X-ray Fluorescence Computed Tomography Imaging Research Articles

A High-Sensitivity Benchtop X-Ray Fluorescence Emission Tomography (XFET) System With a Full-Ring of X-Ray Imaging-Spectrometers and a Compound-Eye Collimation Aperture.

The advent of metal-based drugs and metal nanoparticles as therapeutic agents in anti-tumor treatment has motivated the advancement of X-ray fluorescence computed tomography (XFCT) techniques. An XFCT imaging modality can detect, quantify, and image the biodistribution of metal elements using the X-ray fluorescence signal emitted upon X-ray irradiation. However, the majority of XFCT imaging systems and instrumentation developed so far rely on a single or a small number of detectors. This work introduces the first full-ring benchtop X-ray fluorescence emission tomography (XFET) system equipped with 24 solid-state detectors arranged in a hexagonal geometry and a 96-pinhole compound-eye collimator. We experimentally demonstrate the system's sensitivity and its capability of multi-element detection and quantification by performing imaging studies on an animal-sized phantom. In our preliminary studies, the phantom was irradiated with a pencil beam of X-rays produced using a low-powered polychromatic X-ray source (90kVp and 60W max power). This investigation shows a significant enhancement in the detection limit of gadolinium to as low as 0.1 mg/mL concentration. The results also illustrate the unique capabilities of the XFET system to simultaneously determine the spatial distribution and accurately quantify the concentrations of multiple metal elements.

Full-field in vivo imaging of nanoparticles using benchtop cone-beam XFCT system with pixelated photon counting detector

Objective. X-ray fluorescence computed tomography (XFCT) is a promising noninvasive technique for in vivo imaging of high-Z elements (e.g. gadolinium (Gd) or gold (Au)). In this study we upgraded our experimental XFCT system using a flat panel photon counting detector with redesigned pinhole collimation in order to achieve 3D XFCT images during one scan. Approach. Aiming at the characteristics of pinhole-collimated cone-beam XFCT imaging, a new scatter correction algorithm was proposed to estimate the normalized spectrum of scatter background based on K–N formula and realize correction by a weighted least squares method. Then, images were quantitatively reconstructed by a maximum likelihood iterative algorithm with the attenuation correction. Main results. The potential on full-field in vivo XFCT imaging of this new system was investigated. An imaging experiment of a PMMA phantom with the diameter of 35 mm was carried out for quantitative evaluation of the system performance. Results show that 2 mg ml−1 Gd solutions can be successfully reconstructed with a 45 min cone-beam XFCT scan. In vivo XFCT imaging experiments of mice with injection of Gd nanoparticles (GdNPs) were also performed and demonstrated in this paper. A mouse was injected through the tail vein with 20 mg ml−1 NaGdF4 solution and then anesthetized with isoflurane during the cone-beam XFCT scan. Significance. The distribution of the GdNPs inside the mouse can be well reconstructed so that the deposition of NPs in vivo can be clearly observed, which indicates the feasibility of the proposed system for full-field XFCT of small animals and further potential in relevant in vivo research.

Numerical and Monte Carlo Simulation for Polychromatic L-shell X-ray Fluorescence Computed Tomography Based on Pinhole Collimator with Sheet-Beam Geometry

X-ray fluorescence computed tomography (XFCT) has attracted wide attention due to its ability to simultaneously and nondestructively obtain structural and elemental distribution information within samples. In this paper, we presented an image system based on the pinhole collimator for the polychromatic L-shell XFCT to reduce time consumption and improve the detection limit. First, the imaging system model was expressed by formulas and discretized. Then, two phantoms (A and B) were scanned by numerical simulation and Monte Carlo simulation. Both phantoms with the same diameter (10 mm) and height (10 mm) were cylinders filled with PMMA, and embedded with GNP-loaded cylinders. The phantom A was inserted by six 1.5 mm-diameter cylinders with different Au concentrations ranging from 0.2% to 1.2%. The phantom B was inserted by eight cylinders with the same Au concentration (1%), but a radius ranging from 0.1 mm to 0.8 mm. Finally, the reconstruction of the XFCT images was performed using the method with and without absorption correction, respectively. The feasibility of XFCT system presented in this paper was demonstrated by the numerical simulation and the Monte Carlo simulation. The results show that absorption attenuation can be corrected by the presented method, and the contrast to noise ratio (CNR) is proportional to Au concentration but almost remains unchanged with the radius of GNP-loaded cylinders, which may provide the necessary justification for further optimization of the imaging system.

