartilage and hyaline cartilage—tissues that, compared with pure hyaline cartilage, have a lower proteoglycan concentration and a less-organized collagen network, which can lead to early deterioration after ACI. Until recently, quantitative evaluation of reparative cartilage could be achieved only by using invasive methods such as second-look arthroscopy with biopsy.

Magnetic resonance (MR) imaging has the potential to enable the determination of tissue composition, and several MR imaging techniques for monitoring the structure of articular cartilage have been developed and evaluated (20,21). An MR technique called delayed gadolinium-enhanced MR imaging of cartilage has been developed as a sensitive and specific method of measuring the concentration of glycosaminoglycan (GAG), a component of articular cartilage that is critical to its mechanical strength (22–25). The biochemical basis of delayed gadolinium-enhanced MR imaging of cartilage is as follows: Because GAG is composed of abundant carboxyl and sulfate groups, it is negatively charged within the cartilage matrix. Anionic gadopentetate dimeglumine (Magnevist; Schering, Berlin, Germany), given a sufficient time after its injection to penetrate the cartilage, will distribute inversely to the concentration of negatively charged cartilaginous GAG. Thus, as a noninvasive method of indirectly monitoring the GAG concentration in cartilage, delayed gadolinium-enhanced MR imaging is potentially a useful method of assessing the extent to which reparative cartilage is composed of articular cartilage, which is tolerant of mechanical stress.

In published clinical studies (26) to evaluate the effectiveness of gadolinium-enhanced MR imaging for measuring cartilage degeneration, the concentration of anionic gadopentetate dimeglumine has been estimated by using measurements of the R1 (in 1/sec) after intravenous contrast material injection (ie, postcontrast R1 [R1post]) only, because differences in the R1 before contrast material injection (ie, precontrast R1 [R1pre]) between degenerated and normal cartilage were so slight that the influence of R1pre was thought to be negligible. However, it remains unknown whether the influence of R1pre is negligible also in the evaluation of reparative cartilage after ACI, especially since the histologic appearance of reparative cartilage may be considerably different from that of normal cartilage. Thus, the aim of our study was to prospectively evaluate delayed gadolinium-enhanced MR imaging of cartilage for assessment of the GAG concentration in reparative cartilage after ACI.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 References
 
Patients
The study group comprised nine knees (two right knees, seven left knees) of nine patients (six male, three female) who had undergone ACI and second-look arthroscopy with biopsy. At the time of ACI, the patients' mean age was 21.2 years ± 7.5 (standard deviation) (age range, 13–35 years) and their mean defect size was 4.6 cm2± 2.2 (range, 2.3–10.5 cm2). The implantation sites were seven medial femoral condyles and two lateral femoral condyles. Six patients had osteochondritis dissecans, and three had a trauma-induced osteochondral defect. The study was approved by the ethics review committee of the National Institute of Radiological Sciences, and informed consent was obtained from all patients.

Chondrocyte Implantation Surgery
The ACI procedure described by Brittberg et al (14) was performed. Briefly, cartilage was removed from a non–weight-bearing area of the affected knee during the initial arthroscopy. Chondrocytes were then isolated from the cartilage and cultured for approximately 4 weeks in a laboratory (Genzyme Tissue Repair, Cambridge, Mass). The cultured chondrocytes were injected into the defect covered with a periosteal flap. The patients began active movements of the knee without weight bearing immediately after surgery. Weight bearing was resumed at postoperative week 6 and increased to full activity during the next 4 weeks.

MR Imaging
MR imaging was performed a mean of 22.7 months ± 11.0 (standard deviation) (range, 13–38 months) after the ACI by using a 1.5-T MR system (Gyroscan Intera; Philips Medical Systems, Best, the Netherlands) with a quadrature knee coil. All patients were examined before and 2 hours after an intravenous injection of anionic gadopentetate dimeglumine by using the same MR imaging protocol on both occasions. For the precontrast MR imaging examination, two authors (A.W. and T.O., with 7 and 16 years of experience in knee MR imaging, respectively) identified the section that depicted the center of the reparative cartilage on a set of routine T1-weighted sagittal images. The T1-weighted imaging parameters were as follows: 500/17 (repetition time msec/echo time msec), a 150 x 150-mm field of view, a 3.0-mm section thickness, a 512 x 512 matrix, two signals acquired, a 52.6-kHz bandwidth, and a fast spin-echo factor of six.

