- Email: [email protected]
Quantitative Magnetic Resonance Imaging of Cartilage Resurfacing Procedures
Quantitative Magnetic Resonance Imaging of Cartilage Resurfacing Procedures Drew A. Lansdown, MD,* Musa Zaid, BS,† and C. Benjamin Ma, MD* Recent advances in imaging technology have provided clinicians with multiple options for the evaluation of patients after cartilage resurfacing procedures. These methods, primarily performed with magnetic resonance imaging, provide a noninvasive assessment of cartilage health. Novel imaging sequences can evaluate the structure of the collagen network and biochemical composition of the repair tissue, among other properties. Quantitative imaging, including T1ρ, T2 T2 star, diffusion-weighted imaging, and sodium imaging, has the potential to replace second-look arthroscopy as the gold standard for a longitudinal assessment after cartilage resurfacing. Multiple clinical studies have employed these methods after various resurfacing methods, with promising early results. The purpose of this article is to review multiple different imaging methods for quantitative evaluation of cartilage, including advantages and disadvantages of these techniques and an overview of preclinical and clinical studies of quantitative imaging after cartilage resurfacing. Oper Tech Orthop 24:293-299 C 2014 Published by Elsevier Inc. KEYWORDS Quantitative MR imaging, cartilage imaging, T1ρ, T2 mapping
Introduction
T
he clinical evaluation of a patient following a cartilage restoration procedure is often challenging. The physical examination may not provide much information regarding the recovery process. Conventional imaging modalities, such as radiography, computed tomography (CT), and magnetic resonance imaging (MRI), are difficult to interpret, with postoperative changes often appearing similar to otherwise concerning findings. Although the previous gold standard for the in vivo postoperative evaluation of cartilage restoration procedures was a second-look arthroscopy, recent advances in quantitative imaging allow for a more comprehensive, noninvasive evaluation of cartilage changes.1,2 These modalities, summarized in the Table, provide surgeons with powerful information and may help guide rehabilitation and further treatment. In this article, we review the current options for quantitative cartilage
*Department of Orthopaedic Surgery, University of California, San Francisco, CA. †School of Medicine, University of California, San Francisco, CA. Address reprint requests to C. Benjamin Ma, MD, Department of Orthopaedic Surgery, University of California, San Francisco, 500 Parnassus Ave, MU 320W Box 0728, San Francisco, CA 94143-0728. E-mail: maben@ orthosurg.ucsf.edu, [email protected]
http://dx.doi.org/10.1053/j.oto.2014.05.002 1048-6666/& 2014 Published by Elsevier Inc.
imaging as well as the feasibility of using these imaging techniques to assess cartilage health following repair.
Current Quantitative Imaging Modalities MRI Scoring Systems Standard clinical imaging sequences may be used with reproducible joint scoring systems to systematically quantify changes after cartilage repair. MR-based scoring systems have been used to evaluate patients after cartilage repair, with the most common system being the magnetic resonance observation of cartilage repair tissue.3 This system uses standard clinical MR sequences to evaluate multiple parameters after cartilage repair, including thickness, integration, adhesions, signal intensity, presence of an effusion, and other parameters. This system affords high interuser and intrauser reliability for both surgeons and radiologists, though does not use the full potential of MR sequences to evaluate articular cartilage.3
Delayed Gadolinium-Enhanced MRI of Cartilage Gadolinium, a commonly used exogenous contrast agent for MRI, is a chelated ion used in multiple forms of MRI. The 293
D.A. Lansdown et al.
294 Table Advantages and Limitations of Quantitative Imaging Modalities Imaging Modality
Information Provided
dGEMRIC
Glycosaminoglycan concentration
T1ρ
Glycosaminoglycan concentration
T2
Integrity of collagen network Concentration of collagen Water concentration Collagen structure or content Water content
T2 star
Diffusion-weighted imaging
Sodium MRI
Contrast CT
Integrity of collagen network Proteoglycan concentration Proteoglycan concentration Proteoglycan concentration
Advantages Direct assessment of glycosaminoglycan concentration Reproducible assessment of biochemical composition No exogenous contrast needed Structural and biochemical assessment No exogenous contrast Structural assessment of cartilage No exogenous contrast 3-D acquisition Fast scan time No exogenous contrast Structural and biochemical assessment No exogenous contrast Assessment of biochemical composition of cartilage Signal directly proportional to proteoglycan contrast
molecule is a negatively charged ion, which is repelled by the negatively charged glycosaminoglycans (GAG) of articular cartilage. Delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) involves the administration of gadolinium, followed by a delay before imaging, approximately 30-45 minutes.4,5 During this time, the contrast agent diffuses into the articular cartilage and distributes in a pattern that is inversely correlated with proteoglycan content. This method has been used frequently in prior studies, given the ability to provide additional information regarding the molecular makeup of articular cartilage.6-8 A clear disadvantage with dGEMRIC is the need for contrast agent administration. Gadolinium is associated with nephrogenic systemic fibrosis and should not be administered in the setting of a decreased creatinine clearance.9
T1ρ Magnetic Resonance Imaging One common MR-based methodology with applicability to cartilage imaging is T1ρ. This technique measures spin-lattice relaxation time in the rotating spatial frame.10,11 Images are acquired at various echo times, and an exponential fit is used to determine the T1ρ relaxation time. The proteoglycan content of cartilage can be interrogated with T1ρ imaging (Fig. 1), owing to the negatively charged GAG. Histologic studies of animal cartilage and explanted human specimens have correlated the content of proteoglycan with the T1ρ relaxation times, with increasing values of T1ρ associated with decreased levels of proteoglycan.12,13 Additional in vivo work has shown that significant changes are present regarding the T1ρ relaxation time in early osteoarthritis.14 Owing to the need for a high signal-to-
Limitations Need for contrast administration
Potential for energy deposition in tissue Signal effected by alignment of cartilage relative to magnetic field Signal effected by alignment of cartilage relative to magnetic field
Most sensitive to patient motion Low signal-to-noise ratio Low signal-to-noise ratio Requires specialized hardware Need for contrast administration Poor visualization of whole knee joint
noise ratio and gradient strength, a field strength Z1.5 T is required for adequate image acquisition. This sequence requires no contrast administration and be acquired with routine clinical sequences. Disadvantages of this method include the need for manual cartilage segmentation for quantification and the potential for high amounts of energy deposition within tissues.11
