Effect of Contrast Agent Charge on Visualization of Articular Cartilage Using Computed Tomography: Exploiting Electrostatic Interactions for Improved Sensitivity

Joshi, Neel; Bansal, Prashant N.; Stewart, Rachel C.; Snyder, Brian D.; Grinstaff, Mark W.

doi:10.1021/ja9053306

Cited by 92 publications

(134 citation statements)

References 16 publications

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“…The second set was used for investigating how CA4+ chondron accumulation would affect the analysis conducted with lower resolution µCT systems. The CA4+ solutions were prepared as previously described [7].…”

Section: Methodsmentioning

confidence: 99%

“…Cationic contrast agents (especially CA4+), compared to anionic ones, demonstrate strong positive correlation to GAG content and reveal GAG distribution in articular cartilage even when used at low concentrations [5][6][7]. Successful application of these cationic contrast agents in ex vivo and in vivo studies [7,8] indicate significant research potential.…”

Section: Introductionmentioning

confidence: 99%

“…Successful application of these cationic contrast agents in ex vivo and in vivo studies [7,8] indicate significant research potential. The distribution of CA4+ in AC is based on the attraction between the positive CA4+ and the negatively charged GAG macromolecules [5].…”

Section: Introductionmentioning

confidence: 99%

“…Thus, we hypothesize that cationic CA4+ will accumulate in the chondrons or in the close proximity of the chondrons. However, the previous studies using CA4+ enhanced micro-computed tomography (µCT) [5][6][7][8][9] have been conducted with insufficient resolution to answer this hypothesis. The insufficient resolution has also prevented to answer the question whether CA4+ accumulation in chondrons could lead to an erroneous quantification of GAG distribution with low resolution µCT setups.…”

Section: Introductionmentioning

confidence: 99%

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Micro-Scale Distribution of CA4+ in Ex vivo Human Articular Cartilage Detected with Contrast-Enhanced Micro-Computed Tomography Imaging

et al. 2017

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Contrast-enhanced micro-computed tomography (CEµCT) with cationic and anionic contrast agents reveals glycosaminoglycan (GAG) content and distribution in articular cartilage (AC). The advantage of using cationic stains (e.g., CA4+) compared to anionic stains (e.g., Hexabrix ® ), is that it distributes proportionally with GAGs, while anionic stain distribution in AC is inversely proportional to the GAG content. To date, studies using cationic stains have been conducted with sufficient resolution to study its distributions on the macro-scale, but with insufficient resolution to study its distributions on the micro-scale. Therefore, it is not known whether the cationic contrast agents accumulate in extra/pericellular matrix and if they interact with chondrocytes. The insufficient resolution has also prevented to answer the question whether CA4+ accumulation in chondrons could lead to an erroneous quantification of GAG distribution with low-resolution µCT setups. In this study, we use high-resolution µCT to investigate whether CA4+ accumulates in chondrocytes, and further, to determine whether it affects the low-resolution ex vivo µCT studies of CA4+ stained human AC with varying degree of osteoarthritis. Human osteochondral samples were immersed in three different concentrations of CA4+ (3 mgI/ml, 6 mgI/ml, and 24 mgI/ml) and imaged with high-resolution µCT at several timepoints. Different uptake diffusion profiles of CA4+ were observed between the segmented chondrons and the rest of the tissue. While the X-ray -detected CA4+ concentration in chondrons was greater than in the rest of the AC, its contribution to the uptake into the whole tissue was negligible and in line with macro-scale GAG Karhula et al. CA4+ Accumulation in Human Cartilagecontent detected from histology. The efficient uptake of CA4+ into chondrons and surrounding territorial matrix can be explained by the micro-scale distribution of GAG content. CA4+ uptake in chondrons occurred regardless of the progression stage of osteoarthritis in the samples and the relative difference between the interterritorial matrix and segmented chondron area was less than 4%. To conclude, our results suggest that GAG quantification with CEµCT is not affected by the chondron uptake of CA4+. This further confirms the use of CA4+ for macro-scale assessment of GAG throughout the AC, and highlight the capability of studying chondron properties in 3D at the micro scale.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Micro-Scale Distribution of CA4+ in Ex vivo Human Articular Cartilage Detected with Contrast-Enhanced Micro-Computed Tomography Imaging

et al. 2017

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“…Three plugs were randomly therapies entering preclinical and clinical studies for the treatment of damaged cartilage. In 2009, we reported the synthesis of new cationic iodinated CT contrast agents for imaging articular cartilage that were designed on the basis of favorable electrostatic interactions between negatively charged glycosaminoglycans (GAGs) and the positively charged contrast agent (1). Use of these agents to image individual ex vivo rabbit femurs with x-ray CT has shown that the greater cationic charge on the agents yields higher CT attenuation.…”

