Feasibility of Dark-Field Radiography to Enhance Detection of Nondisplaced Fractures.

Background Many clinically relevant fractures are occult on conventional radiographs and therefore challenging to diagnose reliably. X-ray dark-field radiography is a developing method that uses x-ray scattering as an additional signal source. Purpose To investigate whether x-ray dark-field radiography enhances the depiction of radiographically occult fractures in an experimental model compared with attenuation-based radiography alone and whether the directional dependence of dark-field signal impacts observer ratings. Materials and Methods Four porcine loin ribs had nondisplaced fractures experimentally introduced. Microstructural changes were visually verified using high-spatial-resolution three-dimensional micro-CT. X-ray dark-field radiographs were obtained before and after fracture, with the before-fracture scans serving as control images. The presence of a fracture was scored by three observers using a six-point scale (6, surely; 5, very likely; 4, likely; 3, unlikely; 2, very unlikely; and 1, certainly not). Differences between scores based on attenuation radiographs alone (n = 96) and based on combined attenuation and dark-field radiographs (n = 96) were evaluated by using the DeLong method to compare areas under the receiver operating characteristic curve. The impact of the dark-field signal directional sensitivity on observer ratings was evaluated using the Wilcoxon test. The dark-field data were split into four groups (24 images per group) according to their sensitivity orientation and tested against each other. Musculoskeletal dark-field radiography was further demonstrated on human finger and foot specimens. Results The addition of dark-field radiographs was found to increase the area under the receiver operating characteristic curve to 1 compared with an area under the receiver operating characteristic curve of 0.87 (95% CI: 0.80, 0.94) using attenuation-based radiographs alone (P < .001). There were similar observer ratings for the four different dark-field sensitivity orientations (P = .16-.65 between the groups). Conclusion These results suggested that the inclusion of dark-field radiography has the potential to help enhance the detection of nondisplaced fractures compared with attenuation-based radiography alone. © RSNA, 2024 See also the editorial by Rubin in this issue.

High-energy X-ray diffraction experiment employing a compact synchrotron X-ray source based on inverse Compton scattering.

X-ray diffraction (XRD) is an important material analysis technique with a widespread use of laboratory systems. These systems typically operate at low X-ray energies (from 5 keV to 22 keV) since they rely on the small bandwidth of K-lines like copper. The narrow bandwidth is essential for precise measurements of the crystal structure in these systems. Inverse Compton X-ray source (ICS) could pave the way to XRD at high X-ray energies in a laboratory setting since these sources provide brilliant energy-tunable and partially coherent X-rays. This study demonstrates high-energy XRD at an ICS with strongly absorbing mineralogical samples embedded in soft tissue. A quantitative comparison of the measured XRD patterns with calculations of their expected shapes validates the performance of ICSs for XRD. This analysis was performed for two types of kidney stones of different materials. Since these stones are not isolated in a human body, the influence of the surrounding soft tissue on the XRD pattern is investigated and a correction for this soft tissue contribution is introduced.

X-ray Stain Localization with Near-Field Ptychographic Computed Tomography.

Although X-ray contrast agents offer specific characteristics in terms of targeting and attenuation, their accumulation in the tissue on a cellular level is usually not known and difficult to access, as it requires high resolution and sensitivity. Here, quantitative near-field ptychographic X-ray computed tomography is demonstrated to assess the location of X-ray stains at a resolution sufficient to identify intracellular structures by means of a basis material decomposition. On the example of two different X-ray stains, the nonspecific iodine potassium iodide, and eosin Y, which mostly interacts with proteins and peptides in the cell cytoplasm, the distribution of the stains within the cells in murine kidney samples is assessed and compared to unstained samples with similar structural features. Quantitative nanoscopic stain concentrations are in good agreement with dual-energy micro computed tomography measurements, the state-of-the-art modality for material-selective imaging. The presented approach can be applied to a variety of X-ray stains advancing the development of X-ray contrast agents.

Simultaneous two-color X-ray absorption spectroscopy using Laue crystals at an inverse-compton scattering X-ray facility.

X-ray absorption spectroscopy (XAS) is an element-selective technique that provides electronic and structural information of materials and reveals the essential mechanisms of the reactions involved. However, the technique is typically conducted at synchrotrons and usually only probes one element at a time. In this paper, a simultaneous two-color XAS setup at a laboratory-scale synchrotron facility is proposed based on inverse Compton scattering (ICS) at the Munich Compact Light Source (MuCLS), which is based on inverse Compton scattering (ICS). The setup utilizes two silicon crystals in a Laue geometry. A proof-of-principle experiment is presented where both silver (Ag) and palladium (Pd) K-edge X-ray absorption near-edge structure spectra were simultaneously measured. The simplicity of the setup facilitates its migration to other ICS facilities or maybe to other X-ray sources (e.g. a bending-magnet beamline). Such a setup has the potential to study reaction mechanisms and synergistic effects of chemical systems containing multiple elements of interest, such as a bimetallic catalyst system.