Use of the Fully Spectroscopic Pixelated Cadmium Telluride Detector for Benchtop X-Ray Fluorescence Computed Tomography.

In this work, we integrated a commercially-available fully-spectroscopic pixelated cadmium telluride (CdTe) detector system as a two-dimensional (2D) array detector into our existing benchtop cone-beam x-ray fluorescence computed tomography (XFCT) system. After integrating this detector, known as High-Energy X-ray Imaging Technology (HEXITEC), we performed quantitative imaging of gold nanoparticle (GNP) distribution in a small animal-sized phantom using our benchtop XFCT system. Owing to the upgraded detector component within our benchtop XFCT system, we were able to conduct this phantom imaging in an unprecedented manner by volumetric XFCT scans followed by XFCT image reconstruction in 3D. The current results showed that adoption of HEXITEC, in conjunction with a custom-made parallel-hole collimator, drastically reduced the XFCT scan time/dose. Compared with the previous work performed with our original benchtop XFCT system adopting a single crystal CdTe detector, the currently observed reduction was up to a factor of 5, while achieving comparable GNP detection limit under similar experimental conditions. Overall, we demonstrated, for the first time to the best our knowledge, the feasibility of benchtop XFCT imaging of small animal-sized objects containing biologically relevant GNP concentrations (on the order of 0.1 mg Au/cm3 or 100 parts-per-million/ppm), with the scan time (on the order of 1 minute)/x-ray dose (on the order of 10 cGy) that are likely meeting the minimum requirements for routine preclinical imaging applications.

Prostate Cancer Targeted X-Ray Fluorescence Imaging via Gold Nanoparticles Functionalized With Prostate-Specific Membrane Antigen (PSMA).

The gold nanoparticle (GNP) as a promising theranostic probe has been increasingly studied. The tumor-targeting efficiency of GNPs is crucial to increase the therapeutic ratio. In this study, we developed PSMA-targeted GNPs to enhance GNP uptake in prostate cancer and developed an x-ray fluorescence imaging system to noninvasively monitor and assess GNP delivery. For targeted therapy of prostate cancer, anti-prostate-specific membrane antigen (PSMA) antibodies were conjugated onto PEGylated GNPs through 1-ethyl-3-(-3-dimethylaminopropyl) carbodiimide (EDC) and N-hydroxysuccinimide (NHS) (EDC/NHS) chemistry. In vivo imaging was implemented using an in-house-developed dual-modality computed tomography (CT) and x-ray fluorescence CT (XFCT) system on mice bearing subcutaneous LNCaP prostate tumors. After intravenous administration of GNPs (15 mg/mL, 200 μL), the x-ray fluorescence signals from the tumor were collected at various time points (5 minutes to approximately 30 hours) for GNP pharmacokinetics analysis. At 24 hours after administration, x-ray fluorescence projection (XRFproj) and XFCT imaging were conducted to evaluate the prostate tumor uptake of active- and passive-targeting GNPs. Inductively coupled plasma mass spectrometry analysis was adopted as a benchmark to verify the quantification accuracy of XRFproj/XFCT imaging. Fluorescence microscopic imaging confirmed the enhanced (approximately 4 times) targeting efficiency of PSMA-targeted GNPs in vitro. The pharmacokinetics analysis showed enhanced tumor uptake/retention of PSMA-targeted GNPs and revealed that the peak tumor accumulation appeared at approximately 24 hours after intravenous administration. Both XRFproj and XFCT imaging presented their accuracy in quantifying GNPs within tumors noninvasively. Moreover, XFCT imaging verified its unique capabilities to simultaneously determine the heterogeneous spatial distribution and the concentration of GNPs within tumors in vivo. In conjunction with PSMA-targeted GNPs, XRFproj/XFCT would be a highly sensitive tool for targeted imaging of prostate cancer, benefiting the elucidation of mechanisms of GNP-assisted prostate-cancer therapy.

