X-ray Fluorescence Computed Tomography System Research Articles

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.

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.

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.

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.

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.

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.

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.

Preliminary study on X-ray fluorescence computed tomography imaging of gold nanoparticles: Acceleration of data acquisition by multiple pinholes scheme

Gold nanoparticles (GNPs) have recently attracted attention in nanomedicine as novel contrast agents for cancer imaging. A decisive tomographic imaging technique has not yet been established to depict the 3-D distribution of GNPs in an object. An imaging technique known as pinhole-based X-ray fluorescence computed tomography (XFCT) is a promising method that can be used to reconstruct the distribution of GNPs from the X-ray fluorescence emitted by GNPs. We address the acceleration of data acquisition in pinhole-based XFCT for preclinical use using a multiple pinhole scheme. In this scheme, multiple projections are simultaneously acquired through a multi-pinhole collimator with a 2-D detector and full-field volumetric beam to enhance the signal-to-noise ratio of the projections; this enables fast data acquisition. To demonstrate the efficacy of this method, we performed an imaging experiment using a physical phantom with an actual multi-pinhole XFCT system that was constructed using the beamline AR-NE7A at KEK. The preliminary study showed that the multi-pinhole XFCT achieved a data acquisition time of 20 min at a theoretical detection limit of approximately 0.1 Au mg/ml and at a spatial resolution of 0.4 mm.

Full-field fan-beam x-ray fluorescence computed tomography system design with linear-array detectors and pinhole collimation: a rapid Monte Carlo study

We present the design concept and initial simulations for a polychromatic full-field fan-beam x-ray fluorescence computed tomography (XFCT) device with pinhole collimators and linear-array photon counting detectors. The phantom is irradiated by a fan-beam polychromatic x-ray source filtered by copper. Fluorescent photons are stimulated and then collected by two linear-array photon counting detectors with pinhole collimators. The Compton scatter correction and the attenuation correction are applied in the data processing, and the maximum-likelihood expectation maximization algorithm is applied for the image reconstruction of XFCT. The physical modeling of the XFCT imaging system was described, and a set of rapid Monte Carlo simulations was carried out to examine the feasibility and sensitivity of the XFCT system. Different concentrations of gadolinium (Gd) and gold (Au) solutions were used as contrast agents in simulations. Results show that 0.04% of Gd and 0.065% of Au can be well reconstructed with the full scan time set at 6 min. Compared with using the XFCT system with a pencil-beam source or a single-pixel detector, using a full-field fan-beam XFCT device with linear-array detectors results in significant scanning time reduction and may satisfy requirements of rapid imaging, such as in vivo imaging experiments.

Monte Carlo Simulation for Polychromatic X-Ray Fluorescence Computed Tomography with Sheet-Beam Geometry.

X-ray fluorescence computed tomography (XFCT) based on sheet beam can save a huge amount of time to obtain a whole set of projections using synchrotron. However, it is clearly unpractical for most biomedical research laboratories. In this paper, polychromatic X-ray fluorescence computed tomography with sheet-beam geometry is tested by Monte Carlo simulation. First, two phantoms (A and B) filled with PMMA are used to simulate imaging process through GEANT 4. Phantom A contains several GNP-loaded regions with the same size (10 mm) in height and diameter but different Au weight concentration ranging from 0.3% to 1.8%. Phantom B contains twelve GNP-loaded regions with the same Au weight concentration (1.6%) but different diameter ranging from 1 mm to 9 mm. Second, discretized presentation of imaging model is established to reconstruct more accurate XFCT images. Third, XFCT images of phantoms A and B are reconstructed by filter back-projection (FBP) and maximum likelihood expectation maximization (MLEM) with and without correction, respectively. Contrast-to-noise ratio (CNR) is calculated to evaluate all the reconstructed images. Our results show that it is feasible for sheet-beam XFCT system based on polychromatic X-ray source and the discretized imaging model can be used to reconstruct more accurate images.

