X-ray luminescence computed tomography (XLCT) is an emerging hybrid molecular imaging modality with great promises in overcoming the strong optical scattering in deep tissues for good spatial resolution. Though the narrow x-ray beam 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 12.5 minutes per section imaging for a mouse sized object. Following this previous work, in this current study, we have performed XLCT imaging using our focused x-ray beam for both a tissue-mimicking phantom and for the first time, with a euthanized mouse embedded with a capillary tube target filled with 10.0 mg/mL of GOS:Eu3+ microphosphors and have shown that the data acquisition time could be reduced substantially to less than 10 milliseconds per linear scan step compared to the previous study which used 1 second per linear step. In addition, the targets were reconstructed with a high location accuracy and good shape. In the current setup, the total measurement time for a mouse sized object could be reduced to about 7.5 seconds per section imaging, a major improvement from previous studies.
Conical mirror is a preferred choice for fluorescence molecular tomography (FMT) because of its ability to collect fluorescent emission photons from the whole surface of the imaged object such as mice. Conical mirror, however, would lead to a fraction of photons to be reflected back to the mice surface, including excitation photons and emission photons, which result in inaccurate source positions and measurements errors in the FMT forward modeling and reconstruction. Based on Monte Carlo simulations, we have studied systematically the effects of multiple reflections of different conical mirror designs. We first generated a multiple reflected photon map for each design of the conical mirror, and then we applied Monte Carlo simulations to model photon propagation inside tissues. Finally, we evaluated the ratio of the multiple reflected photons to the total photons, and figured out the optimized size of the conical mirror. Our simulations demonstrated that a single conical mirror configuration could eliminate the multiple reflection issue while keep the imaging system setup simple when its small aperture radius is larger than 5 centimeters. We then fabricated a conical mirror with the optimized size according to the Monte Carlo simulation results, and performed phantom experiments with both the optimized conical mirror and the non-optimized one. Phantom experiment results show that noises in the reconstructed images are reduced with the optimized conical mirror, and the reconstruction accuracy is improved as well.
Photodynamic therapy (PDT) is a noninvasive phototherapy method that has been clinically approved for many years. During this type of therapy, the photosensitizing agent will be excited by optical photons to generate reactive oxygen species which can kill nearby cancer cells. However, due to the strong optical scattering and absorption of tissue, optical photons can only penetrate tissues in few millimeters which result in the limited applications of PDT to superficial lesions like skin cancers. In this study, to overcome the penetration limitations, we used high-energy photons to excite photosensitizers directly by assuming that high-energy photons generate low-energy optical photons in tissues to excite photosensitizers. Cesium- 137 irradiator has been used as the high-energy photon source. A fiber pigtailed diode laser was used to validate the photosensitizer’s efficacy. We used MPPa as the photosensitizer to treat A549 cancer cell line with different concentrations of drug (10μM/ ml, 5 μM/ml, 2.5 μM/ml, 1 μM/ml and 0 μM/ml). We have performed an irradiation experiment for different time durations of 30 min, 15 min, 7 min to 3 min, respectively, and we also compared different drug concentrations and different exposure durations. Our study not only proved the MPPa PDT method was effective, but also indicated that high-energy photons enhanced PDT could potentially overcome the penetration limitations thus making PDT feasible for deep tissue cancer.
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.
X-ray luminescence computed tomography (XLCT) is a hybrid molecular imaging modality that uses high energy x-ray photons to excite nanophosphors (e.g. Europium doped Gadolinium Oxysulfide – GOS: Eu3+) emitting optical photons to be measured by a sensitive detector for image reconstruction. XLCT has potentials to combine both the merits of x-ray imaging (high spatial resolution) and optical imaging (high sensitivity), which makes XLCT an attractive imaging modality to image nanophosphor targets deeply embedded in turbid media. In this study, we have evaluated the sensitivity of XLCT with phantom experiments by scanning targets of different phosphor concentrations at different depths. Cylindrical phantoms embedded with a cylindrical target with varying concentrations of GOS: Eu3+ (27.6 mM, 2.76 mM, 276 μM, and 27.6 μM) were scanned inside our lab made XLCT imaging system for varying scanning depths (6, 11, 16, and 21 mm). 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 also little variation in the reconstructed target size for different imaging depths for XLCT. We have 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.
Image reconstruction in diffuse optical tomography (DOT) is challenging because its inverse problem is nonlinear, ill-posed and ill-conditioned. Anatomical guidance from high spatial resolution imaging modalities can substantially improve the quality of reconstructed DOT images. In this paper, inspired by the kernel methods in machine learning, we propose the kernel method to introduce anatomical information into the DOT image reconstruction algorithm. In this kernel method, optical absorption coefficient at each finite element node is represented as a function of a set of features obtained from anatomical images such as computed tomography (CT). The kernel based image model is directly incorporated into the forward model of DOT, which exploits the sparseness of the image in the feature space. Compared with Laplacian approaches to include structural priors, the proposed method does not require the image segmentation of distinct regions. The proposed kernel method is validated with numerical simulations of 3D DOT reconstruction using synthetic CT data. We added 15% Gaussian noise onto both the numerical DOT measurements and the simulated CT image. We have also validated the proposed method by agar phantom experiment with anatomical guidance from a CT scan. We have studied the effects of voxel size and number of nearest neighborhood size in kernel method on the reconstructed DOT images. Our results indicate that the spatial resolution and the accuracy of the reconstructed DOT images have been improved substantially after applying the anatomical guidance with the proposed kernel method.
