Quantitative X-ray phase contrast computed tomography with grating interferometry : Biomedical applications of quantitative X-ray grating-based phase contrast computed tomography.

The ability of biomedical imaging data to be of quantitative nature is getting increasingly important with the ongoing developments in data science. In contrast to conventional attenuation-based X-ray imaging, grating-based phase contrast computed tomography (GBPC-CT) is a phase contrast micro-CT imaging technique that can provide high soft tissue contrast at high spatial resolution. While there is a variety of different phase contrast imaging techniques, GBPC-CT can be applied with laboratory X-ray sources and enables quantitative determination of electron density and effective atomic number. In this review article, we present quantitative GBPC-CT with the focus on biomedical applications.

Early detection of radiation-induced lung damage with X-ray dark-field radiography in mice.

OBJECTIVE: Assessing the advantage of x-ray dark-field contrast over x-ray transmission contrast in radiography for the detection of developing radiation-induced lung damage in mice. METHODS: Two groups of female C57BL/6 mice (irradiated and control) were imaged obtaining both contrasts monthly for 28 weeks post irradiation. Six mice received 20 Gy of irradiation to the entire right lung sparing the left lung. The control group of six mice was not irradiated. A total of 88 radiographs of both contrasts were evaluated for both groups based on average values for two regions of interest, covering (irradiated) right lung and healthy left lung. The ratio of these average values, R, was distinguished between healthy and damaged lungs for both contrasts. The time-point when deviations of R from healthy lung exceeded 3σ was determined and compared among contrasts. The Wilcoxon-Mann-Whitney test was used to test against the null hypothesis that there is no difference between both groups. A selection of 32 radiographs was assessed by radiologists. Sensitivity and specificity were determined in order to compare the diagnostic potential of both contrasts. Inter-reader and intra-reader accuracy were rated with Cohen's kappa. RESULTS: Radiation-induced morphological changes of lung tissue caused deviations from the control group that were measured on average 10 weeks earlier with x-ray dark-field contrast than with x-ray transmission contrast. Sensitivity, specificity, and accuracy doubled using dark-field radiography. CONCLUSION: X-ray dark-field radiography detects morphological changes of lung tissue associated with radiation-induced damage earlier than transmission radiography in a pre-clinical mouse model. KEY POINTS: • Significant deviations from healthy lung due to irradiation were measured after 16 weeks with x-ray dark-field radiography (p = 0.004). • Significant deviations occur on average 10 weeks earlier for x-ray dark-field radiography in comparison to x-ray transmission radiography. • Sensitivity and specificity doubled when using x-ray dark-field radiography instead of x-ray transmission radiography.

Three-dimensional virtual histology enabled through cytoplasm-specific X-ray stain for microscopic and nanoscopic computed tomography.

Many histological methods require staining of the cytoplasm, which provides instrumental details for diagnosis. One major limitation is the production of 2D images obtained by destructive preparation of 3D tissue samples. X-ray absorption micro- and nanocomputed tomography (microCT and nanoCT) allows for a nondestructive investigation of a 3D tissue sample, and thus aids to determine regions of interest for further histological examinations. However, application of microCT and nanoCT to biological samples (e.g., biopsies) is limited by the missing contrast within soft tissue, which is important to visualize morphological details. We describe an eosin-based preparation overcoming the challenges of contrast enhancement and selectivity for certain tissues. The eosin-based staining protocol is suitable for whole-organ staining, which then enables high-resolution microCT imaging of whole organs and nanoCT imaging of smaller tissue pieces retrieved from the original sample. Our results demonstrate suitability of the eosin-based staining method for diagnostic screening of 3D tissue samples without impeding further diagnostics through histological methods.

Quality and parameter control of X-ray absorption gratings by angular X-ray transmission.

Here we report on a non-destructive, spatially resolving and easy to implement quality and parameter control method for high aspect ratio X-ray absorption gratings. Based on angular X-ray transmission measurements, our proposed technique allows to determine the duty cycle, the transmittance, the height, as well as the local inclination of the absorbing grating structures. A key advantage of the presented method is a fast and extensive grating quality evaluation without the need of implementing an entire grating interferometer. In addition to the local and surface-based analysis using a scanning electron microscope, our non-destructive method provides global averaged macroscopic and spatially resolved grating structure information without the requirement of resolving individual grating lines.

