Contrast‐enhanced CT using a cationic contrast agent enables non‐destructive assessment of the biochemical and biomechanical properties of mouse tibial plateau cartilage

Lakin, Benjamin A.; Patel, Harsh K.; Holland, C.S.; Freedman, Jonathan D.; Shelofsky, Joshua S.; Snyder, Brian D.; Stok, Kathryn S.; Grinstaff, Mark W.

doi:10.1002/jor.23141

Cited by 50 publications

(77 citation statements)

References 51 publications

(119 reference statements)

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“…This observation limits the maximum accuracy of GAG content analyses conducted from the data obtained from low-resolution µCT or from clinical CT. However, strong correlations between the bulk GAG content and CA4+ distribution in several species are reported [6,9], and with immersion times less than 24 h this small inaccuracy is even further decreased (maximum relative difference <1.5%).…”

Section: Discussionmentioning

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: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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“…Mean cartilage thickness was measured (analyze) from the baseline scan at the central apex of the hemispherical cartilage surface prior to indentation testing. The indentation equilibrium modulus ( E ) of each sample was evaluated using a standard, four‐step indentation testing procedure (see Supplementary Information, SI) …”

Section: Methodsmentioning

confidence: 99%

“…Contrast‐enhanced computed tomography (CECT) agents like Ioxaglate (Iox1−) partition in an inverse relationship to cartilage GAG content, whereas conversely, cationic contrast agents (e.g., CA4+) partition in a direct relationship to cartilage GAG content. Uptake of charged contrast agents correlates with cartilage equilibrium modulus and coefficient of friction . CECT studies demonstrate that cationic contrast agents accumulate throughout the bovine cartilage and are more sensitive to changes in the concentration of GAGs than anionic contrast agents .…”

mentioning

confidence: 98%

“…CECT studies demonstrate that cationic contrast agents accumulate throughout the bovine cartilage and are more sensitive to changes in the concentration of GAGs than anionic contrast agents . Cationic agents are also successfully used to image ex vivo murine, rabbit, equine, and human articular cartilage as well as human menisci . Additionally, CECT with CA4+ is used to image and characterize murine intervertebral disks …”

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confidence: 99%

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dGEMRIC and CECT Comparison of Cationic and Anionic Contrast Agents in Cadaveric Human Metacarpal Cartilage

Freedman

Ellis

Lusic

et al. 2019

Journal Orthopaedic Research

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Magnetic resonance imaging (MRI) and computed tomography (CT) are widely used to image cartilage and their diagnostic capability is enhanced in the presence of contrast agents. The aim of the study is to directly compare the performance between commercial anionic MRI (Gd(DTPA), Gd2−) and CT (Ioxaglate, Iox1−) contrast agents with novel cationic MRI (Gd(DTPA)Lys2, Gd4+) and CT (CA4+) contrast agents for assessment of cartilage mechanical and biochemical properties using the ex vivo human osteoarthritis metacarpal cartilage model. First, indentation testing was conducted to obtain the compressive modulus of the human fifth metacarpals. The samples were then immersed in the anionic and cationic contrast agents prior to delayed gadolinium‐enhanced MRI of cartilage and CT scanning, respectively. The cartilage glycosaminoglycan (GAG) content and distribution were determined using the 1,9‐dimethylmethylene blue assay and Safranin‐O histology. Cationic agents significantly accumulate in cartilage compared with anionic agents. Significant positive correlations (p < 0.05) exist between imaging results of cationic agents and GAG content (Gd4+: R2 = 0.43; CA4+: R2 = 0.67) and indentation equilibrium modulus (Gd4+: R2 = 0.48; CA4+: R2 = 0.77). Significant negative correlations are observed between anionic MRI relaxation times, but not contrast‐enhanced computed tomography attenuation and cartilage GAG content (Gd2−: R2 = 0.56, p < 0.05; Iox1−: R2 = 0.31, p > 0.05) and indentation equilibrium modulus (Gd2−: R2 = 0.38, p < 0.05; Iox1−: R2 = 0.17, p > 0.05). MRI or CT with cationic contrast agents provides greater sensitivity than their anionic analogs at assessing the biochemical and biomechanical properties of ex vivo human metacarpal cartilage. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:719‐725, 2020

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Contrast‐enhanced micro‐computed tomography of compartment and time‐dependent changes in femoral cartilage and subchondral plate in a murine model of osteoarthritis

Chan

Mashiatulla

et al. 2022

The Anatomical Record

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A lack of understanding of the mechanisms underlying osteoarthritis (OA) progression limits the development of effective long‐term treatments. Quantitatively tracking spatiotemporal patterns of cartilage and bone degeneration is critical for assessment of more appropriately targeted OA therapies. In this study, we use contrast‐enhanced micro‐computed tomography (μCT) to establish a timeline of subchondral plate (SCP) and cartilage changes in the murine femur after destabilization of the medial meniscus (DMM). We performed DMM or sham surgery in 10–12‐week‐old male C57Bl/6J mice. Femora were imaged using μCT after 0, 2, 4, or 8 weeks. Cartilage‐optimized scans were performed after immersion in contrast agent CA4+. Bone mineral density distribution (BMDD), cartilage attenuation, SCP, and cartilage thickness and volume were measured, including lateral and medial femoral condyle and patellar groove compartments. As early as 2 weeks post‐DMM, cartilage thickness significantly increased and cartilage attenuation, SCP volume, and BMDD mean significantly decreased. Trends in cartilage and SCP metrics within each joint compartment reflected those seen in global measurements, and both BMDD and SCP thickness were consistently greater in the lateral and medial condyles than the patellar groove. Sham surgery also resulted in significant changes to SCP and cartilage metrics, highlighting a potential limitation of using surgical models to study tissue morphology or composition changes during OA progression. Contrast‐enhanced μCT analysis is an effective tool to monitor changes in morphology and composition of cartilage, and when combined with bone‐optimized μCT, can be used to assess the progression of degenerative changes after joint injury.

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Contrast‐enhanced CT using a cationic contrast agent enables non‐destructive assessment of the biochemical and biomechanical properties of mouse tibial plateau cartilage

Cited by 50 publications

References 51 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

dGEMRIC and CECT Comparison of Cationic and Anionic Contrast Agents in Cadaveric Human Metacarpal Cartilage

Contrast‐enhanced micro‐computed tomography of compartment and time‐dependent changes in femoral cartilage and subchondral plate in a murine model of osteoarthritis

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