Phase-contrast x-ray imaging (PCI) is an innovative method that is sensitive to the refraction of the x-rays in matter. PCI is particularly adapted to visualize weakly absorbing details like those often encountered in biology and medicine. In past years, PCI has become one of the most used imaging methods in laboratory and preclinical studies: its unique characteristics allow high contrast 3D visualization of thick and complex samples even at high spatial resolution. Applications have covered a wide range of pathologies and organs, and are more and more often performed in vivo. Several techniques are now available to exploit and visualize the phase-contrast: propagation- and analyzer-based, crystal and grating interferometry and non-interferometric methods like the coded aperture. In this review, covering the last five years, we will give an overview of the main theoretical and experimental developments and of the important steps performed towards the clinical implementation of PCI.

http://iopscience.iop.org/article/10.1088/0031-9155/58/1/R1/pdf

X-ray phase-contrast imaging: from pre-clinical applications towards clinics

Novel radiography approaches based on the wave nature of x-rays when propagating through matter have a great potential for improved future x-ray diagnostics in the clinics. Here, we present a significant milestone in this imaging method: in-vivo multi-contrast x-ray imaging of a mouse using a compact scanner. Of particular interest is the enhanced contrast in regions related to the respiratory system, indicating a possible application in diagnosis of lung diseases (e.g. emphysema).

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In-vivo dark-field and phase-contrast x-ray imaging

Grating interferometer based imaging with X-rays and neutrons has proven to hold huge potential for applications in key research fields conveying biology and medicine as well as engineering and magnetism, respectively. The thereby amenable dark-field imaging modality implied the promise to access structural information beyond reach of direct spatial resolution. However, only here a yet missing approach is reported that finally allows exploiting this outstanding potential for non-destructive materials characterizations. It enables to obtain quantitative structural small angle scattering information combined with up to 3-dimensional spatial image resolution even at lab based x-ray or at neutron sources. The implied two orders of magnitude efficiency gain as compared to currently available techniques in this regime paves the way for unprecedented structural investigations of complex sample systems of interest for material science in a vast range of fields.

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General solution for quantitative dark-field contrast imaging with grating interferometers.

We show that a distribution of micrometer-sized calcifications in the human breast which are not visible in clinical x-ray mammography at diagnostic dose levels can produce a significant dark-field signal in a grating-based x-ray phase-contrast imaging setup with a tungsten anode x-ray tube operated at 40 kVp. A breast specimen with invasive ductal carcinoma was investigated immediately after surgery by Talbot-Lau x-ray interferometry with a design energy of 25 keV. The sample contained two tumors which were visible in ultrasound and contrast-agent enhanced MRI but invisible in clinical x-ray mammography, in specimen radiography and in the attenuation images obtained with the Talbot-Lau interferometer. One of the tumors produced significant dark-field contrast with an exposure of 0.85 mGy air-kerma. Staining of histological slices revealed sparsely distributed grains of calcium phosphate with sizes varying between 1 and 40 μm in the region of this tumor. By combining the histological investigations with an x-ray wave-field simulation we demonstrate that a corresponding distribution of grains of calcium phosphate in the form of hydroxylapatite has the ability to produce a dark-field signal which would-to a substantial degree-explain the measured dark-field image. Thus we have found the appearance of new information (compared to attenuation and differential phase images) in the dark-field image. The second tumor in the same sample did not contain a significant fraction of these very fine calcification grains and was invisible in the dark-field image. We conclude that some tumors which are invisible in x-ray absorption mammography might be detected in the x-ray dark-field image at tolerable dose levels.

https://iopscience.iop.org/article/10.1088/0031-9155/58/8/2713/pdf

On a dark-field signal generated by micrometer-sized calcifications in phase-contrast mammography

Statistical analysis based on the joint distribution of transmission and dark-field signals obtained with a compact cone-beam preclinical small-animal scanner yielded a clear distinction between the lungs with pulmonary emphysema and the control samples.

https://pubs.rsna.org/doi/pdf/10.1148/radiol.13122413

Pulmonary emphysema diagnosis with a preclinical small-animal X-ray dark-field scatter-contrast scanner.