X-ray Fluorescence Computed Tomography (XFCT) Imaging with a Superfine Pencil Beam X-ray Source

X-ray fluorescence computed tomography (XFCT) is a molecular imaging technique that can be used to sense different elements or nanoparticle (NP) agents inside deep samples or tissues. However, XFCT has not been a popular molecular imaging tool because it has limited molecular sensitivity and spatial resolution. We present a benchtop XFCT imaging system in which a superfine pencil-beam X-ray source and a ring of X-ray spectrometers were simulated using GATE (Geant4 Application for Tomographic Emission) Monte Carlo software. An accelerated majorization minimization (MM) algorithm with an L1 regularization scheme was used to reconstruct the XFCT image of molybdenum (Mo) NP targets. Good target localization was achieved with a DICE coefficient of 88.737%. The reconstructed signal of the targets was found to be proportional to the target concentrations if detector number, detector placement, and angular projection number are optimized. The MM algorithm performance was compared with the maximum likelihood expectation maximization (ML-EM) and filtered back projection (FBP) algorithms. Our results indicate that the MM algorithm is superior to the ML-EM and FBP algorithms. We found that the MM algorithm was able to reconstruct XFCT targets as small as 0.25 mm in diameter. We also found that measurements with three angular projections and a 20-detector ring are enough to reconstruct the XFCT images.

Longitudinal In-Vivo X-Ray Fluorescence Computed Tomography With Molybdenum Nanoparticles

X-ray fluorescence computed tomography (XFCT) with nanoparticles (NPs) as contrast agents shows potential for molecular biomedical imaging with higher spatial resolution than present methods. To date the technique has been demonstrated on phantoms and mice, however, parameters such as radiation dose, exposure times and sensitivity have not yet allowed for high-spatial-resolution in vivo longitudinal imaging, i.e., imaging of the same animal at different time points. Here we show in vivo XFCT with spatial resolution in the 200- [Formula: see text] range in a proof-of-principle longitudinal study where mice are imaged five times each during an eight-week period following tail-vein injection of NPs. We rely on a 24 keV x-ray pencil-beam-based excitation of in-house-synthesized molybdenum oxide NPs (MoO2) to provide the high signal-to-background x-ray fluorescence detection necessary for XFCT imaging with low radiation dose and short exposure times. We quantify the uptake and clearance of NPs in vivo through imaging, and monitor animal well-being over the course of the study with support from histology and DNA stability analysis to assess the impact of x-ray exposure and NPs on animal welfare. We conclude that the presented imaging arrangement has potential for in vivo longitudinal studies, putting emphasis on designing biocompatible NPs as the future focus for active-targeting preclinical XFCT.

Experimental Demonstration of X-Ray Fluorescence CT Using a Spatially Distributed Multi-Beam X-Ray Source

X-ray fluorescence computed tomography (XFCT) is a high sensitivity imaging modality for high-atomic elements such as gadolinium (Gd) or gold (Au). In order to improve the contrast of x-ray fluorescent (XRF) signal in the raw projection data, common XFCT systems use the single-pixel x-ray spectrometer to record XRF photons stimulated by the pencil-beam x-ray source and achieve line-by-line scan of the whole object by translating the x-ray source or the object. However, this kind of design results in waiting time of translation device. One improvement would be to replace the traditional x-ray tube with the spatially distributed multi-beam x-ray source and scan the whole object by switching the exposure of each focus. In this study, we present a design of XFCT system using the spatially distributed multi-beam source and a XFCT imaging experiment was performed to investigate its feasibility. Each cold cathode of the x-ray source used in this study was made of carbon nanotubes and each focus was independently controlled by the electronic control system. The incident beam was collimated by a pinhole array to produce pencil-beam source. The object scanned by the system was a PMMA cylinder (8cm in diameter) with Gd (20mg/mL) and I (100mg/mL) insertions. Results show that the distribution of I and Gd in a PMMA phantom was successfully reconstructed but the imaging performance was limited by the collimation and exposure mode of current distributed x-ray source. The practicality of current distributed x-ray source used for XFCT scan and further optimization of the proposed system are discussed according to the experimental results.

Theranostic PSMA-Targeted Gold Nanoparticles using X-ray Fluorescence Imaging Guided Prostate Tumor Radiotherapy