Accurate effective atomic number determination with polychromatic grating-based phase-contrast computed tomography.

The demand for quantitative medical imaging is increasing in the ongoing digitalization. Conventional computed tomography (CT) is energy-dependent and therefore of limited comparability. In contrast, dual-energy CT (DECT) allows for the determination of absolute image contrast quantities, namely the electron density and the effective atomic number, and is already established in clinical radiology and radiation therapy. Grating-based phase-contrast computed tomography (GBPC-CT) is an experimental X-ray technique that also allows for the measurement of the electron density and the effective atomic number. However, the determination of both quantities is challenging when dealing with polychromatic GBPC-CT setups. In this paper, we present how to calculate the effective atomic numbers with a polychromatic, laboratory GBPC-CT setup operating between 35 and 50\,kVp. First, we investigated the accuracy of the measurement of the attenuation coefficients and electron densities. For this, we performed a calibration using the concept of effective energy. With the reliable experimental quantitative values, we were able to evaluate the effective atomic numbers of the investigated materials using a method previously shown with monochromatic X-ray radiation. In detail, we first calculated the ratio of the electron density and attenuation coefficient, which were experimentally determined with our polychromatic GBPC-CT setup. Second, we compared this ratio with tabulated total attenuation cross sections from literature values to determine the effective atomic numbers. Thus, we were able to calculate two physical absolute quantities -- the electron density and effective atomic number -- that are in general independent of the specific experimental conditions like the X-ray beam spectrum or the setup design.

Analysis and correction of bias induced by phase stepping jitter in grating-based X-ray phase-contrast imaging.

Grating-based X-ray phase-contrast (gbPC) is an X-ray phase-contrast imaging method involving optical gratings that typically employs the Talbot self-imaging effect. X-ray phase contrast is known to provide significant benefits for biomedical imaging. To investigate these benefits for gbPC, a high-sensitivity gbPC micro-CT setup for small biological samples has been constructed. A gbPC projection measurement simultaneously retrieves the transmittance, differential-phase and dark-field modalities of a sample. Phase stepping, the most common gbPC acquisition technique, involves several acquisitions at different lateral positions of one of the gratings. The three modalities can then be retrieved by least-squares- or FFT-based methods. Unfortunately, increasing differential-phase sensitivity also leads to an increased magnitude of artifacts introduced during retrieval of the modalities from the phase-stepping data, which limits image quality. Most importantly, processing of phase-stepping data with incorrect stepping positions (i.e., spatial sampling jitter) can introduce artifacts to the modalities. Using data from the high-sensitivity gbPC setup, as well as simulations, we show that an artifact is introduced by the jitter which is correlated with the phase of the stepping curve. We present a theoretical explanation for this correlation by introducing small deviations to an equidistant sampling of a stepping curve and approximating the effect on the calculation of the three gbPC modalities with a first-order Taylor approximation. Finally, we present an algorithm for the detection and removal of these artifacts that exploits these correlations. We show that this algorithm is able to eliminate these artifacts without degrading true image information.

Assessment of quantification accuracy and image quality of a full-body dual-layer spectral CT system.

The performance of a recently introduced spectral computed tomography system based on a dual-layer detector has been investigated. A semi-anthropomorphic abdomen phantom for CT performance evaluation was imaged on the dual-layer spectral CT at different radiation exposure levels (CTDIvol of 10 mGy, 20 mGy and 30 mGy). The phantom was equipped with specific low-contrast and tissue-equivalent inserts including water-, adipose-, muscle-, liver-, bone-like materials and a variation in iodine concentrations. Additionally, the phantom size was varied using different extension rings to simulate different patient sizes. Contrast-to-noise (CNR) ratio over the range of available virtual mono-energetic images (VMI) and the quantitative accuracy of VMI Hounsfield Units (HU), effective-Z maps and iodine concentrations have been evaluated. Central and peripheral locations in the field-of-view have been examined. For all evaluated imaging tasks the results are within the calculated theoretical range of the tissue-equivalent inserts. Especially at low energies, the CNR in VMIs could be boosted by up to 330% with respect to conventional images using iDose/spectral reconstructions at level 0. The mean bias found in effective-Z maps and iodine concentrations averaged over all exposure levels and phantom sizes was 1.9% (eff. Z) and 3.4% (iodine). Only small variations were observed with increasing phantom size (+3%) while the bias was nearly independent of the exposure level (±0.2%). Therefore, dual-layer detector based CT offers high quantitative accuracy of spectral images over the complete field-of-view without any compromise in radiation dose or diagnostic image quality.

