X-ray computed tomography (CT) is a crucial tool for non-invasive medical diagnosis that uses differences in materials' attenuation coefficients to generate contrast and provide 3D information. Grating-based dark-field-contrast X-ray imaging is an innovative technique that utilizes small-angle scattering to generate additional co-registered images with additional microstructural information. While it is already possible to perform human chest dark-field radiography, it is assumed that its diagnostic value increases when performed in a tomographic setup. However, the susceptibility of Talbot-Lau interferometers to mechanical vibrations coupled with a need to minimize data acquisition times has hindered its application in clinical routines and the combination of X-ray dark-field imaging and large field-of-view (FOV) tomography in the past. In this work, we propose a processing pipeline to address this issue in a human-sized clinical dark-field CT prototype. We present the corrective measures that are applied in the employed processing and reconstruction algorithms to mitigate the effects of vibrations and deformations of the interferometer gratings. This is achieved by identifying spatially and temporally variable vibrations in air reference scans. By translating the found correlations to the sample scan, we can identify and mitigate relevant fluctuation modes for scans with arbitrary sample sizes. This approach effectively eliminates the requirement for sample-free detector area, while still distinctly separating fluctuation and sample information. As a result, samples of arbitrary dimensions can be reconstructed without being affected by vibration artifacts. To demonstrate the viability of the technique for human-scale objects, we present reconstructions of an anthropomorphic thorax phantom.

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 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.

Dark-field radiography, a new X-ray imaging method, has recently been applied to human chest imaging for the first time. It employs conventional X-ray devices in combination with a Talbot-Lau interferometer with a large field of view, providing both attenuation and dark-field radiographs. It is well known that sample scatter creates artifacts in both modalities. Here, we demonstrate that also X-ray scatter generated by the interferometer as well as detector crosstalk create artifacts in the dark-field radiographs, in addition to the expected loss of spatial resolution. We propose deconvolution-based correction methods for the induced artifacts. The kernel for detector crosstalk is measured and fitted to a model, while the kernel for scatter from the analyzer grating is calculated by a Monte-Carlo simulation. To correct for scatter from the sample, we adapt an algorithm used for scatter correction in conventional radiography. We validate the obtained corrections with a water phantom. Finally, we show the impact of detector crosstalk, scatter from the analyzer grating and scatter from the sample and their successful correction on dark-field images of a human thorax.

Grating-based phase- and dark-field-contrast X-ray imaging is a novel technology that aims to extend conventional attenuation-based X-ray imaging by unlocking two additional contrast modalities. The so called phase-contrast and dark-field channels provide enhanced soft tissue contrast and additional microstructural information. Accessing this additional information comes at the expense of a more intricate measurement setup and necessitates sophisticated data processing. A big challenge for translating grating-based dark-field computed tomography to medical applications lies in minimizing the data acquisition time. While a continuously moving detector is ideal, it prohibits conventional phase stepping techniques that require multiple projections under the same angle with different grating positions. One solution to this problem is the so-called sliding window processing approach that is compatible with continuous data acquisition. However, conventional sliding window techniques lead to crosstalk-artifacts between the three image channels, if the projection of the sample moves too fast on the detector within a processing window. In this work we introduce a new interpretation of the phase retrieval problem for continuous acquisitions as a demodulation problem. In this interpretation, we identify the origin of the crosstalk-artifacts as partially overlapping modulation side bands. Furthermore, we present three algorithmic extensions that improve the conventional sliding-window-based phase retrieval and mitigate crosstalk-artifacts. The presented algorithms are tested in a simulation study and on experimental data from a human-scale dark-field CT prototype. In both cases they achieve a substantial reduction of the occurring crosstalk-artifacts.

X-ray computed tomography (CT) is an invaluable imaging technique for non-invasive medical diagnosis. However, for soft tissue in the human body the difference in attenuation is inherently small. Grating-based X-ray phase-contrast is a relatively novel imaging method which detects additional interaction mechanisms between photons and matter, namely refraction and small-angle scattering, to generate additional images with different contrast. The experimental setup involves a Talbot-Lau interferometer whose susceptibility to mechanical vibrations hindered acquisition schemes suitable for clinical routine in the past. We present a processing pipeline to identify spatially and temporally variable fluctuations occurring in an interferometer installed on a continuously rotating clinical CT gantry. The correlations of the vibrations in the modular grating setup are exploited to identify a small number of relevant fluctuation modes, allowing for a sample reconstruction free of vibration artifacts.

