Imaging of proteoglycan and water contents in human articular cartilage with full-body CT using dual contrast technique

Abstract

Assessment of cartilage composition via tomographic imaging is critical after cartilage injury to prevent post-traumatic osteoarthritis. Diffusion of cationic contrast agents in cartilage is affected by proteoglycan loss and elevated water content. These changes have opposite effects on diffusion and, thereby, reduce the diagnostic accuracy of cationic agents. Here, we apply, for the first time, a clinical full-body CT for dual contrast imaging of articular cartilage. We hypothesize that full-body CT can simultaneously determine the diffusion and partitioning of cationic and non-ionic contrast agents and that normalization of the cationic agent partition with that of the non-ionic agent minimizes the effect of water content and tissue permeability, especially at early diffusion time points. Cylindrical (d = 8 mm) human osteochondral samples (n = 45; four cadavers) of a variable degenerative state were immersed in a mixture of cationic iodinated CA4+ and non-charged gadoteridol contrast agents and imaged with a full-body CT scanner at various time points. Determination of contrast agents' distributions within cartilage was possible at all phases of diffusion. At early time points, gadoteridol, and CA4+ distributed throughout cartilage with lower concentrations in the deep cartilage. At ≥24 h, the gadoteridol concentration remained nearly constant, while the CA4+ concentration increased toward deep cartilage. Normalization of the CA4+ partition with that of gadoteridol significantly (p < 0.05) enhanced correlation with proteoglycan content and Mankin score at the early time points. To conclude, the dual contrast technique was found advantageous over single contrast imaging enabling more sensitive diagnosis of cartilage degeneration. © 2019 The Authors. Journal of Orthopaedic Research Published by Wiley Periodicals, Inc. J Orthop Res 9999:1-12, 2019.

Keywords: cartilage; cationic contrast agent; contrast enhanced computed tomography; dual contrast agent; dual energy computed tomography.

Figure 1

(A) Contrast agent, CA4+ (iodine, I) and gadoteridol (gadolinium, Gd) solutions of different concentrations were imaged separately using 70 and 140 kV tube voltages, to determine mass attenuation coefficients for I (CA4 +) and Gd (gadoteridol). (B) The true and measured contrast agent partitions in contrast agent mixtures determined by using the mass attenuation coefficients derived as the slopes of linear fits in the subfigure A.

Figure 2

The sample extraction locations and number of samples extracted from each location. The samples (n = 45, d = 8 mm) were extracted from cadaver (n = 4) left and right knee joints. The halves used for histological reference analysis were slightly larger than the halves for the DECT to allow extracting the histological slices from the center of the sample.

Figure 3

(A) Light microscopic image of Safranin‐O stained cartilage section. (B) CT image of the same cartilage sample immersed in phosphate buffered saline (PBS). (C–G) CT images of the same cartilage sample after immersion in dual contrast agent for 1, 2, 24, 48, and 72 h. Articular surface is marked with a white dashed line and subchondral bone colored with black.

Figure 4

Sample specific contrast agent partition profiles (n = 45, dotted lines) and mean partition profiles for CA4+ (iodine, solid lines) and gadoteridol (gadolinium, dashed lines) at 1, 2, 24, 48, and 72 h after immersion in the dual contrast agent mixture. In horizontal axis, 0 denotes the articular surface and 1 the cartilage‐bone interface. Please, note axis break and different scaling on vertical axis.