Spectral Photon-counting CT: Initial Experience with Dual-Contrast Agent K-Edge Colonography.

Purpose To investigate the feasibility of using spectral photon-counting computed tomography (CT) to differentiate between gadolinium-based and nonionic iodine-based contrast material in a colon phantom by using the characteristic k edge of gadolinium. Materials and Methods A custom-made colon phantom was filled with nonionic iodine-based contrast material, and a gadolinium-filled capsule representing a contrast material-enhanced polyp was positioned on the colon wall. The colon phantom was scanned with a preclinical spectral photon-counting CT system to obtain spectral and conventional data. By fully using the multibin spectral information, material decomposition was performed to generate iodine and gadolinium maps. Quantitative measurements were performed within the lumen and polyp to quantitatively determine the absolute content of iodine and gadolinium. Results In a conventional CT section, absorption values of both contrast agents were similar at approximately 110 HU. Contrast material maps clearly differentiated the distributions, with gadolinium solely in the polyp and iodine in the lumen of the colon. Quantitative measurements of contrast material concentrations in the colon and polyp matched well with those of actual prepared mixtures. Conclusion Dual-contrast spectral photon-counting CT colonography with iodine-filled lumen and gadolinium-tagged polyps may enable ready differentiation between polyps and tagged fecal material. © RSNA, 2016.

AHA classification of coronary and carotid atherosclerotic plaques by grating-based phase-contrast computed tomography.

OBJECTIVES: To evaluate the potential of grating-based phase-contrast computed-tomography (gb-PCCT) to classify human carotid and coronary atherosclerotic plaques according to modified American Heart Association (AHA) criteria. METHODS: Experiments were carried out at a laboratory-based set-up consisting of X-ray tube (40 kVp), grating-interferometer and detector. Eighteen human carotid and coronary artery specimens were examined. Histopathology served as the standard of reference. Vessel cross-sections were classified as AHA lesion type I/II, III, IV/V, VI, VII or VIII plaques by two independent reviewers blinded to histopathology. Conservative measurements of diagnostic accuracies for the detection and differentiation of plaque types were evaluated. RESULTS: A total of 127 corresponding gb-PCCT/histopathology sections were analyzed. Based on histopathology, lesion type I/II was present in 12 (9.5 %), III in 18 (14.2 %), IV/V in 38 (29.9 %), VI in 16 (12.6 %), VII in 34 (26.8 %) and VIII in 9 (7.0 %) cross-sections. Sensitivity, specificity and positive and negative predictive value were ≥0.88 for most analyzed plaque types with a good level of agreement (Cohen's kappa = 0.90). Overall, results were better in carotid (kappa = 0.97) than in coronary arteries (kappa = 0.85). Inter-observer agreement was high with kappa = 0.85, p < 0.0001. CONCLUSIONS: These results indicate that gb-PCCT can reliably classify atherosclerotic plaques according to modified AHA criteria with excellent agreement to histopathology. KEY POINTS: • Different atherosclerotic plaque types display distinct morphological features in phase-contrast CT. • Phase-contrast CT can detect and differentiate AHA plaque types. • Calcifications caused streak artefacts and reduced sensitivity in type VI lesions. • Overall agreement was higher in carotid than in coronary arteries.

Quantitative imaging using high-energy X-ray phase-contrast CT with a 70 kVp polychromatic X-ray spectrum.