Spectroscopic imaging at compact inverse Compton X-ray sources.

While K-edge subtraction (KES) imaging is a commonly applied technique at synchrotron sources, the application of this imaging method in clinical imaging is limited although results have shown its superiority to conventional clinical subtraction imaging. Over the past decades, compact synchrotron X-ray sources, based on inverse Compton scattering, have been developed to fill the gap between conventional X-ray tubes and synchrotron facilities. These so called inverse Compton sources (ICSs) provide a tunable, quasi-monochromatic X-ray beam in a laboratory setting with reduced spatial and financial requirements. This allows for the transfer of imaging techniques that have been limited to synchrotrons until now, like KES imaging, into a laboratory environment. This review article presents the first studies that have successfully performed KES at ICSs. These have shown that KES provides improved image quality in comparison to conventional X-ray imaging. The results indicate that medical imaging could benefit from monochromatic imaging and KES techniques. Currently, the clinical application of KES is limited by the low K-edge energy of available iodine contrast agents. However, several ICSs are under development or already in commissioning which will provide monochromatic X-ray beams with higher X-ray energies and will enable KES using high-Z elements as contrast media. With these developments, KES at an ICS has the ability to become an important tool in pre-clinical research and potentially advancing existing clinical imaging techniques.

The versatile X-ray beamline of the Munich Compact Light Source: design, instrumentation and applications.

Inverse Compton scattering provides means to generate low-divergence partially coherent quasi-monochromatic, i.e. synchrotron-like, X-ray radiation on a laboratory scale. This enables the transfer of synchrotron techniques into university or industrial environments. Here, the Munich Compact Light Source is presented, which is such a compact synchrotron radiation facility based on an inverse Compton X-ray source (ICS). The recent improvements of the ICS are reported first and then the various experimental techniques which are most suited to the ICS installed at the Technical University of Munich are reviewed. For the latter, a multipurpose X-ray application beamline with two end-stations was designed. The beamline's design and geometry are presented in detail including the different set-ups as well as the available detector options. Application examples of the classes of experiments that can be performed are summarized afterwards. Among them are dynamic in vivo respiratory imaging, propagation-based phase-contrast imaging, grating-based phase-contrast imaging, X-ray microtomography, K-edge subtraction imaging and X-ray spectroscopy. Finally, plans to upgrade the beamline in order to enhance its capabilities are discussed.

Technical and dosimetric realization of in vivo x-ray microbeam irradiations at the Munich Compact Light Source.

PURPOSE: X-ray microbeam radiation therapy is a preclinical concept for tumor treatment promising tissue sparing and enhanced tumor control. With its spatially separated, periodic micrometer-sized pattern, this method requires a high dose rate and a collimated beam typically available at large synchrotron radiation facilities. To treat small animals with microbeams in a laboratory-sized environment, we developed a dedicated irradiation system at the Munich Compact Light Source (MuCLS). METHODS: A specially made beam collimation optic allows to increase x-ray fluence rate at the position of the target. Monte Carlo simulations and measurements were conducted for accurate microbeam dosimetry. The dose during irradiation is determined by a calibrated flux monitoring system. Moreover, a positioning system including mouse monitoring was built. RESULTS: We successfully commissioned the in vivo microbeam irradiation system for an exemplary xenograft tumor model in the mouse ear. By beam collimation, a dose rate of up to 5.3 Gy/min at 25 keV was achieved. Microbeam irradiations using a tungsten collimator with 50 µm slit size and 350 µm center-to-center spacing were performed at a mean dose rate of 0.6 Gy/min showing a high peak-to-valley dose ratio of about 200 in the mouse ear. The maximum circular field size of 3.5 mm in diameter can be enlarged using field patching. CONCLUSIONS: This study shows that we can perform in vivo microbeam experiments at the MuCLS with a dedicated dosimetry and positioning system to advance this promising radiation therapy method at commercially available compact microbeam sources. Peak doses of up to 100 Gy per treatment seem feasible considering a recent upgrade for higher photon flux. The system can be adapted for tumor treatment in different animal models, for example, in the hind leg.

Dynamic K-edge Subtraction Fluoroscopy at a Compact Inverse-Compton Synchrotron X-ray Source.