Gold nanoparticles (GNPs) are promising as radiosensitizers, owing to their strong absorption of ionizing radiation and capacity to intensify the production of secondary electrons and reactive oxygen species. Although GNPs do passively leak into the tumor interstitium through enhanced permeability and retention (EPR) effect, its efficiency is low and whether the EPR effect is relevant in humans is still controversial. One purpose of our study is to design PSMA-targeted GNPs, to enhance targeting efficiency for prostate tumors, as well as to bring nanoparticles closer to the cellular nucleus for greater DNA damage following radiotherapy. We also developed an x-ray fluorescence computed tomography (XFCT) system to noninvasively monitor and assess the delivery of the targeted GNPs. Thiol-terminated polyethylene glycol is used to functionalize the GNP surface, to keep GNPs from aggregating and to avoid uptake by the reticular endothelial system. Simultaneously, the anti-PSMA antibodies were conjugated using 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide and N-hydroxy sulfosuccinimide. GNP imaging was carried out on an in-house-developed dual-modality transmission CT and XFCT system. The performance of XFCT, in terms of quantitative and sensitive GNP imaging, was firstly evaluated on water phantoms containing GNP inserts of various concentration (0.02∼0.16 wt.%). Then in vivo imaging was conducted on LNCaP prostate tumor model to compare the tumor GNP concentration between active-targeting (GNP-anti-PSMA, n = 3) and passive-targeting (GNP-IgG, n = 3) groups. After GNPs (15 mg/ml, 200μL) were intravenous injected, tumor x-ray fluorescence signals were collected at various timepoints (5 min∼30 hr) for pharmacokinetics analysis, and in vivo 3D tumor XFCT imaging was conducted 24 hr post GNP injection. In vitro fluorescent microscopic imaging confirms the enhanced (∼4 times) targeting efficiency of PSMA-targeted GNPs. Phantom experiments validate that XFCT could accurately localize GNP targets with <0.6 mm offset, and sensitively quantify GNPs at a concentration of 0.02 wt.%. In vivo x-ray fluorescence-based tumor pharmacokinetics demonstrates the higher accumulation and longer retention of PSMA-targeted GNPs compared to passively administered GNPs. Active-targeting GNPs reached their peak accumulation in tumor at ∼24 hr after intravenous injection. In vivo tumor XFCT imaging shows its unique capabilities to simultaneously determine the heterogeneous spatial distribution and concentration of GNPs, wherein the maximum concentration of PSMA-targeted GNPs was ∼4 times higher than that of passive-targeting GNPs. PSMA-targeted GNPs exhibit enhanced prostate tumor targeting efficiency, showing their potential as targeted radiosensitizers. XFCT imaging localizes GNP targets and accurately quantifies GNP concentration, which is helpful to elucidate the mechanism of GNP-induced radiosensitization.

Design of a combined X-ray fluorescence Computed Tomography (CT) and photon-counting CT table-top imaging system

This paper demonstrates the capability of a table-top x-ray imaging system to simultaneously image a small animal phantom loaded with Gd and Au contrast agents with photon-counting computed tomography (PCCT) and x-ray fluorescence CT (XFCT). Our table-top system consisted of a diagnostic x-ray tube, translation and rotation stages, a 330 μm-pitch cadmium zinc telluride (CZT) photon-counting detector with six energy bins, and two CdTe spectrometers which detected fluorescent x-rays in 0.5 keV bins. The energy bin thresholds on the CZT detector matched the contrast agent K-edge energies, enabling K-edge PCCT. A 3 cm-diameter phantom containing vials of 1% and 5% Gd and Au solutions by weight, including a mixed 1% Gd/Au vial, was scanned with 0.5 mm Cu-filtered 120 kVp x-rays at 2 mA. A pencil beam geometry was used with 33 translation and 30 rotation steps to form XFCT and K-edge PCCT images. A cone beam geometry with 180 rotation steps was used to form higher-resolution K-edge PCCT images. Three mice were each injected post-mortem with 0.2 mL of 5% Gd, Au, or mixed Gd/Au solutions in the upper torso and imaged similarly to the phantom. The lowest detectable concentration based on the Rose criterion for Gd and Au phantom data was 0.75% and 3.0% for XFCT, 0.81% and 0.82% for pencil beam K-edge PCCT, and 0.79% and 1.5% for cone beam K-edge PCCT. However, cone beam K-edge PCCT images have a much higher spatial resolution than the pencil beam images. The mixed 1% Gd/Au signal was diminished in the K-edge PCCT phantom images. Preliminary mouse images of Gd and Au among the imaging techniques were similar in image quality as the phantom images. This is the first demonstration of simultaneously-acquired XFCT and PCCT of both Gd and Au in a phantom on a table-top imaging system. On our system, cone beam PCCT is best for imaging Gd, pencil beam PCCT is best for imaging Au, and pencil beam XFCT is better suited toward resolving mixtures of contrast agents.

