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X-ray-induced luminescence (XIL) is a hybrid x-ray/optical imaging modality that employs nanophosphors that luminescence in response to x-ray irradiation. X-ray-activated phosphorescent nanoparticles have potential applications in radiation therapy as theranostics, nanodosimeters, or radiosensitizers. Extracting clinically relevant information from the luminescent signal requires the development of a robust imaging model that can determine nanophosphor distributions at depth in an optically scattering environment from surface radiance measurements. The applications of XIL in radiotherapy will be limited by the dose-dependent sensitivity at depth in tissue. We propose a novel geometry called selective plane XIL (SPXIL), and apply it to experimental measurements in optical gel phantoms and sensitivity simulations.An imaging model is presented based on the selective plane geometry which can determine the detected diffuse optical signal for a given x-ray dose and nanophosphor distribution at depth in a semi-infinite, optically homogenous material. The surface radiance in the model is calculated using an analytical solution to the extrapolated boundary condition. Y2O3:Eu3+ nanoparticles are synthesized and inserted into various optical phantom in order to measure the luminescent output per unit dose for a given concentration of nanophosphors and calibrate an imaging model for XIL sensitivity simulations. SPXIL imaging with a dual-source optical gel phantom is performed, and an iterative Richardson–Lucy deconvolution using a shifted Poisson noise model is applied to the measurements in order to reconstruct the nanophosphor distribution.Nanophosphor characterizations showed a peak emission at 611 nm, a linear luminescent response to tube current and nanoparticle concentration, and a quadratic luminescent response to tube voltage. The luminescent efficiency calculation accomplished with calibrated bioluminescence mouse phantoms determines 1.06 photons were emitted per keV of x-ray radiation absorbed per g/mL of nanophosphor concentration. Sensitivity simulations determined that XIL could detect a concentration of 1 mg/mL of nanophosphors with a dose of 1 cGy at a depth ranging from 2 to 4 cm, depending on the optical parameters of the homogeneous diffuse optical environment. The deconvolution applied to the SPXIL measurements could resolve two sources 1 cm apart up to a depth of 1.75 cm in the diffuse phantom.We present a novel imaging geometry for XIL in a homogenous, diffuse optical environment. Basic characterization of Y2O3:Eu3+ nanophosphors are presented along with XIL/SPXIL measurements in optical gel phantoms. The diffuse optical imaging model is validated using these measurements and then calibrated in order to execute initial sensitivity simulations for the dose-depth limitations of XIL imaging. The SPXIL imaging model is used to perform a deconvolution on a dual-source phantom, which successfully reconstructs the nanophosphor distributions.