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Musculoskeletal Imaging |
1 From the MR Center, Department of Radiology (G.H.W., S.T.), Department of Orthopedic Surgery (S.E.D., R.D.), and Department of Trauma Surgery (F.K., S.M.), Medical University of Vienna, Lazarettgasse 14, A-1090 Vienna, Austria; Department of Orthopedic Surgery, University of Berne, Berne, Switzerland (T.C.M.); and Department of Medical Imaging, Mount Sinai Hospital, University of Toronto, Toronto, Canada (L.M.W.). Received April 18, 2007; revision requested June 14; revision received July 15; accepted August 16; final version accepted October 8. Supported by Austrian Science Fund, FWF-TRP-Project L243-B15. Address correspondence to G.H.W. (e-mail: welsch{at}bwh.harvard.edu).
| ABSTRACT |
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Materials and Methods: The study had institutional review board approval by the ethics committee of the Medical University of Vienna; informed consent was obtained. Twenty patients who underwent MFX or MACT (10 in each group) were enrolled. For comparability, patients of each group were matched by mean age (MFX, 40.0 years ± 15.4 [standard deviation]; MACT, 41.0 years ± 8.9) and postoperative interval (MFX, 28.6 months ± 5.2; MACT, 27.4 months ± 13.1). Magnetic resonance (MR) imaging was performed with a 3-T MR imager, and T2 maps were calculated from a multiecho spin-echo measurement. Global, as well as zonal, quantitative T2 values were calculated within the cartilage repair area and within cartilage sites determined to be morphologically normal articular cartilage. Additionally, with consideration of the zonal organization, global regions of interest were subdivided into deep and superficial areas. Differences between cartilage sites and groups were calculated by using a three-way analysis of variance.
Results: Quantitative T2 assessment of normal native hyaline cartilage showed similar results for all patients and a significant trend of increasing T2 values from deep to superficial zones (P < .05). In cartilage repair areas after MFX, global mean T2 was significantly reduced (P < .05), whereas after MACT, mean T2 was not reduced (P
.05). For zonal variation, repair tissue after MFX showed no significant trend between different depths (P
.05), in contrast to repair tissue after MACT, in which a significant increase from deep to superficial zones (P < .05) could be observed.
Conclusion: Quantitative T2 mapping seems to reflect differences in repair tissues formed after two surgical cartilage repair procedures.
© RSNA, 2008
| INTRODUCTION |
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The development of MR imaging techniques to help visualize and quantify extracellular matrix components of articular cartilage would improve the evaluation of cartilage repair procedures. A technique that demonstrates promising results is quantitative T2 mapping, which provides information about the interaction of water molecules and the collagen network within the articular cartilage (13,14). Alterations in T2 values have been shown to correlate with changes in water content, as well as collagen structure and organization, associated with changes in hyaline cartilage and its degradation (15–17). In animal studies, T2 mapping helped to differentiate hyaline cartilage from fibrocartilage after cartilage repair (18,19).
A frequently used treatment for the repair of articular cartilage lesions of the knee is the microfracture therapy (MFX) technique (20,21). With this method, the subchondral bone is penetrated to allow fibrin clot formation within the defect and the subsequent maturation of repair tissue, which fills the cartilage defect. In studies (5,8) with comparable patient populations and treatment protocols, histologic evaluation of repair-tissue biopsy specimens obtained at 12- and 24-month follow-up arthroscopic examinations after MFX has been reported to reveal fibrocartilage. Another technique that is becoming increasingly important for the treatment of full-thickness cartilage defects is matrix-associated autologous chondrocyte transplantation (MACT) (22–24). This two-step surgical procedure is based on the implantation of chondrocyte cells on a hyaluronan polymer scaffold as a carrier that are cultivated for several weeks and then implanted into an articular cartilage defect. With this cartilage repair procedure, the repair tissue acquired at 12- and 24-month follow-up arthroscopic examinations has been reported to be hyaline or "hyaline-like" at histologic evaluation (2,25).
The objective of our preliminary cross-sectional study was to prospectively compare cartilage T2 values after MFX and MACT repair procedures.
| MATERIALS AND METHODS |
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For inclusion in the study, the patients of both groups had to have a single symptomatic full-thickness cartilage defect on the femoral condyle. Cause of all defects was trauma or osteochondritis dissecans. Clinical indication for MFX or MACT was primarily based on defect size. Exclusion criteria were advanced or severe osteoarthritis, instability, and deformity. The solitary nature of the cartilage defect and the lack of advanced or severe osteoarthritis were preoperatively defined with conventional radiography and MR imaging and were intraoperatively proved and documented at surgical repair. Instability and deformity were excluded with clinical evaluation. In both groups, the cartilage defect was located on the medial femoral condyle in eight patients and on the lateral femoral condyle in two patients. Mean defect size was 2.55 cm2 (range, 1.3–4.3 cm2) for the MFX group and 5.34 cm2 (range, 2.4–10.1 cm2) for the MACT group.
