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Objective: X-ray phase contrast imaging generates contrast from refraction of X-rays, enhancing soft tissue contrast compared to conventional absorption-based imaging. Our goal is to develop a contrast agent for X-ray in-line phase contrast imaging (PCI) based on ultrasound microbubbles (MBs), by assessing size, shell material, and concentration. Methods: Polydisperse perfluorobutane-core lipid-shelled MBs were synthesized and size separated into five groups between 1 and 10 μm. We generated two size populations of polyvinyl-alcohol (PVA)-MBs, 2-3 μm and 3-4 μm, whose shells were either coated or integrated with iron oxide nanoparticles (SPIONs). Microbubbles were then embedded in agar at three concentrations: 5 × 107, 5 × 106 and 5 × 105 MBs/ml. In-line phase contrast imaging was performed at the Canadian Light Source with filtered white beam micro-computed tomography. Phase contrast intensity was measured by both counting detectable MBs, and comparing mean pixel values (MPV) in minimum and maximum intensity projections of the overall samples. Results: Individual lipid-MBs 6-10 μm, lipid-MBs 4-6 μm and PVA-MBs coated with SPIONs were detectable at each concentration. At the highest concentration, lipid-MBs 6-10 μm and 4-6 μm showed an overall increase in positive contrast, whereas at a moderate concentration, only lipid-MBs 6-10 μm displayed an increase. Negative contrast was also observed from two largest lipid-MBs at high concentration. Conclusion: These data indicate that lipid-MBs larger than 4 μm are candidates for PCI, and 5 × 106 MBs/ml may be the lowest concentration suitable for generating visible phase contrast in vivo. Significance: Identifying a suitable MB for PCI may facilitate future clinical translation. [ABSTRACT FROM AUTHOR]

A number of phase based X-ray imaging methods have been developed that derive contrast from phase effects from the object which make them particularly interesting because of the ability to visualize soft tissues. Shack–Hartmann is a wave-front diagnostic technique that emerged from optics which uses ray-line beams (beamlets) to interrogate the differences in the wave-front across a beam can also be used for X-ray imaging applications with phase sensitivity. This method, which has been applied in the X-ray regime, is very simple in that it only requires a screen to prepare an array of beamlets that then pass through the object and are allowed to propagate a distance onto a pixelated detector. Absorption and refraction information can be extracted from the detected beamlets. An untapped property is the additional ability to extract scatter distribution information based on the observed width of the detected spots. This paper describes experiments done at a synchrotron facility investigating the use of a Shack–Hartmann system for biomedical applications and include our method and examples of scatter contrast extraction from the method. [ABSTRACT FROM AUTHOR]