X-ray fluoroscopy is a commonly applied diagnostic tool for morphological and functional evaluation of the intestine in clinical routine. Acquisition of repetitive X-ray images following oral or rectal application of iodine contrast agent visualizes the time dependent distribution of the contrast medium, and helps to detect for example leakages, tumors or functional disorders. However, movements of the intestine and air trapped inside usually prevent temporal subtraction imaging to be applied to fluoroscopy of the gastrointestinal tract. K-edge subtraction (KES) imaging would enable subtraction fluoroscopy because it allows for imaging of moving organs with little artefacts. Although KES imaging is a well established technique at synchrotron sources, this imaging method is not applied in clinical routine as it relies on brilliant synchrotron radiation. Recently emerging compact synchrotron X-ray sources could provide a quasi-monochromatic, high-flux X-ray beam and allow for the application of KES in a laboratory environment. Here, we present a filter-based dynamic KES approach at the Munich Compact Light Source (MuCLS), the first user-dedicated installation of a compact synchrotron X-ray source worldwide. Compared to conventional temporal subtraction X-ray radiography, our approach increases the contrast while reducing the generated image artefacts.

Single spectrum three-material decomposition with grating-based x-ray phase-contrast CT.

Grating-based x-ray phase-contrast imaging provides three simultaneous image channels originating from a single image acquisition. While the phase signal provides direct access to the electron density in tomography, there is additional information on sub-resolutional structural information which is called dark-field signal in analogy to optical microscopy. The additional availability of the conventional attenuation image qualifies the method for implementation into existing diagnostic routines. The simultaneous access to the attenuation coefficient and the electron density allows for quantitative two-material discrimination as demonstrated lately for measurements at a quasi-monochromatic compact synchrotron source. Here, we investigate the transfer of the method to conventional polychromatic x-ray sources and the additional inclusion of the dark-field signal for three-material decomposition. We evaluate the future potential of grating-based x-ray phase-contrast CT for quantitative three-material discrimination for the specific case of early stroke diagnosis at conventional polychromatic x-ray sources. Compared to conventional CT, the method has the potential to discriminate coagulated blood directly from contrast agent extravasation within a single CT acquisition. Additionally, the dark-field information allows for the clear identification of hydroxyapatite clusters due to their micro-structure despite a similar attenuation as the applied contrast agent. This information on materials with sub-resolutional microstructures is considered to comprise advantages relevant for various pathologies.

Energy-Dispersive X-ray Absorption Spectroscopy with an Inverse Compton Source.

Novel compact x-ray sources based on inverse Compton scattering can generate brilliant hard x-rays in a laboratory setting. Their collimated intense beams with tunable well-defined x-ray energies make them well suited for x-ray spectroscopy techniques, which are typically carried out at large facilities. Here, we demonstrate a first x-ray absorption spectroscopy proof-of-principle experiment using an inverse Compton x-ray source with a flux of >1010 photons/s in <5% bandwidth. We measured x-ray absorption near edge structure and extended x-ray absorption fine structure at the silver K-edge (~25.5 keV) for a series of silver samples. We propose an energy-dispersive geometry specifically adapted to the x-ray beam properties of inverse Compton x-ray sources together with a fast concentration correction method that corrects sample inhomogeneities very effectively. The combination of our setup with the inverse Compton source generates x-ray absorption spectra with high energy resolution in exposure times down to one minute. Our results unravel the great benefit of inverse Compton scattering sources for x-ray absorption techniques in a laboratory environment, especially in the hard x-ray regime, which allows to probe absorption edges of high Z materials.

K-edge subtraction imaging for iodine and calcium separation at a compact synchrotron x-ray source.

Purpose: About one third of all deaths worldwide can be traced to some form of cardiovascular disease. The gold standard for the diagnosis and interventional treatment of blood vessels is digital subtraction angiography (DSA). An alternative to DSA is K-edge subtraction (KES) imaging, which has been shown to be advantageous for moving organs and for eliminating image artifacts caused by patient movement. As highly brilliant, monochromatic x-rays are required for this method, it has been limited to synchrotron facilities so far, restraining the applicability in the clinical routine. Over the past decades, compact synchrotron x-ray sources based on inverse Compton scattering have been evolving; these provide x-rays with sufficient brilliance and meet spatial and financial requirements for laboratory settings or university hospitals. Approach: We demonstrate a proof-of-principle KES imaging experiment using the Munich Compact Light Source (MuCLS), the first user-dedicated installation of a compact synchrotron x-ray source worldwide. A series of experiments were performed both on a phantom and an excised human carotid to demonstrate the ability of the proposed KES technique to separate the iodine contrast agent and calcifications. Results: It is shown that the proposed filter-based KES method allows for the iodine-contrast agent and calcium to be clearly separated, thereby providing x-ray images only showing one of the two materials. Conclusions: The results show that the quasimonochromatic spectrum of the MuCLS enables filter-based KES imaging and can become an important tool in preclinical research and possible future clinical diagnostics.