TH-AB-209-01: Making Benchtop X-Ray Fluorescence Computed Tomography (XFCT) Practical for in Vivo Imaging by Integration of a Dedicated High-Performance X-Ray Source in Conjunction with Micro-CT Functionality

Purpose: To make benchtop x-ray fluorescence computed tomography (XFCT) practical for routine preclinical imaging tasks with gold nanoparticles (GNPs) by deploying, integrating, and characterizing a dedicated high-performance x-ray source and addition of simultaneous micro-CT functionality. Methods: Considerable research effort is currently under way to develop a polychromatic benchtop cone-beam XFCT system capable of imaging GNPs by stimulation and detection of gold K-shell x-ray fluorescence (XRF) photons. Recently, an ad hoc high-power x-ray source was incorporated and used to image the biodistribution of GNPs within a mouse, postmortem. In the current work, a dedicated x-ray source system featuring a liquid-cooled tungsten-target x-ray tube (max 160 kVp, ∼3 kW power) was deployed. The source was operated at 125 kVp, 24 mA. The tube's compact dimensions allowed greater flexibility for optimizing both the irradiation and detection geometries. Incident x-rays were shaped by a conical collimator and filtered by 2 mm of tin. A compact “OEM” cadmium-telluride x-ray detector was implemented for detecting XRF/scatter spectra. Additionally, a flat panel detector was installed to allow simultaneous transmission CT imaging. The performance of the system was characterized by determining the detection limit (10-second acquisition time) for inserts filled with water/GNPs at various concentrations (0 and 0.010–1.0 wt%) and embedded in a small-animal-sized phantom. The phantom was loaded with 0.5, 0.3, and 0.1 wt% inserts and imaged using XFCT and simultaneous micro-CT. Results: An unprecedented detection limit of 0.030 wt% was experimentally demonstrated, with a 33% reduction in acquisition time. The reconstructed XFCT image accurately localized the imaging inserts. Micro-CT imaging did not provide enough contrast to distinguish imaging inserts from the phantom under the current conditions. Conclusion: The system is immediately capable of in vivo preclinical XFCT imaging with GNPs. Micro-CT imaging will require optimization of irradiation parameters to improve contrast. Supported by NIH/NCI grant R01CA155446; This investigation was supported by NIH/NCI grant R01CA155446

Element Mapping in Organic Samples Utilizing a Benchtop X-Ray Fluorescence Emission Tomography (XFET) System.

X-ray fluorescence computed tomography (XFCT) is an emerging imaging modality that maps the three-dimensional distribution of elements, generally metals, in ex vivo specimens and potentially in living animals and humans. Building on our previous synchrotron-based work, we experimentally explored the use of a benchtop X-ray fluorescence computed tomography system for mapping trace-metal ions in biological samples. This system utilizes a scanning pencil-beam to stimulate the object and then relies on a detection system, with single or multiple slit apertures placed in front of position-sensitive X-ray detectors, to collect the fluorescence X-rays and to form 3-D elemental map without the need for tomographic imaging reconstruction. The technique was used to generate images of the elemental distributions of a triple-tube phantom and an osmium-stained zebrafish.

TH-AB-204-10: Drastic Performance Improvement of a Polychromatic Cone- Beam X-Ray Fluorescence Computed Tomography (XFCT) System Using a Kilowatt-Range X-Ray Source