T2 Magnetic Resonance Imaging The T2 relaxation is a second possible MRI sequence for quantitative cartilage evaluation (Fig. 1). Similar to T1ρ, multiple images are acquired at various echo times, and the T2 relaxation time is calculated as an exponential fit of the signal decay. T2 appears to provide more information on the macrostructure of articular cartilage, specifically the collagen network.15 There is also likely some contribution from increased water within the cartilage. Similar to T1ρ, T2 imaging can be conducted on clinical scanners and does not require an exogenous contrast agent. Disadvantages of this technique include the need for image postprocessing and segmentation. The T2 relaxation time shows increased susceptibility to the alignment of the cartilage within the magnetic field.15,16
T2 Star Magnetic Resonance Imaging Quantitative T2 MRI uses the relaxation constant to provide information about the interaction of water molecules and collagen in cartilage.17 T2 star (T2*) MRI measures T2 relaxation times; however, it uses a sequence that accounts for field inhomogeneity when inferring information of the
Quantitative MRI of cartilage resurfacing procedures
295 composition and density. The apparent diffusion coefficient has been shown to increase following the enzymatic breakdown of cartilage.21,22 The signal from DWI relies on the anisotropic movement of protons within tissue. The collagen network of cartilage restricts diffusion along the fiber direction, so this modality gives information regarding the structure of cartilage.23 Additionally, diffusion properties have been correlated with the proteoglycan content of cartilage as measured by dGEMRIC (Mlynarik).24
Sodium MRI Although most quantitative MRI methods rely on hydrogen nuclei, new developments in MRI technology has allowed the ability to use sodium nuclei in MR image acquisition. Sodium content in articular cartilage is directly proportional to the GAG content as the carboxyl and sulfate groups on GAG impart a negative fixed charge density to the cartilage matrix.25 This quality of sodium makes it an ideal proxy to measure GAG content in cartilage. Although sodium MRI does not require the administration of contrast, it does require propriety coils tuned to a frequency specific for sodium.26
Contrast CT In addition to quantitative MRI, contrast enhanced CT could also provide a noninvasive method to assess cartilage health. Similar to sodium MRI, contrast enhanced CT relies on the negative fixed charge density of cartilage imparted by proteoglycan molecules.8 Owing to this negative charge, the uptake of cationic contrast agents, such as gadolinium, is directly proportional to the amount of proteoglycan content in the cartilage.27 As a result, healthy cartilage with increased proteoglycan content will bind more gadolinium and lead to an attenuation of signal, whereas damaged cartilage with less proteoglycan will uptake less contrast and have increased signal.28 Cockman et al27 have demonstrated a strong correlation between cationic gadolinium uptake and proteoglycan concentration in cartilage suggesting that this imaging modality may allow for the quantification of cartilage health. The ability to use contrast enhanced CT to assess cartilage health following cartilage repair has yet to be examined.
Figure 1 Quantitative imaging of the normal knee, overlaid on a sagittal, fluid-sensitive MR image, with (A) T1ρ cartilage map and (B) T2 cartilage map, with mean relaxation time in milliseconds, according to the color bar.
biochemical composition of tissues.18 Compared with standard T2 imaging, T2* MRI is advantageous in that it requires shorter scan times, is more sensitive for cartilage damage, and may provide the ability for 3-dimensional acquisition.19,20
Diffusion-Weighted MRI Diffusion-weighted imaging (DWI) is an additional MR-based modality that takes advantage of known properties of articular cartilage. The diffusivity of cartilage is dependent on its
Evaluation of Cartilage Restoration Procedures With Quantitative Imaging These recent advances in imaging capabilities, combined with improvements in surgical techniques, have resulted in multiple studies evaluating the abilities of various imaging modalities to assess and monitor patients after cartilage restoration procedures. MR-based scoring systems have been evaluated extensively, many of which were summarized in a systematic review of 26 studies that scored MR images of the knee in patients treated with autologous chondrocyte implantation, osteochondral autograft (OATS), or microfracture.29 This study found that there was no significant correlation between clinical outcomes and MR-based scoring systems. The lack of sensitivity of these qualitative methods supports the need for more
D.A. Lansdown et al.
296 sophisticated means of evaluating patients after cartilage repair procedures. Advanced quantitative imaging sequences as described previously have the ability to offer additional information regarding the health of cartilage. One parameter of interest when assessing postsurgical tissue is the structural organization of cartilage. Normal articular cartilage comprises a distinct arrangement of collagen, with fibers perpendicular to the joint adjacent to the subchondral bone and parallel to the joint in the superficial layer, which contributes to the function of cartilage.30 Different repair techniques result in unique tissue properties, and understanding the role that these properties play in patient function, subjective outcomes, and durability of repair will allow for improved treatment recommendations. T2 mapping probes the structure of the collagen network of articular cartilage. T2 mapping after microfracture in goat and equine cartilage have shown consistently higher T2 values in repair tissue relative to healthy articular cartilage.7,16 The normal cartilage displayed a transitional pattern, with lower values in the deep zone and increased values at the superficial zone. Microfracture repair tissue did not exhibit this property, showing no difference in values in the deep, transitional, and superficial layers.7 White et al16 also qualitatively graded the T2 maps according to their organization, determining that microfracture maps were consistently disorganized, whereas normal cartilage maps were organized. When evaluating T2 maps after OATS treatment, the T2 map more closely approximated the pattern observed in normal cartilage, suggesting that the