X-ray computed tomography (CT) is an important non-destructive imaging technique, particularly in clinical diagnostics. Even with the latest innovations like dual-energy and photon-counting CT, the image contrast is solely generated from attenuation in the tissue. An extension - fully compatible with these novelties - is dark-field CT, which retrieves an additional, so-called dark-field contrast. Unlike the attenuation channel, the dark-field channel is sensitive to tissue microstructure and porosity below the resolution of the imaging system, which allows additional insights into the health of the lung tissue or the structure of calcifications. The potential clinical value has been demonstrated in several preclinical studies and recently also in radiography patient studies. Just recently the first dark-field CT for the human body was established at the Technical University of Munich and in this paper, we discuss the performance of this prototype. We evaluate the interferometer components and the imposed challenges that the integration into the CT gantry brings by comparing the results to simulations and measurements at a laboratory setup. The influence of the clinical X-ray source on the Talbot-Lau interferometer and the impact of vibrations, which are immanent on the clinical CT gantry, are analyzed in detail to reveal their characteristic frequencies and origin. A beam hardening correction is introduced as an important step to adapt to the poly-chromatic spectrum and make quantitative dark-field imaging possible. We close with an analysis of the image resolution and the applied patient dose, and conclude that the performance is sufficient to suggest initial patient studies using the presented dark-field CT system.

Computed tomography (CT) as an important clinical diagnostics method can profit from extension with dark-field imaging, as it is currently restricted to X-rays' attenuation contrast only. Dark-field imaging allows access to more tissue properties, such as micro-structural texture or porosity. The up-scaling process to clinical scale is complex because several design constraints must be considered. The two most important ones are that the finest grating is limited by current manufacturing technology to a [Formula: see text] period and that the interferometer should fit into the CT gantry with minimal modifications only. In this work we discuss why an inverse interferometer and a triangular G1 profile are advantageous and make a compact and sensitive interferometer implementation feasible. Our evaluation of the triangular grating profile reveals a deviation in the interference pattern compared to standard grating profiles, which must be considered in the subsequent data processing. An analysis of the grating orientation demonstrates that currently only a vertical layout can be combined with cylindrical bending of the gratings. We also provide an in-depth discussion, including a new simulation approach, of the impact of the extended X-ray source spot which can lead to large performance loss and present supporting experimental results. This analysis reveals a vastly increased sensitivity to geometry and grating period deviations, which must be considered early in the system design process.

Histopathology as a diagnostic mainstay for tissue evaluation is strictly a 2D technology. Combining and supplementing this technology with 3D imaging has been proposed as one future avenue towards refining comprehensive tissue analysis. To this end, we have developed a laboratory-based X-ray method allowing for the investigation of tissue samples in three dimensions with isotropic volume information. To assess the potential of our method for micro-morphology evaluation, we selected several kidney regions from three patients with cystic kidney disease, obstructive nephropathy and diabetic glomerulopathy. Tissue specimens were processed using our in-house-developed X-ray eosin stain and investigated with a commercial microCT and our in-house-built NanoCT. The microCT system provided overview scans with voxel sizes of [Formula: see text] and the NanoCT was employed for higher resolutions including voxel sizes from [Formula: see text] to 210 nm. We present a methodology allowing for a precise micro-morphologic investigation in three dimensions which is compatible with conventional histology. Advantages of our methodology are its versatility with respect to multi-scale investigations, being laboratory-based, allowing for non-destructive imaging and providing isotropic volume information. We believe, that after future developmental work this method might contribute to advanced multi-modal tissue diagnostics.

Dual-energy imaging is a clinically well-established technique that offers several advantages over conventional X-ray imaging. By performing measurements with two distinct X-ray spectra, differences in energy-dependent attenuation are exploited to obtain material-specific information. This information is used in various imaging applications to improve clinical diagnosis. In recent years, grating-based X-ray dark-field imaging has received increasing attention in the imaging community. The X-ray dark-field signal originates from ultra small-angle scattering within an object and thus provides information about the microstructure far below the spatial resolution of the imaging system. This property has led to a number of promising future imaging applications that are currently being investigated. However, different microstructures can hardly be distinguished with current X-ray dark-field imaging techniques, since the detected dark-field signal only represents the total amount of ultra small-angle scattering. To overcome these limitations, we present a novel concept called dual-energy X-ray dark-field material decomposition, which transfers the basic material decomposition approach from attenuation-based dual-energy imaging to the dark-field imaging modality. We develop a physical model and algorithms for dual-energy dark-field material decomposition and evaluate the proposed concept in experimental measurements. Our results suggest that by sampling the energy-dependent dark-field signal with two different X-ray spectra, a decomposition into two different microstructured materials is possible. Similar to dual-energy imaging, the additional microstructure-specific information could be useful for clinical diagnosis.