Purpose: To demonstrate drastic performance improvement of a polychromatic cone-beam x-ray fluorescence computed tomography (XFCT) system using a kilowatt-range x-ray source. Methods: An experimental polychromatic cone-beam XFCT system capable of imaging gold nanoparticles (GNPs) within small-animal-sized objects by stimulating K-shell XRF from gold and detection using a cadmium-telluride detector has been under development. Originally configured with a low-power (∼50 W) x-ray source (105 kVp, 0.45 mA, 0.9-mm tin filter), the system has now been retrofitted with a high-power (∼3 kW) source, operated at 125 kVp, 25 mA. The higher flux allowed the use of a 2-mm tin filter to harden the incident x-ray spectrum, thereby optimizing XRF production. The material detection limit was determined at these settings using GNP/water-containing calibration phantoms (0, 0.1, 0.5, 1, 2 wt. % of GNPs). Subsequently, a 3-cm-diameter PMMA phantom with 0.2, 0.5, and 1 wt. % GNP/water inserts was imaged. The image reconstruction algorithm was modified with Compton-scatter-based background fitting for accurate XRF signal extraction and empirical attenuation correction. Results: Under the optimized conditions, the detection limit was remarkably lower (factor of 2.5), compared to the original configuration, allowing imaging of GNP concentrations as low as 0.2 wt. %. The reconstructed image demonstrated accurate localization of all inserts. Scan time was drastically decreased (factor of 4), enabling imaging of the phantom in 1.5 hours with just one detector translated 11 times. By reverting to the 0.9-mm filter, as used previously, scan time could be lowered to 30 minutes, at the expense of sensitivity. Implementation of additional/array detectors for parallel data acquisition will lower scan time further. Conclusion: By adopting a high-power source for the XFCT system, dramatic improvements were made, while meeting realistic constraints. This work shows the practicality of performing XFCT for routine preclinical ex-/in-vivo imaging using GNPs.

Improving x‐ray fluorescence signal for benchtop polychromatic cone‐beam x‐ray fluorescence computed tomography by incident x‐ray spectrum optimization: A Monte Carlo study

To develop an accurate and comprehensive Monte Carlo (MC) model of an experimental benchtop polychromatic cone-beam x-ray fluorescence computed tomography (XFCT) setup and apply this MC model to optimize incident x-ray spectrum for improving production/detection of x-ray fluorescence photons from gold nanoparticles (GNPs). A detailed MC model, based on an experimental XFCT system, was created using the Monte Carlo N-Particle (MCNP) transport code. The model was validated by comparing MC results including x-ray fluorescence (XRF) and scatter photon spectra with measured data obtained under identical conditions using 105 kVp cone-beam x-rays filtered by either 1 mm of lead (Pb) or 0.9 mm of tin (Sn). After validation, the model was used to investigate the effects of additional filtration of the incident beam with Pb and Sn. Supplementary incident x-ray spectra, representing heavier filtration (Pb: 2 and 3 mm; Sn: 1, 2, and 3 mm) were computationally generated and used with the model to obtain XRF/scatter spectra. Quasimonochromatic incident x-ray spectra (81, 85, 90, 95, and 100 keV with 10 keV full width at half maximum) were also investigated to determine the ideal energy for distinguishing gold XRF signal from the scatter background. Fluorescence signal-to-dose ratio (FSDR) and fluorescence-normalized scan time (FNST) were used as metrics to assess results. Calculated XRF/scatter spectra for 1-mm Pb and 0.9-mm Sn filters matched (r ≥ 0.996) experimental measurements. Calculated spectra representing additional filtration for both filter materials showed that the spectral hardening improved the FSDR at the expense of requiring a much longer FNST. In general, using Sn instead of Pb, at a given filter thickness, allowed an increase of up to 20% in FSDR, more prominent gold XRF peaks, and up to an order of magnitude decrease in FNST. Simulations using quasimonochromatic spectra suggested that increasing source x-ray energy, in the investigated range of 81-100 keV, increased the FSDR up to a factor of 20, compared to 1 mm Pb, and further facilitated separation of gold XRF peaks from the scatter background. A detailed MC model of an experimental benchtop XFCT system has been developed and validated. In exemplary calculations to illustrate the usefulness of this model, it was shown that potential use of quasimonochromatic spectra or judicious choice of filter material/thickness to tailor the spectrum of a polychromatic x-ray source can significantly improve the performance of benchtop XFCT, while considering trade-offs between FSDR and FNST. As demonstrated, the current MC model is a reliable and powerful computational tool that can greatly expedite the further development of a benchtop XFCT system for routine preclinical molecular imaging with GNPs and other metal probes.