structural properties were restored. These findings were confirmed with histologic evaluation. Several human studies have validated the utility of T2 mapping. Theologis et al31 found a similar result, 1 year after microfracture surgery in a group of 10 patients, with no observed difference between the deep and superficial layers of repair tissue. A study of the T2 maps in 20 patients after microfracture or matrix-associated autologous chondrocyte transplantation (MACT) confirmed the lack of a spatial signal pattern in microfracture repair tissue.32 The site of MACT exhibited an increase from the deep to the superficial layer, suggesting that the spatial relationship of articular cartilage was restored. These investigations demonstrate the utility of T2 mapping in evaluating the macrostructure of cartilage repair and the feasibility of applying this technique for monitoring repair tissue in human subjects (Fig. 2). The biochemical composition of repair tissue is a second property of interest following cartilage repair. The type of tissue present at a repair site depends on the surgical treatment. Microfracture results in primarily fibrocartilage, whereas OATS and autologous chondrocyte implantation or MACT procedures produce tissue that is more similar to hyaline cartilage.33 Multiple imaging modalities provide information on the proteoglycan content of cartilage, including dGEMRIC, T1ρ, and sodium imaging. An animal investigation of dGEMRIC following microfracture showed a correlation of the change in the ratio of the precontrast and postcontrast relaxation times of repair tissue and the GAG concentration within the repair
Figure 2 Sagittal double-echo steady-state MR image (15.1/5.1; 251 flip angle) (left), sagittal spin-echo raw T2 image (1650/ 12.9, 25.8, 38.7, 51.6, 65.5, 77.4; flip angle, 1801) (middle), and corresponding fused sagittal cartilage colored T2 map (right) in patient after (A) MFX and (B) MACT. Cartilage repair area is located between the 2 arrows. Note ROI analysis of cartilage repair (outlined between 2 arrows) and control cartilage (outlined area on left) on colored T2 map. MFX, microfracture; ROI, region of interest. (Reproduced with permission from Welsch et al.38)
Quantitative MRI of cartilage resurfacing procedures
297
Figure 3 R1 precalculated map (A), R1 postcalculated map (B), and DR1-calculated map (C) of a representative cartilage specimen that was harvested 48 months after surgery. The cartilage specimen in this figure is the same as that in Figures 5 and 6. The R1 precalculated map of repair tissue (arrows) appears lower than that of adjacent native cartilage. The R1 postcalculated map of repair tissue appears slightly higher than that of adjacent native cartilage. The DR1 of repair tissue appears considerably higher than that of adjacent native cartilage. (Reproduced with permission from Watanabe et al.7)
tissue, as assessed through high-performance liquid chromatography (Fig. 3).7 A comparison of the precontrast and postcontrast values for repair tissue was proposed as the baseline signal of repair cartilage was abnormal, and the postcontrast relaxation time alone was not significantly correlated to the measurements of GAG content. A subsequent human study determined the change in precontrast and postcontrast relaxation times with dGEMRIC (delta R1) in 20 patients treated with microfracture or MACT.34 The delta R1 value was higher in microfracture relative to MACT, which suggests a lower proteoglycan content in the microfracture repair tissue. Diffusion imaging, which is thought to evaluate both the structure and composition of cartilage, has been correlated with patient-reported outcomes after cartilage repair. It can reliably distinguish between normal and repair tissues, and DWI signal is negatively correlated with the Lysholm score.32 This technique has been validated after both microfracture and MACT and provides information that is more sensitive than the
magnetic resonance observation of cartilage repair tissue score or standard morphologic assessment. Sodium imaging also probes the biochemical properties following cartilage repair through the measurement of negatively charged molecules like GAG. Trattnig et al34 validated the measurements of GAG concentration through sodium MRI by comparing results from 12 patients with dGEMRIC values. There was a strong correlation between these 2 modalities, showing that sodium MRI is a viable noncontrast modality for evaluating cartilage repair tissue. An evaluation of 18 patients after microfracture or MACT was performed using sodium MRI on a 7-T scanner (Fig. 4).35 The signal intensity of the repair tissue after both surgical procedures was significantly lower than normal cartilage, indicating lower content of GAG after both restoration procedures. The relative decrease in MACT was less than what was observed in microfracture, once again suggesting different types of repair tissues from these surgical methods. Sodium imaging is currently used primarily only for research purposes, as the high field strength and
Figure 4 Sagittal proton density–weighted 2D-TSE MR image with fat suppression (left), sagittal sodium 3D-GRE image (middle), and color-coded sagittal sodium 3D-GRE image (right) in a 43-year-old woman obtained 42 months after an MFX procedure. Cartilage repair tissue is situated between the 2 arrows. Red contours in the middle image represent the ROI analysis of repair tissue (right contour) and reference cartilage (left contour). Please note that repair tissue voxels situated closest to the repair tissue-native cartilage interface are not included into the ROI evaluations. Color scale represents the sodium signal intensity values. 2D-TSE, 2-dimensional turbo spin-echo; 3D-GRE, 3-dimensional gradient-echo; MFX, microfracture; ROI, region of interest. (Reproduced with permission from Zbyn et al.35)
D.A. Lansdown et al.
298 specialized systems required make this process difficult to implement in a clinical practice. The T1ρ relaxation time is correlated with the proteoglycan content in cartilage.11 The feasibility of using T1ρ in human subjects after microfracture and mosaicplasty has been demonstrated, with highly reproducible values and information that is complimentary to T2 mapping.36 A longitudinal study of T1ρ values in 10 patients after microfracture found a decreasing value in the deep layer of cartilage over 1 year but a persistent elevation of T1ρ in the superficial layer (Fig. 5). These findings suggest that the proteoglycan content of the deep layer of repair tissue matures with time, whereas the superficial layer may remain underdeveloped.31 Our preference for quantitative imaging of cartilage is a standard clinical protocol with a sagittal, 3-dimensional, fatsaturated, fast spin-echo sequence for morphologic evaluation and a combined T1ρ and T2 sequence for quantitative cartilage
evaluation.37 This method offers the advantages of a reproducible imaging method that can be acquired on a clinical MR scanner. No contrast agent is administered, and patients avoid the risks of ionizing radiation associated with CT. Postprocessing is required, which may currently limit the widespread clinical application of these sequences. The information acquired from these sequences allows for reliable longitudinal tracking of these patients, and the color maps produced can provide clinicians and patients with a better understanding of the health of their cartilage.
Conclusion Quantitative imaging allows clinicians and researchers to monitor cartilage repair tissue. Multiple different modalities are available for use, with different imaging techniques offering the potential to evaluate different aspects of the repair tissue. The information acquired from these sequences can be used to compare different surgical techniques in research studies and, in the future, may be used to direct rehabilitation programs.