Super fine collimated x-ray beam based x-ray luminescence computed tomography (XLCT) has the potential to reconstruct the deeply embedded targets with a spatial resolution of hundreds of micrometers. However, due to the low x-ray photon utilization efficiency and low optical signal sensitivity of the electron multiplying charge coupled device (EMCCD) camera, XLCT usually requires a long measurement time. To overcome this limitation, we propose a fiber based, fast XLCT design, in which optical fiber bundles are applied to collect the emitted optical photons on the phantom surface. Highly sensitive photomultiplier tubes (PMT) with a cooling unit and pre-amplifier are used to measure the photons from the fiber bundles. The PMT outputs are collected by a high-speed data acquisition board. A linear scan is estimated to take about 130 seconds, thus for an XLCT scan with 6 projections, we require 13 minutes for each section, which makes it feasible to have a whole body scan of XLCT. To validate our design, numerical simulations and phantom experiments have been performed. In numerical simulation studies, we have investigated the effect of the number of optical fiber bundle on the XLCT reconstruction. We found that one optical fiber bundle is sufficient to reconstruct the deeply embedded targets if measurements from 6 projections are used. Phantom experiments with multiple targets have been performed to validate the proposed fast XLCT imaging.
We performed numerical simulations and phantom experiments with a conical mirror based fluorescence molecular tomography (FMT) imaging system to optimize its performance. With phantom experiments, we have compared three measurement modes in FMT: the whole surface measurement mode, the transmission mode, and the reflection mode. Our results indicated that the whole surface measurement mode performed the best. Then, we applied two different neutral density (ND) filters to improve the measurement's dynamic range. The benefits from ND filters are not as much as predicted. Finally, with numerical simulations, we have compared two laser excitation patterns: line and point. With the same excitation position number, we found that the line laser excitation had slightly better FMT reconstruction results than the point laser excitation. In the future, we will implement Monte Carlo ray tracing simulations to calculate multiple reflection photons, and create a look-up table accordingly for calibration.
Diffuse optical tomography (DOT) has attracted attentions in the last two decades due to its intrinsic sensitivity in imaging chromophores of tissues such as blood, water, and lipid. However, DOT has not been clinically accepted yet due to its low spatial resolution caused by strong optical scattering in tissues. Structural guidance provided by an anatomical imaging modality enhances the DOT imaging substantially. Here, we propose a computed tomography (CT) guided multispectral DOT imaging system for breast cancer detection. To validate its feasibility, we have built a prototype DOT imaging system which consists of a laser at wavelengths of 650 and an electron multiplying charge coupled device (EMCCD) camera. We have validated the CT guided DOT reconstruction algorithms with numerical simulations and phantom experiments, in which different imaging setup parameters, such as projection number of measurements, the width of measurement patch, have been investigated. Our results indicate that an EMCCD camera with air cooling is good enough for the transmission mode DOT imaging. We have also found that measurements at six projections are sufficient for DOT to reconstruct the optical targets with 4 times absorption contrast when the CT guidance is applied. Finally, we report our effort and progress on the integration of the multispectral DOT imaging system into a breast CT scanner.
X-ray luminescence computed tomography (XLCT) is a new hybrid imaging modality, which has the capability to improve optical spatial resolution to hundreds of micrometers for deep targets. In this paper, we report a multiple pinhole collimator based microscopic X-ray luminescence computed tomography (microXLCT) system for small animal imaging. Superfine collimated X-ray pencil beams are used to excite deeply embedded phosphor particles, allowing us to obtain sub-millimeter optical spatial resolution in deep tissues. Multiple collimated X-ray beams are generated by mounting an array of pinholes in the front of a powerful X-ray tube. With multiple X-ray beams scanning, the phosphor particles in the region of the multiple beams are excited simultaneously, which requires less scanning time compared with a single beam scanning. The emitted optical photons on the top surface of the phantom are measured with an electron multiplying charge-coupled device (EMCCD) camera. Meanwhile, an X-ray detector is used to determine the X-ray beam size and position, which are used as structural guidance in the microXLCT image reconstruction. To validate the performance of our proposed multiple pinhole based microXLCT imaging system, we have performed numerical simulations and a phantom experiment. In the numerical simulations, we simulated a cylindrical phantom with two and six embedded targets, respectively. In the simulations, we used four parallel X-ray beams with the beam diameter of 0.1 mm and the beam interval of 3.2 mm. We can reconstruct deeply embedded multiple targets with a target diameter of 0.2 mm using measurements in six projections, which indicated that four parallel X-ray beam scan could reduce scanning time without comprising the reconstructed image quality. In the phantom experiment, we generated two parallel X-ray beams with the beam diameter of 0.5 mm and the beam interval of 4.2 mm. We scanned a phantom of one target with the two parallel X-ray beams. The target was reconstructed successfully, which indicated that multiple collimated X-ray beam scan approach is feasible in small animal imaging.
Dynamic fluorescence molecular tomography (FMT) has the potential to quantify physiological or biochemical information, known as pharmacokinetic parameters, which are important for cancer detection, drug development and delivery etc. To image those parameters, there are indirect methods, which are easier to implement but tend to provide images with low signal-to-noise ratio, and direct methods, which model all the measurement noises together and are statistically more efficient. The direct reconstruction methods in dynamic FMT have attracted a lot of attention recently. However, the coupling of tomographic image reconstruction and nonlinearity of kinetic parameter estimation due to the compartment modeling has imposed a huge computational burden to the direct reconstruction of the kinetic parameters. In this paper, we propose to take advantage of both the direct and indirect reconstruction ideas through a variable splitting strategy under the augmented Lagrangian framework. Each iteration of the direct reconstruction is split into two steps: the dynamic FMT image reconstruction and the node-wise nonlinear least squares fitting of the pharmacokinetic parameter images. Through numerical simulation studies, we have found that the proposed algorithm can achieve good reconstruction results within a small amount of time. This will be the first step for a combined dynamic PET and FMT imaging in the future.
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