X-ray luminescence and X-ray fluorescence computed tomography (CT) are two emerging technologies in X-ray imaging that provide functional and molecular imaging capability. Both emission-type tomographic imaging modalities use external X-rays to stimulate secondary emissions, either light or secondary X-rays, which are then acquired for tomographic reconstruction. These modalities surpass the limits of sensitivity in current X-ray imaging and have the potential of enabling X-ray imaging to extract molecular imaging information. These new modalities also promise to break through the spatial resolution limits of other in vivo molecular imaging modalities. This paper reviews the development of X-ray luminescence and X-ray fluorescence CT and their relative merits. The discussion includes current problems and future research directions and the role of these modalities in future molecular imaging applications.

X-Ray Luminescence and X-Ray Fluorescence Computed Tomography: New Molecular Imaging Modalities

X-ray and optical technologies are the two central pillars for human imaging and therapy. The strengths of x-rays are deep tissue penetration, effective cytotoxicity, and the ability to image with robust projection and computed-tomography methods. The major limitations of x-ray use are the lack of molecular specificity and the carcinogenic risk. In comparison, optical interactions with tissue are strongly scatter dominated, leading to limited tissue penetration, making imaging and therapy largely restricted to superficial or endoscopically directed tissues. However, optical photon energies are comparable with molecular energy levels, thereby providing the strength of intrinsic molecular specificity. Additionally, optical technologies are highly advanced and diversified, being ubiquitously used throughout medicine as the single largest technology sector. Both have dominant spatial localization value, achieved with optical surface scanning or x-ray internal visualization, where one often is used with the other. Therapeutic delivery can also be enhanced by their synergy, where radio-optical and optical-radio interactions can inform about dose or amplify the clinical therapeutic value. An emerging trend is the integration of nanoparticles to serve as molecular intermediates or energy transducers for imaging and therapy, requiring careful design for the interaction either by scintillation or Cherenkov light, and the nanoscale design is impacted by the choices of optical interaction mechanism. The enhancement of optical molecular sensing or sensitization of tissue using x-rays as the energy source is an important emerging field combining x-ray tissue penetration in radiation oncology with the molecular specificity and packaging of optical probes or molecular localization. The ways in which x-rays can enable optical procedures, or optics can enable x-ray procedures, provide a range of new opportunities in both diagnostic and therapeutic medicine. Taken together, these two technologies form the basis for the vast majority of diagnostics and therapeutics in use in clinical medicine.

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Optical and x-ray technology synergies enabling diagnostic and therapeutic applications in medicine.

X-ray luminescence computed tomography (XLCT), which aims to achieve molecular and functional imaging by X-rays, has recently been proposed as a new imaging modality. Combining the principles of X-ray excitation of luminescence-based probes and optical signal detection, XLCT naturally fuses functional and anatomical images and provides complementary information for a wide range of applications in biomedical research. In order to improve the data acquisition efficiency of previously developed narrow-beam XLCT, a cone beam XLCT (CB-XLCT) mode is adopted here to take advantage of the useful geometric features of cone beam excitation. Practically, a major hurdle in using cone beam X-ray for XLCT is that the inverse problem here is seriously ill-conditioned, hindering us to achieve good image quality. In this paper, we propose a novel Bayesian method to tackle the bottleneck in CB-XLCT reconstruction. The method utilizes a local regularization strategy based on Gaussian Markov random field to mitigate the ill-conditioness of CB-XLCT. An alternating optimization scheme is then used to automatically calculate all the unknown hyperparameters while an iterative coordinate descent algorithm is adopted to reconstruct the image with a voxel-based closed-form solution. Results of numerical simulations and mouse experiments show that the self-adaptive Bayesian method significantly improves the CB-XLCT image quality as compared with conventional methods.

Cone Beam X-ray Luminescence Computed Tomography Based on Bayesian Method

Lanthanide (Ln) nanocrystals using soft X-ray as an excitation source have received significant research interest due to the advantages of unlimited penetration depth of X-ray light. In this study, we demonstrated an efficient scintillator based on NaYF4:Gd nanorods (denoted as NRs) doped with different contents of terbium (Tb) ions for optical bioimaging under X-ray irradiation. The experimental results showed that the emission intensity was correlated to the doping contents of Tb3+, and the largest emission intensity was achieved by doping 15% Tb under excitation by soft X-ray light. In addition, the emission intensity of the as-prepared NRs can be significantly improved by increasing the excitation power and irradiation times of the X-ray. Owing to the efficient X-ray-induced emission, these NRs were successfully used as probes for X-ray-induced optical bioimaging with high sensitivity. In addition, the dual-modal X-ray imaging and X-ray induced optical bioimaging were performed on a mouse, which indicated that the NRs were promising dual-modal bioprobes. Therefore, the X-ray activation nature of the designed NRs makes them promising probes for biomedicine and X-ray-induced photodynamic therapy (PDT) applications owing to the unlimited penetration depth of X-ray excitation source and absence of autofluorescence.