Imaging of large and dense objects with grating-based X-ray phase-contrast computed tomography requires high X-ray photon energy and large fields of view. It has become increasingly possible due to the improvements in the grating manufacturing processes. Using a high-energy X-ray phase-contrast CT setup with a large (10 cm in diameter) analyzer grating and operated at an acceleration tube voltage of 70 kVp, we investigate the complementarity of both attenuation and phase contrast modalities with materials of various atomic numbers (Z). We confirm experimentally that for low-Z materials, phase contrast yields no additional information content over attenuation images, yet it provides increased contrast-to-noise ratios (CNRs). The complementarity of both signals can be seen again with increasing Z of the materials and a more comprehensive material characterization is thus possible. Imaging of a part of a human cervical spine with intervertebral discs surrounded by bones and various soft tissue types showcases the benefit of high-energy X-ray phase-contrast system. Phase-contrast reconstruction reveals the internal structure of the discs and makes the boundary between the disc annulus and nucleus pulposus visible. Despite the fact that it still remains challenging to develop a high-energy grating interferometer with a broad polychromatic source with satisfactory optical performance, improved image quality for phase contrast as compared to attenuation contrast can be obtained and new exciting applications foreseen.

Improved visualization of breast cancer features in multifocal carcinoma using phase-contrast and dark-field mammography: an ex vivo study.

OBJECTIVES: Conventional X-ray attenuation-based contrast is inherently low for the soft-tissue components of the female breast. To overcome this limitation, we investigate the diagnostic merits arising from dark-field mammography by means of certain tumour structures enclosed within freshly dissected mastectomy samples. METHODS: We performed grating-based absorption, absolute phase and dark-field mammography of three freshly dissected mastectomy samples containing bi- and multifocal carcinoma using a compact, laboratory Talbot-Lau interferometer. Preoperative in vivo imaging (digital mammography, ultrasound, MRI), postoperative histopathological analysis and ex vivo digital mammograms of all samples were acquired for the diagnostic verification of our results. RESULTS: In the diagnosis of multifocal tumour growth, dark-field mammography seems superior to standard breast imaging modalities, providing a better resolution of small, calcified tumour nodules, demarcation of tumour boundaries with desmoplastic stromal response and spiculated soft-tissue strands extending from an invasive ductal breast cancer. CONCLUSIONS: On the basis of selected cases, we demonstrate that dark-field mammography is capable of outperforming conventional mammographic imaging of tumour features in both calcified and non-calcified tumours. Presuming dose optimization, our results encourage further studies on larger patient cohorts to identify those patients that will benefit the most from this promising additional imaging modality. KEY POINTS: • X-ray dark-field mammography provides significantly improved visualization of tumour features • X-ray dark-field mammography is capable of outperforming conventional mammographic imaging • X-ray dark-field mammography provides imaging sensitivity towards highly dispersed calcium grains.

Emphysema diagnosis using X-ray dark-field imaging at a laser-driven compact synchrotron light source.

In early stages of various pulmonary diseases, such as emphysema and fibrosis, the change in X-ray attenuation is not detectable with absorption-based radiography. To monitor the morphological changes that the alveoli network undergoes in the progression of these diseases, we propose using the dark-field signal, which is related to small-angle scattering in the sample. Combined with the absorption-based image, the dark-field signal enables better discrimination between healthy and emphysematous lung tissue in a mouse model. All measurements have been performed at 36 keV using a monochromatic laser-driven miniature synchrotron X-ray source (Compact Light Source). In this paper we present grating-based dark-field images of emphysematous vs. healthy lung tissue, where the strong dependence of the dark-field signal on mean alveolar size leads to improved diagnosis of emphysema in lung radiographs.

Absorption and Phase Contrast X-Ray Imaging in Paleontology Using Laboratory and Synchrotron Sources.

X-ray micro-computed tomography (µCT) is commonly used for imaging of samples in biomedical or materials science research. Owing to the ability to visualize a sample in a nondestructive way, X-ray µCT is perfectly suited to inspect fossilized specimens, which are mostly unique or rare. In certain regions of the world where important sedimentation events occurred in the Precambrian geological time, several fossilized animals are studied to understand questions related to their origin, environment, and life evolution. This article demonstrates the advantages of applying absorption and phase-contrast CT on the enigmatic fossil Corumbella werneri, one of the oldest known animals capable of building hard parts, originally discovered in Corumbá (Brazil). Different tomographic setups were tested to visualize the fossilized inner structures: a commercial laboratory-based µCT device, two synchrotron-based imaging setups using conventional absorption and propagation-based phase contrast, and a commercial X-ray microscope with a lens-coupled detector system, dedicated for radiography and tomography. Based on our results we discuss the strengths and weaknesses of the different imaging setups for paleontological studies.

