Triple contrast computed tomography reveals site-specific biomechanical differences in the human knee joint-A proof of concept study.

Cartilage and synovial fluid are challenging to observe separately in native computed tomography (CT). We report the use of triple contrast agent (bismuth nanoparticles [BiNPs], CA4+, and gadoteridol) to image and segment cartilage in cadaveric knee joints with a clinical CT scanner. We hypothesize that BiNPs will remain in synovial fluid while the CA4+ and gadoteridol will diffuse into cartilage, allowing (1) segmentation of cartilage, and (2) evaluation of cartilage biomechanical properties based on contrast agent concentrations. To investigate these hypotheses, triple contrast agent was injected into both knee joints of a cadaver (N = 1), imaged with a clinical CT at multiple timepoints during the contrast agent diffusion. Knee joints were extracted, imaged with micro-CT (µCT), and biomechanical properties of the cartilage surface were determined by stress-relaxation mapping. Cartilage was segmented and contrast agent concentrations (CA4+ and gadoteridol) were compared with the biomechanical properties at multiple locations (n = 185). Spearman's correlation between cartilage thickness from clinical CT and reference µCT images verifies successful and reliable segmentation. CA4+ concentration is significantly higher in femoral than in tibial cartilage at 60 min and further timepoints, which corresponds to the higher Young's modulus observed in femoral cartilage. In this pilot study, we show that (1) large BiNPs do not diffuse into cartilage, facilitating straightforward segmentation of human knee joint cartilage in a clinical setting, and (2) CA4+ concentration in cartilage reflects the biomechanical differences between femoral and tibial cartilage. Thus, the triple contrast agent CT shows potential in cartilage morphology and condition estimation in clinical CT.

Cationic tantalum oxide nanoparticle contrast agent for micro computed tomography reveals articular cartilage proteoglycan distribution and collagen architecture alterations.

OBJECTIVE: Cationic tantalum oxide nanoparticles (Ta2O5-cNPs), as a newly introduced contrast agent for computed tomography of cartilage, offer quantitative evaluation of proteoglycan (PG) content and biomechanical properties. However, knowledge on the depth-wise impact of cartilage constituents on nanoparticle diffusion, particularly the influence of the collagen network, is lacking. In this study, we aim to establish the depth-dependent relationship between Ta2O5-cNP diffusion and cartilage constituents (PG content, collagen content and network architecture). METHODS: Osteochondral samples (n = 30) were harvested from healthy equine stifle joints (N = 15) and the diffusion of 2.55 nm diameter cationic Ta2O5-cNPs into the cartilage was followed with micro computed tomography (µCT) imaging for up to 96 hours. The diffusion-related parameters, Ta2O5-cNP maximum partition (Pmax) and diffusion time constant, were compared against biomechanical and depth-wise structural properties. Biomechanics were assessed using stress-relaxation and sinusoidal loading protocols, whereas PG content, collagen content and collagen network architecture were determined using digital densitometry, Fourier-transform infrared spectroscopy and polarized light microscopy, respectively. RESULTS: The Pmax correlates with the depth-wise distribution of PGs (bulk Spearman's ρ = 0.87, p < 0.001). More open collagen network architecture at the superficial zone enhances intake of Ta2O5-cNPs, but collagen content overall decreases the intake. The Pmax values correlate with the equilibrium modulus (ρ = 0.80, p < 0.001) of articular cartilage. CONCLUSION: This study establishes the feasibility of Ta2O5-cNPs for the precise and comprehensive identification of biomechanical and structural changes in articular cartilage via contrast-enhanced µCT.

Tantalum Oxide Nanoparticles for the Quantitative Contrast-Enhanced Computed Tomography of Ex Vivo Human Cartilage: Assessment of Biochemical Composition and Biomechanics.

Nanoparticle-based contrast agents, when used in concert with imaging modalities such as computed tomography (CT), enhance the visualization of tissues and boundary interfaces. However, the ability to determine the physiological state of the tissue via the quantitative assessment of biochemical or biomechanical properties remains elusive. We report the synthesis and characterization of tantalum oxide (Ta2O5) nanoparticle (NP) contrast agents for rapid, nondestructive, and quantitative contrast-enhanced computed tomography (CECT) to assess both the glycosaminoglycan (GAG) content and the biomechanical integrity of human metacarpal phalangeal joint (MCPJ) articular cartilage. Ta2O5 NPs 3-6 nm in diameter and coated with either nonionic poly(ethylene) glycol (PEG) or cationic trimethylammonium ligands readily diffuse into both healthy and osteoarthritic MCPJ cartilage. The CECT attenuation for the cationic and neutral NPs correlates with the glycosaminoglycan (GAG) content (R2 = 0.8975, p < 0.05 and 0.7054, respectively) and the equilibrium modulus (R2 = 0.8285, p < 0.05 and 0.9312, p < 0.05, respectively). The results highlight the importance of the surface charge and size in the design of NP agents for targeting and imaging articular cartilage. Further, nanoparticle CECT offers the visualization of both soft tissue and underlying bone unlike plain radiography, which is the standard for imaging bone in musculoskeletal diseases, and the ability to provide a real-time quantitative assessment of both hard and soft tissues to provide a comprehensive image of the disease stage, as demonstrated herein.