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DOI: 10.1148/radiol.2392050360
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(Radiology 2006;239:406-414.)
© RSNA, 2006

Experimental Studies

Gadolinium-enhanced MR Images of the Growing Piglet Skeleton: Ionic versus Nonionic Contrast Agent1

Nina M. Menezes, PhD, Elizabeth A. Olear, MA, Xiaoming Li, MD, Susan A. Connolly, MD, David Zurakowski, PhD, Mary Foley, RT(R), Frederic Shapiro, MD and Diego Jaramillo, MD, MPH2

1 From the Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Mass (N.M.M., E.A.O., D.J.); Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and the Harvard-Massachusetts Institute of Technology Division of Health Sciences and Technology, 149 13th St, Rm 2301, Boston, MA 02129 (N.M.M., M.F.); Division of MRI, Department of Radiology, Tongji Hospital, Tongji Medical University, Huazhong University of Science and Technology, Hubei, Wuhan, China (X.L.); Departments of Radiology (S.A.C.) and Orthopaedic Surgery (D.Z., F.S.), Children's Hospital Boston and Harvard Medical School, Boston, Mass; and Department of Pathology, Children's Hospital Boston, Boston, Mass (F.S.). Received March 1, 2005; revision requested April 14; revision received June 25; final version accepted July 8. Supported by National Institutes of Health grant R01 AR042396-09. Address correspondence to N.M.M. (e-mail: nmenezes{at}nmr.mgh.harvard.edu).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Purpose: To determine whether there are differences in the distribution of ionic and nonionic gadolinium-based contrast agents by evaluating contrast enhancement of the physis, epiphyseal cartilage, secondary ossification center, and metaphysis in the knees of normal piglets.

Materials and Methods: Following approval from the Subcommittee on Research Animal Care, knees of 12 3-week-old piglets were imaged at 3-T magnetic resonance (MR) imaging after intravenous injection of gadoteridol (nonionic contrast agent; n = 6) or gadopentetate dimeglumine (ionic contrast agent; n = 6). Early enhancement evaluation with gradient-echo MR imaging was quantified and compared (Student t test) by means of enhancement ratios. Distribution of contrast material was assessed and compared (Student t test) by means of T1 measurements obtained before and at three 15-minute intervals after contrast agent administration. The relative visibility of the physis, epiphyseal cartilage, secondary ossification center, and metaphysis was qualitatively assessed by two observers and compared (Wilcoxon signed rank test). Differences in matrix content and cellularity that might explain the imaging findings were studied at histologic evaluation.

Results: Enhancement ratios were significantly higher for gadoteridol than for gadopentetate dimeglumine in the physis, epiphyseal cartilage, and secondary ossification center (P < .05). After contrast agent administration, T1 values decreased sharply for both agents—but more so for gadoteridol. Additionally, there was less variability in T1 values across structures with this contrast agent. Gadoteridol resulted in greater visibility of the physis, while gadopentetate dimeglumine resulted in greater contrast between the physis and metaphysis (P < .05).

Conclusion: The results suggest different roles for the two gadolinium-based contrast agents: The nonionic contrast medium is better suited for evaluating perfusion and anatomic definition in the immature skeleton, while the ionic contrast medium is better for evaluating cartilage fixed-charge density.

© RSNA, 2006


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Gadolinium is used frequently for magnetic resonance (MR) imaging of children with skeletal neoplasms (1), osteomyelitis (2), arthritis (3), and ischemia of the bone (4) and cartilage (5). Gadolinium-enhanced MR images depict abnormal epiphyseal and metaphyseal perfusion, which is a common cause of growth disorders (6–8). More recently, gadolinium has been used to evaluate early cartilage degeneration in hip dysplasia (9). The normal distribution of gadolinium-based contrast material in the immature skeleton is determined by means of developmental changes in bone and cartilage. In growing bones, the pattern of contrast enhancement follows the changing distribution of the highly vascular hematopoietic marrow (10). In immature cartilage, the pattern of contrast enhancement is also influenced by vascular supply. Unlike mature articular cartilage, which is normally avascular, epiphyseal cartilage contains blood vessels within numerous vascular canals, which are referred to as cartilage canals (11–14). The vessels in cartilage canals are continuous with perichondrial vessels. Each canal contains a continuum of arterioles, capillaries, sinusoids, and venules all embedded in a connective tissue matrix. Gadolinium-based contrast material is distributed in immature cartilage (11) by epiphyseal vessels (12–14) that provide the epiphysis and physis with oxygen and nutrients and by metaphyseal vessels (15) that are necessary for endochondral ossification.

