Visualization of Small Vessels by Micro–Computed Tomography Using Titanium Dioxide Nanoparticles as a Novel Contrast Agent

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Angiography by means of micro–computed tomography (m‐CT) is extensively used for the diagnosis of vasculature disorders. To establish a connection between m‐CT images and genuine histopathology findings, we developed two novel titanium dioxide nanoparticle (TiO2‐NP)–based perfusion contrast agents: TiNpCA‐1 and TiNpCA‐2. Three‐dimensionally reconstructed m‐CT images in mice perfused with these contrast agents showed high resolution and accuracy in various organs without deformation or dilation of vessels. Vessels < 20 μm in diameter were clearly visualized by m‐CT, and capillaries of 4 μm in diameter were visualized by nano‐CT. After perfusion, the contrast agents were kept in the vessels by the formation of an aggregate with ethanol. Histological samples were prepared from CT‐scanned specimens. No perfusion‐induced damage or abnormal structures were observed. The signals of the contrast agents were detected clearly, and the tissue histology was of adequate quality for pathological diagnosis. Agglomerates of TiO2‐NPs were present in both agents; their approximate sizes were 1.0 and 6.0 μm in TiNpCA‐1 and 1.5 μm in TiNpCA‐2. We considered that these agglomerates were trapped within capillaries at the beginning of perfusion. And at the end of perfusion, vessels of larger size were filled with agglomerates. These findings suggest a direct correlation between the signal intensity in m‐CT imaging and the volume of contrast agent entering the vessels, indicating a quantitative aspect to the system. The low K‐edge value of titanium (4.6 KeV) ensures that the signal intensity of the contrast agent remains unaffected at low energies (40 KeV). Lower energy levels improve the contrast‐to‐noise ratio. Consequently, using titanium dioxide as a contrast agent allows us to achieve a higher contrast‐to‐noise ratio while maintaining a favorable signal‐to‐noise ratio. Our results strongly support the notion that TiO2‐NPs as a contrast agents hold promise not only for investigating circulatory disorders in experimental pathology but also for uncovering new insights in anatomical physiology.