Simulation Research of Multi-Pinhole Collimated L-Shell XFCT Imaging System

Polychromatic source X-ray fluorescence computed tomography (XFCT) is a novel imaging method, which is applied for the diagnosis and treatment studies of early stage cancer. In this paper, we propose a fast multi-pinhole L-shell XFCT imaging system to reduce the scan time and radiation dose, which has potential in detecting lower concentration of contrast agents (gold nanoparticles, GNPs). Two kinds of phantoms - the concentration-phantom 1 and the size-phantom 2 are designed to verify imaging performance for low-concentration and small-size ROI. The scanning processes are simulated by Geant4, and images are reconstructed by Optimized EM-TV algorithm. It is concluded that this imaging system is more sensitive in detecting low concentration GNPs than K-shell imaging system. Simulation experiments show the reconstructed images can achieve the highest CNR both for phantom 1 and phantom 2 with iterating 10 times. The detection limit can reach 0.16% when pinhole radius is 0.08mm.

Reconstruction of X-Ray Fluorescence Computed Tomography From Sparse-View Projections via L1-Norm Regularized EM Algorithm

X-ray fluorescence computed tomography (XFCT) as a molecular imaging modality can simultaneously identify the localization and quantify the concentration of high-atomic-number contrast agents such as gold nanoparticles (GNPs). Commonly used benchtop pencil-beam XFCT, consisting of a polychromatic x-ray source and a single-pixel spectrometer, suffers from long scanning time and high imaging dose. Sparse-view strategy benefits XFCT to reduce both scanning time and imaging dose. Nevertheless, its reconstruction undergoes ill-posedness induced by the compressive sampling. To preserve consistent imaging quality for sparse-view XFCT, we proposed an iterative Bayesian algorithm based on L1-norm constraint, wherein the L1-norm regularization is included in the one-step-late expectation maximization (OSL-EM) algorithm with regularization parameter determined based on L-curve criteria. The proposed algorithm was verified by imaging a 3-cm-diameter water phantom with 4 inserts containing GNP solutions with concentrations of 0.02, 0.04, 0.08, and 0.16 wt.%, on an in-house-developed dual-modality transmission CT and XFCT system. Different numbers (i.e. 36, 18, 9, and 6) of projection views were used for XFCT reconstruction, to evaluate the performance of various reconstruction algorithms. L1-regularized EM algorithm demonstrated the consistent robustness to suppress background artifacts and localize low-concentration GNPs (0.02 wt.%) with submillimeter accuracy, when the number of projection views reduces from 36 to 9. Moreover, our method’s potential for small tumor spare-view XFCT imaging was validated on a mouse surgically implanted with a 6-mm GNP target.

The feasibility of NaGdF4 nanoparticles as an x-ray fluorescence computed tomography imaging probe for the liver and lungs.

As a novel imaging modality, x-ray fluorescence computed tomography (XFCT) can provide distribution and concentration information of contrast agents containing high atomic number elements, such as iodine, gadolinium, barium, gold, and platinum. Since XFCT has a better sensitivity and detection limit of high-Z elements compared with traditional and spectral CT, it becomes a powerful quantitative imaging tool for biological studies. The main problem of current XFCT imaging is its low emission and detection efficiency of x-ray fluorescence (XRF) photons. Increasing XRF photons generation by choosing a high atomic element as a contrast agent is essential to improve the imaging quality of XFCT. Gadolinium emits at least a few times more of XRF photons than gold under the same x-ray excitation condition, leading to a detection limit at a level of sub-mg/mL as the next generation of clinical imaging modality. However, most current XFCT studies have utilized gadolinium salt as the contrast agent, which could not accumulate in organs or tumors efficiently, making in vivo XFCT imaging quite difficult. In this study, we present NaGdF4 nanoparticles with ultra-small size as nanoprobes to test the feasibility for in vivo XFCT application for the first time. NaGdF4 nanoparticles with different sizes (3-10nm) were successfully synthesized via a coprecipitation process by controlling the reaction time at temperature of 290 °C. The morphology, crystal phase, chemical composition, and size of such NPs were further characterized with HR-TEM, XRD, and EDX. The abilities of XRF photons from different sizes of NPs were quantified by our customized XFCT imaging system. To access the in vivo application of as-synthesized NPs, such hydrophobic NPs capped OA molecules were further modified with AEP via a ligand-exchange process and characterized with FT-IR. For in vivo XFCT imaging, 0.1mL of 30mg/mL NPs were injected into nude mice via the tail vein. The Varian G-297 x-ray tube was set to 150kV and 0.5mA. The XRF photons were captured by a Kromek eV-3500 photon counting detector at each 8° for 10s. The successfully synthesized NaGdF4 nanoparticles (3-10nm) were monodisperse, highly uniform spherical morphology and hexagonal crystalline phases. No significant influence on XRF photons yields or XFCT imaging quality were found by varying the nanoparticle size. The XRF photons were 2.5 times more emitted from NaGdF4 nanoparticles (NPs) compared to gold nanoparticles, thereby leading to a better image quality. With the AEP surface modification, such NPs were readily adapted for use in in vivo XFCT applications with monodispersity in aqueous solution and negligible cytotoxicity. With the tail-vein injection, the liver, spleen, and lungs could be clearly imaged with XFCT at a sub-mg/mL level. Such NaGdF4 NPs, which were synthesized with coprecipitation process, were modified with AEP for in vivo XFCT applications. With both the phantom and in vivo experiments, such NPs were proved to be appropriate probes for XFCT application with the detection limit at a sub-mg/mL level. In the future research, such NPs could be further functionalized with targeting molecules for early-phase cancer detection.