Gadolinium compounds can be nonionic, such as gadoteridol (Prohance; Bracco, Princeton, NJ), or ionic, such as gadopentetate dimeglumine (Magnevist; Berlex, Wayne, NJ). In mature articular cartilage, the distribution of the ionic contrast agent gadopentetate dimeglumine reflects the fixed charge density of cartilage imparted by its negatively charged molecules of glycosaminoglycan (16–18), which is a major macromolecular constituent of cartilage and an important determinant of its mechanical properties. In comparison, the distribution of nonionic gadolinium-based contrast material in mature cartilage is not affected by fixed charge (17) and, therefore, should reflect differences in delivery only. This raises the question as to whether, when evaluating the early enhancement of immature, vascular cartilage by contrast materials, the charge of the gadolinium-based contrast agent influences the enhancement of cartilage and adjacent bone. Furthermore, it is not clear whether the charge of the contrast agent will affect its distribution within cartilaginous structures at equilibrium (eg, after 30 minutes, when gadopentetate dimeglumine has been reported to penetrate the full thickness of mature articular cartilage in vivo [19]) or whether the presumably greater delivery and clearance rate for vascular cartilage would limit the ability to image an equilibrium distribution of gadolinium-based contrast material.

Ionic and nonionic gadolinium-based contrast agents have been used interchangeably for the evaluation of ischemia in the growing skeleton (5,20). On the basis of prior work in mature cartilage, we hypothesized that the charge of the contrast agent would affect its distribution in immature cartilage during early enhancement and at equilibrium. If this hypothesis is proved correct, ionic and nonionic gadolinium-based contrast materials should not be used interchangeably but should be used for different specific indications. Thus, the purpose of our study was to determine whether there are differences in the distribution of ionic and nonionic gadolinium-based contrast agents by evaluating enhancement of the physis, epiphyseal cartilage, secondary ossification center, and metaphysis in the knees of normal piglets.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Animals
We studied the knees of 12 3-week-old piglets, with approval from the institutional Subcommittee on Research Animal Care (Massachusetts General Hospital) and in compliance with the National Institutes of Health guidelines. Piglets of this age have recently ossified femoral epiphyses; their skeletal development is comparable with that of a 3–5-year-old human child. We injected the piglets in random order with gadoteridol (n = 6) (Prohance; Bracco) or gadopentetate dimeglumine (n = 6) (Magnevist; Berlex). We evaluated contrast enhancement, contrast agent distribution, and visibility of structures in a manner that was blinded to the type of contrast material used. The number of animals was estimated from a power analysis based on experience with prior enhancement studies in piglets.

Prior to MR imaging, the piglets were anesthetized with an intramuscular injection of 40 mg of midazolam hydrochloride (Baxter, Deerfield, Ill) and 20 mg of ketamine hydrochloride (Abbott, Chicago, Ill) per kilogram of body weight. A second dose of anesthetic that comprised 20 mg of ketamine hydrochloride and 20 mg of xylazine (Xyla-ject; Phoenix, St Joseph, Mo) per kilogram of body weight was administered approximately 30 minutes later. This was followed by continuous intravenous infusion of propofol 1% (Diprivan; Baxter, Irvine, Calif) diluted in normal saline at 0.002 (mg · kg–1)/min. The animals were imaged with an oral airway and received blow-by oxygen at 4 L/min. At the end of the MR evaluation, piglets were sacrificed and their knees removed for histologic evaluation. The animals were sacrificed with an intracardiac injection of 10 mg pentobarbital sodium (Nembutal; Abbott) per 5 kg of body weight immediately after MR imaging.

