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Refraction-contrast computed tomography (RCT) using a refractive angle analyzer of Si perfect crystal can reconstruct the three-dimensional structure of biological soft tissue with contrast comparable to that of stained two-dimensional pathological images. However, the blurring of X-ray beam by the analyzer has prevented improvement of the spatial resolution of RCT, and the currently possible observation of tissue structure at a scale of approximately 20 µm provides only limited medical information. As in pathology, to differentiate between benign and malignant forms of cancer, it is necessary to observe the distribution of the cell nucleus, which is approximately 5-10 µm in diameter. In this study, based on the X-ray dynamical diffraction theory using the Takagi-Taupin equation, which calculates the propagation of X-ray energy in crystals, an analyzer crystal optical system depicting the distribution of cell nuclei was investigated by RCT imaging simulation experiments in terms of the thickness of the Laue-case analyzer, the camera pixel size and the difference in spatial resolution between the Bragg-case and Laue-case analyzers., (© 2022. The Author(s).)

Purpose: The integration process used as a pre-processing step in the reconstruction of differential phase-contrast X-ray CT (d-PCCT) causes the measurement noise to propagate throughout the projection image, which is leading to increased ring artifacts (RA) in the reconstructed image. It is difficult to eliminate the RA using conventional RA removal methods that were developed for the absorption-based CT field. We propose an effective method that can remove RA of d-PCCT images., Methods: The proposed method uses Laplacian images reconstructed from second-derivative projections of d-PCCT. This method is based on a conditional generative adversarial network (cGAN), whose loss function is designed by adding the L1- and L2-norm to the original cGAN. The training data were taken from a numerical phantom generated by a d-PCCT imaging simulator. To validate the applicability of the trained network, we tested its RA removal effect on test data from numerical phantoms generated randomly and actual experimental data., Results: The results of numerical validation using numerical phantoms showed that the proposed method improved the RA removal effect compared to conventional methods. In addition, image comparison by visual evaluation showed that only the proposed method was able to remove RA while preserving original structures in the actual biological d-PCCT images., Conclusion: We proposed a cGAN-based method for RA removal that exploits the physical properties of d-PCCT. The proposed method was able to completely remove RA from d-PCCT images on both simulated data and biological data. We believe that this method is useful for the observation of various types of biological soft tissue., (© 2021. CARS.)

X-ray dark-field imaging (XDFI) utilizing a thin silicon crystal under Laue case enables visualizing three-dimensional (3D) morphological alterations of human tissue. XDFI uses refraction-contrast derived from phase shift rather than absorption as the main X-ray image contrast source to render 2D and 3D images of tissue specimens in unprecedented detail. The unique features of XDFI are its extremely high sensitivity (approximately 1000:1 compared to absorption for soft tissues under X-ray energy of around 20 keV, theoretically) and excellent resolution (8.5 μm) without requiring contrast medium or staining. Thus, XDFI-computed tomography can generate 3D virtual histological images equivalent to those of stained histological sections pathologists observe under low-power light microscopy as far as organs and tissues selected as samples in preliminary studies. This paper reviews the fundamental principles and the potential of XDFI, describes two optical setups for XDFI with examples, illustrates features of XDFI that are salient for histopathology, and presents XDFI examples of refraction-contrast images of atherosclerotic plaques, musculoskeletal tissue, neuronal tissue, and breast cancer specimens. Availability of this X-ray imaging in routine histopathological evaluations of tissue specimens would help guide clinical decision making by highlighting suspicious areas in unstained, thick sections for further sampling and analysis using conventional histopathological techniques. XDFI is a promising tool for 3D virtual histopathology., (© 2021. World Molecular Imaging Society.)

The basic idea of X-ray dark-field imaging (XDFI), first presented in 2000, was based on the concepts used in an X-ray interferometer. In this article, we review 20 years of developments in our theoretical understanding, scientific instrumentation, and experimental demonstration of XDFI and its applications to medical imaging. We first describe the concepts underlying XDFI that are responsible for imparting phase contrast information in projection X-ray images. We then review the algorithms that can convert these projection phase images into three-dimensional tomographic slices. Various implementations of computed tomography reconstructions algorithms for XDFI data are discussed. The next four sections describe and illustrate potential applications of XDFI in pathology, musculoskeletal imaging, oncologic imaging, and neuroimaging. The sample applications that are presented illustrate potential use scenarios for XDFI in histopathology and other clinical applications. Finally, the last section presents future perspectives and potential technical developments that can make XDFI an even more powerful tool., (Copyright © 2020 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.)