Section: Imaging Protocol For Uptake Experimentsmentioning

confidence: 99%

Contrast-enhanced CT with a High-Affinity Cationic Contrast Agent for Imaging ex Vivo Bovine, Intact ex Vivo Rabbit, and in Vivo Rabbit Cartilage

Stewart

Bansal²,

Entezari³

et al. 2013

Radiology

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Purpose:To quantify the affinity of a cationic computed tomography (CT) contrast agent (CA 4+ ) and that of an anionic contrast agent (ioxaglate) to glycosaminoglycans (GAGs) in ex vivo cartilage tissue explants and to characterize the in vivo diffusion kinetics of CA 4+ and ioxaglate in a rabbit model. Materials and Methods:All in vivo procedures were approved by the institutional animal care and use committee. The affinities of ioxaglate and CA 4+ to GAGs in cartilage (six bovine osteochondral plugs) were quantified by means of a modified binding assay using micro-CT after plug equilibration in serial dilutions of each agent. The contrast agents were administered intraarticularly to the knee joints of five New Zealand white rabbits to determine the in vivo diffusion kinetics and cartilage tissue imaging capabilities. Kinetics of diffusion into the femoral groove cartilage and relative contrast agent uptake into bovine plugs were characterized by means of nonlinear mixed-effects models. Diffusion time constants (t) were compared by using a Student t test. Results:The uptake of CA 4+ in cartilage was consistently over 100% of the reservoir concentration, whereas it was only 59% for ioxaglate. In vivo, the contrast material-enhanced cartilage reached a steady CT attenuation for both CA 4+ and ioxaglate, with t values of 13.8 and 6.5 minutes, respectively (P = .04). The cartilage was easily distinguishable from the surrounding tissues for CA 4+ (12 mg of iodine per milliliter); comparatively, the anionic contrast agent provided less favorable imaging results, even when a higher concentration was used (80 mg of iodine per milliliter). Conclusion:The affinity of the cationic contrast agent CA 4+ to GAGs enables high-quality imaging and segmentation of ex vivo bovine and rabbit cartilage, as well as in vivo rabbit cartilage.q RSNA, 2012 Supplemental material: http://radiology.rsna.org/lookup /suppl

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Tantalum Oxide Nanoparticles for the Imaging of Articular Cartilage Using X‐Ray Computed Tomography: Visualization of Ex Vivo/In Vivo Murine Tibia and Ex Vivo Human Index Finger Cartilage

et al. 2014

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The synthesis and characterization of tantalum oxide (Ta2O5) nanoparticles (NPs) as new X‐ray contrast media for microcomputed tomography (μCT) imaging of articular cartilage are reported. NPs, approximately 5–10 nm in size, and possessing distinct surface charges, were synthesized using phosphonate (neutral), ammonium (cationic), and carboxylate (anionic) ligands as end functional groups. Assessment of a cartilage defect in a human cadaver distal metacarpophalangeal (MCP) joint with the ammonium nanoparticles showed good visualization of damage and preferential uptake in areas surrounding the defect. Finally, an optimized nontoxic cationic NP contrast agent was evaluated in an in vivo murine model and the cartilage was imaged. These nanoparticles represent a new type of contrast agent for imaging articular cartilage, and the results demonstrate the importance of surface charge in the design of nanoparticulate agents for targeting the surface or interior zones of articular cartilage.

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Effect of Contrast Agent Charge on Visualization of Articular Cartilage Using Computed Tomography: Exploiting Electrostatic Interactions for Improved Sensitivity

Cited by 92 publications

References 16 publications

Micro-Scale Distribution of CA4+ in Ex vivo Human Articular Cartilage Detected with Contrast-Enhanced Micro-Computed Tomography Imaging

Micro-Scale Distribution of CA4+ in Ex vivo Human Articular Cartilage Detected with Contrast-Enhanced Micro-Computed Tomography Imaging

Contrast-enhanced CT with a High-Affinity Cationic Contrast Agent for Imaging ex Vivo Bovine, Intact ex Vivo Rabbit, and in Vivo Rabbit Cartilage

Tantalum Oxide Nanoparticles for the Imaging of Articular Cartilage Using X‐Ray Computed Tomography: Visualization of Ex Vivo/In Vivo Murine Tibia and Ex Vivo Human Index Finger Cartilage

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