For MACT, a hyaluronan-based scaffold (Hyalograft C; Fidia Advanced Biopolymers, Abano Terme, Italy) was used. This hyaluronan-based scaffold is composed of autologous chondrocytes grown on a three-dimensional hyaluronan polymer (HYAFF 11; Fidia Advanced Biopolymers) scaffold, which promotes in vitro proliferation of chondrocytes and favors the expression and maintenance of a cell-differentiated phenotype (26). MACT was performed by one surgeon (S.M.; with 12 years of experience); MFX was performed by another surgeon (R.D.; with 9 years of experience). Within their group, all patients after MACT and all patients after MFX underwent the same rehabilitation, and accepted modern protocols were followed (21,27).
In consideration of the postoperative time points and repair tissue alteration over time, we subdivided each patient group into a shorter and a longer imaging follow-up group, with five patients imaged at each time frame (group I, 12–24 months; group II, >24 months) in each treatment cohort. The mean postoperative interval was 18.0 months (range, 12–24 months) for MFX and 17.6 months (range, 12–22 months) for MACT within group I, whereas within group II, the postoperative interval was 38.8 months (range, 28–64 months) for MFX and 37.2 months (range, 26–54 months) for MACT.
Image Acquisition
MR imaging was performed with a 3-T MR imager (Magnetom Trio; Siemens Medical Solutions, Erlangen, Germany) with a gradient strength of 40 mT/m by using a dedicated eight-channel high-spatial-resolution knee array coil (Invivo, Gainesville, Fla). Special attention was paid to ensure that all patients were positioned consistently in a reproducible fashion with the joint space in the middle of the coil and the knee extended in the coil. Patients were imaged after at least half an hour of rest in the supine position.
For morphologic evaluation, an isotropic three-dimensional double-echo steady-state sequence (repetition time msec/echo time, 15.1/5.1; flip angle, 25°) was used. Field of view was 150 x 150 mm, pixel matrix was 250 x 250, and voxel size was 0.6 x 0.6 x 0.6 mm. Total imaging time was 6 minutes 32 seconds. After multiplanar reconstruction of the isotropic three-dimensional double-echo steady-state acquisitions by using a three-dimensional viewing tool and with the use of surgical reports, the cartilage repair site was identified, which facilitated planning of appropriate anatomic coverage and localization of subsequent two-dimensional multiecho spin-echo T2 mapping acquisitions.
T2 relaxation times were obtained from T2 maps reconstructed by using a sagittal multiecho spin-echo acquisition with a repetition time of 1650 msec and six echo times (12.9, 25.8, 38.7, 51.6, 65.5, and 77.4 msec). Field of view was 200 x 200 mm, pixel matrix was 320 x 320, and voxel size was 0.63 x 0.63 x 1 mm. The bandwidth was 240 Hz/pixel, one signal was acquired, 16 sections were acquired, and total acquisition time was 8 minutes 46 seconds. The total imaging time, including that for localizers and positioning, was 20 minutes.
Image Analysis
To evaluate the morphologic condition after a cartilage repair procedure by using the double-echo steady-state images, the MR observation of cartilage repair tissue scoring system was used (28). This scoring system was designed to systematically record the constitution of the area of cartilage repair and surrounding tissues, has been shown to be reliable and reproducible, and can be applied to different surgical cartilage repair techniques (29,30). The maximum score achievable in the evaluation of nine variables is 100. The variables are defect filling, integration, surface and structure of the cartilage repair tissue and its borders, signal intensity, state of subchondral lamina and bone, possible adhesions, and effusion.
T2 maps were obtained by using a pixelwise monoexponential nonnegative least-squares fit analysis. With the morphologic images obtained by using the double-echo steady-state sequence and the intraoperative documentation, sections that covered the cartilage repair tissue were selected on the T2 map images. Regions of interest (ROIs) were manually drawn by an experienced senior musculoskeletal radiologist (S.T., with 22 years of experience) in consensus with an orthopedic surgeon with special interest in musculoskeletal MR imaging (G.H.W., with 8 years of experience).
The ROIs covering the full thickness of cartilage repair tissue were positioned within the identified cartilage repair sites. In all cases, cartilage repair sites were seen on three to four contiguous sagittal sections, and two to three ROIs were placed within the repair tissue per section. Thus, altogether, six to 12 ROIs were placed within each cartilage repair site, depending on its dimensions. A region of morphologically normal–appearing cartilage within the same knee was selected as a reference (control), with three ROIs positioned along the control cartilage tissue. Cartilage was defined as normal on the double-echo steady-state image if cartilage thickness was preserved in correlation to its surroundings, if the surface was intact, and if no intrachondral signal intensity alterations were visible. Because all areas of cartilage repair were located within the weight-bearing zone of the femoral condyle, reference (control) cartilage sites were also selected from the weight-bearing aspect of the femoral articular surface, but had to be more than 2 cm away from cartilage repair tissue. For all ROIs of global (from subchondral to superficial) T2 measurements, the number of pixels evaluated was kept similar as much as possible, with a mean ROI size of 45 pixels ± 5 (range, 36–57 pixels) (Figs 1, 2).