Simulated cystic renal lesions: quantitative X-ray phase-contrast CT--an in vitro phantom study.

PURPOSE: To determine if grating-based x-ray phase-contrast computed tomography (CT) can allow differentiation of simulated simple, protein-rich, hemorrhagic, and enhancing cystic renal lesions in an in vitro phantom. MATERIALS AND METHODS: An in vitro phantom specifically designed to simulate simple, protein-rich, hemorrhagic, and enhancing renal cysts was scanned with an experimental grating-based phase-contrast CT setup consisting of a Talbot-Lau interferometer with a rotating anode x-ray tube and a single photon counting detector. Various combinations of serum and saline (100% and 0% to 0% and 100%), blood and saline, blood and serum (100% and 0% to 6.25% and 93.75% for both), and an iodinated contrast agent and saline (7.6-1.6 mg per milliliter of saline) were used to reproduce the chemical composition of the different types of cysts. A thickened solution of an iodinated contrast agent calibrated with a clinical multidetector CT scanner served as contrast agent-enhanced renal parenchyma (195 HU at 80 kVp, 400 mAs and 98 HU at 140 kVp, 200 mAs). Standard attenuation- and phase-contrast images were reconstructed from the raw projection data. Quantitative values for attenuation and phase contrast and image noise were determined. Contrast-to-noise ratios were calculated. Simulated lesions were assessed for visual differentiability by means of pairwise comparison of the attenuation- and phase-contrast images and both images simultaneously. RESULTS: Attenuation-contrast imaging showed large differences in Hounsfield units with increasing concentrations of iodine (118.9 HU for 1.6 mg/mL vs 331.4 HU for 7.6 mg/mL). Values for phase-contrast imaging were substantially distinguishable for saline, serum, and blood (7.9, 23.7, and 52.8 HU, respectively). Both imaging modalities combined allowed differentiation of all four types of simulated cysts (100% saline, 100% serum, 100% blood, and 1.6-7.6 mg of iodine per milliliter of saline) with one imaging acquisition. CONCLUSION: Grating-based phase-contrast CT allows differentiation of simulated simple, protein-rich, hemorrhagic, and enhancing renal cysts in an in vitro phantom through simultaneous assessment of their distinct attenuation- and phase-contrast signal.

Phase-contrast CT: qualitative and quantitative evaluation of atherosclerotic carotid artery plaque.

PURPOSE: To evaluate the potential of phase-contrast computed tomography (CT) for atherosclerotic plaque imaging in human carotid arteries in an experimental ex vivo study. MATERIALS AND METHODS: The study was approved by the institutional review board, and informed consent was obtained from the patients' relatives. Seven postmortem human carotid artery specimens were imaged at a laboratory setup by using a conventional x-ray tube and grating interferometer. After histologic processing, phase-contrast imaging and histopathologic data were matched. Characteristics of the necrotic core (NC) covered by a fibrous cap (FC), intraplaque hemorrhage (IPH), and calcifications (CAs) were established, and sensitivity, specificity, and accuracy of phase-contrast CT for plaque detection and the potential for accurate quantification were assessed. The Cohen κ and Pearson correlation coefficient R were used to determine the agreement between phase-contrast imaging and histopathologic findings for plaque characterization and correlation of quantitative plaque measurements, respectively. A difference with a P value of less than .05 was considered significant. RESULTS: Characteristic criteria were found in all analyzed plaque components. Applying these criteria, phase-contrast CT had a good sensitivity for the detection of the FC and NC, IPH, and CAs (all, >80%) and excellent specificity and accuracy (all, >90%), with good interreader agreement (κ ≥ 0.72, P < .0001). There were excellent correlations for quantitative measurements of FC, NC, and CAs between phase-contrast imaging and histopathologic findings (R ≥ 0.92). Interreader reproducibility was excellent, with an intraclass correlation coefficient of 0.98 or higher for all measurements. CONCLUSION: The results of this study indicate that ex vivo phase-contrast CT can help identify and quantify atherosclerotic plaque components, with excellent correlation to histopathologic findings. Although not yet applicable in vivo, phase-contrast CT may become a valuable tool to monitor atherosclerotic disease process noninvasively.

X-ray dark-field computed tomography for monitoring of tissue freezing.

