Contrast agents for x-ray luminescence computed tomography.

Imaging probes are an important consideration for any type of contrast agent-based imaging method. X-ray luminescence imaging (XLI) and x-ray luminescence computed tomography (XLCT) are both contrast agent-based imaging methods that employ x-ray excitable scintillating imaging probes that emit light to be measured for optical imaging. In this work, we compared the performance of several select imaging probes, both commercial and self-synthesized, for application in XLI/XLCT imaging. Commercially available cadmium telluride quantum dots (CdTe QDs) and europium-doped gadolinium oxysulfide (GOS:Eu) microphosphor as well as synthesized NaGdF4 nanophosphors doped with either europium or terbium were compared through their x-ray luminescence emission spectra, luminescence intensity, and also by performing XLCT scans using phantoms embedded with each of the imaging probes. Each imaging probe displayed a unique emission spectrum that was ideal for deep-tissue optical imaging. In terms of luminescence intensity, due to the large particle size, GOS:Eu had the brightest emission, followed by NaGdF4:Tb, NaGdF4:Eu, and finally the CdTe QDs. Lastly, XLCT scans showed that each imaging probe could be reconstructed with good shape and location accuracy.

Background luminescence in x-ray luminescence computed tomography (XLCT) imaging.

X-ray luminescence computed tomography (XLCT) is an emerging hybrid imaging modality. It has been recently reported that materials such as water, tissue, or even air can generate optical photons upon x-ray irradiation, which can increase the noises in measurements of XLCT. In this study, we have investigated the x-ray luminescence from water, air, as well as tissue mimicking phantoms, including one embedded with a 0.01 mg/mL GOS:Eu3+ microphosphor target. We have measured the optical emission spectrum from each sample, including samples of meat and fat, using a spectrograph. Our results indicate that there are plenty of optical photons emitted by x-ray irradiation, and a small nanophosphor concentration, as low as 5.28 µM in a deep background, can provide enough contrast for XLCT imaging.

Sensitivity study of x-ray luminescence computed tomography.

X-ray luminescence computed tomography (XLCT) is a hybrid molecular imaging modality that combines the merits of both x-ray imaging (high resolution) and optical imaging (high sensitivity). In this study, we have evaluated the sensitivity of XLCT with phantom experiments by scanning targets of different phosphor concentrations at different depths. We found that XLCT is capable of imaging targets of very low concentrations (27.6 µM or 0.01 mg/mL) at significant depths, such as 21 mm. Our results demonstrate that there is little variation in the reconstructed target size with a maximum target size error of 4.35% for different imaging depths for XLCT. We have, we believe for the first time, compared the sensitivity of XLCT with that of traditional computed tomography (CT) for phosphor targets. We found that XLCT's use of x-ray-induced photons provides much higher measurement sensitivity and contrast compared to CT, which provides image contrast solely based on x-ray attenuation.

Superfast Scan of Focused X-Ray Luminescence Computed Tomography Imaging.

X-ray luminescence computed tomography (XLCT) is a hybrid molecular imaging modality having the high spatial resolution of x-ray imaging and high measurement sensitivity of optical imaging. Narrow x-ray beam based XLCT imaging has shown promise for high spatial resolution imaging of luminescent targets in deep tissues, but the slow acquisition speed limits its applications. In this work, we have introduced a superfast XLCT scan scheme based on the photon counter detector and a fly-scanning method. The new scan scheme is compared with three other scan methods. We have also designed and built a single-pixel x-ray detector to detect object boundaries automatically. With the detector, we can perform the parallel beam CT imaging with the XLCT imaging simultaneously. We have built the prototype XLCT imaging system to verify the proposed scan scheme. A phantom embedded with a set of four side-by-side cylindrical targets was scanned. With the proposed superfast scan scheme, we have achieved 43 seconds per transverse scan, which is 28.6 times faster than before with slightly better XLCT image quality. The superfast scan allows us to perform 3D pencil beam XLCT imaging in the future.

Super-Fast Three-Dimensional Focused X-ray Luminescence Computed Tomography with a Gated Photon Counter.