References
Figure 5 Representative T1ρ color map of a knee 3-6 months after microfracture surgery for the treatment of a focal cartilage defect. The repaired tissue is seen in the medial femoral condyle as an area with increased signal intensity. The inset (lower left corner) illustrates the boundaries of the repaired tissue (RT, red lines) as well as the separation between deep and superficial layers (black line). It should be noted that the deep and superficial layers of the RT have higher T1ρ signal than the respective layers in the normal cartilage (NC) and that the superficial layer of the RT has higher signal intensity than the deep layer of RT. (Reproduced with permission from Theologis et al.31)
1. Gudas R, Kalesinskas RJ, Kimtys V, et al: A prospective randomized clinical study of mosaic osteochondral autologous transplantation versus microfracture for the treatment of osteochondral defects in the knee joint in young athletes. Arthroscopy 21:1066-1075, 2005 2. Bentley G, Biant LC, Carrington RWJ, et al: A prospective, randomised comparison of autologous chondrocyte implantation versus mosaicplasty for osteochondral defects in the knee. J Bone Joint Surg Br 85-B:223-230, 2003 3. Marlovits S, Singer P, Zeller P, et al: Magnetic resonance observation of cartilage repair tissue (MOCART) for the evaluation of autologous chondrocyte transplantation: Determination of interobserver variability and correlation to clinical outcome after 2 years. Eur Radiol 57:16-23, 2006 4. Bashir A, Gray ML, Burstein D: Gd-DTPA2 as a measure of cartilage degradation. Magn Reson Med 36:665-673, 1996 5. Bashir A, Gray ML, Boutin RD, et al: Glycosaminoglycan in articular cartilage: In vivo assessment with delayed gd(DTPA)(2 )-enhanced MR imaging. Radiology 205:551-558, 1997 6. Kurkijarvi JE, Mattila L, Ojala RO, et al: Evaluation of cartilage repair in the distal femur after autologous chondrocyte transplantation using T2 relaxation time and dGEMRIC. Osteoarthritis Cartilage 15:372-378, 2007 7. Watanabe A, Boesch C, Anderson SE, et al: Ability of dGEMRIC and T2 mapping to evaluate cartilage repair after microfracture: A goat study. Osteoarthritis Cartilage 17:1341-1349, 2009 8. Taylor C, Carballido-Gamio J, Majumdar S, et al: Comparison of quantitative imaging of cartilage for osteoarthritis: T2, T1ρ, dGEMRIC, and contrast-enhanced computed tomography. Magn Reson Imaging 27:779-784, 2009 9. Thomsen HS, Morcos SK, Almen T, et al: Nephrogenic systemic fibrosis and gadolinium-based contrast media: Updated ESUR contrast medium safety committee guidelines. Eur Radiol 23:307-318, 2013 10. Li X, Ma CB, Link TM, et al: In vivo T1ρ and T2 mapping of articular cartilage in osteoarthritis of the knee using 3 T MRI. Osteoarthritis Cartilage 15:789-797, 2007 11. Duvvuri U, Kudchodkar S, Reddy R, et al: T1ρ relaxation can assess longitudinal proteoglycan loss from articular cartilage in vitro. Osteoarthritis Cartilage 10:838-844, 2002 12. Regatte RR, Akella SV, Borthakur A, et al: Proteoglycan depletion-induced changes in transverse relaxation maps of cartilage: Comparison of T2 and T1ρ. Acad Radiol 9:1388-1394, 2002
Quantitative MRI of cartilage resurfacing procedures 13. Li X, Cheng J, Lin K, et al: Quantitative MRI using T1ρ and T2 in human osteoarthritic cartilage specimens: Correlation with biochemical measurements and histology. Magn Reson Imaging 29:324-334, 2011 14. Li X, Han ET, Busse RF, et al: In vivo T1ρ mapping in cartilage using 3D magnetization-prepared angle-modulated partitioned k-space spoiled gradient echo snapshots (3D MAPSS). Magn Reson Med 59:298-307, 2008 15. Nieminen MT, Rieppo J, Toyras J, et al: T2 relaxation reveals spatial collagen architecture in articular cartilage: A comparative quantitative MRI and polarized light macroscopic study. Magn Reson Med 46:487-493, 2001 16. White LM, Sussman MS, Hurtig M, et al: Cartilage T2 assessment: Differentiation of normal hyaline cartilage and reparative tissue after arthroscopic cartilage repair in equine subjects. Radiology 241:407-414, 2006 17. Burstein D, Gray ML: Is MRI fulfilling its promise for molecular imaging of cartilage in arthritis? Osteoarthritis Cartilage 14:1087-1090, 2006 18. Palmer AJ, Brown CP, McNally EG, et al: Non-invasive imaging of cartilage in early osteoarthritis. Bone Joint J 95-B:738-746, 2013 19. Bittersohl B, Miese FR, Hosalkar HS, et al: T2* mapping of acetabular and femoral hip joint cartilage at 3 T: A prospective controlled study. Invest Radiol 47:392-397, 2012 20. Mamisch TC, Hughes T, Mosher TJ, et al: T2 star relaxation times for assessment of articular cartilage at 3 T: A feasibility study. Skeletal Radiol 41:287-292, 2012 21. Burstein D, Gray ML, Hartman AL, et al: Diffusion of small solutes in cartilage as measured by nuclear magnetic resonance (NMR) spectroscopy and imaging. J Orthop Res 11:465-478, 1993 22. Deng X, Farley M, Nieminen MT, et al: Diffusion tensor imaging of native and degenerated human articular cartilage. Magn Reson Imaging 25:168-171, 2007 23. Mamisch TC, Menzel MI, Welsch GH, et al: Steady-state diffusion imaging for MR in-vivo evaluation of cartilage after matrix-associated autologous chondrocyte transplantation at 3 Tesla—Preliminary results. Eur Radiol 65:72-79, 2008 24. Mlynarik V, Sulzbacher I, Bittsansky M, et al: Investigation of apparent diffusion constant as an indicator of early degenerative disease in articular cartilage. J Magn Reson Imaging 17:440-444, 2003 25. Borthakur A, Mellon E, Niyogi S, et al: Sodium and T1ρ for molecular and diagnostic imaging of articular cartilage. NMR Biomed 19:781-821, 2006 26. Chang G, Madelin G, Sherman OH, et al: Improved assessment of cartilage repair tissue using fluid-suppressed 23Na inversion recovery at 7 Tesla: Preliminary results. Eur Radiol 22:1341-1349, 2012
299 27. Cockman MD, Blanton CA, Chmielewski PA, et al: Quantitative imaging of proteoglycan in cartilage using a gadolinium probe and microCT. Osteoarthritis Cartilage 14:210-214, 2006 28. Bansal PN, Joshi NS, Entezari V, et al: Cationic contrast agents improve quantification of glycosaminoglycan (GAG) content by contrast enhance CT imaging of cartilage. J Orthop Res 29:704-709, 2011 29. Blackman AJ, Smith MV, Flanigan DC, et al: Correlation between magnetic resonance imaging and clinical outcomes after cartilage repair surgery in the knee: A systematic review and meta-analysis. Am J Sports Med 41:1426-1434, 2013 30. Jeffery AK, Blunn GW, Archer CW, et al: Three-dimensional collagen architecture in bovine articular cartilage. J Bone Joint Surg Br 73:795-801, 1991 31. Theologis AA, Schairer WW, Carballido-Gamio J, et al: Longitudinal analysis of T1ρ and T2 quantitative MRI of knee cartilage laminar organization following microfracture surgery. Knee 19:652-657, 2012 32. Welsch GH, Trattnig S, Domayer SE, et al: Multimodal approach in the use of clinical scoring, morphological MRI and biochemical T2-mapping and diffusion-weighted imaging in their ability to assess differences between cartilage repair tissue after microfracture therapy and matrixassociated autologous chondrocyte transplantation: A pilot study. Osteoarthritis Cartilage 17:1219-1227, 2009 33. Knutsen G, Engebretsen L, Ludvigsen TC, et al: Autologous chondrocyte implantation compared with microfracture in the knee. A randomized trial. J Bone Joint Surg Am 86-A:455-464, 2004 34. Trattnig S, Mamisch TC, Pinker K, et al: Differentiating normal hyaline cartilage from post-surgical repair tissue using fast gradient echo imaging in delayed gadolinium-enhanced MRI (dGEMRIC) at 3 Tesla. Eur Radiol 18:1251-1259, 2008 35. Zbyn S, Stelzeneder D, Welsch GH, et al: Evaluation of native hyaline cartilage and repair tissue after two cartilage repair surgery techniques with 23 Na MR imaging at 7 T: Initial experience. Osteoarthritis Cartilage 20:837-845, 2002 36. Holtzman DJ, Theologis AA, Carballido-Gamio J, et al: T1ρ and T2 quantitative magnetic resonance imaging analysis of cartilage regeneration following microfracture and mosaicplasty cartilage resurfacing procedures. J Magn Reson Imaging 32:914-923, 2010 37. Li X, Wyatt C, Rivoire J, et al: Simultaneous acquisition of T1ρ and T2 quantification in knee cartilage: Repeatability and diurnal variation. J Magn Reson Imaging 39:1287-1293, 2014 38. Welsch GH, Mamisch TC, Domayer SE, et al: Cartilage T2 assessment at 3T MR imaging: In vivo differentiation of normal hyaline cartilage from reparative tissue after two cartilage repair procedures—Initial experience. Radiology 247:154-161, 2008
Introduction
T
he clinical evaluation of a patient following a cartilage restoration procedure is often challenging. The physical examination may not provide much information regarding the recovery process. Conventional imaging modalities, such as radiography, computed tomography (CT), and magnetic resonance imaging (MRI), are difficult to interpret, with postoperative changes often appearing similar to otherwise concerning findings. Although the previous gold standard for the in vivo postoperative evaluation of cartilage restoration procedures was a second-look arthroscopy, recent advances in quantitative imaging allow for a more comprehensive, noninvasive evaluation of cartilage changes.1,2 These modalities, summarized in the Table, provide surgeons with powerful information and may help guide rehabilitation and further treatment. In this article, we review the current options for quantitative cartilage
*Department of Orthopaedic Surgery, University of California, San Francisco, CA. †School of Medicine, University of California, San Francisco, CA. Address reprint requests to C. Benjamin Ma, MD, Department of Orthopaedic Surgery, University of California, San Francisco, 500 Parnassus Ave, MU 320W Box 0728, San Francisco, CA 94143-0728. E-mail: maben@ orthosurg.ucsf.edu, [email protected]
http://dx.doi.org/10.1053/j.oto.2014.05.002 1048-6666/& 2014 Published by Elsevier Inc.