Accurately monitoring the extent of freezing in biological tissue is an important requirement for cryoablation, a minimally invasive cancer treatment that induces cell death by freezing tissue with a cryoprobe. During the procedure, monitoring is required to avoid unnecessary harm to the surrounding healthy tissue and to ensure the tumor is properly encapsulated. One commonly used monitoring method is attenuation-based computed tomography (CT), which visualizes the ice ball by utilizing its hypoattenuating properties compared to unfrozen tissue. However, the contrast between frozen and unfrozen tissue remains low. In a proof-of-principle experiment, we show that the contrast between frozen and unfrozen parts of a porcine phantom mimicking breast tissue can be greatly enhanced by acquiring X-ray dark-field images that capture the increasing small-angle scattering caused by the ice crystals formed during the procedure. Our results show that, compared to X-ray attenuation, the frozen region is detected significantly better in dark-field radiographs and CT scans of the phantom. These findings demonstrate that X-ray dark-field imaging could be a potential candidate for improved monitoring of cryoablation procedures.

X-Ray Dark-Field Signal Reduction Due to Hardening of the Visibility Spectrum.

X-ray dark-field imaging enables a spatially-resolved visualization of ultra-small-angle X-ray scattering. Using phantom measurements, we demonstrate that a material's effective dark-field signal may be reduced by modification of the visibility spectrum by other dark-field-active objects in the beam. This is the dark-field equivalent of conventional beam-hardening, and is distinct from related, known effects, where the dark-field signal is modified by attenuation or phase shifts. We present a theoretical model for this group of effects and verify it by comparison to the measurements. These findings have significant implications for the interpretation of dark-field signal strength in polychromatic measurements.

Grating-based phase-contrast computed tomography for breast tissue at an inverse compton source.

The introduction of mammography screening programs has significantly reduced breast cancer mortality rates. Nevertheless, some lesions remain undetected, especially in dense breast tissue. Studies have shown that phase-contrast imaging can improve breast cancer diagnosis by increasing soft tissue contrast. Furthermore, grating-based phase-contrast imaging enables the simultaneous acquisition of absorption, phase-contrast, and scattering, so-called dark-field images. The latter allows the classification of microcalcifications. In addition, breast computed tomography (BCT) systems can identify and discriminate overlapping but clinically relevant structures. This study investigates the benefit of combining grating-based phase-contrast with BCT. We explore the potential of grating-based phase-contrast breast computed tomography (gbpc-BCT) with a breast phantom and a freshly dissected fibroadenoma. Improved image contrast could be achieved with radiation doses comparable to those used in clinical BCT.

Correction for Mechanical Inaccuracies in a Scanning Talbot-Lau Interferometer.

Grating-based X-ray phase-contrast and in particular dark-field radiography are promising new imaging modalities for medical applications. Currently, the potential advantage of dark-field imaging in early-stage diagnosis of pulmonary diseases in humans is being investigated. These studies make use of a comparatively large scanning interferometer at short acquisition times, which comes at the expense of a significantly reduced mechanical stability as compared to tabletop laboratory setups. Vibrations create random fluctuations of the grating alignment, causing artifacts in the resulting images. Here, we describe a novel maximum likelihood method for estimating this motion, thereby preventing these artifacts. It is tailored to scanning setups and does not require any sample-free areas. Unlike any previously described method, it accounts for motion in between as well as during exposures.

Quantitative X-ray phase-contrast computed tomography at 82 keV.

Potential applications of grating-based X-ray phase-contrast imaging are investigated in various fields due to its compatibility with laboratory X-ray sources. So far the method was mainly restricted to X-ray energies below 40 keV, which is too low to examine dense or thick objects, but a routine operation at higher energies is on the brink of realisation. In this study, imaging results obtained at 82 keV are presented. These comprise a test object consisting of well-defined materials for a quantitative analysis and a tooth to translate the findings to a biomedical sample. Measured linear attenuation coefficients ? and electron densities ?e are in good agreement with theoretical values. Improved contrast-to-noise ratios were found in phase contrast compared to attenuation contrast. The combination of both contrast modalities further enables to simultaneously assess information on density and composition of materials with effective atomic numbers Z? > 8. In our biomedical example, we demonstrate the possibility to detect differences in mass density and calcium concentration within teeth.