In grating-based x-ray phase sensitive imaging, dark-field contrast refers to the extinction of the interference fringes due to small-angle scattering. For configurations where the sample is placed before the beamsplitter grating, the dark-field contrast has been quantified with theoretical wave propagation models. Yet when the grating is placed before the sample, the dark-field contrast has only been modeled in the geometric optics regime. Here we attempt to quantify the dark-field effect in the grating-before-sample geometry with first-principle wave calculations and understand the associated particle-size selectivity. We obtain an expression for the dark-field effect in terms of the sample material’s complex refractive index, which can be verified experimentally without fitting parameters. A dark-field computed tomography experiment shows that the particle-size selectivity can be used to differentiate materials of identical x-ray absorption.

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Interpretation of dark-field contrast and particle-size selectivity in grating interferometers.

We describe the design and fabrication trials of x-ray absorption gratings of 200?nm period and up to 100:1 depth-to-period ratios for full-field hard x-ray imaging applications. Hard x-ray phase-contrast imaging relies on gratings of ultra-small periods and sufficient depth to achieve high sensitivity. Current grating designs utilize lithographic processes to produce periodic vertical structures, where grating periods below 2.0??m are difficult due to the extreme aspect ratios of the structures. In our design, multiple bilayers of x-ray transparent and opaque materials are deposited on a staircase substrate, and mostly on the floor surfaces of the steps only. When illuminated by an x-ray beam horizontally, the multilayer stack on each step functions as a micro-grating whose grating period is the thickness of a bilayer. The array of micro-gratings over the length of the staircase works as a single grating over a large area when continuity conditions are met. Since the layers can be nanometers thick and many microns wide, this design allows sub-micron grating periods and sufficient grating depth to modulate hard x-rays. We present the details of the fabrication process and diffraction profiles and contact radiography images showing successful intensity modulation of a 25?keV x-ray beam.

https://iopscience.iop.org/article/10.1088/0960-1317/22/10/105007/pdf

Fabrication of 200 nm period centimeter area hard x-ray absorption gratings by multilayer deposition

X-ray imaging techniques based on grating interferometers rely on transmission gratings to detect x-ray refraction and
scattering in a sample. Gratings periods below 2 microns are challenging to realize due to the high aspect ratio of the
structures. We propose a method to fabricate transmission gratings with sub-micron periods over centimeter areas by
multilayer coating of a staircase (echelle) substrate. The advantage of this approach is the high aspect ratio of multilayer
coating and the large area of the echelle substrate. The staircase pattern is etched on the surface of a silicon wafer
through anisotropic etching. Multiple layers are deposited on the horizontal surfaces of the stairs by magnetron
sputtering in a single run. The layers alternate between two materials of different absorption coefficients or refractive
indices. The layer thickness d is designed to be (stair height)/2N, where 2N is the total number of layers. The incident xray
beam is parallel to the layers and oblique to the wafer surface. Each stair of the echelle substrate forms a micro
grating of period 2d, and the array of micro gratings together act as a single grating over a large area given the right
continuity conditions. The grating period potentially can be below 100 nm. We present theoretical description of wave
diffraction by the grating array, and results of the first fabrication test with magnetron sputtering deposition.

Multilayer-coated micro-grating array for x-ray phase-contrast imaging

We constructed X-ray detectors using consumer-grade digital cameras coupled to commercial X-ray phosphors. Several detector configurations were tested against the Varian PaxScan 3024M (Varian 3024M) digital flat panel detector. These include consumer cameras (Nikon D800, Nikon D700, and Nikon D3X) coupled to a green emission phosphor in a back-lit, normal incidence geometry, and in a front-lit, oblique incidence geometry. We used the photon transfer method to evaluate detector sensitivity and dark noise, and the edge test method to evaluate their spatial resolution. The essential specifications provided by our evaluation include discrete charge events captured per mm2 per unit exposure surface dose, dark noise in equivalents of charge events per pixel, and spatial resolution in terms of the full width at half maximum (FWHM) of the detector`s line spread function (LSF). Measurements were performed using a tungsten anode X-ray tube at 50 kVp. The results show that the home-built detectors provide better sensitivity and lower noise than the commercial flat panel detector, and some have better spatial resolution. The trade-off is substantially smaller imaging areas. Given their much lower costs, these home-built detectors are attractive options for prototype development of low-dose imaging applications.

http://iopscience.iop.org/article/10.1088/1748-0221/10/05/T05005/pdf

H. Wen

Papers

Interpretation of dark-field contrast and particle-size selectivity in grating interferometers.

Fabrication of 200 nm period centimeter area hard x-ray absorption gratings by multilayer deposition

Multilayer-coated micro-grating array for x-ray phase-contrast imaging

Performance of low-cost X-ray area detectors with consumer digital cameras