imaging as well as the feasibility of using these imaging techniques to assess cartilage health following repair.
Current Quantitative Imaging Modalities MRI Scoring Systems Standard clinical imaging sequences may be used with reproducible joint scoring systems to systematically quantify changes after cartilage repair. MR-based scoring systems have been used to evaluate patients after cartilage repair, with the most common system being the magnetic resonance observation of cartilage repair tissue.3 This system uses standard clinical MR sequences to evaluate multiple parameters after cartilage repair, including thickness, integration, adhesions, signal intensity, presence of an effusion, and other parameters. This system affords high interuser and intrauser reliability for both surgeons and radiologists, though does not use the full potential of MR sequences to evaluate articular cartilage.3
Delayed Gadolinium-Enhanced MRI of Cartilage Gadolinium, a commonly used exogenous contrast agent for MRI, is a chelated ion used in multiple forms of MRI. The 293
D.A. Lansdown et al.
294 Table Advantages and Limitations of Quantitative Imaging Modalities Imaging Modality
Information Provided
dGEMRIC
Glycosaminoglycan concentration
T1ρ
Glycosaminoglycan concentration
T2
Integrity of collagen network Concentration of collagen Water concentration Collagen structure or content Water content
T2 star
Diffusion-weighted imaging
Sodium MRI
Contrast CT
Integrity of collagen network Proteoglycan concentration Proteoglycan concentration Proteoglycan concentration
Advantages Direct assessment of glycosaminoglycan concentration Reproducible assessment of biochemical composition No exogenous contrast needed Structural and biochemical assessment No exogenous contrast Structural assessment of cartilage No exogenous contrast 3-D acquisition Fast scan time No exogenous contrast Structural and biochemical assessment No exogenous contrast Assessment of biochemical composition of cartilage Signal directly proportional to proteoglycan contrast
molecule is a negatively charged ion, which is repelled by the negatively charged glycosaminoglycans (GAG) of articular cartilage. Delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) involves the administration of gadolinium, followed by a delay before imaging, approximately 30-45 minutes.4,5 During this time, the contrast agent diffuses into the articular cartilage and distributes in a pattern that is inversely correlated with proteoglycan content. This method has been used frequently in prior studies, given the ability to provide additional information regarding the molecular makeup of articular cartilage.6-8 A clear disadvantage with dGEMRIC is the need for contrast agent administration. Gadolinium is associated with nephrogenic systemic fibrosis and should not be administered in the setting of a decreased creatinine clearance.9
T1ρ Magnetic Resonance Imaging One common MR-based methodology with applicability to cartilage imaging is T1ρ. This technique measures spin-lattice relaxation time in the rotating spatial frame.10,11 Images are acquired at various echo times, and an exponential fit is used to determine the T1ρ relaxation time. The proteoglycan content of cartilage can be interrogated with T1ρ imaging (Fig. 1), owing to the negatively charged GAG. Histologic studies of animal cartilage and explanted human specimens have correlated the content of proteoglycan with the T1ρ relaxation times, with increasing values of T1ρ associated with decreased levels of proteoglycan.12,13 Additional in vivo work has shown that significant changes are present regarding the T1ρ relaxation time in early osteoarthritis.14 Owing to the need for a high signal-to-
Limitations Need for contrast administration
Potential for energy deposition in tissue Signal effected by alignment of cartilage relative to magnetic field Signal effected by alignment of cartilage relative to magnetic field
Most sensitive to patient motion Low signal-to-noise ratio Low signal-to-noise ratio Requires specialized hardware Need for contrast administration Poor visualization of whole knee joint
noise ratio and gradient strength, a field strength Z1.5 T is required for adequate image acquisition. This sequence requires no contrast administration and be acquired with routine clinical sequences. Disadvantages of this method include the need for manual cartilage segmentation for quantification and the potential for high amounts of energy deposition within tissues.11
T2 Magnetic Resonance Imaging The T2 relaxation is a second possible MRI sequence for quantitative cartilage evaluation (Fig. 1). Similar to T1ρ, multiple images are acquired at various echo times, and the T2 relaxation time is calculated as an exponential fit of the signal decay. T2 appears to provide more information on the macrostructure of articular cartilage, specifically the collagen network.15 There is also likely some contribution from increased water within the cartilage. Similar to T1ρ, T2 imaging can be conducted on clinical scanners and does not require an exogenous contrast agent. Disadvantages of this technique include the need for image postprocessing and segmentation. The T2 relaxation time shows increased susceptibility to the alignment of the cartilage within the magnetic field.15,16
T2 Star Magnetic Resonance Imaging Quantitative T2 MRI uses the relaxation constant to provide information about the interaction of water molecules and collagen in cartilage.17 T2 star (T2*) MRI measures T2 relaxation times; however, it uses a sequence that accounts for field inhomogeneity when inferring information of the
Quantitative MRI of cartilage resurfacing procedures
295 composition and density. The apparent diffusion coefficient has been shown to increase following the enzymatic breakdown of cartilage.21,22 The signal from DWI relies on the anisotropic movement of protons within tissue. The collagen network of cartilage restricts diffusion along the fiber direction, so this modality gives information regarding the structure of cartilage.23 Additionally, diffusion properties have been correlated with the proteoglycan content of cartilage as measured by dGEMRIC (Mlynarik).24
Sodium MRI Although most quantitative MRI methods rely on hydrogen nuclei, new developments in MRI technology has allowed the ability to use sodium nuclei in MR image acquisition. Sodium content in articular cartilage is directly proportional to the GAG content as the carboxyl and sulfate groups on GAG impart a negative fixed charge density to the cartilage matrix.25 This quality of sodium makes it an ideal proxy to measure GAG content in cartilage. Although sodium MRI does not require the administration of contrast, it does require propriety coils tuned to a frequency specific for sodium.26
Contrast CT In addition to quantitative MRI, contrast enhanced CT could also provide a noninvasive method to assess cartilage health. Similar to sodium MRI, contrast enhanced CT relies on the negative fixed charge density of cartilage imparted by proteoglycan molecules.8 Owing to this negative charge, the uptake of cationic contrast agents, such as gadolinium, is directly proportional to the amount of proteoglycan content in the cartilage.27 As a result, healthy cartilage with increased proteoglycan content will bind more gadolinium and lead to an attenuation of signal, whereas damaged cartilage with less proteoglycan will uptake less contrast and have increased signal.28 Cockman et al27 have demonstrated a strong correlation between cationic gadolinium uptake and proteoglycan concentration in cartilage suggesting that this imaging modality may allow for the quantification of cartilage health. The ability to use contrast enhanced CT to assess cartilage health following cartilage repair has yet to be examined.