Reduced acquisition time for L-shell x-ray fluorescence computed tomography using polycapillary x-ray optics.

X-ray fluorescence computed tomography (XFCT) is an emerging molecular imaging modality for preclinical and clinical applications with high atomic number contrast agents. XFCT allows detection of molecular biomarkers at tissue depths of 4-9mm at L-shell energies and several centimeters for K-shell energies, while maintaining high spatial resolution. This is typically not possible for other molecular imaging modalities. The purpose of this study is to demonstrate XFCT imaging with reduced acquisition times. To accomplish this, x-ray focusing polycapillary optics are utilized to simultaneously increase x-ray fluence rate and spatial resolution in L-shell XFCT imaging. A prototype imaging system using a polycapillary focusing optic was demonstrated. The optic, which was custom-designed for this prototype, provided a high fluence rate with a focal spot size of 2.6mm at a source to isocenter distance of 3cm with a ten times higher fluence rate compared to standard collimation. The study evaluates three different phantoms to explore different trade-offs and limitations of L-shell XFCT imaging. A low-contrast gold phantom and a high-contrast gold phantom, each with three target regions with gold concentrations of 60, 80, and 100 μgml for low contrast and 200, 600, and 1000μgml for high contrast, and a mouse-sized water phantom with gold concentrations between 300 and 500μgml were imaged. X-ray fluorescence photons were measured using a silicon drift detector (SDD) with an energy resolution of 180eV FWHM at an x-ray energy of 11keV. Images were reconstructed with an iterative image reconstruction algorithm and analyzed for contrast to noise ratio (CNR) and signal to noise ratio (SNR). The XFCT data acquisition could be reduced from 17h to under 1h. The polycapillary x-ray optic increases the x-ray fluence rate and lowers the amount of background scatter which leads to reduced imaging time and improved sensitivity. The quantitative analysis of the reconstructed images validates that concentrations of 60μgml of gold can be visualized with L-shell XFCT imaging. For a mouse-sized phantom, a concentration of 300μgml gold was detected within a 66min measurement. With a high fluence rate pencil beam from a polycapillary x-ray source, a reduction in signal integration time is achieved. It is presented that subtle amounts of contrast agents can be detected with L-shell XFCT within biologically relevant time frames. Our basic measurements show that the polycapillary x-ray source technology is appropriate to realize preclinical L-shell XFCT imaging. The integration of more SDDs into the system will lower the dose and increase the sensitivity.

Quantitative Imaging of Gd Nanoparticles in Mice Using Benchtop Cone-Beam X-ray Fluorescence Computed Tomography System.