MR Imaging
MR imaging was performed at 3.0 T (Siemens, Erlangen, Germany) by using an 8-cm receive-only surface coil. Prior to contrast agent injection, one set of T1-weighted inversion-recovery MR images (5000/15/300–2500 [repetition time msec/echo time msec/inversion time msec]) was obtained. Imaging parameters included field of view of 150 x 113 mm, matrix of 512 x 384, section thickness of 2 mm with a 0.4-mm gap, and two signals acquired. Piglets were imaged in the left-lateral position. Only one knee of each animal, the knee closest to the magnet isocenter, was imaged.

Gadoteridol (Prohance; Bracco) or gadopentetate dimeglumine (Magnevist; Berlex) was manually injected at 0.2 mmol/kg in a rapid bolus into an ear vein 10 seconds after the beginning of the gradient-echo (perfusion) MR imaging. The injection lasted approximately 5 seconds; injected volumes ranged from 2.8 to 3.2 mL. Twenty-five series of gradient-echo MR images were obtained immediately before, during, and after contrast agent administration, with 30/4.5, flip angle of 35°, field of view of 150 x 150 mm, matrix of 128 x 256, and section thickness of 2 mm. The temporal resolution was 9 seconds. Subsequently, four sets of T1-weighted inversion-recovery MR images (3000/15, with inversion delays ranging from 150 to 2000) were obtained.

Image Analysis
Enhancement ratios.—For all 12 piglets, enhancement ratios were obtained for anatomic regions of the distal femur and proximal tibia. Enhancement ratio values were derived (by X.L. and D.J.) from the signal intensity of the gradient-echo (perfusion) MR images: enhancement ratio = (SIpeak – SIbase)/SIbase, where SIpeak is the maximum signal intensity following injection of contrast material and SIbase is the precontrast signal intensity. Regions of interest were selected (by X.L. and D.J.) from the distal femoral and proximal tibial as follows: physis, epiphyseal cartilage, secondary ossification center, and the metaphysis adjacent to the physis (metaphyseal spongiosa). Region of interest size, which depended on the size of the anatomic feature, ranged from 50 to 100 voxels.

Temporal variation of T1 values after contrast agent administration.—T1 values were calculated by curve-fitting the inversion-recovery MR images voxel by voxel to assess the tissue concentration of contrast material (18) by using Matlab software (Mathworks, Natick, Mass). Regions of interest were selected (by N.M.M.) from the distal femur and proximal tibia. Values from cartilaginous structures (physis, epiphyseal cartilage, and secondary ossification center) were pooled. The metaphyseal spongiosa was excluded because it does not contain cartilaginous extracellular matrix and therefore does not have fixed charge density that would alter signal intensity for one contrast agent versus another. Region of interest size ranged from 70 to 400 voxels. T1 measurements for the first five piglets were excluded because of artifacts caused by motion and cross talk. In the remaining seven piglets, T1 changes were measured prior to and during the course of approximately 1 hour following the administration of nonionic gadoteridol (n = 4) or ionic gadopentetate dimeglumine (n = 3).

Equilibrium T1 values.—T1 values at the 30-minute time point were selected as the equilibrium on the basis of the measured temporal variation of T1. Profiles were then generated of the variation in T1 values across the metaphysis and epiphysis for the two contrast agents.

Vascular enhancement.—Two pediatric musculoskeletal radiologists (S.A.C. and D.J., with 11 and 15 years of experience, respectively, in pediatric musculoskeletal MR imaging) performed a qualitative evaluation of the 12 knees independently and were blinded to the type of contrast material used. For each knee, the relative visibility of each structure was graded on a five-point scale: score of 0, no enhancement; 1, barely discernible enhancement; 2, clearly discernible enhancement; 3, structure is conspicuous but less so than the blood vessels; and 4, structure is as conspicuous as the blood vessels. MR images for blinded reading were presented to the radiologists in random order. The evaluation was performed, by using the first set of T1-weighted inversion-recovery MR images obtained after contrast administration (inversion time, 500 msec), on the following anatomic structures: physis, epiphyseal vascular canals, secondary ossification center, physis of the secondary ossification center (secondary physis), and metaphyseal spongiosa.