Purpose: This paper describes and experimentally validates a methodology for improving contrast and spatial resolution of the x-ray dark-field imaging (XDFI) by cutting the monochromator-collimator asymmetrically and thinning the Laue angle analyzer., Methods: We measure the spatial resolution of our XDFI setup using a test object consisting of wolfram tungsten meshes and compare it with the theoretical prediction. Using x-ray dark-field computed tomography of breast cancer specimens (lobular carcinoma in situ), we demonstrate that the resolution of XDFI is sufficient for histopathologic analysis., Results: Our experimental results show that the overall spatial resolution of XDFI can be improved by approximately a factor of 2 when these modifications are implemented. The reconstructed images of breast cancer specimens provide sufficient details for radiologic histopathology., Conclusions: By cutting the monochromator-collimator and thinning the Laue angle analyzer, XDFI can achieve the resolution sufficient for radiologic histopathology., (© 2020 American Association of Physicists in Medicine.)

Purpose: The three-dimensional (3D) structure of the human nipple has not been fully clarified. However, its importance has increased in recent years because it has become common practice to preoperatively explore the spread of breast cancer to the nipple with needle biopsy, ductoscopy, and/or ductal lavage for nipple-sparing mastectomy. Here, we demonstrated that X-ray dark-field computed tomography (XDFI-CT) is a powerful tool for reconstructing the 3D distribution pattern of human lactiferous ducts non-destructively, without contrast agent, and with high tissue contrast., Methods: Nipples amputated from mastectomy specimens of 51 patients with breast cancer were visualized three-dimensionally by XDFI-CT. First, CT images and conventionally stained tissue sections were compared to demonstrate that XDFI-CT provides 3D anatomical information. Next, the number of ducts in the nipple and the number of ducts sharing an ostium near the tip of the nipple were measured from the volume set of XDFI-CT. Finally, the 3D distribution pattern of the ducts was determined., Results: XDFI-CT can provide images almost equivalent to those of low-magnification light microscopy of conventional hematoxylin-eosin-stained histological sections. The mean number of ducts in all cases was 28.0. The total number of ducts sharing an ostium near the tip of the nipple was 525 of 1428. The 3D distribution patterns of the ducts were classified into three types that we defined as convergent (22%), straight (39%), or divergent (39%)., Conclusions: XDFI-CT is useful for exploring the microanatomy of the human nipple and might be used for non-invasive nipple diagnosis in the future.

This manuscript describes the first known case of a patient with multiple system atrophy whose parasympathetic dominant disturbance might have been associated with the relative constriction of the superior mesenteric artery, leading to nonocclusive mesenteric ischemia and subsequent portomesenteric venous gas with pneumatosis intestinalis on abdominal computed tomography approaching death.

We propose a pinhole-based fluorescent x-ray computed tomography (p-FXCT) system with a 2-D detector and volumetric beam that can suppress the quality deterioration caused by scatter components. In the corresponding p-FXCT technique, projections are acquired at individual incident energies just above and below the K-edge of the imaged trace element; then, reconstruction is performed based on the two sets of projections using a maximum likelihood expectation maximization algorithm that incorporates the scatter components. We constructed a p-FXCT imaging system and performed a preliminary experiment using a physical phantom and an I imaging agent. The proposed dual-energy p-FXCT improved the contrast-to-noise ratio by a factor of more than 2.5 compared to that attainable using mono-energetic p-FXCT for a 0.3 mg/ml I solution. We also imaged an excised rat's liver infused with a Ba contrast agent to demonstrate the feasibility of imaging a biological sample.