Figure 1 Quantitative imaging of the normal knee, overlaid on a sagittal, fluid-sensitive MR image, with (A) T1ρ cartilage map and (B) T2 cartilage map, with mean relaxation time in milliseconds, according to the color bar.
biochemical composition of tissues.18 Compared with standard T2 imaging, T2* MRI is advantageous in that it requires shorter scan times, is more sensitive for cartilage damage, and may provide the ability for 3-dimensional acquisition.19,20
Diffusion-Weighted MRI Diffusion-weighted imaging (DWI) is an additional MR-based modality that takes advantage of known properties of articular cartilage. The diffusivity of cartilage is dependent on its
Evaluation of Cartilage Restoration Procedures With Quantitative Imaging These recent advances in imaging capabilities, combined with improvements in surgical techniques, have resulted in multiple studies evaluating the abilities of various imaging modalities to assess and monitor patients after cartilage restoration procedures. MR-based scoring systems have been evaluated extensively, many of which were summarized in a systematic review of 26 studies that scored MR images of the knee in patients treated with autologous chondrocyte implantation, osteochondral autograft (OATS), or microfracture.29 This study found that there was no significant correlation between clinical outcomes and MR-based scoring systems. The lack of sensitivity of these qualitative methods supports the need for more
D.A. Lansdown et al.
296 sophisticated means of evaluating patients after cartilage repair procedures. Advanced quantitative imaging sequences as described previously have the ability to offer additional information regarding the health of cartilage. One parameter of interest when assessing postsurgical tissue is the structural organization of cartilage. Normal articular cartilage comprises a distinct arrangement of collagen, with fibers perpendicular to the joint adjacent to the subchondral bone and parallel to the joint in the superficial layer, which contributes to the function of cartilage.30 Different repair techniques result in unique tissue properties, and understanding the role that these properties play in patient function, subjective outcomes, and durability of repair will allow for improved treatment recommendations. T2 mapping probes the structure of the collagen network of articular cartilage. T2 mapping after microfracture in goat and equine cartilage have shown consistently higher T2 values in repair tissue relative to healthy articular cartilage.7,16 The normal cartilage displayed a transitional pattern, with lower values in the deep zone and increased values at the superficial zone. Microfracture repair tissue did not exhibit this property, showing no difference in values in the deep, transitional, and superficial layers.7 White et al16 also qualitatively graded the T2 maps according to their organization, determining that microfracture maps were consistently disorganized, whereas normal cartilage maps were organized. When evaluating T2 maps after OATS treatment, the T2 map more closely approximated the pattern observed in normal cartilage, suggesting that the
structural properties were restored. These findings were confirmed with histologic evaluation. Several human studies have validated the utility of T2 mapping. Theologis et al31 found a similar result, 1 year after microfracture surgery in a group of 10 patients, with no observed difference between the deep and superficial layers of repair tissue. A study of the T2 maps in 20 patients after microfracture or matrix-associated autologous chondrocyte transplantation (MACT) confirmed the lack of a spatial signal pattern in microfracture repair tissue.32 The site of MACT exhibited an increase from the deep to the superficial layer, suggesting that the spatial relationship of articular cartilage was restored. These investigations demonstrate the utility of T2 mapping in evaluating the macrostructure of cartilage repair and the feasibility of applying this technique for monitoring repair tissue in human subjects (Fig. 2). The biochemical composition of repair tissue is a second property of interest following cartilage repair. The type of tissue present at a repair site depends on the surgical treatment. Microfracture results in primarily fibrocartilage, whereas OATS and autologous chondrocyte implantation or MACT procedures produce tissue that is more similar to hyaline cartilage.33 Multiple imaging modalities provide information on the proteoglycan content of cartilage, including dGEMRIC, T1ρ, and sodium imaging. An animal investigation of dGEMRIC following microfracture showed a correlation of the change in the ratio of the precontrast and postcontrast relaxation times of repair tissue and the GAG concentration within the repair
Figure 2 Sagittal double-echo steady-state MR image (15.1/5.1; 251 flip angle) (left), sagittal spin-echo raw T2 image (1650/ 12.9, 25.8, 38.7, 51.6, 65.5, 77.4; flip angle, 1801) (middle), and corresponding fused sagittal cartilage colored T2 map (right) in patient after (A) MFX and (B) MACT. Cartilage repair area is located between the 2 arrows. Note ROI analysis of cartilage repair (outlined between 2 arrows) and control cartilage (outlined area on left) on colored T2 map. MFX, microfracture; ROI, region of interest. (Reproduced with permission from Welsch et al.38)
Quantitative MRI of cartilage resurfacing procedures
297
Figure 3 R1 precalculated map (A), R1 postcalculated map (B), and DR1-calculated map (C) of a representative cartilage specimen that was harvested 48 months after surgery. The cartilage specimen in this figure is the same as that in Figures 5 and 6. The R1 precalculated map of repair tissue (arrows) appears lower than that of adjacent native cartilage. The R1 postcalculated map of repair tissue appears slightly higher than that of adjacent native cartilage. The DR1 of repair tissue appears considerably higher than that of adjacent native cartilage. (Reproduced with permission from Watanabe et al.7)