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Knee Function
To evaluate clinical outcomes for each patient, knee function was assessed by using the Lysholm score (31,32) from a scoring system that divides clinical outcome into groups for excellent, good, fair, and poor outcome. The Lysholm knee scale is a condition-specific outcome measure that has been validated for chondral disorders of the knee and that includes parameters such as pain, instability, walking abnormalities, and swelling (33); it was applied at the same time MR imaging was performed.
Data and Statistical Analysis
For comparison of the different groups, arithmetic mean values and standard deviations of T2 relaxation times from all ROIs within each cartilage repair tissue site were calculated and compared with mean values and standard deviations of T2 relaxation times from all ROIs of control articular cartilage sites within the same group. Quantitative evaluation was performed by using three-way analyses of variance with random factors, with the consideration of different measurements within each patient. To determine the trend between the cartilage layers, a three-way analysis of variance with random effects and two repeated-measure factors was performed. Software (SPSS for Windows, version 14.0; SPSS Institute, Chicago, Ill) was used. Differences between cartilage repair regions and normal hyaline cartilage sites with a P value of less than .05 were considered statistically significant. Because of the small number of patients, the results of the subdivision into the postoperative intervals are just descriptive.
| RESULTS |
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T2 Values
Mean T2 values (in milliseconds) in control articular cartilage areas were similar in all patients (MFX group: 57.8 msec ± 8.7; range, 40–66 msec) (MACT group: 56.7 msec ± 6.0; range, 50–67 msec). The cartilage repair tissue in patients after MFX showed a significantly (P < .05) reduced mean T2 value of 47.3 msec ± 10.3 (range, 33–64 msec) relative to that of control tissue (Fig 3), whereas cartilage repair tissue in patients after MACT showed a mean T2 value of 56.4 msec ± 9.6 (range, 45–72 msec), with no significant difference relative to that of control tissue (P
.05) (Fig 4).
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Quantitative T2 measurements of zonal variation related to depth (deep and superficial) of articular cartilage showed differences between the control cartilage sites and the different cartilage repair procedures. Healthy control cartilage sites for both groups showed a highly significant increase in T2 values from deep to superficial areas. The cartilage repair tissue after MACT showed a slight but still significant increase in T2 value. Repair tissue after MFX showed no increase at all (Fig 5, Table).
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| DISCUSSION |
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By means of quantitative T2 mapping in patients after different cartilage repair procedures, we found significantly lower global mean T2 values of cartilage repair tissue after MFX, whereas after MACT, no significant change in mean T2 values could be observed relative to those in morphologically normal control sites. These findings imply that the generated repair tissue after the two different procedures may vary. T2 relaxation times have been shown to be relatively sensitive to macromolecular content and especially to the orientation of collagen fibrils through residual dipolar interaction (magic angle effect) (17). Dardzinski et al (36) concluded that the T2 characteristics in cartilage are strongly influenced by the orientation of the collagen framework and that the dipole-dipole interaction anisotropy in the presence of restricted water mobility has an important influence on spin-spin relaxation in the deep layers of cartilage. Additionally, results of in vitro T2 relaxation studies and animal studies (18,37,38) have also demonstrated a close relationship between T2 and the architecture of collagen. Moreover, results of an in vitro study (39) for the evaluation of reconstituted cartilage showed changing T2 values during the cultivation of cartilage implants by using hyaluronan-based scaffolds. However, this study was limited to the phase of cultivation lasting up to 6 weeks preceding human implantation. In a recent study (40), stability of T2 values after a follow-up period of more than 12 months after MACT was observed. Nevertheless, the T2 values observed in our study could also have been altered by the implant scaffold effects, such as water content, cellular density, and reduced collagen content; even so, this alteration should reduce over time because of maturation of cartilage transplants (40).
In a recent study by White et al (19), normal hyaline cartilage and cartilage repair tissue could be differentiated in horses. Arthroscopic osteochondral autograft transplantation (OAT) and MFX were performed, and evaluation of zonal T2 variation showed a significant trend across cartilage depth in control and OAT sites of low T2 values near the subchondral bone and higher T2 values near the cartilage surface; however, no zonal variation within MFX areas was found. T2 measurement results in this study were compared with histologic findings and collagen structural anisotropy as assessed by using polarized light microscopy, with OAT and normal hyaline cartilage sites illustrating a normal zonal collagen organization, whereas after MFX, only disorganized fibrous reparative tissue was visible.