This paper describes an X-ray phase contrast imaging technique using analyzer-based optics called X-ray Dark-Field Imaging that has been under development for the past 10years. We describe the theory behind XDFI, the X-ray optics required for implementing it in practice, and algorithms used for 2D, 2.5D, and 3D image reconstruction. The XDFI optical chain consists of an asymmetrically cut, Bragg-type monochromator-collimator that provides a planar monochromatic X-ray beam, a positioning stage for the specimens, a Laue-case angle analyzer, and one or two cameras to capture the dark and bright field images. We demonstrate the soft-tissue discrimination capabilities of XDFI by reconstructing images with absorption and phase contrast. By using a variety of specimens such as breast tissue with cancer, joints with articular cartilage, ex-vivo human eye specimen, and others, we show that refraction-based contrast derived from XDFI is more effective in characterizing anatomical features, articular pathology, and neoplastic disease than conventional absorption-based images. For example, XDFI of breast tissue can discriminate between the normal and diseased terminal duct lobular unit, and between invasive and in-situ cancer. The final section of this paper is devoted to potential future developments to enable clinical and histo-pathological applications of this technique., (Copyright © 2016. Published by Elsevier Ltd.)

X-ray phase-contrast tomography can significantly increase the contrast-resolution of conventional attenuation-contrast imaging, especially for soft-tissue structures that have very similar attenuation. Just as in attenuation-based tomography, phase contrast tomography requires a linear dependence of aggregate beam direction on the incremental direction alteration caused by individual voxels along the path of the X-ray beam. Dense objects such as calcifications in biological specimens violate this condition. There are extensive beam deflection artefacts in the vicinity of such structures because they result in large distortion of wave front due to the large difference of refractive index; for such large changes in beam direction, the transmittance of the silicon analyzer crystal saturates and is no longer linearly dependent on the angle of refraction. This paper describes a method by which these effects can be overcome and excellent soft-tissue contrast of phase tomography can be preserved in the vicinity of such artefact-producing structures.

We propose a 3-dimensional fluorescent x-ray computed tomography (CT) pinhole collimator, aimed at providing molecular imaging with quantifiable measures and sub-millimeter spatial resolution. In this study, we demonstrate the feasibility of this concept and investigate imaging properties such as spatial resolution, contrast resolution and quantifiable measures, by imaging physical phantoms using a preliminary imaging system developed with monochromatic synchrotron x rays constructed at the BLNE-7A experimental line at KEK, Japan.

We derive a reconstruction algorithm for refraction-contrast computed tomography (CT) using dark-field imaging (DFI) optics, which can extract refraction information by a single shot, from the ray equation in geometrical optics. The proposed algorithm is similar to the convolution reconstruction technique widely used in conventional CT. Thus, this algorithm can be implemented simply while also being fast and stable. To demonstrate its validity, we constructed the imaging system based on DFI optics composed of a transmission Laue-type angular analyzer at the vertical wiggler beamline BL-14C in KEK and performed a preliminary imaging experiment using a physical phantom to successfully obtain the DFI-CT image using the proposed algorithm.

Synchrotron-based scattered radiation form low-contrast phantom materials prepared from polyethylene, polystyrene, nylon, and Plexiglas is used as test objects in X-ray CT was examined with 8, 10 and 12 keV X-rays. These phantom materials of medical interest will contains varying proportions of low atomic number elements. The assessment will allowed us to estimate the fluorescence to total scattered radiation. Detected the fluorescence spectra and the associated scattered radiation from calcium hydroxyapatite phantom with 8, 10 and 12 keV synchrotron X-rays. Samples with Bonefil (60% and 70% of calcium hydroxyapatite) and Bone cream (35 approximately 45% of calcium hydroxyapatite), were used. Utilized the X-ray micro-spectroscopy beamline facility, X27A, available at NSLS, BNL, USA. The primary beam with a spot size of the order of approximately 10 mum, has been used for focusing. With this spatial resolution and high flux throuput, the synchrotron-based scattered radiation from the phantom materials were measured using a liquid-nitrogen-cooled 13-element energy-dispersive high-purity germanium detector.