Diagnostic lung imaging is often associated with high radiation dose and lacks sensitivity, especially for diagnosing early stages of structural lung diseases. Therefore, diagnostic imaging methods are required which provide sound diagnosis of lung diseases with a high sensitivity as well as low patient dose. In small animal experiments, the sensitivity of grating-based X-ray dark-field imaging to structural changes in the lung tissue was demonstrated. The energy-dependence of the X-ray dark-field signal of lung tissue is a function of its microstructure and not yet known. Furthermore, conventional X-ray dark-field imaging is not capable of differentiating different types of pathological changes, such as fibrosis and emphysema. Here we demonstrate the potential diagnostic power of grating-based X-ray dark-field in combination with spectral imaging in human chest radiography for the direct differentiation of lung diseases. We investigated the energy-dependent linear diffusion coefficient of simulated lung tissue with different diseases in wave-propagation simulations and validated the results with analytical calculations. Additionally, we modeled spectral X-ray dark-field chest radiography scans to exploit these differences in energy-dependency. The results demonstrate the potential to directly differentiate structural changes in the human lung. Consequently, grating-based spectral X-ray dark-field imaging potentially contributes to the differential diagnosis of structural lung diseases at a clinically relevant dose level.

For fully characterizing renal cell carcinoma (RCC), information about the 3D tissue microstructure is essential. Histopathology, which represents the current diagnostic gold standard, is destructive and only provides 2D information. 3D X-ray histology endeavors to overcome these limitations by generating 3D data. In a laboratory environment, most techniques struggle with limited resolution and the weak X-ray attenuation contrast of soft tissue. We recently developed a laboratory-based method combining nanoscopic X-ray CT with a cytoplasm-specific X-ray stain. Here, we present the application of this method to human RCC biopsies. The NanoCT slices enable pathological characterization of crucial structures by reproducing tissue morphology with a similar detail level as corresponding histological light microscopy images. Beyond that, our data offer deeper insights into the 3D configuration of the tumor. By demonstrating the compatibility of the X-ray stain with standard pathological stains, we highlight the feasibility of integrating staining based NanoCT into the pathological routine.

Propagation-based phase-contrast X-ray computed tomography is a valuable tool for high-resolution visualization of biological samples, giving distinct improvements in terms of contrast and dose requirements compared to conventional attenuation-based computed tomography. Due to its ease of implementation and advances in laboratory X-ray sources, this imaging technique is increasingly being transferred from synchrotron facilities to laboratory environments. This however poses additional challenges, such as the limited spatial coherence and flux of laboratory sources, resulting in worse resolution and higher noise levels. Here we extend a previously developed iterative reconstruction algorithm for this imaging technique to include models for the reduced spatial coherence and the signal spreading of efficient scintillator-based detectors directly into the physical forward model. Furthermore, we employ a noise model which accounts for the full covariance statistics of the image formation process. In addition, we extend the model describing the interference effects such that it now matches the formalism of the widely-used single-material phase-retrieval algorithm, which is based on the sample-homogeneity assumption. We perform a simulation study as well as an experimental study at a laboratory inverse Compton source and compare our approach to the conventional analytical approaches. We find that the modeling of the source and the detector inside the physical forward model can tremendously improve the resolution at matched noise levels and that the modeling of the covariance statistics reduces overshoots (i.e. incorrect increase / decrease in sample properties) at the sample edges significantly.

We investigate the combination of two emerging X-ray imaging technologies, namely spectral imaging and differential phase contrast imaging. By acquiring spatially and temporally registered images with several different X-ray spectra, spectral imaging can exploit differences in the energy-dependent attenuation to generate material selective images. Differential phase contrast imaging uses an entirely different contrast generation mechanism: The phase shift that an X-ray wave exhibits when traversing an object. As both methods can determine the (projected) electron density, we propose a novel material decomposition algorithm that uses the spectral and the phase contrast information simultaneously. Numerical experiments show that the combination of these two imaging techniques benefits from the strengths of the individual methods while the weaknesses are mitigated: Quantitatively accurate basis material images are obtained and the noise level is strongly reduced, compared to conventional spectral X-ray imaging.

X-ray grating interferometry is a powerful emerging tool in biomedical imaging, providing access to three complementary image modalities. In addition to the conventional attenuation modality, interferometry provides a phase modality, which visualizes soft tissue structures, and a dark-field modality, which relates to the number and size of sub-resolution scattering objects. A particularly strong dark-field signal originates from the alveoli or air sacs in the lung. Dark-field lung radiographs in animal models have already shown increased sensitivity in diagnosing lung diseases, such as lung cancer or emphysema, compared to conventional X-ray chest radiography. However, to date, X-ray dark-field lung imaging has either averaged information over several breaths or has been captured during a breath hold. In this paper, we demonstrate the first time-resolved dark-field imaging of a breath cycle in a mechanically ventilated mouse, in vivo, which was obtained using a grating interferometer. We achieved a time resolution of 0.1 s, visualizing the changes in the dark-field, phase, and attenuation images during inhalation and exhalation. These measurements show that the dark-field signal depends on the air volume and, hence, the alveolar dimensions of the lung. Conducting this type of scan with animal disease models would help to locate the optimum breath point for single-image diagnostic dark-field imaging and could indicate if the changes in the dark-field signal during breath provide a diagnostically useful complementary measure.