tissue, as assessed through high-performance liquid chromatography (Fig. 3).7 A comparison of the precontrast and postcontrast values for repair tissue was proposed as the baseline signal of repair cartilage was abnormal, and the postcontrast relaxation time alone was not significantly correlated to the measurements of GAG content. A subsequent human study determined the change in precontrast and postcontrast relaxation times with dGEMRIC (delta R1) in 20 patients treated with microfracture or MACT.34 The delta R1 value was higher in microfracture relative to MACT, which suggests a lower proteoglycan content in the microfracture repair tissue. Diffusion imaging, which is thought to evaluate both the structure and composition of cartilage, has been correlated with patient-reported outcomes after cartilage repair. It can reliably distinguish between normal and repair tissues, and DWI signal is negatively correlated with the Lysholm score.32 This technique has been validated after both microfracture and MACT and provides information that is more sensitive than the
magnetic resonance observation of cartilage repair tissue score or standard morphologic assessment. Sodium imaging also probes the biochemical properties following cartilage repair through the measurement of negatively charged molecules like GAG. Trattnig et al34 validated the measurements of GAG concentration through sodium MRI by comparing results from 12 patients with dGEMRIC values. There was a strong correlation between these 2 modalities, showing that sodium MRI is a viable noncontrast modality for evaluating cartilage repair tissue. An evaluation of 18 patients after microfracture or MACT was performed using sodium MRI on a 7-T scanner (Fig. 4).35 The signal intensity of the repair tissue after both surgical procedures was significantly lower than normal cartilage, indicating lower content of GAG after both restoration procedures. The relative decrease in MACT was less than what was observed in microfracture, once again suggesting different types of repair tissues from these surgical methods. Sodium imaging is currently used primarily only for research purposes, as the high field strength and
Figure 4 Sagittal proton density–weighted 2D-TSE MR image with fat suppression (left), sagittal sodium 3D-GRE image (middle), and color-coded sagittal sodium 3D-GRE image (right) in a 43-year-old woman obtained 42 months after an MFX procedure. Cartilage repair tissue is situated between the 2 arrows. Red contours in the middle image represent the ROI analysis of repair tissue (right contour) and reference cartilage (left contour). Please note that repair tissue voxels situated closest to the repair tissue-native cartilage interface are not included into the ROI evaluations. Color scale represents the sodium signal intensity values. 2D-TSE, 2-dimensional turbo spin-echo; 3D-GRE, 3-dimensional gradient-echo; MFX, microfracture; ROI, region of interest. (Reproduced with permission from Zbyn et al.35)
D.A. Lansdown et al.
298 specialized systems required make this process difficult to implement in a clinical practice. The T1ρ relaxation time is correlated with the proteoglycan content in cartilage.11 The feasibility of using T1ρ in human subjects after microfracture and mosaicplasty has been demonstrated, with highly reproducible values and information that is complimentary to T2 mapping.36 A longitudinal study of T1ρ values in 10 patients after microfracture found a decreasing value in the deep layer of cartilage over 1 year but a persistent elevation of T1ρ in the superficial layer (Fig. 5). These findings suggest that the proteoglycan content of the deep layer of repair tissue matures with time, whereas the superficial layer may remain underdeveloped.31 Our preference for quantitative imaging of cartilage is a standard clinical protocol with a sagittal, 3-dimensional, fatsaturated, fast spin-echo sequence for morphologic evaluation and a combined T1ρ and T2 sequence for quantitative cartilage
evaluation.37 This method offers the advantages of a reproducible imaging method that can be acquired on a clinical MR scanner. No contrast agent is administered, and patients avoid the risks of ionizing radiation associated with CT. Postprocessing is required, which may currently limit the widespread clinical application of these sequences. The information acquired from these sequences allows for reliable longitudinal tracking of these patients, and the color maps produced can provide clinicians and patients with a better understanding of the health of their cartilage.
Conclusion Quantitative imaging allows clinicians and researchers to monitor cartilage repair tissue. Multiple different modalities are available for use, with different imaging techniques offering the potential to evaluate different aspects of the repair tissue. The information acquired from these sequences can be used to compare different surgical techniques in research studies and, in the future, may be used to direct rehabilitation programs.
References
Figure 5 Representative T1ρ color map of a knee 3-6 months after microfracture surgery for the treatment of a focal cartilage defect. The repaired tissue is seen in the medial femoral condyle as an area with increased signal intensity. The inset (lower left corner) illustrates the boundaries of the repaired tissue (RT, red lines) as well as the separation between deep and superficial layers (black line). It should be noted that the deep and superficial layers of the RT have higher T1ρ signal than the respective layers in the normal cartilage (NC) and that the superficial layer of the RT has higher signal intensity than the deep layer of RT. (Reproduced with permission from Theologis et al.31)
1. Gudas R, Kalesinskas RJ, Kimtys V, et al: A prospective randomized clinical study of mosaic osteochondral autologous transplantation versus microfracture for the treatment of osteochondral defects in the knee joint in young athletes. Arthroscopy 21:1066-1075, 2005 2. Bentley G, Biant LC, Carrington RWJ, et al: A prospective, randomised comparison of autologous chondrocyte implantation versus mosaicplasty for osteochondral defects in the knee. J Bone Joint Surg Br 85-B:223-230, 2003 3. Marlovits S, Singer P, Zeller P, et al: Magnetic resonance observation of cartilage repair tissue (MOCART) for the evaluation of autologous chondrocyte transplantation: Determination of interobserver variability and correlation to clinical outcome after 2 years. Eur Radiol 57:16-23, 2006 4. Bashir A, Gray ML, Burstein D: Gd-DTPA2 as a measure of cartilage degradation. Magn Reson Med 36:665-673, 1996 5. Bashir A, Gray ML, Boutin RD, et al: Glycosaminoglycan in articular cartilage: In vivo assessment with delayed gd(DTPA)(2 )-enhanced MR imaging. Radiology 205:551-558, 1997 6. Kurkijarvi JE, Mattila L, Ojala RO, et al: Evaluation of cartilage repair in the distal femur after autologous chondrocyte transplantation using T2 relaxation time and dGEMRIC. Osteoarthritis Cartilage 