Histologic Comparison
The knees of the seven animals in which T1 measurements were available were prepared for and assessed by means of histologic evaluation (F.S., with 25 years of experience in bone pathology) in order to evaluate glycosaminoglycan content. After the animals were sacrificed, the distal femora and proximal tibiae were cut at the metaphyseal level, freed from attached soft tissues, and fixed in 10% neutral buffered formalin for 2 weeks. The bones were then decalcified in 25% formic acid until soft. The bone ends were cut with a razor in the midline sagittal plane, photographed, and cut into smaller pieces to assess specific regions. The tissues were infiltrated with JB4 solution (Polysciences, Warrington, Pa), embedded in JB4 plastic, sectioned at 5-µm thickness, and stained with 1% toluidine blue, a glycosaminoglycan-avid stain.

Statistical Analysis
Enhancement ratios and T1 value differences between the two contrast agents were compared by using a two-sample Student t test (nondirectional). A nonparametric Wilcoxon signed rank test was performed by using Stata software (Stata, College Station, Tex) to evaluate differences between physeal and epiphyseal enhancement in the tibia and femur within each piglet. Interobserver reliability was assessed by using the {kappa} statistic: almost perfect ({kappa} = 0.81–1.00), excellent ({kappa} = 0.61–0.80), moderate ({kappa} = 0.41–0.60), fair ({kappa} = 0.21–0.40), slight ({kappa} = 0.00–0.20), and poor ({kappa} < 0) (21). Significant agreement was considered for P < .05, which was evaluated by using SPSS software (SPSS, Chicago, Ill). For all statistics reported, two-tailed tests with P < .05 were considered to indicate statistically significant differences.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Enhancement Ratios
Enhancement ratios (given as mean ± standard deviation) following administration of gadoteridol were significantly greater than were those following administration of gadopentetate dimeglumine in the physis (0.62 ± 0.05 vs 0.43 ± 0.08, P < .001), epiphyseal cartilage (0.38 ± 0.05 vs 0.24 ± 0.08, P = .01) (Fig 1), and secondary ossification center (0.57 ± 0.04 vs 0.45 ± 0.10, P = .02). No significant difference in enhancement ratios was observed between gadoteridol and gadopentetate dimeglumine in the metaphyseal spongiosa (0.60 ± 0.13 vs 0.54 ± 0.12, P = .4).


Figure 1
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  		Figure 1a: (a) Graph of gadoteridol (Nonionic Gd) and gadopentetate dimeglumine (Ionic Gd) enhancement of epiphyseal cartilage immediately after contrast injection shows the increase in gadoteridol enhancement compared with gadopentetate dimeglumine enhancement of the femoral head. Both curves show gradual enhancement before reaching a plateau, but enhancement with gadoteridol is greater. (b) Bar graph of regional differences in enhancement ratios. The enhancement ratios of the physis, epiphyseal cartilage, and secondary ossification center (SOC) were significantly greater after the administration of gadoteridol (Nonionic Gd) compared with gadopentetate dimeglumine (Ionic Gd). * = P < .05.

 

Figure 1
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  		Figure 1b: (a) Graph of gadoteridol (Nonionic Gd) and gadopentetate dimeglumine (Ionic Gd) enhancement of epiphyseal cartilage immediately after contrast injection shows the increase in gadoteridol enhancement compared with gadopentetate dimeglumine enhancement of the femoral head. Both curves show gradual enhancement before reaching a plateau, but enhancement with gadoteridol is greater. (b) Bar graph of regional differences in enhancement ratios. The enhancement ratios of the physis, epiphyseal cartilage, and secondary ossification center (SOC) were significantly greater after the administration of gadoteridol (Nonionic Gd) compared with gadopentetate dimeglumine (Ionic Gd). * = P < .05.

 
Temporal Variation of T1 after Contrast Agent Administration
Prior to contrast agent administration, there was no significant difference in T1 values between gadoteridol and gadopentetate dimeglumine tissue groups. Following administration of contrast material, T1 values decreased rapidly for both groups. Following injection of contrast material (Fig 2), T1 was always significantly lower for nonionic gadoteridol than for ionic gadopentetate dimeglumine in cartilaginous structures (epiphysis, physis, and secondary ossification center). The difference in T1 values between the two groups increased with time. Whereas T1 for the nonionic contrast agent appeared to remain constant from 30 minutes and onward (the last time point was at approximately 75 minutes), T1 for the ionic contrast agent increased slightly over this same period, which possibly indicates washout.