An attempt at refraction-based 2D, 2.5D and 3D X-ray imaging of articular cartilage and breast carcinoma is reported. We are developing very high contrast X-ray 2D imaging with XDFI (X-ray dark-field imaging), X-ray CT whose data are acquired by DEI (diffraction-enhanced imaging) and tomosynthesis due to refraction contrast. 2D and 2.5D images were taken with nuclear plates or with X-ray films. Microcalcification of breast cancer and articular cartilage are clearly visible. 3D data were taken with an X-ray sensitive CCD camera. The 3D image was successfully reconstructed by the use of an algorithm newly made by our group. This shows a distinctive internal structure of a ductus lactiferi (milk duct) that contains inner wall, intraductal carcinoma and multifocal calcification in the necrotic core of the continuous DCIS (ductal carcinoma in situ). Furthermore consideration of clinical applications of these contrasts made us to try tomosynthesis. This attempt was satisfactory from the view point of articular cartilage image quality and the skin radiation dose.

Stereomicroscopic observations of thick sections, or three-dimensional (3-D) reconstructions from serial sections, have provided insights into histopathology. However, they generally require time-consuming and laborious procedures. Recently, we have developed a new algorithm for refraction-based X-ray computed tomography (CT). The aim of this study is to apply this emerging technology to visualize the 3-D structure of a high-grade ductal carcinomas in situ (DCIS) of the breast. The high-resolution two-dimensional images of the refraction-based CT were validated by comparing them with the sequential histological sections. Without adding any contrast medium, the new CT showed strong contrast and was able to depict the non-calcified fine structures such as duct walls and intraductal carcinoma itself, both of which were barely visible in a conventional absorption-based CT. 3-D reconstruction and virtual endoscopy revealed that the high-grade DCIS was located within the dichotomatous branches of the ducts. Multiple calcifications occurred in the necrotic core of the continuous DCIS, resulting in linear and branching (casting type) calcifications, a hallmark of high-grade DCIS on mammograms. In conclusion, refraction-based X-ray CT approaches the low-power light microscopic view of the histological sections. It provides high quality slice data for 3-D reconstruction and virtual ductosocpy.

Fluorescent X-ray computed tomography (FXCT) using synchrotron radiation reveals the cross-sectional distribution of specific elements in biomedical objects. The aim of this study was to investigate the feasibility of FXCT imaging to assess the myocardial metabolic state quantitatively. Hearts labelled with non-radioactive iodine myocardial fatty acid agent 15-p-(iodophenyl)-3-methylpentadecanoic acid (BMIPP) from cardiomyopathic and normal hamsters were imaged. FXCT images were compared with optical microscope images. Myocardial fatty acid metabolism enhanced with BMIPP was clearly depicted by FXCT, which showed an almost homogeneous image for normal and a heterogeneous image for cardiomyopathic hearts. Morphological structures of the heart such as the left ventricle and myocardial wall were also visualized by FXCT. Optical microscopy showed no fibrosis in normal and slight interstitial fibrosis in cardiomyopathic hearts. In the case of cardiomyopathy, the area of significantly reduced BMIPP uptake was 39% in the short axis of the mid-left ventricle in the FXCT image, whereas a slight interstitial fibrosis of around 12% was recognized by optical microscopy for the same slice. This result indicated that reduced BMIPP uptake was caused by the myocardial fatty acid metabolic abnormality, not by the fibrosis in cardiomyopathy. Thus, FXCT images might be used to assess the quantitative metabolic analysis in small animal models of heart diseases.

We consider x-ray computed tomography (CT) technique based on refractive effects, which has advantages for delineating biological weakly-absorbing soft-tissues over the conventional absorption-contrast CT (computed tomography) because of the use of phase sensitive detection. The refraction-based CT described here detects the angular deviation of the beam, refracted by a sample, from the incident beam in a cross-sectional plane of interest, based on the diffraction enhanced imaging (DEI) method using the Bragg-case analyzing crystal, which is arranged behind the sample on a positioning device for collecting projection data from various directions. The set of angular deviation data from various directions, which corresponds to the projection data in the conventional absorption-contrast CT, are used for reconstruction of the refractive-index gradient vector field. So far, some groups have proposed the distinct DEI-based CT protocols. We theoretically summarize and compare the algorithms from the viewpoint of geometrical optics.

