Europium-doped cerium oxide nanoparticle-impregnated Hyalgan® (CartiOxgel): an intra-articular contrast agent for X-ray CT and optical imaging

Abstract

Cartilage internalizing metal-oxide gel (“CartiOxgel”), a novel hybrid contrast agent, was developed for enhanced X-ray computed tomography (CT) and optical intra-articular (IA) imaging. The formulation comprises europium (Eu)-doped cerium oxide nanoparticles (CeO_2−x NPs, C), denoted as Eu_x%Cy NPs, which were incorporated into Hyalgan®, a commercial intra-articular (IA) injectable gel. Eu doping at 2% and 10% was achieved using a one-pot combustion method (as-prepared at 200 °C, y = 2), followed by thermal treatment at 700 °C (y = 7) to investigate the effect of heat treatment on hybrid NP formation. Physicochemical characterization confirmed the structural stability and biocompatibility of the C7 NPs (host) and Eu_10%C7 NPs. These NPs were integrated into Hyalgan® to form H–C7 and H–Eu_10%C7, collectively termed CartiOxgel. The formulated gel exhibited superior CT attenuation (∼1750–1900 Hounsfield units, HU), significantly outperforming Omnipaque™ (H-Iodine, ∼890 HU). In vivo X-ray CT imaging in Wistar rats following IA injection of CartiOxgel demonstrated sustained retention up to 48 h compared with the rapid clearance of H-Iodine. Ex vivo optical imaging revealed that the Eu_10%C7 NPs exhibited effective tissue penetration due to the hypersensitive transition (⁵D₀ → ⁷F₂) of _10%Eu. Histological analyses (H&E and Safranin-O staining) confirmed the absence of inflammatory response or extracellular matrix (ECM) degradation after 48 h, indicating excellent biocompatibility and cartilage penetration. CartiOxgel with hybrid-NPs holds promise for advanced IA imaging and has potential clinical applications in knee diagnostics.