Dose and spatial resolution analysis of grating-based phase-contrast mammography using an inverse Compton x-ray source.

Purpose: Although the mortality rate of breast cancer was reduced with the introduction of screening mammography, many women undergo unnecessary subsequent examinations due to inconclusive diagnoses. Superposition of anatomical structures especially within dense breasts in conjunction with the inherently low soft tissue contrast of absorption images compromises image quality. This can be overcome by phase-contrast imaging. Approach: We analyze the spatial resolution of grating-based multimodal mammography using a mammographic phantom and one freshly dissected mastectomy specimen at an inverse Compton x-ray source. Here, the focus was on estimating the spatial resolution with the sample in the beam path and discussing benefits and drawbacks of the method used and the estimation of the mean glandular dose. Finally, the possibility of improving the spatial resolution is investigated by comparing monochromatic grating-based mammography with the standard one. Results: The spatial resolution is constant or also higher for the image acquired with monochromatic radiation and the contrast-to-noise ratio (CNR) is higher in our approach while the dose can be reduced by up to 20%. Conclusions: In summary, phase-contrast imaging helps to improve tumor detection by advanced diagnostic image quality. We demonstrate a higher spatial resolution for one mastectomy specimen and increased CNR at an equal or lower dose for the monochromatic measurements.

Nanoscopic X-ray tomography for correlative microscopy of a small meiofaunal sea-cucumber.

In the field of correlative microscopy, light and electron microscopy form a powerful combination for morphological analyses in zoology. Due to sample thickness limitations, these imaging techniques often require sectioning to investigate small animals and thereby suffer from various artefacts. A recently introduced nanoscopic X-ray computed tomography (NanoCT) setup has been used to image several biological objects, none that were, however, embedded into resin, which is prerequisite for a multitude of correlative applications. In this study, we assess the value of this NanoCT for correlative microscopy. For this purpose, we imaged a resin-embedded, meiofaunal sea cucumber with an approximate length of 1 mm, where microCT would yield only little information about the internal anatomy. The resulting NanoCT data exhibits isotropic 3D resolution, offers deeper insights into the 3D microstructure, and thereby allows for a complete morphological characterization. For comparative purposes, the specimen was sectioned subsequently to evaluate the NanoCT data versus serial sectioning light microscopy (ss-LM). To correct for mechanical instabilities and drift artefacts, we applied an alternative alignment procedure for CT reconstruction. We thereby achieve a level of detail on the subcellular scale comparable to ss-LM images in the sectioning plane.

Author Correction: K-edge Subtraction Computed Tomography with a Compact Synchrotron X-ray Source.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Model-Based Iterative Reconstruction for Propagation-Based Phase-Contrast X-Ray CT including Models for the Source and the Detector.

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.

A proof of principle experiment for microbeam radiation therapy at the Munich compact light source.

Microbeam radiation therapy (MRT), a preclinical form of spatially fractionated radiotherapy, uses an array of microbeams of hard synchrotron X-ray radiation. Recently, compact synchrotron X-ray sources got more attention as they provide essential prerequisites for the translation of MRT into clinics while overcoming the limited access to synchrotron facilities. At the Munich compact light source (MuCLS), one of these novel compact X-ray facilities, a proof of principle experiment was conducted applying MRT to a xenograft tumor mouse model. First, subcutaneous tumors derived from the established squamous carcinoma cell line FaDu were irradiated at a conventional X-ray tube using broadbeam geometry to determine a suitable dose range for the tumor growth delay. For irradiations at the MuCLS, FaDu tumors were irradiated with broadbeam and microbeam irradiation at integral doses of either 3 Gy or 5 Gy and tumor growth delay was measured. Microbeams had a width of 50 µm and a center-to-center distance of 350 µm with peak doses of either 21 Gy or 35 Gy. A dose rate of up to 5 Gy/min was delivered to the tumor. Both doses and modalities delayed the tumor growth compared to a sham-irradiated tumor. The irradiated area and microbeam pattern were verified by staining of the DNA double-strand break marker γH2AX. This study demonstrates for the first time that MRT can be successfully performed in vivo at compact inverse Compton sources.