Figure 2
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  		Figure 2: Graph shows differences in T1 values before and approximately 30, 45, 60, and 75 minutes after injection of gadoteridol (Nonionic) or gadopentetate dimeglumine (Ionic). All cartilaginous structures (ie, physis, epiphyseal cartilage, and secondary ossification center) from the femora and tibiae of all animals were pooled. (Metaphyseal spongiosa was excluded since it does not contain cartilaginous extracellular matrix and therefore does not have fixed charge density that would alter signal intensity for one contrast agent vs another.) Only postcontrast T1 differences are significant (P < .05). Postcontrast T1 values are higher for the ionic than for the nonionic contrast agent, presumably reflecting the effect of glycosaminoglycans. In addition, postcontrast T1 values increase slightly with time for the ionic but not for the nonionic contrast agent, which possibly indicates a greater rate of clearance.

 
Equilibrium T1 Values
The equilibrium distribution of T1 values (Fig 3a) showed typical T1 maps obtained after the administration of gadoteridol and gadopentetate dimeglumine. T1 values (Fig 3b) were lower in all anatomic regions after the administration of gadoteridol in comparison with gadopentetate dimeglumine, and there was more heterogeneity in T1 values across structures with the latter, presumably because the heterogeneity in gadopentetate dimeglumine reflects variations in fixed charge density. The temporal evolution of T1 following gadopentetate dimeglumine administration was not significantly different between the physis and the epiphyseal cartilage (Fig 4) until the 75-minute time point, at which point physeal T1 values rose above epiphyseal values.


Figure 3
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  		Figure 3a: (a) Sagittal MR T1 maps (in milliseconds) show T1 distribution after contrast agent administration (30 minutes). (b) Graph of T1 profiles (in direction shown in a) shows that T1 values were lower in all anatomic regions after administration of gadoteridol (Nonionic Gd) in comparison with gadopentetate dimeglumine (Ionic Gd). Administration of gadoteridol produced less variability in enhancement than did the more heterogeneous gadopentetate dimeglumine (large spike in both curves corresponds to joint fluid).

 

Figure 3
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  		Figure 3b: (a) Sagittal MR T1 maps (in milliseconds) show T1 distribution after contrast agent administration (30 minutes). (b) Graph of T1 profiles (in direction shown in a) shows that T1 values were lower in all anatomic regions after administration of gadoteridol (Nonionic Gd) in comparison with gadopentetate dimeglumine (Ionic Gd). Administration of gadoteridol produced less variability in enhancement than did the more heterogeneous gadopentetate dimeglumine (large spike in both curves corresponds to joint fluid).

 

Figure 4
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  		Figure 4: Graph shows differences in T1 values before and after injection of gadopentetate dimeglumine for physis compared with epiphyseal cartilage (n = 3). Only the T1 values at the 75-minute time point are significantly different (P < .05). In comparison, no significant differences in T1 values at any time point were found between the physis and the epiphyseal cartilage after administration of gadoteridol, which suggests that the sensitivity of gadopentetate dimeglumine to differences in fixed charge density contributes to difference seen between the physis and the epiphyseal cartilage after gadopentetate dimeglumine administration.

 
Vascular Enhancement
The physis and secondary physis had greater visibility with gadoteridol (P < .05). Visibility was nearly significantly higher in the vascular canals and lower in the metaphyseal spongiosa (P < .10; Fig 5) with gadoteridol. Gadopentetate dimeglumine resulted in greater contrast between the spongiosa (which reflects vascularity only) and the physis (which reflects vascularity in addition to fixed charge density; P < .05). Interobserver agreement ranged from good ({kappa} = 0.70) for the metaphyseal spongiosa to excellent ({kappa} = 0.87) for the physis.