15:372-378, 2007 7. Watanabe A, Boesch C, Anderson SE, et al: Ability of dGEMRIC and T2 mapping to evaluate cartilage repair after microfracture: A goat study. Osteoarthritis Cartilage 17:1341-1349, 2009 8. Taylor C, Carballido-Gamio J, Majumdar S, et al: Comparison of quantitative imaging of cartilage for osteoarthritis: T2, T1ρ, dGEMRIC, and contrast-enhanced computed tomography. Magn Reson Imaging 27:779-784, 2009 9. Thomsen HS, Morcos SK, Almen T, et al: Nephrogenic systemic fibrosis and gadolinium-based contrast media: Updated ESUR contrast medium safety committee guidelines. Eur Radiol 23:307-318, 2013 10. Li X, Ma CB, Link TM, et al: In vivo T1ρ and T2 mapping of articular cartilage in osteoarthritis of the knee using 3 T MRI. Osteoarthritis Cartilage 15:789-797, 2007 11. Duvvuri U, Kudchodkar S, Reddy R, et al: T1ρ relaxation can assess longitudinal proteoglycan loss from articular cartilage in vitro. Osteoarthritis Cartilage 10:838-844, 2002 12. Regatte RR, Akella SV, Borthakur A, et al: Proteoglycan depletion-induced changes in transverse relaxation maps of cartilage: Comparison of T2 and T1ρ. Acad Radiol 9:1388-1394, 2002
Quantitative MRI of cartilage resurfacing procedures 13. Li X, Cheng J, Lin K, et al: Quantitative MRI using T1ρ and T2 in human osteoarthritic cartilage specimens: Correlation with biochemical measurements and histology. Magn Reson Imaging 29:324-334, 2011 14. Li X, Han ET, Busse RF, et al: In vivo T1ρ mapping in cartilage using 3D magnetization-prepared angle-modulated partitioned k-space spoiled gradient echo snapshots (3D MAPSS). Magn Reson Med 59:298-307, 2008 15. Nieminen MT, Rieppo J, Toyras J, et al: T2 relaxation reveals spatial collagen architecture in articular cartilage: A comparative quantitative MRI and polarized light macroscopic study. Magn Reson Med 46:487-493, 2001 16. White LM, Sussman MS, Hurtig M, et al: Cartilage T2 assessment: Differentiation of normal hyaline cartilage and reparative tissue after arthroscopic cartilage repair in equine subjects. Radiology 241:407-414, 2006 17. Burstein D, Gray ML: Is MRI fulfilling its promise for molecular imaging of cartilage in arthritis? Osteoarthritis Cartilage 14:1087-1090, 2006 18. Palmer AJ, Brown CP, McNally EG, et al: Non-invasive imaging of cartilage in early osteoarthritis. Bone Joint J 95-B:738-746, 2013 19. Bittersohl B, Miese FR, Hosalkar HS, et al: T2* mapping of acetabular and femoral hip joint cartilage at 3 T: A prospective controlled study. Invest Radiol 47:392-397, 2012 20. Mamisch TC, Hughes T, Mosher TJ, et al: T2 star relaxation times for assessment of articular cartilage at 3 T: A feasibility study. Skeletal Radiol 41:287-292, 2012 21. Burstein D, Gray ML, Hartman AL, et al: Diffusion of small solutes in cartilage as measured by nuclear magnetic resonance (NMR) spectroscopy and imaging. J Orthop Res 11:465-478, 1993 22. Deng X, Farley M, Nieminen MT, et al: Diffusion tensor imaging of native and degenerated human articular cartilage. Magn Reson Imaging 25:168-171, 2007 23. Mamisch TC, Menzel MI, Welsch GH, et al: Steady-state diffusion imaging for MR in-vivo evaluation of cartilage after matrix-associated autologous chondrocyte transplantation at 3 Tesla—Preliminary results. Eur Radiol 65:72-79, 2008 24. Mlynarik V, Sulzbacher I, Bittsansky M, et al: Investigation of apparent diffusion constant as an indicator of early degenerative disease in articular cartilage. J Magn Reson Imaging 17:440-444, 2003 25. Borthakur A, Mellon E, Niyogi S, et al: Sodium and T1ρ for molecular and diagnostic imaging of articular cartilage. NMR Biomed 19:781-821, 2006 26. Chang G, Madelin G, Sherman OH, et al: Improved assessment of cartilage repair tissue using fluid-suppressed 23Na inversion recovery at 7 Tesla: Preliminary results. Eur Radiol 22:1341-1349, 2012
299 27. Cockman MD, Blanton CA, Chmielewski PA, et al: Quantitative imaging of proteoglycan in cartilage using a gadolinium probe and microCT. Osteoarthritis Cartilage 14:210-214, 2006 28. Bansal PN, Joshi NS, Entezari V, et al: Cationic contrast agents improve quantification of glycosaminoglycan (GAG) content by contrast enhance CT imaging of cartilage. J Orthop Res 29:704-709, 2011 29. Blackman AJ, Smith MV, Flanigan DC, et al: Correlation between magnetic resonance imaging and clinical outcomes after cartilage repair surgery in the knee: A systematic review and meta-analysis. Am J Sports Med 41:1426-1434, 2013 30. Jeffery AK, Blunn GW, Archer CW, et al: Three-dimensional collagen architecture in bovine articular cartilage. J Bone Joint Surg Br 73:795-801, 1991 31. Theologis AA, Schairer WW, Carballido-Gamio J, et al: Longitudinal analysis of T1ρ and T2 quantitative MRI of knee cartilage laminar organization following microfracture surgery. Knee 19:652-657, 2012 32. Welsch GH, Trattnig S, Domayer SE, et al: Multimodal approach in the use of clinical scoring, morphological MRI and biochemical T2-mapping and diffusion-weighted imaging in their ability to assess differences between cartilage repair tissue after microfracture therapy and matrixassociated autologous chondrocyte transplantation: A pilot study. Osteoarthritis Cartilage 17:1219-1227, 2009 33. Knutsen G, Engebretsen L, Ludvigsen TC, et al: Autologous chondrocyte implantation compared with microfracture in the knee. A randomized trial. J Bone Joint Surg Am 86-A:455-464, 2004 34. Trattnig S, Mamisch TC, Pinker K, et al: Differentiating normal hyaline cartilage from post-surgical repair tissue using fast gradient echo imaging in delayed gadolinium-enhanced MRI (dGEMRIC) at 3 Tesla. Eur Radiol 18:1251-1259, 2008 35. Zbyn S, Stelzeneder D, Welsch GH, et al: Evaluation of native hyaline cartilage and repair tissue after two cartilage repair surgery techniques with 23 Na MR imaging at 7 T: Initial experience. Osteoarthritis Cartilage 20:837-845, 2002 36. Holtzman DJ, Theologis AA, Carballido-Gamio J, et al: T1ρ and T2 quantitative magnetic resonance imaging analysis of cartilage regeneration following microfracture and mosaicplasty cartilage resurfacing procedures. J Magn Reson Imaging 32:914-923, 2010 37. Li X, Wyatt C, Rivoire J, et al: Simultaneous acquisition of T1ρ and T2 quantification in knee cartilage: Repeatability and diurnal variation. J Magn Reson Imaging 39:1287-1293, 2014 38. Welsch GH, Mamisch TC, Domayer SE, et al: Cartilage T2 assessment at 3T MR imaging: In vivo differentiation of normal hyaline cartilage from reparative tissue after two cartilage repair procedures—Initial experience. Radiology 247:154-161, 2008