High-sensitivity imaging and quantification of intratumoral distributions of gold nanoparticles using a benchtop x-ray fluorescence imaging system.

A high-sensitivity benchtop x-ray fluorescence (XRF) imaging system, based on a high-power x-ray source and silicon drift detector, has been developed. This system allows gold L-shell XRF-based quantitative imaging of gold nanoparticles (GNPs) at concentrations as low as 0.007 mg/cm3 (7 ppm) in biological tissues/water. Its capability for biomedical applications was demonstrated by imaging the GNP distribution within a small (∼12×11×2 mm3) ex vivo sample (extracted from a murine tumor after intravenous GNP administration). The results suggest direct translatability for routine preclinical ex vivo imaging tasks involving GNPs, as well as the possibility for in vivo imaging of small/superficial animal tumors.

Investigation of transmission computed tomography (CT) image quality and x-ray dose achievable from an experimental dual-mode benchtop x-ray fluorescence CT and transmission CT system.

OBJECTIVE: To investigate the image quality and x-ray dose associated with a transmission computed tomography (CT) component implemented within the same platform of an experimental benchtop x-ray fluorescence CT (XFCT) system for multimodal preclinical imaging applications. METHODS: Cone-beam CT scans were performed using an experimental benchtop CT + XFCT system and a cylindrically-shaped 3D-printed polymethyl methacrylate phantom (3 cm in diameter, 7 cm in height) loaded with various concentrations (0.05-1 wt. %) of gold nanoparticles (GNPs). Two commercial CT quality assurance phantoms containing 3D line-pair (LP) targets and contrast targets were also scanned. The x-ray beams of 40 and 62 kVp, both filtered by 0.08 mm Cu and 0.4 mm Al, were used with 17 ms of exposure time per projection at three current settings (2.5, 5, and 10 mA). The ordered-subset simultaneous algebraic reconstruction and total variation-minimization methods were used to reconstruct images. Sparse projection and short scan were considered to reduce the x-ray dose. The contrast-to-noise ratio (CNR) and modulation transfer function (MTF) were calculated. RESULTS: The lowest detectable concentration of GNPs (CNR > 5) and the highest spatial resolution (per MTF50%) were 0.10 wt. % and 9.5 LP/CM, respectively, based on the images reconstructed from 360 projections of the 40 kVp beam (or x-ray dose of 3.44 cGy). The background noise for the image resulting in the lowest GNP detection limit was 25 Hounsfield units. CONCLUSION: The transmission CT component within the current experimental benchtop CT + XFCT system produced images deemed acceptable for multimodal (CT + XFCT) imaging purposes, with less than 4 cGy of x-ray dose.

Triple channel analysis of Gafchromic EBT3 irradiated with clinical carbon-ion beams.

Self-developing radiochromic film is widely used in radiotherapy QA procedures. To compensate for typical film inhomogeneities, the triple channel analysis method is commonly used for photon-irradiated film. We investigated the applicability of this method for GafchromicTMEBT3 (Ashland) film irradiated with a clinically used carbon-ion beam. Calibration curves were taken from EBT3 film specimens irradiated with monoenergetic carbon-ion beams of different doses. Measurements of the lateral field shape and homogeneity were performed in the middle of a passively modulated spread-out Bragg peak and compared to simultaneous characterization by means of a 2D ionization chamber array. Additional measurements to investigate the applicability of EBT3 for quality assurance (QA) measurement in carbon-ion beams were performed. The triple-channel analysis reduced the relative standard deviation of the doses in a uniform carbon ion field by 30% (from 1.9% to 1.3%) and reduced the maximum deviation by almost a factor of 3 (from 28.6% to 9.8%), demonstrating the elimination of film artifacts. The corrected film signal showed considerably improved image quality and quantitative agreement with the ionization chamber data, thus providing a clear rationale for the usage of the triple channel analysis in carbon-beam QA.

Characterization of a Pixelated Cadmium Telluride Detector System Using a Polychromatic X-Ray Source and Gold Nanoparticle-Loaded Phantoms for Benchtop X-Ray Fluorescence Imaging.