By acquiring tomographic measurements with several distinct photon energy spectra, spectral computed tomography (spectral CT) is able to provide additional material-specific information compared with conventional CT. This information enables the generation of material selective images, which have found various applications in medical imaging. However, material decomposition typically leads to noise amplification and a degradation of the signal-to-noise ratio. This is still a fundamental problem of spectral CT, especially for low-dose medical applications. Inspired by the success for low-dose conventional CT, several statistical iterative reconstruction algorithms for spectral CT have been developed. These algorithms typically rely on detailed knowledge about the spectrum and the detector response. Obtaining this knowledge is often difficult in practice, especially if photon counting detectors are used to acquire the energy specific information. In this paper, a new algorithm for joint statistical iterative material image reconstruction is presented. It relies on a semi-empirical forward model which is tuned by calibration measurements. This strategy allows to model spatially varying properties of the imaging system without requiring detailed prior knowledge of the system parameters. We employ an efficient optimization algorithm based on separable surrogate functions to accelerate convergence and reduce the reconstruction time. Numerical as well as real experiments show that our new algorithm leads to reduced statistical bias and improved image quality compared with projection-based material decomposition followed by analytical or iterative image reconstruction.

By resolving the energy of the incident X-ray photons, spectral X-ray imaging with photon counting detectors offers additional material-specific information compared to conventional X-ray imaging. This additional information can be used to improve clinical diagnosis for various applications. However, spectral imaging still faces several challenges. Amplified noise and a reduced signal-to-noise ratio on the decomposed basis material images remain a major problem, especially for low-dose applications. Furthermore, it is challenging to construct an accurate model of the spectral measurement acquisition process. In this paper, we present a novel algorithm for projection-based material decomposition. It uses an empirical polynomial model that is tuned by calibration measurements. We combine this method with a statistical model of the measured photon counts and a dictionary-based joint regularization approach. We focused on spectral coronary angiography as a potential clinical application of projection-based material decomposition with photon counting detectors. Numerical and real experiments show that spectral angiography with realistic dose levels and gadolinium contrast agent concentrations are feasible using the proposed decomposition algorithm and currently available photon-counting detector technology.

Grating-based differential phase-contrast imaging has proven to be feasible with conventional X-ray sources. The polychromatic spectrum generally limits the performance of the interferometer but benefit can be gained with an energy-sensitive detector. In the presented work, we employ the energy-discrimination capability to correct for phase-wrapping artefacts. We propose to use the phase shifts, which are measured in distinct energy bins, to estimate the optimal phase shift in the sense of maximum likelihood. We demonstrate that our method is able to correct for phase-wrapping artefacts, to improve the contrast-to-noise ratio and to reduce beam hardening due to the modelled energy dependency. The method is evaluated on experimental data which are measured with a laboratory Talbot-Lau interferometer equipped with a conventional polychromatic X-ray source and an energy-sensitive photon-counting pixel detector. Our work shows, that spectral imaging is an important step to move differential phase-contrast imaging closer to pre-clinical and clinical applications, where phase wrapping is particularly problematic.

The implementation of hybrid fluorescence molecular tomography (FMT) and X-ray computed tomography (CT) has been shown to be a necessary development, not only for combining anatomical with functional and molecular contrast, but also for generating optical images of high accuracy. FMT affords highly sensitive 3-D imaging of fluorescence bio-distribution, but in stand-alone form it offers images of low resolution. It was shown that FMT accuracy significantly improves by considering anatomical priors from CT. Conversely, CT generally suffers from low soft tissue contrast. Therefore utilization of CT data as prior information in FMT inversion is challenging when different internal organs are not clearly differentiated. Instead, we combined herein FMT with emerging X-ray phase-contrast CT (PCCT). PCCT relies on phase shift differences in tissue to achieve soft tissue contrast superior to conventional CT. We demonstrate for the first time FMT-PCCT imaging of different animal models, where FMT and PCCT scans were performed in vivo and ex vivo, respectively. The results show that FMT-PCCT expands the potential of FMT in imaging lesions with otherwise low or no CT contrast, while retaining the cost benefits of CT and simplicity of hybrid device realizations. The results point to the most accurate FMT performance to date.