X-ray luminescence computed tomography (XLCT) is a hybrid molecular imaging modality combining the merits of both x-ray imaging (high spatial resolution) and optical imaging (high sensitivity to tracer nanophosphors). Narrow x-ray beam based XLCT imaging has shown promise for high spatial resolution imaging, but the slow acquisition speed limits its applications for in vivo imaging. We introduced a continuous scanning scheme to replace the selective excitation scheme to improve imaging speed in a previous study. Under the continuous scanning scheme, the main factor that limits the scanning speed is the data acquisition time at each interval position. In this work, we have used a gated photon counter (SR400, Stanford Research Systems) to replace the high-speed oscilloscope (MDO3104, Tektronix) to acquire measurement data. The gated photon counter only counts the photon peaks in each measurement interval, while the oscilloscope records the entire waveform including both background noise data and photon peak data. The photon counter records much less data without losing any relevant information, which makes it ideal for super-fast three-dimensional (3D) imaging. We have built prototype XLCT imaging systems of both types and performed both single target and multiple target phantom experiments in 3D. The results have verified the feasibility of our proposed photon counter based system and good 3D imaging capabilities of XLCT within a reasonable time, yielding a 14 times faster scanning time compared with the oscilloscope based XLCT system. Now, the total scan time is reduced to 27 seconds per transverse section.

Focused x-ray luminescence imaging system for small animals based on a rotary gantry.

SIGNIFICANCE: The ability to detect and localize specific molecules through tissue is important for elucidating the molecular basis of disease and treatment. Unfortunately, most current molecular imaging tools in tissue either lack high spatial resolution (e.g., diffuse optical fluorescence tomography or positron emission tomography) or lack molecular sensitivity (e.g., micro-computed tomography, µCT). X-ray luminescence imaging emerged about 10 years ago to address this issue by combining the molecular sensitivity of optical probes with the high spatial resolution of x-ray imaging through tissue. In particular, x-ray luminescence computed tomography (XLCT) has been demonstrated as a powerful technique for the high-resolution imaging of deeply embedded contrast agents in three dimensions (3D) for small-animal imaging. AIM: To facilitate the translation of XLCT for small-animal imaging, we have designed and built a small-animal dedicated focused x-ray luminescence tomography (FXLT) scanner with a µCT scanner, synthesized bright and biocompatible nanophosphors as contrast agents, and have developed a deep-learning-based reconstruction algorithm. APPROACH: The proposed FXLT imaging system was designed using computer-aided design software and built according to specifications. NaGdF4 nanophosphors doped with europium or terbium were synthesized with a silica shell for increased biocompatibility and functionalized with biotin. A deep-learning-based XLCT image reconstruction was also developed based on the residual neural network as a data synthesis method of projection views from few-view data to enhance the reconstructed image quality. RESULTS: We have built the FXLT scanner for small-animal imaging based on a rotational gantry. With all major imaging components mounted, the motor controlling the gantry can be used to rotate the system with a high accuracy. The synthesized nanophosphors displayed distinct x-ray luminescence emission, which enables multi-color imaging, and has successfully been bound to streptavidin-coated substrates. Lastly, numerical simulations using the proposed deep-learning-based reconstruction algorithm has demonstrated a clear enhancement in the reconstructed image quality. CONCLUSIONS: The designed FXLT scanner, synthesized nanophosphors, and deep-learning-based reconstruction algorithm show great potential for the high-resolution molecular imaging of small animals.

High-resolution x-ray luminescence computed tomography.

High-resolution imaging modalities play a critical role for advancing biomedical sciences. Recently, x-ray luminescence computed tomography (XLCT) imaging was introduced as a hybrid molecular imaging modality that combines the high-spatial resolution of x-ray imaging and molecular sensitivity of optical imaging. The narrow x-ray beam based XLCT imaging has been demonstrated to achieve high spatial resolution, even at depth, with great molecular sensitivity. Using a focused x-ray beam as the excitation source, orders of magnitude of increased sensitivity has been verified compared with previous methods with a collimated x-ray beam. In this work, we demonstrate the high-spatial resolution capabilities of our focused x-ray beam based XLCT imaging system by scanning two sets of targets, differing in the target size, embedded inside of two tissue-mimicking cylindrical phantoms. Gd2O2S:Eu3+ targets of 200 µm and 150 µm diameters were created and embedded with the same edge-to-edge distances as their diameters respectively. We scanned and reconstructed a single transverse section and successfully demonstrated that a focused x-ray beam with an average dual-cone size of 125 µm could separate the targets in both phantoms with good shape and location accuracy. We have also improved the current XLCT imaging system to make it feasible for fast three-dimensional XLCT scanning.

X-ray luminescence imaging for small animals.