Pixelated semi-conductor detectors providing high energy resolution enable parallel acquisition of x-ray fluorescence (XRF) signals, potentially leading to performance enhancement of benchtop XRF imaging or computed tomography (XFCT) systems utilizing ordinary polychromatic x-ray sources. However, little is currently known about the characteristics of such detectors under typical operating conditions of benchtop XRF imaging/XFCT. In this work, a commercially available pixelated cadmium telluride (CdTe) detector system, HEXITEC (High Energy X-ray Imaging Technology), was characterized to address this issue. Specifically, HEXITEC was deployed into our benchtop cone-beam XFCT system, and used to detect gold Kα XRF photons from gold nanoparticle (GNP)-loaded phantoms. To facilitate the detection of XRF photons, various parallel-hole stainless steel collimators were fabricated and coupled with HEXITEC. A pixel-by-pixel spectrum merging algorithm was introduced to obtain well-defined XRF + scatter spectra with parallel-hole collimators. The effect of charge sharing addition (CSA) and discrimination (CSD) algorithms was also investigated for pixel-level CS correction. Finally, the detector energy resolution, in terms of the full-width at half-maximum (FWHM) values at two gold Kα XRF peaks (~68 keV), was also determined. Under the current experimental conditions, CSD provided the best energy resolution of HEXITEC (~1.05 keV FWHM), compared with CSA and no CS correction. This FWHM value was larger (by up to ~0.35 keV) than those reported previously for HEXITEC (at ~60 keV Am-241 peak) and single-crystal CdTe detectors (at two gold Kα XRF peaks). This investigation highlighted characteristics of HEXITEC as well as the necessity for application-specific detector characterization.

Monte Carlo study of x-ray detection configurations for benchtop x-ray fluorescence computed tomography of gold nanoparticle-loaded objects.

Over the last decade, the performance of benchtop x-ray fluorescence computed tomography (XFCT) systems has been significantly enhanced through hardware and software optimizations. Recent studies have indicated the need of energy-resolving pixelated/array detectors in the x-ray detection component to further improve the sensitivity and image resolution of benchtop XFCT systems while meeting the realistic constraints of dose and scan time. Thus, it is of immediate interest in the research community to conduct the following investigations: (a) delineation of strengths/weaknesses of detection configurations that incorporate pixelated/array detectors in combination with two most frequently used (parallel-hole and pinhole) collimators; (b) one-to-one comparison of their performance under identical imaging conditions of benchtop XFCT. In this study, we developed a Geant4-based Monte Carlo model to investigate the effects of the aforementioned detection configurations on the sensitivity and image resolution of a benchtop XFCT system. Using this model, we simulated the detection of x-ray fluorescence and scattered photons from gold nanoparticle-containing phantoms using energy-resolving pixelated detectors coupled with parallel-hole and pinhole collimators. Simulation results demonstrated that the detector consisting of large pixels (1 mm × 1 mm) combined with a parallel-hole collimator had better sensitivity (i.e. lower detection limit) than the detector made of smaller pixels (0.25 mm × 0.25 mm) coupled with a pinhole collimator. In comparison, although slightly less sensitive, the latter detector configuration achieved better image resolution than did the former. Thus, a detection configuration consisting of a pixelated detector with submillimeter pixels and a pinhole collimator is preferable when image resolution is critical for benchtop XFCT applications. On the other hand, the detector with larger pixels coupled with a parallel-hole collimator is better suited for benchtop XFCT applications in which higher sensitivity and shorter scan time are essential.

Evaluation of dose point kernel rescaling methods for nanoscale dose estimation around gold nanoparticles using Geant4 Monte Carlo simulations.

The absence of proper nanoscale experimental techniques to investigate the dose-enhancing properties of gold nanoparticles (GNPs) interacting with radiation has prompted the development of various Monte Carlo (MC)-based nanodosimetry techniques that generally require considerable computational knowledge, time and specific tools/platforms. Thus, this study investigated a hybrid computational framework, based on the electron dose point kernel (DPK) method, by combining Geant4 MC simulations with an analytical approach. This hybrid framework was applied to estimate the dose distributions around GNPs due to the secondary electrons emitted from GNPs irradiated by various photon sources. Specifically, the equivalent path length approximation was used to rescale the homogeneous DPKs for heterogeneous GNPs embedded in water/tissue. Compared with Geant4 simulations, the hybrid framework halved calculation time while utilizing fewer computer resources, and also resulted in mean discrepancies less than 20 and 5% for Yb-169 and 6 MV photon irradiation, respectively. Its appropriateness and computational efficiency in handling more complex cases were also demonstrated using an example derived from a transmission electron microscopy image of a cancer cell containing internalized GNPs. Overall, the currently proposed hybrid computational framework can be a practical alternative to full-fledged MC simulations, benefiting a wide range of GNP- and radiation-related applications.

Development of an attenuation correction method for direct x-ray fluorescence (XRF) imaging utilizing gold L-shell XRF photons.