Figure 5
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  		Figure 5a: (a) Sagittal T1-weighted inversion-recovery MR images (3000/15/500) show qualitative differences in enhancement immediately after contrast agent injection for gadoteridol (left) compared with gadopentetate dimeglumine (right). Note the increased physeal enhancement (arrow) with gadoteridol. (b) Bar graph of qualitative analysis of vascular enhancement shows regional differences in conspicuity. The visibilities of the physis and secondary ossification center (SOC) are significantly greater (*) (P < .05) with gadoteridol (Nonionic Gd) than with gadopentetate dimeglumine (Ionic Gd). Visibility is nearly significantly greater (+) (P < .10) in the vascular canals and nearly significantly smaller in the metaphyseal spongiosa with gadoteridol.

 

Figure 5
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  		Figure 5b: (a) Sagittal T1-weighted inversion-recovery MR images (3000/15/500) show qualitative differences in enhancement immediately after contrast agent injection for gadoteridol (left) compared with gadopentetate dimeglumine (right). Note the increased physeal enhancement (arrow) with gadoteridol. (b) Bar graph of qualitative analysis of vascular enhancement shows regional differences in conspicuity. The visibilities of the physis and secondary ossification center (SOC) are significantly greater (*) (P < .05) with gadoteridol (Nonionic Gd) than with gadopentetate dimeglumine (Ionic Gd). Visibility is nearly significantly greater (+) (P < .10) in the vascular canals and nearly significantly smaller in the metaphyseal spongiosa with gadoteridol.

 
Histologic Comparison
In all animals analyzed, the articular cartilage merged with the epiphyseal cartilage, with no cell or matrix variation noted (Fig 6a). In both regions, chondrocytes were relatively small and uniformly dispersed in an abundant glycosaminoglycan-rich matrix (low cell-to-matrix ratio). In marked contrast, the physeal chondrocytes were more numerous (proliferating zone) and progressively larger (hypertrophic zone) with a less abundant, longitudinally oriented matrix (high cell-to-matrix ratio, Fig 6b) (22). Toluidine blue uptake was markedly greater in physeal cartilage matrix than in epiphyseal cartilage matrix (Fig 6c), which suggests higher glycosaminoglycan content in the physis. Cartilage canals were dispersed throughout the epiphyseal cartilage, merged with the vascular supply of the secondary ossification centers, and occasionally traversed the main physes but were never present within articular cartilage. The secondary ossification centers and metaphyses (Fig 6b, 6d) were well vascularized and showed hematopoietic marrow.


Figure 6
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  		Figure 6a: (a) Photomicrograph shows articular cartilage (top of image) and epiphyseal cartilage (bottom of image) from the distal femur. A cartilage canal is seen at lower left (arrow). (b) Photomicrograph shows physis of proximal tibia, with epiphyseal cartilage at top of image and metaphyseal tissue at bottom. At higher magnifications, the tissue in the metaphysis has vessels, hematopoietic cells, and osteoblasts. (c) Photomicrograph shows proximal tibia. Tissue is heavily stained with Toluidine blue. From top to bottom of image, note secondary ossification center bone, physis of secondary ossification center (deep purple), epiphyseal cartilage (light purple), and physeal cartilage (deep purple). (d) Photomicrograph shows proximal tibial metaphysis. Longitudinally oriented bone-cartilage trabeculae are seen between intact vessels containing red blood cells (stained blue). Surface osteoblasts and osteoclasts are also present in abundance.

 

Figure 6
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  		Figure 6b: (a) Photomicrograph shows articular cartilage (top of image) and epiphyseal cartilage (bottom of image) from the distal femur. A cartilage canal is seen at lower left (arrow). (b) Photomicrograph shows physis of proximal tibia, with epiphyseal cartilage at top of image and metaphyseal tissue at bottom. At higher magnifications, the tissue in the metaphysis has vessels, hematopoietic cells, and osteoblasts. (c) Photomicrograph shows proximal tibia. Tissue is heavily stained with Toluidine blue. From top to bottom of image, note secondary ossification center bone, physis of secondary ossification center (deep purple), epiphyseal cartilage (light purple), and physeal cartilage (deep purple). (d) Photomicrograph shows proximal tibial metaphysis. Longitudinally oriented bone-cartilage trabeculae are seen between intact vessels containing red blood cells (stained blue). Surface osteoblasts and osteoclasts are also present in abundance.