Nanoparticles (NPs) are currently under intensive research for their application in tumor diagnosis and therapy. X-ray fluorescence computed tomography (XFCT) is considered a promising non-invasive imaging technique to obtain the bio-distribution of nanoparticles which include high-Z elements (e.g., gadolinium (Gd) or gold (Au)). In the present work, a set of experiments with quantitative imaging of GdNPs in mice were performed using our benchtop XFCT device. GdNPs solution which consists of 20 mg/mL NaGdF4 was injected into a nude mouse and two tumor-bearing mice. Each mouse was then irradiated by a cone-beam X-ray source produced by a conventional X-ray tube and a linear-array photon counting detector with a single pinhole collimator was placed on one side of the beamline to record the intensity and spatial information of the X-ray fluorescent photons. The maximum likelihood iterative algorithm with scatter correction and attenuation correction method was applied for quantitative reconstruction of the XFCT images. The results show that the distribution of GdNPs in each target slice (containing liver, kidney or tumor) was well reconstructed and the concentration of GdNPs deposited in each organ was quantitatively estimated, which indicates that this benchtop XFCT system provides convenient tools for obtaining accurate concentration distribution of NPs injected into animals and has potential for imaging of nanoparticles in vivo.

A detector’s eye view (DEV)-based OSEM algorithm for benchtop x-ray fluorescence computed tomography (XFCT) image reconstruction

In this study, we developed a detector’s eye view (DEV)-based ordered subsets expectation maximization (OSEM) algorithm for more accurate reconstruction of benchtop x-ray fluorescence computed tomography (XFCT) images. The proposed approach was tested using two sets of benchtop XFCT imaging data derived from a newly performed gold nanoparticle (GNP)-containing phantom imaging study and a previously published postmortem benchtop XFCT imaging study of a tumor-bearing mouse injected with GNPs. DEV-based OSEM resulted in higher spatial resolution (up to ~20% decrease in the full width at half maximum values of the regions of interest), compared with filtered back-projection (FBP) and traditional OSEM. It also resulted in up to an order of magnitude smaller background noise in the reconstructed images than FBP, while producing consistently less background noise than traditional OSEM.

Scattering Noise Model Enhanced EM-TV Algorithm for Benchtop X-ray Fluorescence Computed Tomography Image Reconstruction

Current benchtop x-ray fluorescence computed tomography (XFCT) devices, which use x-ray tubes to stimulate x-ray fluorescence (XRF) photons, suffer from the contamination of Compton scatter background produced by the polychromatic incident beam. The conventional maximum-likelihood expectation-maximization (ML-EM) algorithm only considers the noise model of the XRF signal, which results in high statistical noise in reconstructed images caused by scattered photons. In this study, we proposed a scattering noise model enhanced EM-TV algorithm for benchtop XFCT image reconstruction in order to reduce the noise of scatter background and improve the sensitivity of XFCT images. The statistical noise of scattered photons was considered in the likelihood function and the EM iteration step was modified correspondingly to suppress the statistical noise caused by Compton scattered photons. The robustness of the EM iteration was improved by applying the reweighted total variation (TV) norm as the penalty function. Numerical simulations and imaging experiments of a PMMA phantom consisting of gadolinium (Gd) solutions were performed to validate the proposed algorithm. The phantom was irradiated by a cone-beam polychromatic source and the projection was recorded by a linear-array photon counting detector. For comparison, the XFCT images of Gd were reconstructed using different algorithms. Results indicate that compared with the conventional ML-EM algorithm, the proposed algorithm can obtain XFCT images with lower background noise and higher contrast, which may further improve the sensitivity and image performance of current benchtop XFCT systems.

Optimization of a table-top x-ray fluorescence computed tomography (XFCT) system

Pencil beam x-ray fluorescence computed tomography (XFCT) has typically used a single spectrometer and prohibitively long scan times. However, detecting backscattered fluorescent x-rays from gold nanoparticles (AuNPs) using multiple spectrometers greatly reduces image noise and scan time. The arrangement of eight spectrometers for combined K-shell and L-shell XFCT was investigated along with a variety of conditions. A 2.5 cm-diameter cylindrical water phantom containing 4 mm-diameter vials with 0.1%–2% AuNP concentrations by weight was modeled by TOPAS, a GEANT4-based Monte Carlo software. The phantom was irradiated to 30 mGy by a 0.5 mm Pb-filtered 120 kVp and 1 mm Al-filtered 30 kVp 1 mm2 x-ray pencil beam to yield respective Au K-shell and L-shell fluorescent x-rays, with 50 0.5 mm translation and 2-degree rotation steps. Eight CdTe and silicon drift detector (SDD) spectrometers were placed 2.25 cm away from the isocentre. The respective energy resolution was applied to the detected energy spectra and the spectra were corrected for detector response before extracting the fluorescence signal. Three CdTe and SDD spectrometer configurations (isotropic/backscattered grid/backscattered row arrangements), two CdTe crystal sizes (9 mm2/25 mm2), two scanning techniques (moving/stationary spectrometers) and five vial-edge depths (0–4 mm) were considered in optimizing the contrast-to-noise ratio (CNR) for each XFCT image reconstructed with a maximum-likelihood expectation maximization (MLEM) algorithm. The isotropic spectrometer arrangement had AuNP detection sensitivities of 0.106% for K-shell and 0.132% for L-shell XFCT at 4 mm depth. Comparatively, the backscattered grid arrangement had the best AuNP sensitivity of 0.055% and 0.095%. The highest K-shell (0.044%) and L-shell (0.004%) AuNP sensitivities were found for vials at 0 mm depth. Using stationary spectrometers or the 9 mm2 CdTe crystal compromised the CNR. For the best-case arrangement, L-shell XFCT is superior at vial-edge depths less than 3.0 mm. This work demonstrated the importance of spectrometer arrangement and vial depth for improving AuNP sensitivity and will guide the design for our table-top XFCT system.