TH-A-141-06: Optimization of Incident X-Ray Source Spectrum Through Filtration for a Benchtop X-Ray Fluorescence Computed Tomography (XFCT) System

Purpose: To optimize acquisition of fluorescence photon signal from gold nanoparticles (GNPs) and reduce the effect of Compton scatter in benchtop x-ray fluorescence computed tomography (XFCT). Methods: In polychromatic XFCT, fluorescence signal is obscured by Compton scatter of source photons, and thus the choice of source spectrum is crucial. An experimental XFCT system for irradiation of a GNP-containing small animal-sized phantom was accurately modeled using the MCNP5 code for Monte Carlo simulations. The model used either a lead (Pb) or tin (Sn) filter to harden the 105 kVp source spectrum, and was validated with fluorescence/scatter profile measurements. Spectra (Pb: 1, 2, and 3 mm; Sn: 0.9, 1, 2, and 3 mm) were input into the model and their effect on fluorescence production/detection was investigated. Simulations were also run with hypothetical quasi-monochromatic x-ray sources (81, 85, 90, 95, and 100 keV) to determine the ideal energy for discriminating gold K-shell fluorescence peaks from Compton scatter background. Fluorescence signal-to-dose ratio (FSDR) and relative scan time (RST) were used to assess the degree of optimization during simulations. Results: For both materials, increasing filtration hardened source spectra and significantly decreased fluence available for producing fluorescence photons, while increasing FSDR. The RST increased at a much higher rate for a given increase in FSDR. Compared to Pb, Sn produced generally higher overall fluence, more prominent fluorescence peaks, favorably harder scatter profiles, increased FSDR, and shorter RST. Simulations using hypothetical quasi-monochromatic spectra showed that increasing source energy, between 81 and 100 keV, increased signal-to-background ratio and FSDR. Conclusion: Judicious choice of filter material/thickness to tailor polychromatic x-ray spectrum, considering trade-offs between FSDR and RST, can dramatically improve the performance of benchtop XFCT. This work will foster the further development of a benchtop XFCT system for routine pre-clinical imaging applications with GNPs.Supported by NIH/NCI grant R01CA155446; NIH/NCI grant R01CA155446

WE‐G‐211‐04: Experimental Demonstration of Cone‐Beam Polychromatic X‐Ray Fluorescence Computed Tomography (XFCT) Imaging of Gold Nanoparticle‐Loaded Regions within Small Animal‐Sized Phantoms

Purpose: To demonstrate the feasibility of determining the location and gold concentration of gold nanoparticle (GNP)‐loaded regions within polymethyl methacrylate (PMMA) phantoms using cone‐beam polychromatic x‐ray fluorescence computed tomography (XFCT) technique. Methods: Tubes containing water and GNPs at 2%, 1%, and 0.5% by weight were inserted into two 5 cm‐long cylindrical PMMA phantoms with 3 cm and 5 cm in diameter, respectively. The phantoms were irradiated by a cone‐beam of polychromatic 110 kVp x‐rays filtered by 1.0 mm of lead. Energy‐sensitive cadmium telluride detectors behind a 2.5 mm diameter lead pinhole collimator collected the spectrum of emitted gold K‐shell fluorescence and Compton scattered photons at an angle of 90° relative to the beam central axis as the phantom was rotated to a series of 60 projection angles in 6° steps. Sinograms of gold fluorescence photon signals were constructed by extracting the gold fluorescence peak height from the Compton background, and the image of GNP location and concentration was reconstructed using a maximum likelihood iterative reconstruction algorithm. Results: Using the measured sinograms, images of GNP location were successfully reconstructed for both the 3 cm and 5 cm phantoms. Additionally, the signal intensity was linearly related to gold concentration. The x‐ray dose delivered during the XFCT scanning was measured using the TG‐61 protocol, and it was determined that, using an array detector, it would be possible to acquire these images with roughly 30 cGy of x‐ray dose delivered. Conclusions: This study demonstrates, for the first time to our knowledge, the feasibility of imaging GNP location and concentration within small animal‐sized objects using an ordinary cone‐beam polychromatic x‐ray source under realistic constraints on dose and scan time. This investigation strongly suggests a bench‐top XFCT system will ultimately become a viable option for in‐vivo molecular imaging with conjugated or unconjugated GNPs.