Three authors (A.W., T.O., M.T.) performed quantitative R1 measurements on the selected section by using the inversion-recovery method with a single-section acquisition. Inversion-recovery fast spin-echo MR images were obtained by using inversion times of 50, 100, 200, 400, 800, and 1600 msec. The inversion-recovery imaging parameters were as follows: 1800/28, a 130 x 130-mm field of view, a 3.0-mm section thickness, a 512 x 512 matrix, two signals acquired, a 64.1-kHz bandwidth, and a fast spin-echo factor of six. The total imaging time required to acquire the series of inversion-recovery MR images was about 17 minutes. At MR imaging, the local concentration of anionic gadopentetate dimeglumine in the tissue (Gd-DTPA2–) is determined by using the following equation:

Formula 1(1)
where r is the relaxivity of anionic gadopentetate dimeglumine in the tissue (in mmol/L–1 · sec–1) and R1 equals 1 divided by the longitudinal relaxation time.

During postcontrast MR imaging, a set of routine sagittal T1-weighted images was acquired by using the precontrast T1-weighted imaging parameters described earlier. The postcontrast T1-weighted images were compared with the precontrast T1-weighted images to identify the postcontrast section that corresponded to the precontrast section previously determined to depict the center of the reparative cartilage. If none of the postcontrast sections corresponded closely enough to the precontrast section showing the center of the reparative cartilage, the patient's knee position was adjusted and a new set of routine sagittal T1-weighted images was acquired. Quantitative R1 measurements were then performed on this selected section by using the inversion times and imaging parameters described earlier.

We followed the postcontrast MR imaging protocol reported on by Burstein et al (26). Anionic gadopentetate dimeglumine, at a dose of 0.2 mmol per kilogram of body weight, was intravenously injected in a single bolus. Immediately after the injection, the patient exercised the knee by walking up and down stairs for 10 minutes. Postcontrast MR imaging was performed 2 hours after administration of the contrast agent. The exercise and delay after the injection were necessary to allow the contrast agent to penetrate the cartilage.

Image Analysis
For all nine knees, maps of the cartilage constructed by using R1pre and R1post values were generated from the six precontrast and six postcontrast inversion-recovery MR images, respectively, by using commercially available software (Dr. View; Asahikasei, Tokyo, Japan) with a specialized three-parameter exponential curve fit module. We used a registration technique to correct for patient motion between each inversion-recovery MR imaging examination with the Dr. View software. With use of MATLAB software (The Mathworks, Natick, Mass), a color-coded R1-constructed map of the cartilage, with the cartilage area segmented manually, was overlaid on the inversion-recovery image obtained by using the longest inversion time. On the color scale, blue represented areas of low R1 and red represented areas of high R1.

Measurements of R1pre, R1post, and the difference between R1pre and R1post ({Delta}R1) in both reparative cartilage and normal cartilage were obtained in all patients. For these measurements, the region of interest was drawn over the entire area of the reparative cartilage, with all hypertrophic periosteal tissue excluded. The region of interest in the normal cartilage was drawn over a weight-bearing area of the femoral condyle from the surface to the basal area, and the size of this region was drawn as large as the size of the reparative cartilage (200–300 pixels). To avoid including damaged cartilage, the region of interest in the normal cartilage was drawn approximately 2 cm from the reparative cartilage. To standardize the procedure, all regions of interest were drawn by a single investigator (A.W., with 7 years of experience in knee MR imaging).