Soft X-ray activated NaYF4:Gd/Tb scintillating nanorods for in vivo dual-modal X-ray/X-ray-induced optical bioimaging

X-ray luminescence computed tomography (XLCT) is an emerging hybrid imaging modality, which is able to improve the spatial resolution of optical imaging to hundreds of micrometers for deep targets by using superfine X-ray pencil beams. However, due to the low X-ray photon utilization efficiency in a single pinhole collimator based XLCT, it takes a long time to acquire measurement data. Herein, we propose a multiple pinhole collimator based XLCT, in which multiple X-ray beams are generated to scan a sample at multiple positions simultaneously. Compared with the single pinhole based XLCT, the multiple X-ray beam scanning method requires much less measurement time. Numerical simulations and phantom experiments have been performed to demonstrate the feasibility of the multiple X-ray beam scanning method. In one numerical simulation, we used four X-ray beams to scan a cylindrical object with 6 deeply embedded targets. With measurements from 6 angular projections, all 6 targets have been reconstructed successfully. In the phantom experiment, we generated two X-ray pencil beams with a collimator manufactured in-house. Two capillary targets with 0.6 mm edge-to-edge distance embedded in a cylindrical phantom have been reconstructed successfully. With the two beam scanning, we reduced the data acquisition time by 50%. From the reconstructed XLCT images, we found that the Dice similarity of targets is 85.11% and the distance error between two targets is less than 3%. We have measured the radiation dose during XLCT scan and found that the radiation dose, 1.475 mSv, is in the range of a typical CT scan. We have measured the changes of the collimated X-ray beam size and intensity at different distances from the collimator. We have also studied the effects of beam size and intensity in the reconstruction of XLCT.

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Multiple pinhole collimator based X-ray luminescence computed tomography.

X-ray luminescence computed tomography (XLCT) is a new molecular imaging modality. In this Letter, we first in vivo tomographically image the near-IR-emitting nanophosphor (Gd2O3:Eu3+) in nude mice (N=2). In practically, incorporating the compressive sensing technique, the XLCT reconstruction is performed only using single-view data. The experimental results indicate that the single-view reconstruction is feasible to image XLCT in vivo. The location error is less than 1.5 mm. Further, the imaging time can be greatly reduced compared with previous XLCT systems. Therefore, it is suited for imaging fast distribution of x-ray-excitable nanophosphors within a biological object.

In vivo x-ray luminescence tomographic imaging with single-view data

X-ray luminescence computed tomography (XLCT) opens new possibilities to perform molecular imaging with X-ray. However, challenges remain in dynamic XLCT imaging, where short scan time, good spatial resolution, and whole-body field of view should be considered simultaneously. In this paper, by the use of a single-view XLCT reconstruction method based on a compressive sensing (CS) technique, incorporating a cone beam XLCT imaging system, we implement fast 3-D XLCT imaging. To evaluate the performance of the method, two types of phantom experiments were performed based on a cone beam XLCT imaging system. In Case 1, one tube filled with the X-ray-excitable nanophosphor (Gd $_{2}$ O $_{3}$ :Eu $^{3+}$ ) was immerged in different positions in the phantom to evaluate the effect of the source position on single-view XLCT reconstruction accuracy. In Case 2, two tubes filled with Gd $_{2}$ O $_{3}$ :Eu $^{3+}$ were immerged in different heights in the phantom to evaluate the whole-body imaging performance of single-view XLCT reconstruction. The experimental results indicated that the tubes used in previous phantom experiments can be resolved from single-view XCLT reconstruction images. The location error is less than 1.2 mm. In addition, since only one view data are needed to implement 3-D XLCT imaging, the acquisition time can be greatly reduced (∼1 frame/s) compared with previous XLCT systems. Hence, the technique is suited for imaging the fast distribution of the X-ray-excitable nanophosphors within a biological object.

Fast X-Ray Luminescence Computed Tomography Imaging

. Cone-beam x-ray luminescence computedtomography (CB-XLCT), as an emerging imaging tech-nique, plays an important role in in vivo small animal imag-ing studies. However, CB-XLCT suffers from low-spatialresolution due to the ill-posed nature of reconstruction. Weimprove the imaging performance of CB-XLCT by using amultiband excitation-resolved imaging scheme combinedwith principal component analysis. To evaluate the perfor-mance of the proposed method, the physical phantomexperiment is performed with a custom-made XLCT/XCTimaging system. The experimental results validate the fea-sibility of the method, where two adjacent nanophosphors(with an edge-to-edge distance of 2.4 mm) can be located. © 2015 Society of Photo-Optical Instrumentation Engineers (SPIE) [DOI: 10.1117/1.JBO.20.7.070501] Keywords: image reconstruction techniques; optical tomography;x-ray imaging; hybrid imaging.Paper 150274LR received Apr. 26, 2015; accepted for publicationJun. 9, 2015; published online Jul. 9, 2015.

Qimei Liao

Papers

In vivo x-ray luminescence tomographic imaging with single-view data

Fast X-Ray Luminescence Computed Tomography Imaging

Excitation-resolved cone-beam x-ray luminescence tomography.