 

Figure 6
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  		Figure 6c: (a) Photomicrograph shows articular cartilage (top of image) and epiphyseal cartilage (bottom of image) from the distal femur. A cartilage canal is seen at lower left (arrow). (b) Photomicrograph shows physis of proximal tibia, with epiphyseal cartilage at top of image and metaphyseal tissue at bottom. At higher magnifications, the tissue in the metaphysis has vessels, hematopoietic cells, and osteoblasts. (c) Photomicrograph shows proximal tibia. Tissue is heavily stained with Toluidine blue. From top to bottom of image, note secondary ossification center bone, physis of secondary ossification center (deep purple), epiphyseal cartilage (light purple), and physeal cartilage (deep purple). (d) Photomicrograph shows proximal tibial metaphysis. Longitudinally oriented bone-cartilage trabeculae are seen between intact vessels containing red blood cells (stained blue). Surface osteoblasts and osteoclasts are also present in abundance.

 

Figure 6
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  		Figure 6d: (a) Photomicrograph shows articular cartilage (top of image) and epiphyseal cartilage (bottom of image) from the distal femur. A cartilage canal is seen at lower left (arrow). (b) Photomicrograph shows physis of proximal tibia, with epiphyseal cartilage at top of image and metaphyseal tissue at bottom. At higher magnifications, the tissue in the metaphysis has vessels, hematopoietic cells, and osteoblasts. (c) Photomicrograph shows proximal tibia. Tissue is heavily stained with Toluidine blue. From top to bottom of image, note secondary ossification center bone, physis of secondary ossification center (deep purple), epiphyseal cartilage (light purple), and physeal cartilage (deep purple). (d) Photomicrograph shows proximal tibial metaphysis. Longitudinally oriented bone-cartilage trabeculae are seen between intact vessels containing red blood cells (stained blue). Surface osteoblasts and osteoclasts are also present in abundance.

 
We examined T1 differences between the physis and the epiphyseal cartilage following gadopentetate dimeglumine administration that could be explained by the greater physeal glycosaminoglycan concentration. As demonstrated in Figure 4, following a period of equilibrium where T1 values with gadopentetate dimeglumine administration were similar for the physis and epiphysis (Fig 4), physeal T1 values rose above those of epiphyseal cartilage. However, no significant differences were measured in T1 values between the physis and the epiphyseal cartilage after gadoteridol administration at any time point.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
ADVANCES IN KNOWLEDGE
 References
 
Results of this study show that gadoteridol and gadopentetate dimeglumine are distributed differently in the growing skeleton. Nonionic gadoteridol resulted in greater contrast enhancement and T1 value decrease in bony and cartilaginous structures and yielded greater visibility of the physis and secondary physis in comparison with ionic gadopentetate dimeglumine. Gadopentetate dimeglumine, the distribution of which presumably reflects cartilage fixed charge density, resulted in (a) less physeal and epiphyseal cartilage contrast enhancement relative to that with nonionic gadoteridol, (b) greater variability of T1 values between these regions, (c) greater clearance for the physis relative to the epiphysis, and (d) greater relative visibility of the spongiosa. Our data suggest different optimal roles for nonionic and ionic contrast agents: Nonionic contrast material appears to be better suited for evaluating perfusion of cartilaginous and bony tissues, whereas ionic contrast material may better reflect differences in cartilage composition—namely, glycosaminoglycan content.

Differences in vascularity affect the appearance of contrast-enhanced MR images. In normally avascular mature articular cartilage, gadolinium-based contrast material diffuses into cartilage via synovial fluid (23,24). Unlike articular cartilage, the cartilage of the developing skeleton is vascularized. Vascular canals, which are nonanastomosing spaces within the epiphyseal cartilage that harbor venules and arterioles, provide the vascular supply to the epiphyseal cartilage and the layers of the physis adjacent to the epiphysis, whereas metaphyseal vessels come into close contact with the hypertrophic zone of the physis. Thus, in epiphyseal cartilage, gadolinium-based contrast material diffuses in from vascular canals, and in physeal cartilage, it diffuses in primarily from epiphyseal vessels. Therefore, assumptions based on the normal enhancement of mature articular cartilage, with respect to the pathways involved and the time courses associated with these pathways, cannot be applied to immature cartilage.