Histologic and Biochemical Analyses and Arthroscopy
Two authors (Y.W. and A.W., with 22 and 8 years of experience in arthroscopy, respectively) performed second-look arthroscopy with biopsy a mean of 12.4 months ± 0.5 (range, 12–13 months) after ACI. The mean interval between biopsy and MR imaging was 13.2 months ± 8.4 (range, 1–26 months). Biopsy specimens were taken from all nine reparative cartilage sites and from seven normal cartilage sites by using an 11-gauge biopsy needle (TrapSystem; Medical Device Technologies, Gainesville, Fla).

The reparative cartilage was stained with hematoxylin-eosin and toluidine blue for general histologic analysis and assessment of metachromasia. The reparative cartilage was judged to be hyaline cartilage if it had an abundant extracellular matrix that showed metachromatric staining with toluidine blue and a glassy appearance. The reparative cartilage was judged to be fibrocartilage if it had randomly distributed bundles of collagen fibers and showed no metachromatric staining with toluidine blue. Each reparative cartilage specimen was classified as hyaline cartilage (predominance of hyaline cartilage), fibrocartilage (predominance of fibrocartilage), or mixed cartilage (approximately equal quantities of hyaline cartilage and fibrocartilage). All cartilage classifications were performed by Chiba University staff pathologists. For the purposes of statistical analysis, fibrocartilage and mixed cartilage were grouped together and classified as other cartilage. The concentrations of GAG in the reparative cartilage and normal cartilage biopsy specimens were measured by using high-performance liquid chromatography (27).

Clinical Evaluation
The scoring system of Lysholm and Gillquist (28), a scoring system used for the clinical assessment of knee function, was performed to quantify the clinical status of the patients before the ACI, 1 year after the ACI (mean, 12.4 months ± 0.5 after surgery; range, 12–13 months), and at the time of the last medical examination (mean, 31.4 months ± 9.0 after surgery; range, 23–45 months). This scoring was determined by two authors (Y.W. and A.W., with 12 and 8 years of experience with this scoring system, respectively).

Data and Statistical Analyses
To evaluate the usefulness of delayed gadolinium-enhanced MR imaging for measuring the GAG concentration in reparative cartilage, we calculated the relative {Delta}R1 (ie, {Delta}R1 in reparative cartilage divided by {Delta}R1 in normal cartilage in the same patient) and the relative GAG concentration (ie, GAG concentration in reparative cartilage divided by GAG concentration in normal cartilage in the same patient). We then performed a correlation analysis to determine the relationship between relative {Delta}R1 and relative GAG concentration. The relationships between relative R1pre (R1pre in reparative cartilage divided by R1pre in normal cartilage in the same patient) and relative GAG concentration and between relative R1post (R1post in reparative cartilage divided by R1post in normal cartilage in the same patient) and relative GAG concentration also were studied.

To assess the usefulness of the relative {Delta}R1 in predicting the histologic type of reparative cartilage, differences in relative {Delta}R1 between hyaline reparative cartilage and other reparative cartilage were analyzed.

The time from biopsy for histologic and biochemical analyses to MR imaging evaluation varied among the patients. To investigate the possible effect of the length of time between biopsy and MR imaging on the nature of the reparative cartilage, the patients were divided into two groups—those imaged early (≤12 months) and those imaged late (>12 months) after biopsy—and the differences in relative {Delta}R1 values between the early and late groups were analyzed.

Appropriate statistical tests were used to perform the data analyses and included the Student t test for paired or unpaired samples and the Bartlett test for correlation analysis. P < .05 indicated statistical significance. Statistical computer software (Statview, version 5; SAS Institute, Cary, NC) was used to perform all statistical analyses.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 References
 
Image Analysis Findings
In all patients, the maps of the cartilage constructed by using R1pre and R1post values had similar appearances (Fig 1). The R1pre values for reparative cartilage appeared to be lower than those for normal cartilage, and R1pre values differed significantly between reparative and normal cartilage (t statistic, 4.94; P < .05) (Table 1). In contrast, the R1post values on the calculated maps had a smaller range than the R1pre values throughout the cartilage, and R1post values did not differ significantly between reparative and normal cartilage (t statistic, 1.62; P = .13) (Table 1). All {Delta}R1 values for reparative cartilage were higher than the corresponding {Delta}R1 values for normal cartilage, and {Delta}R1 values differed significantly between reparative and normal cartilage (t statistic, 4.46; P < .05) (Table 1).