In our study, it was possible to evaluate T2 relaxation times in vivo in normal hyaline cartilage sites and in cartilage repair tissue after two different cartilage surgical procedures. After we obtained high-spatial-resolution MR images, it was possible to assess T2 zonal variations within the ROIs and use the measurements as an additional tool to characterize cartilage repair tissues. Similar to White et al (19) in their in vivo animal study, we found no differences between deep and superficial layers of cartilage repair tissue after MFX. After MACT, zonal variation in mean T2 measurements was observed; however, compared with healthy cartilage sites, the increase in mean T2 values from deep to superficial zones was less pronounced.
Limitations of our preliminary investigation included the small number of patients evaluated, the different time points of follow-up, and the lack of direct histologic correlation for the observed T2 measurements. Additionally, the possible problem of location of the cartilage evaluation site with respect to the main magnetic field should be discussed. It is acknowledged that bulk T2 measurements of cartilage may vary depending on the anatomic region of cartilage studied and its orientation relative to the main magnetic field. Similarly, it is acknowledged that repair site location along the femoral condyles may influence quantitative T2 measurements and the magnitude of zonal variation observed. In all cases, normal (control) cartilage sites were selected from the weight-bearing zone of the femoral condyle at a position and orientation as reproducible as possible relative to the main magnetic field, far from the magic angle of 55°. Although quantitative differences in measured T2 values depending on the orientation of hyaline cartilage between perpendicular and parallel to the main magnetic field have been described, these differences are minor and are unlikely to affect the zonal variation observed within normal articular cartilage tissue (41,42).
Another severe limitation of our study was possible partial volume effects, which limit the results concerning zonal variation. However, ROI assessment of global T2 values and an addition of the two zones showed similar results, which may indicate that multiple measurements diminish this error. Because of cartilage ultrastructure, a threefold evaluation without possible partial volume effects is desirable and should force an increase of in-plane resolution, which remains challenging for in vivo cartilage imaging in a clinically realizable imaging time.
Because the size of the lesion is a criterion in selecting the type of repair, this could also bias the results by potentially affecting the incorporation or biomechanical microenvironment of the repair tissue. In a recent review article (30) concerning morphologic MR studies after cartilage repair, 3 months was suggested to be the first time point at which repair tissue can be reasonably assessed, whereas a 1-year follow-up seems to be a sufficiently early stage to assess cartilage maturation. In our study, the later time points of follow-up may be a limitation; however, the maturation of both repair tissues should be more complete.
Although the MR observation of cartilage repair tissue scores were the same after both surgical procedures, the subdivision into groups on the basis of the timing of postoperative follow-up MR imaging revealed differences in T2 mapping characteristics. After MFX, mean T2 values appeared to decline between the 12–24-month group and the more-than-24-month group. This could indicate a decrease in repair tissue water content and an increase in fibrous tissue, possibly indicative of deterioration or increasing fibrocartilage. Two recent clinical studies of Kreuz et al (43,44) support this deterioration in the longitudinal follow-up after MFX. In contrast, patients after MACT showed relatively stable mean T2 values between the two imaging time periods. To further evaluate the association between T2 values and clinical outcome, larger patient studies with longitudinal follow-up should be performed.
With the underlying assumption that reported histologic biopsy specimens obtained at postoperative follow-up arthroscopy in prior studies have shown more fibrocartilage after MFX (5,8) and more hyaline-like cartilage after MACT (2,25), our findings may suggest that quantitative T2 mapping can provide information about the structures of different cartilage repair tissues. However, the source and clinical importance of the observed spatial variation after MACT are unknown; on the basis of our preliminary findings, further investigations in larger patient groups with histologic correlation would be beneficial in comparing T2 findings with repair tissue properties and evaluating the possible clinical utility of this technique as a predictive index of repair efficacy.
| ADVANCE IN KNOWLEDGE |
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.05). | IMPLICATION FOR PATIENT CARE |
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| ACKNOWLEDGMENTS |
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| FOOTNOTES |
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Abbreviations: MACT = matrix-associated autologous chondrocyte transplantation MFX = microfracture therapy ROI = region of interest
Author contributions: Guarantors of integrity of entire study, G.H.W., T.C.M., S.T.; 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, G.H.W., T.C.M., S.E.D., R.D., F.K., S.M., S.T.; clinical studies, G.H.W., T.C.M., S.E.D., R.D., F.K., S.M., S.T.; experimental studies, G.H.W., T.C.M., L.M.W., S.T.; statistical analysis, G.H.W., T.C.M., S.T.; and manuscript editing, all authors
Authors stated no financial relationship to disclose.
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