The unique tomographic imaging method based on refractive effects that was recently developed by Maksimenko et al. [Appl. Phys. Lett. 86, 124105 (2005)] exhibits an excellent imaging property in the hard-x-ray region for phase objects such as soft materials and biological samples. However, there seems to have been little consideration of the physical aspects of the underlying imaging principles. Also, as the method is similar to diffraction-enhanced-imaging (DEI)-based computed tomography (CT), the difference between these two methodologies has not been made clear. We theoretically consider the imaging principles starting from the measurement process to the reconstruction procedures from the viewpoint of geometrical optics and then clarify their difference in relationship to the physical quantities to be depicted. The major feature of this novel method is the in-plane two-dimensional vector-field reconstruction of the refractive-index gradient in an object, while DEI CT obtains the out-of-plane scalar-field gradient component. In other words, the novel method and DEI CT present the transverse and the longitudinal components, respectively, of the three-dimensional vector fields of the gradient refractive index. Therefore they can be considered complementary to each other.

This paper presents theoretical and numerical studies of diffraction tomography using hard x rays, from the viewpoint of imaging and reconstruction methods for cell imaging. The proposed system employs a single-perfect-crystal analyzer in symmetric Laue-case transmission geometry to efficiently detect the higher spatial frequency components of an object's refractive-index distribution, and to effectively suppress interference between the unperturbated wave field and the wave field diffracted by the object. This system features acquisition of a single projection by a single exposure using a simple geometry and aggressive use of diffracted x rays. We present the physical description of the imaging method using the Fourier diffraction theorem derived from the Born approximation. First, we demonstrate that the reconstruction leads to the phase-retrieval problem. We then describe a reconstruction algorithm based on the classical Gerchberg-Saxton-Fienup algorithm. Finally, we show the efficacy of this system by computer simulation. Our simulation demonstrates that the imaging system delineates microstructure 3.5 microm in diameter in a phase object 400 microm in diameter.

The simultaneous observation of various information, such as blood flow, tissue metabolism and distribution of receptors, is quite important in order to understand the functional state of biomedical objects. The simultaneous detectability of contrast agents by fluorescent X-ray computed tomography (FXCT) with synchrotron radiation is examined in this study. The system consisted of a silicon (111) double-crystal monochromator, an X-ray slit system, a scanning table, a PIN diode, a highly purified germanium detector and an X-ray charge-coupled device (CCD) camera. The monochromatic X-ray beam energy was adjusted to 37.0 keV and collimated into a pencil beam of 1 x 1 mm. The fluorescent spectra of the K alpha lines for iodine and xenon were detected simultaneously. FXCT could image the distribution of both iodine and xenon agents in a phantom clearly and the contrast ratio was significantly better than that of transmission X-ray computed tomography images.

New types of X-ray computed tomography (CT), fluorescent X-ray CT and phase-contrast X-ray CT are being developed for biomedical research. While fluorescent scanning X-ray CT (FXCT) can detect specific contrast elements, or endogenous iodine, at very low content (less than 400 pg iodine of tissue in a volume of 8 x 10(-6) ml), the phase-contrast X-ray CT (PCCT) is a highly sensitive imaging technique to differentiate between different biological tissue types (based on their specific gravity variation) without the use of a contrast agent. Therefore, we can expect functional diagnosis with FXCT, and high contrast, high resolution biological imaging with PCCT. In this paper, a human thyroid gland imaged by FXCT, and a metastatic human cancerous lesion depicted using PCCT are presented. The latter method used a newly manufactured, large, monolithic, X-ray interferometer, which is described in this paper in detail.

We investigated computed tomographic (CT) films of 4 pathologically documented cases of progressive supranuclear palsy (PSP) in which the clinical presentations were atypical and compared the findings with those of 15 patients with Parkinson's disease (PD). Dilatation of the third ventricle, atrophy of the midbrain tegmentum, and enlargement of the interpeduncular cistern toward the aqueduct were found to be the characteristic findings in PSP. Thus, radiological findings can be useful when the differential diagnosis between PSP and PD is clinically difficult.