Figure 1
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  		Figure 1a: (a) Color-coded MR map of cartilage constructed by using R1pre values. The R1 in the reparative cartilage (arrow) appears to be lower than that in the normal cartilage. (b) Color-coded MR map of cartilage constructed by using R1post values. Arrow = reparative cartilage. Throughout the cartilage, the R1post values have a smaller range than the R1pre values. On the maps and color scales, blue represents areas of low R1 and red represents areas of high R1.

 

Figure 1
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  		Figure 1b: (a) Color-coded MR map of cartilage constructed by using R1pre values. The R1 in the reparative cartilage (arrow) appears to be lower than that in the normal cartilage. (b) Color-coded MR map of cartilage constructed by using R1post values. Arrow = reparative cartilage. Throughout the cartilage, the R1post values have a smaller range than the R1pre values. On the maps and color scales, blue represents areas of low R1 and red represents areas of high R1.

 

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  		Table 1. R1pre, R1post, and {Delta}R1 in Normal and Reparative Cartilage

 
Histologic and Biochemical Analysis Findings
The reparative cartilage was classified as hyaline cartilage in five patients (two male, three female; age range, 13–35 years; mean age, 23.6 years), as mixed cartilage in three male patients (age range, 15–27 years; mean age, 19.0 years), and as fibrocartilage in one male patient aged 27 years.

The mean GAG concentration in the reparative cartilage biopsy specimens was significantly lower than that in the normal cartilage biopsy specimens (P < .05) (Table 2). In all patients, the GAG concentration in the reparative cartilage was lower than that in the normal cartilage.


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  		Table 2. GAG Concentrations in Normal and Reparative Cartilage Measured with High-Performance Liquid Chromatography

 
Clinical Findings
The patients' knee function scores (Lysholm and Gillquist scoring) improved significantly after ACI, from a mean score of 63.0 ± 12.2 before to a mean score of 94.9 ± 5.1 a year after the surgery (t statistic, 7.2; P < .01). The mean score had further significantly improved, to 97.7 ± 4.9, at the last medical examination (t statistic, 7.9; P < .01). No patient had clinical complaints related to the treated knee at the last examination.

Usefulness of Delayed Gadolinium-enhanced MR Imaging of Cartilage for Measuring GAG Concentration
A significant correlation between relative {Delta}R1 and relative GAG concentration (seven knees, r = 0.818, P = .024) (Fig 2) was observed. However, no significant correlation between relative R1pre and relative GAG concentration (seven knees, r = 0.010, P = .983) (Fig 3) or between relative R1post and relative GAG concentration (seven knees, r = 0.661, P = .106) (Fig 4) was observed.


Figure 2
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  		Figure 2: Quantitative correlation of relative {Delta}R1 and relative GAG concentration. A significant correlation between relative {Delta}R1 and relative GAG concentration (r = 0.818, P = .024) was observed.

 

Figure 3
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  		Figure 3: Quantitative correlation of relative R1pre and relative GAG concentration. No significant correlation between relative R1pre and relative GAG concentration (r = 0.010, P = .983) was observed.

 

Figure 4
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  		Figure 4: Quantitative correlation of relative R1post and relative GAG concentration. No significant correlation between relative R1post and relative GAG concentration (r = 0.661, P = .106) was observed.

 
Differences in Relative {Delta}R1 between Hyaline Reparative Cartilage and Other Reparative Cartilage
The relative {Delta}R1 was slightly lower in hyaline reparative cartilage (mean, 1.23 per second ± 0.14 for five knees) than in other reparative cartilage (mean, 1.50 per second ± 0.18 for four knees). This difference was not significant (t statistic, 2.20; P = .06).

