Effects of human articular cartilage constituents on simultaneous diffusion of cationic and nonionic contrast agents

Abstract

Contrast-enhanced computed tomography is an emerging diagnostic technique for osteoarthritis. However, the effects of increased water content, as well as decreased collagen and proteoglycan concentrations due to cartilage degeneration, on the diffusion of cationic and nonionic agents, are not fully understood. We hypothesize that for a cationic agent, these variations increase the diffusion rate while decreasing partition, whereas, for a nonionic agent, these changes increase both the rate of diffusion and partition. Thus, we examine the diffusion of cationic and nonionic contrast agents within degraded tissue in time-and depth-dependent manners. Osteochondral plugs (N = 15, d = 8 mm) were extracted from human cadaver knee joints, immersed in a mixture of cationic CA4+ and nonionic gadoteridol contrast agents, and imaged at multiple time-points, using the dual-contrast method. Water content, and collagen and proteoglycan concentrations were determined using lyophilization, infrared spectroscopy, and digital densitometry, respectively. Superficial to mid (0%-60% depth) cartilage CA4+ partitions correlated with water content (R < −0.521, P < .05), whereas in deeper (40%-100%) cartilage, CA4+ correlated only with proteoglycans (R > 0.671, P < .01). Gadoteridol partition correlated inversely with collagen concentration (0%-100%, R < −0.514, P < .05). Cartilage degeneration substantially increased the time for CA4+ compared with healthy tissue (248 ± 171 vs 175 ± 95 minute) to reach the bonecartilage interface, whereas for gadoteridol the time (111 ± 63 vs 179 ± 163 minute) decreased. The work clarifies the diffusion mechanisms of two different contrast agents and presents depth and time-dependent effects resulting from articular cartilage constituents. The results will inform the development of new contrast agents and optimal timing between agent administration and joint imaging.

Contrast solution properties and scan parameters influence the apparent diffusivity of computed tomography contrast agents in articular cartilage

“…Neither of these treatments replicates the type or pattern of degeneration associated with early-stage OA, and studies on human tissues will be required to determine how well this approach translates to the detection of clinically realistic degradation patterns. A recent study [53] found an inverse correlation between maximum concentration of gadoteridol, another non-ionic CA and collagen content in human articular cartilage at equilibrium, suggesting that patterns in human tissue may be similar to the ones presented here.…”

Dual‐contrast micro‐CT enables cartilage lesion detection and tissue condition evaluation ex vivo

“…39,40 Moreover, the diagnostic sensitivity of the cationic agent can be further enhanced with a non-ionic compound, nullifying the variation in the diffusion caused by changes in tissue water content and permeability. 41,42 Our results form a good basis to proceed on this path, as these show clear differences in ioxaglate partition values between lesions and healthy tissue, even though cationic agent have exhibited stronger correlation with PGs (R 2 = 0.83) than negatively charged agents (R 2 = 0.20). 19 In conclusion, in the current study the dual-contrast method was, for the first time, applied to evaluate the cartilage condition…”

“…One proposed alternative is to substitute ioxaglate with a cationic agent that diffuses into cartilage proportionally to the PG content 39,40 . Moreover, the diagnostic sensitivity of the cationic agent can be further enhanced with a non‐ionic compound, nullifying the variation in the diffusion caused by changes in tissue water content and permeability 41,42 . Our results form a good basis to proceed on this path, as these show clear differences in ioxaglate partition values between lesions and healthy tissue, even though cationic agent have exhibited stronger correlation with PGs ( R 2 = 0.83) than negatively charged agents ( R 2 = 0.20) 19 …”

A Cationic Contrast Agent in X-ray Imaging of Articular Cartilage: Pre-Clinical Evaluation of Diffusion and Attenuation Properties

“…The sample preparation for the present work did not include the use of any agent preventing cartilage degradation (i.e., antimycotic, antibiotic, protease inhibitors), unlike previous studies [ 17 , 18 , 20 , 21 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 33 , 35 , 36 ]. Though deterioration processes are expected to affect cartilage following the harvesting of samples, the use of preserving agents could alter cartilage pristine properties, including the interaction with CA4+.…”

“…A novel cationic iodinated contrast agent, CA4+, was specifically designed to electrostatically interact with glycosaminoglycans (GAGs) bound in proteoglycans [ 16 ]. In particular, the Coulomb attraction between negative fixed charges of GAGs and positively-charged CA4+ molecules showed superior contrast enhancement compared to commercially available contrast agents, (even at lower concentrations [ 17 , 18 , 19 ]), in animal [ 20 , 21 , 22 , 23 ] and human [ 24 , 25 , 26 , 27 , 28 , 29 ] samples, on several types of tissue containing GAGs [ 13 , 30 , 31 ] and cartilage tissue-engineered constructs [ 32 ]. The use of CA4+ was investigated in combination with synchrotron radiation as well, exploiting the high brilliance and monochromaticity of X-ray beam [ 33 , 34 , 35 , 36 ].…”