PURPOSE: This work proposes a semiempirical correction method for attenuation of x-ray fluorescence (XRF) photons and/or an excitation beam during direct XRF imaging (i.e., mapping) of gold nanoparticle (GNP) distribution utilizing gold L-shell XRF photons. METHODS: The current method was first devised by finding the two following relationships: (a) ratio of gold XRF peak intensity (Lα at ~9.7 keV and Lß at ~11.4 keV) vs pathlength of XRF photons; (b) XRF photon counts produced (Nxrf ) vs scattered photon counts produced (Nscat ). Monte Carlo simulations were performed using the Geant4 tool kit to characterize the aforementioned relationships for different tissue-like media. The applicability of the method was tested experimentally by acquiring 2D L-shell XRF images of custom-made phantoms using an experimental benchtop x-ray fluorescence computed tomography setup. RESULTS: The results show that the ratio of gold L-shell XRF peak intensities allowed an estimation of the pathlength of XRF photons, thus can be utilized to correct for attenuation of XRF photons after emission. The results also demonstrate that Nscat , through a proportionality N xrf ∝ N scat T where the exponent T depends on the energy of scattered photons, could be used to correct for attenuation of an excitation beam prior to producing XRF photons. The corrected XRF signal was found independent of the densities of tissue-like media present along the passage of an excitation beam or emitted XRF photons. CONCLUSIONS: The current results suggest that the developed attenuation correction method plays an essential role for the detection of GNPs on the order of parts-per-million, and also for the determination of GNP concentration/location within the imaging object made of tissue-like media, without any prior knowledge of the imaging object shape, under the conditions deemed relevant to biomedical applications of gold L-shell XRF-based imaging.

A Monte Carlo Model of a Benchtop X-Ray Fluorescence Computed Tomography System and Its Application to Validate a Deconvolution-Based X-Ray Fluorescence Signal Extraction Method.

In this study, we developed and validated a Geant4-based Monte Carlo (MC) model of an experimental benchtop X-ray fluorescence (XRF) computed tomography (XFCT) system for quantitative imaging of metallic nanoparticles such as gold nanoparticles (GNPs) injected into small animals for preclinical testing of various NP-based diagnostic and therapeutic approaches. Detailed hardware components of the current benchtop XFCT system, including the X-ray source, excitation beam collimation and filtration, custom imaging phantoms with GNP solutions, and single/ring/linear array detectors with custom collimation, were incorporated into the MC model. In conjunction with a known CdTe detector response function, a deconvolution-based XRF signal extraction method was also developed in this study, which enabled complete separation of gold K-shell XRF peaks even when they almost overlapped and facilitated extraction of XRF signals from a broadband Compton scattered photon background. The extracted signal-to-background ratios were comparable with those expected using an ideal detector with high enough energy resolution (e.g., 0.1 keV full-width at half-maximum). Once convoluted with the CdTe detector response function, the MC-calculated spectra for excitation beams or emitted photons and XFCT image spatial resolutions agreed well with those measured experimentally. Thus, the current MC model can be used to optimize the beam/imaging parameters (e.g., beam geometry, excitation X-ray beam energy, and X-ray filter material) as well as the design of critical hardware components (e.g., detector collimators) within the current benchtop XFCT system. Also, the current XRF signal extraction method can relax the usual stringent requirement of detector energy resolution while not degrading the sensitivity of benchtop XFCT.

Pixel Bleeding Correction in Laser Scanning Luminescence Imaging Demonstrated Using Optically Stimulated Luminescence.

This paper describes and investigates the performance of an algorithm to correct for "pixel bleeding" caused by slow luminescence centers in laser scanning imaging (e.g., X-ray imaging using photostimulable phosphors and 2D dosimetry using optically stimulated luminescence). The algorithm is based on a deconvolution procedure that takes into account the lifetime of the slow luminescence center and is further constrained by the detection of fast and slow luminescence centers and combining rows scanned in opposite directions. The algorithm was tested using simulated data and demonstrated experimentally by applying it to image reconstruction of two types of Al2O3 X-ray detector films ( Al2O3:C and Al2O3 :C,Mg), whose use in 2D dosimetry in conjunction with laser-scanning readout has so far been prevented by slow luminescence centers (F-centers, 35 ms lifetime). We show that the algorithm allows the readout of Al2O3 film detectors 300-500 times faster than generally allowed considering the lifetime of the main luminescence centers. By relaxing the stringent requirements on the detector's luminescence lifetime, the algorithm opens the possibility of using new materials in 2D dosimetry as well as other laser scanning applications, such as X-ray imaging using storage phosphors and scanning confocal microscopy, although the effect of the noise introduced must be investigated for each specific application.