{Delta}R1 Changes in Reparative Cartilage as a Function of Time between Biopsy and MR Imaging
The mean relative {Delta}R1 was 1.42 per second ± 0.24 in the early group (two male patients, two female patients; age range, 15–35 years; mean age, 26.0 years) versus 1.26 per second ± 0.12 in the late group (four male patients, one female patient; age range, 13–27 years; mean age, 18.0 years). This difference was not significant (t statistic, 1.10; P = .31).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
References
 
The R1pre, which can directly affect the evaluation of contrast agent concentration (Eq [1]), is known to vary according to tissue composition. In previous clinical studies in which early degenerative changes in cartilage were evaluated, the differences in R1pre between degenerative cartilage and normal cartilage were so small that the authors concluded that the R1pre had a negligible influence in shortening the acquisition time (23,24,29). In contrast, a comparison between normal cartilage and experimentally prepared cartilage that simulated late degenerative changes revealed noticeable differences in R1pre between degenerated cartilage and normal cartilage (30).

To our knowledge, before the present study, a detailed investigation of the differences in R1pre between reparative cartilage and normal cartilage in patients after ACI had not been performed. Among the currently available cartilage repair methods, ACI has yielded some of the best reported results (15,16). However, the concentration of macromolecular tissue components and the collagen arrangement in reparative cartilage are not equivalent to those in normal cartilage (17–19). In our study, the reparative cartilage after ACI had a lower GAG concentration and a different histologic appearance compared with the normal cartilage, and the R1pre in the reparative cartilage was significantly lower than that in the normal cartilage. Although R1post measurements alone did not enable the detection of differences in GAG concentration between reparative cartilage and normal cartilage, {Delta}R1 measurements did enable the detection of such differences.

Correlation analysis revealed a significant correlation between relative {Delta}R1 and relative GAG concentration only. This finding suggests that delayed gadolinium-enhanced MR imaging evaluation of the GAG concentration in reparative cartilage after ACI requires measurement of the {Delta}R1. Thus, methods that involve the use of R1post measurements only might not be suitable for evaluating reparative cartilage after ACI.

A decreased R1pre in reparative cartilage may result from increased tissue water content, a decreased concentration of macromolecular matrix components, or differences in the collagen network structure (31). Measurement of the R1pre may be necessary for tissue with R1pre values that could differ markedly from the R1pre in the surrounding normal cartilage, tissue such as spontaneously reparative cartilage after a traumatic defect, the reparative cartilage generated with therapeutic intervention, and cartilage with locally advanced degeneration. The necessity of performing both precontrast MR imaging and 2-hour-delay postcontrast MR imaging makes it difficult to routinely use delayed gadolinium-enhanced MR imaging of cartilage in the clinical setting. However, evaluation with postcontrast MR imaging alone might lead to an overestimation of the GAG concentration in reparative cartilage after ACI.

Gillis et al (32) reported that delayed gadolinium-enhanced MR imaging of cartilage has potential as a noninvasive MR imaging technique for monitoring the GAG concentration in autologous cartilage transplants. Their study findings suggest that the GAG concentration in reparative cartilage measured 12 months or longer after ACI is comparable to the GAG concentration in the surrounding normal cartilage. However, these authors performed postcontrast MR imaging only and thus may have overestimated the GAG content in the grafts that they evaluated. In all the patients in our study, GAG concentrations were lower in the reparative cartilage than in the normal cartilage.

Relaxivity, a second parameter that can affect the evaluation of contrast material concentration (Eq [1]), is known to vary as a function of the tissue composition and the magnetic field strength of the MR imaging system (30,33). Measuring relaxivity is difficult in clinically limited situations, and the difference in relaxivity between reparative cartilage after ACI and normal cartilage is unknown. Because differences in relaxivity may result in an underestimation of the anionic gadopentetate dimeglumine concentration as well as the R1pre in reparative cartilage, further investigation is necessary.