A Geant4-based Monte Carlo study of a benchtop multi-pinhole X-ray fluorescence computed tomography imaging.

BackgroundX-ray fluorescence (XRF) computed tomography (XFCT) has shown promise for molecular imaging of metal nanoparticles such as gold nanoparticles (GNPs) and benchtop XFCT is under active development due to its easy access, low-cost instrumentation and operation.PurposeTo validate the performance of a Geant4-based Monte Carlo (MC) model of a benchtop multi-pinhole XFCT system for quantitative imaging of GNPs.MethodsThe MC mode consisted of a fan-beam x-ray source (125 kVp), which was used to stimulate the emission of XRF from the GNPs, a phantom (3 cm in diameter) which included six or nine inserts (3 mm in diameter), each of which contained the same (1 wt. %) or various (0.08–1 wt. %) concentrations of GNPs, a multi-pinhole collimator which could acquire multiple projections simultaneously and a one-sided or two-sided two-dimensional (2D) detector. Various pinhole diameters (3.7, 2, 1, 0.5 and 0.25 mm) and various particle numbers (20, 40, 80 and 100 billion) were simulated and the results for single pinhole and multi-pinhole (9 pinholes) imaging were compared.ResultsThe image resolution for a 1 mm multi-pinhole was between 0.88 and 1.38 mm. The detection limit for multi-pinhole operation was about 0.09 wt. %, while that for the single pinhole was about 0.13 wt. %. For a fixed number of pinholes, noise increased with decreasing number of photons.ConclusionThe MC mode could acquire 2D slice images of the object without rotation and demonstrated that a multi-pinhole XFCT imaging system could be a potential bioimaging modality for nanomedical applications.

Technical Note: A benchtop cone-beam x-ray fluorescence computed tomography (XFCT) system with a high-power x-ray source and transmission CT imaging capability.

This report describes upgrades and performance characterization of an experimental benchtop cone-beam x-ray fluorescence computed tomography (XFCT) system capable of determining the spatial distribution and concentration of metal probes such as gold nanoparticles (GNPs). Specifically, a high-power (~3kW) industrial x-ray source and transmission CT capability were deployed in the same platform under the cone-beam geometry. All components of the system are described in detail, including the x-ray source, imaging stage, cadmium-telluride detector for XFCT, and flat-panel detector for transmission CT imaging. The general data acquisition scheme for XFCT and transmission CT is also explicated. The detection limit of the system was determined using calibration samples containing water and GNPs at various concentrations. Samples were then embedded in a small-animal-sized phantom and imaged with XFCT and CT. The reconstructed XFCT and CT images were compared and analyzed using the contrast-to-noise ratio for each GNP-containing region of interest. Also, measurements of the incident beam spectra used for XFCT and CT imaging were made and the corresponding x-ray dose rates were estimated, along with the imaging dose. The present configuration produced a GNP detection limit of 0.03wt. % with the delivery of an effective dose of 1.87cGy per projection. XFCT scan of an animal-sized phantom containing low concentrations (down to 0.03wt. %) of GNP-loaded inserts can be performed within an hour. The high performance of the system combined with the ability to perform transmission CT in tandem with XFCT suggests that the currently developed benchtop cone-beam XFCT/CT system, in conjunction with GNPs, can be used for routine multimodal preclinical imaging tasks with less stringent dose constraints such as exvivo imaging. With further effort to minimize XFCT imaging dose as discussed in this report, it may also be used for invivo imaging.