Methods for dynamic synchrotron X-ray respiratory imaging in live animals.

Small-animal physiology studies are typically complicated, but the level of complexity is greatly increased when performing live-animal X-ray imaging studies at synchrotron and compact light sources. This group has extensive experience in these types of studies at the SPring-8 and Australian synchrotrons, as well as the Munich Compact Light Source. These experimental settings produce unique challenges. Experiments are always performed in an isolated radiation enclosure not specifically designed for live-animal imaging. This requires equipment adapted to physiological monitoring and test-substance delivery, as well as shuttering to reduce the radiation dose. Experiment designs must also take into account the fixed location, size and orientation of the X-ray beam. This article describes the techniques developed to overcome the challenges involved in respiratory X-ray imaging of live animals at synchrotrons, now enabling increasingly sophisticated imaging protocols.

Multimodal Precision Imaging of Pulmonary Nanoparticle Delivery in Mice: Dynamics of Application, Spatial Distribution, and Dosimetry.

Targeted delivery of nanomedicine/nanoparticles (NM/NPs) to the site of disease (e.g., the tumor or lung injury) is of vital importance for improved therapeutic efficacy. Multimodal imaging platforms provide powerful tools for monitoring delivery and tissue distribution of drugs and NM/NPs. This study introduces a preclinical imaging platform combining X-ray (two modes) and fluorescence imaging (three modes) techniques for time-resolved in vivo and spatially resolved ex vivo visualization of mouse lungs during pulmonary NP delivery. Liquid mixtures of iodine (contrast agent for X-ray) and/or (nano)particles (X-ray absorbing and/or fluorescent) are delivered to different regions of the lung via intratracheal instillation, nasal aspiration, and ventilator-assisted aerosol inhalation. It is demonstrated that in vivo propagation-based phase-contrast X-ray imaging elucidates the dynamic process of pulmonary NP delivery, while ex vivo fluorescence imaging (e.g., tissue-cleared light sheet fluorescence microscopy) reveals the quantitative 3D drug/particle distribution throughout the entire lung with cellular resolution. The novel and complementary information from this imaging platform unveils the dynamics and mechanisms of pulmonary NM/NP delivery and deposition for each of the delivery routes, which provides guidance on optimizing pulmonary delivery techniques and novel-designed NM for targeting and efficacy.

Contrast-enhanced spectral mammography with a compact synchrotron source.

For early breast cancer detection, mammography is nowadays the commonly used standard imaging approach, offering a valuable clinical tool for visualization of suspicious findings like microcalcifications and tumors within the breast. However, due to the superposition of anatomical structures, the sensitivity of mammography screening is limited. Within the last couple of years, the implementation of contrast-enhanced spectral mammography (CESM) based on K-edge subtraction (KES) imaging helped to improve the identification and classification of uncertain findings. In this study, we introduce another approach for CESM based on a two-material decomposition, with which we expect fundamental improvements compared to the clinical procedure. We demonstrate the potential of our proposed method using the quasi-monochromatic radiation of a compact synchrotron source-the Munich Compact Light Source (MuCLS)-and a modified mammographic accreditation phantom. For direct comparison with the clinical CESM approach, we also performed a standard dual-energy KES at the MuCLS, which outperformed the clinical CESM images in terms of contrast-to-noise ratio (CNR) and spatial resolution. However, the dual-energy-based two-material decomposition approach achieved even higher CNR values. Our experimental results with quasi-monochromatic radiation show a significant improvement of the image quality at lower mean glandular dose (MGD) than the clinical CESM. At the same time, our study indicates the great potential for the material-decomposition instead of clinically used KES to improve the quantitative outcome of CESM.

K-edge Subtraction Computed Tomography with a Compact Synchrotron X-ray Source.

In clinical diagnosis, X-ray computed tomography (CT) is one of the most important imaging techniques. Yet, this method lacks the ability to differentiate similarly absorbing substances like commonly used iodine contrast agent and calcium which is typically seen in calcifications, kidney stones and bones. K-edge subtraction (KES) imaging can help distinguish these materials by subtracting two CT scans recorded at different X-ray energies. So far, this method mostly relies on monochromatic X-rays produced at large synchrotron facilities. Here, we present the first proof-of-principle experiment of a filter-based KES CT method performed at a compact synchrotron X-ray source based on inverse-Compton scattering, the Munich Compact Light Source (MuCLS). It is shown that iodine contrast agent and calcium can be clearly separated to provide CT volumes only showing one of the two materials. These results demonstrate that KES CT at a compact synchrotron source can become an important tool in pre-clinical research.