Direct measurement of the GAG concentration in reparative cartilage with delayed gadolinium-enhanced MR imaging has been considered as a possible method of tracking the time course of the GAG concentration in reparative cartilage after ACI. However, direct measurement of the GAG concentration with delayed gadolinium-enhanced MR imaging of cartilage is not feasible currently because it requires knowledge of the actual concentration of anionic gadopentetate dimeglumine in the synovial fluid of the knee joint, which is very difficult to measure. Thus, in our study, we used instead the relative {Delta}R1 as a parameter for comparing GAG concentrations in reparative and normal cartilage, and we investigated whether the {Delta}R1 correlated with the relative GAG concentration, which is the ratio of the actual tissue GAG concentrations in reparative and normal cartilage. Our analysis revealed a significant correlation between relative {Delta}R1 and relative GAG concentration, which suggests that the relative {Delta}R1 may be useful for the quantitative evaluation of reparative cartilage.

Our study had several limitations. First, the sample size was relatively small. In our study, no significant difference in relative {Delta}R1 between hyaline reparative cartilage and other reparative cartilage or between the early group and the late group was observed. These findings might have been caused by the relatively small number of patients. A larger-scale study is needed.

Second, the time from biopsy for histologic and biochemical analyses to MR imaging evaluation varied among the patients. For some patients, this interval was considerably long because the patients had already undergone second-look arthroscopy with biopsy when the delayed gadolinium-enhanced MR imaging of cartilage technique became available at our institute. If the maturation and degeneration of the reparative cartilage were ongoing processes, then changes in the cartilage composition could have developed between the time of MR imaging and the time of biopsy. The effects of this long interval on the results of our study are unknown; however, we believe that no substantial changes in the cartilage composition occurred during the period between tissue biopsy and MR imaging. One reason for this belief is that the tissue biopsy procedures were performed 12–13 months after surgery, by which time—according to some reports—the maturation of implanted cartilage would have already been completed (34–36). A second reason for this belief is that because our study patients had femoral condyle lesions, which are known to have better clinical results than patellar or trochlear lesions (16), their reparative cartilage may have benefited from an environment that was unfavorable for degeneration. However, performing concurrent biopsy and MR imaging might improve the correlation between GAG concentration and findings of delayed gadolinium-enhanced MR imaging of cartilage.

Third, because MR imaging was performed after second-look arthroscopy in all patients, the biopsy procedure itself may have produced cartilaginous changes that affected the appearance of and R1 in the reparative cartilage at subsequent MR imaging. We believe the effect of the biopsy on the cartilage repair process was small because we used a small biopsy needle during arthroscopy, which is a minimally invasive procedure. Nonetheless, the optimal time for MR imaging would be just before the biopsy.

In conclusion, ACI is a promising method of treating cartilage injury, and various studies to assess methods of producing reparative cartilage tissue similar to normal hyaline cartilage are underway (16). To improve the ability to obtain stable clinical results and good long-term outcomes with ACI, evaluation of the time course of the cartilage repair with use of an effective noninvasive qualitative method is important. The results of our study indicate that pre- and postcontrast imaging is necessary for delayed gadolinium-enhanced MR imaging evaluation of reparative cartilage after ACI. Additional, larger-scale studies are needed to validate the usefulness of delayed gadolinium-enhanced MR imaging for evaluating reparative cartilage after ACI.


   ACKNOWLEDGMENTS
 
The authors thank Yoko Kanazawa, PhD, Eiji Yoshitome, and Yoko Ikoma, PhD, of the National Institute of Radiological Sciences for their valuable technical advice and Shoji Mizuno of Seikagaku, Tokyo, Japan, for technical support in the high-performance liquid chromatography measurements.


   FOOTNOTES
 

Abbreviations: ACI = autologous chondrocyte implantation • GAG = glycosaminoglycan • {Delta}R1 = difference between R1pre and R1post • R1post = postcontrast R1 • R1pre = precontrast R1

Authors stated no financial relationship to disclose.

Author contributions: Guarantors of integrity of entire study, A.W., T.O.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; manuscript final version approval, all authors; literature research, all authors; clinical studies, all authors; statistical analysis, all authors; and manuscript editing, all authors


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

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