Minimally invasive and non-destructive methods to quantify glycosaminoglycans (GAGs) in articular cartilage extracellular matrix are of significant interest for the biochemical analysis of cartilage and diagnosis and tracking of osteoarthritis in vivo. Here, we report the use of cationic iodinated contrast agents in comparison to conventional anionic contrast agents for the quantitative monitoring of GAG concentrations with peripheral quantitative computed tomography. Using an ex vivo bovine osteochondral plug model, the cationic contrast agents were evaluated for their ability to distribute into articular cartilage and generate a positive relationship with GAG content. The cationic agents resulted in much higher equilibrium X-ray attenuations in cartilage extracellular matrix (ECM) than anionic agents. Experiments with samples subjected to enzymatic GAG degradation demonstrated that the cationic agents were up to five times more sensitive ( p ¼ 0.0001) to changes in GAG content and had a 24% higher correlation ( p ¼ 0.002) compared to the anionic agent (R 2 ¼ 0.86, p < 0.0001 compared with R 2 ¼ 0.62, p ¼ 0.004). The natural inhomogeneous distribution of GAGs in the ECM could clearly be identified in undegraded samples. ß

The synthesis and evaluation of a new class of cationic iodinated contrast agents for the imaging of cartilage using computed tomography (CT) are described. In direct comparisons with anionic contrast agents, the cationic contrast agents afforded higher equilibrium concentrations in the articular cartilage of ex vivo rabbit femurs and thus greater imaging sensitivity. Variations in CT intensity across the sample reflected the inhomogeneous distribution of glycosaminoglycans in the tissue as confirmed by histological analysis. We anticipate that this work represents the first step in the development of sensitive, nondestructive CT-based methods to characterize the biochemical properties of cartilage using cationic contrast agents.

Electrostatic attraction of CA4+ allowed effective imaging of the GAG components of articular cartilage at 50% lower molar concentration than Ioxaglate and 20-fold lower molar concentration than Gadopentetate. The CA4+ contrast agent exhibited a significant correlation between CT attenuation and GAG content in ex vivo bovine osteochondral plugs.