X-ray luminescence imaging emerged for about a decade and combines both the high spatial resolution of x-ray imaging with the high measurement sensitivity of optical imaging, which could result in a great molecular imaging tool for small animals. So far, there are two types of x-ray luminescence computed tomography (XLCT) imaging. One uses a pencil beam x-ray for high spatial resolution at a cost of longer measurement time. The other uses cone beam x-ray to cover the whole mouse to obtain XLCT images at a very short time but with a compromised spatial resolution. Here we review these two methods in this paper and highlight the synthesized nanophosphors by different research groups. We are building a focused x-ray luminescence tomography (FXLT) imaging system, developing a machine-learning based FXLT reconstruction algorithm, and synthesizing nanophosphors with different emission wavelengths. In this paper, we will report our current progress from these three aspects. Briefly, we mount all main components, including the focused x-ray tube, the fiber detector, and the x-ray tube and x-ray detector for a microCT system, on a rotary which is a heavy-duty ring track. A microCT scan will be performed before FXLT scan. For a FXLT scan, we will have four PMTs to measure four fiber detectors at two different wavelengths simultaneously for each linear scan position. We expect the spatial resolution of the FXLT imaging will be around 100 micrometers and a limit of detection of approximately 2 µg/mL (for Gd2O2S:Eu).

Focused x-ray luminescence computed tomography: experimental studies.

X-ray luminescence computed tomography (XLCT) is an emerging hybrid molecular imaging modality and has shown great promises in overcoming the strong optical scattering in deep tissues. Though the narrow x-ray beam based XLCT imaging has been demonstrated to obtain high spatial resolution at depth, it suffers from a relatively long measurement time, hindering its practical applications. Recently, we have designed a focused x-ray beam based XLCT imaging system and have successfully performed imaging in about 7.5 seconds per section for a mouse sized object. However, its high spatial resolution capacity has not been fully implemented yet. In this paper, with a superfine focused x-ray beam we design a focused-x-ray luminescence tomography (FXLT) system for spatial resolution up to 94 µm. First, we have described our design in details. Then, we estimate the performance of the designed FXLT imaging system. Lastly, we have found that the spatial resolution of FXLT can be further improved by reducing the scan step size, which has been demonstrated by numerical simulations.

Method for improving the spatial resolution of narrow x-ray beam-based x-ray luminescence computed tomography imaging.

X-ray luminescence computed tomography (XLCT) is an emerging hybrid imaging modality which has the potential for achieving both high sensitivity and spatial resolution simultaneously. For the narrow x-ray beam-based XLCT imaging, based on previous work, a spatial resolution of about double the x-ray beam size can be achieved using a translate/rotate scanning scheme, taking step sizes equal to the x-ray beam width. To break the current spatial resolution limit, we propose a scanning strategy achieved by reducing the scanning step size to be smaller than the x-ray beam size. We performed four sets of numerical simulations and a phantom experiment using cylindrical phantoms and have demonstrated that our proposed scanning method can greatly improve the XLCT-reconstructed image quality compared with the traditional scanning approach. In our simulations, by using a fixed x-ray beam size of 0.8 mm, we were able to successfully reconstruct six embedded targets as small as 0.5 mm in diameter and with the same edge-to-edge distances by using a scanning step as small as 0.2 mm which is a 1.6 times improvement in the spatial resolution compared with the traditional approach. Lastly, the phantom experiment further demonstrated the efficacy of our proposed method in improving the XLCT image quality, with all image quality metrics improving as the step size decreased.

X-ray luminescence computed tomography using a focused x-ray beam.

Due to the low x-ray photon utilization efficiency and low measurement sensitivity of the electron multiplying charge coupled device camera setup, the collimator-based narrow beam x-ray luminescence computed tomography (XLCT) usually requires a long measurement time. We, for the first time, report a focused x-ray beam-based XLCT imaging system with measurements by a single optical fiber bundle and a photomultiplier tube (PMT). An x-ray tube with a polycapillary lens was used to generate a focused x-ray beam whose x-ray photon density is 1200 times larger than a collimated x-ray beam. An optical fiber bundle was employed to collect and deliver the emitted photons on the phantom surface to the PMT. The total measurement time was reduced to 12.5 min. For numerical simulations of both single and six fiber bundle cases, we were able to reconstruct six targets successfully. For the phantom experiment, two targets with an edge-to-edge distance of 0.4 mm and a center-to-center distance of 0.8 mm were successfully reconstructed by the measurement setup with a single fiber bundle and a PMT.