The rapid increase in signal intensity in all tissue zones with both contrast media likely reflects the fact that in richly vascularized tissue, gadolinium-based contrast material is delivered relatively quickly (25). The T1 graph shows that equilibrium is reached very rapidly and that T1 shortening persists for approximately 45 minutes for both contrast agents. The implication is that T1 measurements for both contrast agents are feasible in immature cartilage within a window of nearly 1 hour. Any increase in T1 value that occurs within this time frame presumably reflects washout. Only use of gadopentetate dimeglumine showed any T1 value increase within this time frame. Contrast enhancement was greater and more rapid with gadoteridol. The difference in contrast enhancement between the two contrast agents is present for several minutes after injection, which suggests that it is not simply an intravascular phenomenon. However, it is possible that, compared with gadoteridol, a greater fraction of injected gadopentetate dimeglumine remains intravascular because the cartilage fixed charge affects the passage of the contrast agent from the vessel lumen to the interstitium. When a contrast agent remains intravascular, peak contrast enhancement in the tissue is lower and there is faster washout. Differences comparable with those seen between ionic and nonionic gadolinium enhancement resemble those observed in a recent study comparing a blood pool agent with a tissue contrast agent (26).

Throughout the postcontrast period, T1 values after injection of gadopentetate dimeglumine were higher than those after injection of gadoteridol, and there was more heterogeneity across cartilaginous structures with gadopentetate dimeglumine than with gadoteridol, presumably reflecting the variation in fixed charge density to which only gadopentetate dimeglumine is sensitive. The smaller difference in contrast material distribution between cartilage and marrow with gadoteridol implies that gadoteridol distribution is primarily dependent on differences in local perfusion; this finding is consistent with those of previous studies (25,27). Differences in vascularity and the relatively high and variable cellularity of immature cartilage hinder the ability to quantify glycosaminoglycan content in this tissue type. Articular cartilage has low cellularity—less than 2% by volume (28). In comparison, some epiphyseal and physeal regions have much greater cell-to-matrix ratios (29), which can be as high as 75% in the hypertrophic zone of the neonate (30). This has implications for the volume of distribution of contrast material: Greater cellularity leaves less matrix volume for gadolinium-based contrast agents, which complicates, for this tissue type, the quantification of fixed charge density using gadopentetate dimeglumine, as previously described (18–20). It should be noted that charge may not be the only key difference between gadoteridol and gadopentetate dimeglumine, and it is possible that other differences account for some of our results. However, at least in articular cartilage, relaxivity and diffusion of gadoteridol and gadopentetate dimeglumine are comparable (31).

Practical application: When performing gadolinium-enhanced MR imaging studies of the immature skeleton, it is important to realize that charge affects contrast enhancement and visibility. Our data in an animal model suggest that, in growing cartilage, gadoteridol is delivered more readily from the vessels into cartilage, distributes more uniformly throughout cartilage, and washes out more slowly than gadopentetate dimeglumine. This indicates different uses for nonionic and ionic gadolinium-based contrast materials. The nonionic contrast material results in greater enhancement of cartilage and greater visibility of all structures except spongiosa. Therefore, we expect it to be better suited for the evaluation of epiphyseal ischemia or other entities that result in abnormal perfusion, such as infection. Glycosaminoglycan content could potentially be assessed with ionic gadolinium-based contrast material. Ionic gadolinium-based contrast material may be a better agent for evaluating diseases in which there is glycosaminoglycan breakdown of epiphyseal cartilage, such as juvenile chronic arthritis. Future work should focus on evaluating the differences between the two contrast agents in children.


   ADVANCES IN KNOWLEDGE
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
References
 


   FOOTNOTES
 
2 Current address: Department of Radiology, Children's Hospital of Philadelphia, Philadelphia, Pa. Back

Authors stated no financial relationship to disclose.

Author contributions: Guarantors of integrity of entire study, N.M.M., D.J.; 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, E.A.O., D.J.; experimental studies, N.M.M., E.A.O., X.L., S.A.C., M.F., F.S., D.J.; statistical analysis, N.M.M., D.Z., D.J.; and manuscript editing, N.M.M., E.A.O., S.A.C., D.Z., D.J.


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 

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