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PurposeTo implement a tool for real time image quality feedback for chest radiographs into the clinical routine and to evaluate the effect of the system on the image quality of the acquired radiographs.Materials and MethodsA real time Artificial Intelligence (AI) image quality feedback tool is developed that analyzes chest PA x-rays right after the completion of the examination at the x-ray system and provides visual feedback to the system operator with respect to adherence to desired standards of collimation, patient rotation and inspiration. In order to track image quality changes over time, results were compared to image quality assessment for images, acquired prior to system implementation.ResultsCompared to the image quality prior to the installation of the real time image quality feedback solution, it is shown that a relative increase of images with optimal image quality with respect to collimation, patient rotation and inspiration is achieved by 30% (pDiscussionThis study shows that it is possible to significantly improve image quality using a real time AI-based image quality feedback tool. The developed tool not only provides objective and impartial criticism and helps x-ray operators identify areas for improvement, but also gives positive feedback.Key FindingsA substantial amount of images acquired in the clinical routine does not suffice the international guidelinesContinuous AI-based image quality feedback to the x-ray system operator in the clinical routine leads to a significant image quality improvement over timeUsing the developed tool, the overall fraction of images with optimal patient positioning could be improved by 30%, followed by a 34% decrease of unnecessarily exposed area.

SummaryBackgroundDiseases of the respiratory system are leading global causes of chronic morbidity and mortality. While advanced medical imaging technologies of today deliver detailed diagnostic information, a low-dose, fast, and inexpensive option for early detection and/or follow-ups is still lacking. Here, we report on the first human application of a novel modality, namely X-ray dark-field chest imaging, which might fill this gap. Enabling the assessment of microstructural changes in lung parenchyma, this technique presents a more sensitive alternative to conventional chest X-rays, and yet requires only a fraction of the dose applied in computed tomography (CT).MethodsFor this first clinical evaluation, we have built a novel dark-field chest X-ray system, which is also capable of simultaneously acquiring a conventional thorax radiograph (7 seconds, 0·035 mSv effective dose). Representing a major medical condition, we selected chronic obstructive pulmonary disease as study subject to obtain a first impression of potential diagnostic benefits relevant to humans. For a collective of 77 patients with different disease stages, X-ray dark-field- and CT-images were acquired and visually assessed by 5 readers. In addition, pulmonary function tests were performed for every patient. The individual data sets were evaluated in a statistical work-up using correlation testing, rank-based analysis of variance, and pair-wise post-hoc comparison.FindingsCompared to CT-based parameters (quantitative emphysema: ρ=–0·27, p=0·0893 and visual emphysema: ρ=–0·45, p=0·0028), the dark-field signal (ρ=0·62, pInterpretationX-ray dark-field chest imaging allows the diagnosis of pulmonary emphysema as it provides relevant information representing the structural condition of lung parenchyma. Significant diagnostic benefits are also expected for other lung disorders.FundingEuropean Research Council, Royal Philips, Karlsruhe Nano Micro Facility.Research in contextEvidence before this studyWith a rising number of examinations in the last decades, X-rays play an indispensable role in clinical routine. Contrast formation in medical X-ray imaging such as radiography, fluoroscopy, and computed tomography is based on attenuation, which generally benefits from large differences in atomic number and/or mass density between involved materials. If these conditions are not prevalent, or the resolution of the imaging system is not sufficient, diagnostic capabilities are limited. However, attenuation is not the only physical effect X-rays are subjected to when penetrating matter. Variations in an object’s electron density lead to refraction and coherent small-angle scattering of incident X-rays. Phase-sensitive imaging techniques can detect these wave-optical phenomena, yielding additional object information. The dark-field signal, being a function of small-angle scattering, can provide structural information on the micron scale, generally below the resolution limit of the imaging system. Due to their very stringent requirements to X-ray source coherence, these techniques were originally limited to large-scale synchrotron facilities. The proposal of a three-grating interferometer in 2006, however, enabled the use of low-brilliance sources for X-ray phase-contrast imaging and thereby paved the way into the clinics. Such an apparatus elegantly allows the simultaneous acquisition of the conventional attenuation, differential phase-contrast, and novel dark-field signals. In a compact table-top system suitable for investigating murine disease models, numerous studies on pulmonary disorders such as chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, pneumothorax, ventilator-associated lung injury, lung cancer, and pneumonia have been conducted and demonstrated a broad diagnostic value of the dark-field modality in particular. Adapting the system to enable imaging of the human body is a technical challenge due to limitations of the micrometer-fine, high aspect ratio grating structures in terms of fabricable size and performance at clinically relevant X-ray energies. The first evidences that these limitations are manageable were delivered in 2017 and 2018 by in-vivo porcine and human cadaver studies with an experimental prototype system.Added value of this studyWith this work we present the first X-ray dark-field chest images of human subjects in-vivo and demonstrate the method’s feasibility in a clinical surrounding. To enable this study, we have conceived, constructed, and commissioned a custom-built first demonstrator system suitable for patient use. This includes satisfying clinical demands regarding safety, usability, acquisition time, radiation dose, field of view, and image quality. This study marks the transition from investigating artificially induced disease models to evaluating the modality’s actual diagnostic performance in patients.Implications of all available evidenceOur findings indicate that X-ray dark-field radiography provides image-type information of the lungs’ underlying microstructure in humans. In view of the strong link between alveolar structure and the functional condition of the lung, this capability is highly relevant for respiratory medicine and might help to establish a better understanding of pulmonary disorders. With regard to early detection of COPD, which is generally accompanied by structural impairments of the lung, this novel technique might support resolving the prevalent under-diagnosis reported in literature. With an effective dose significantly lower (about a factor of hundred) compared to thorax computed tomography, dark-field radiography could be used as broadly deployed screening tool.

The aim of this study was to assess the diagnostic value of x-ray dark-field radiography to detect pneumothoraces in a pig model. Eight pigs were imaged with an experimental grating-based large-animal dark-field scanner before and after induction of a unilateral pneumothorax. Image contrast-to-noise ratios between lung tissue and the air-filled pleural cavity were quantified for transmission and dark-field radiograms. The projected area in the object plane of the inflated lung was measured in dark-field images to quantify the collapse of lung parenchyma due to a pneumothorax. Means and standard deviations for lung sizes and signal intensities from dark-field and transmission images were tested for statistical significance using Student’s two-tailed t-test for paired samples. The contrast-to-noise ratio between the air-filled pleural space of lateral pneumothoraces and lung tissue was significantly higher in the dark-field (3.65 ± 0.9) than in the transmission images (1.13 ± 1.1; p = 0.002). In case of dorsally located pneumothoraces, a significant decrease (−20.5%; p > 0.0001) in the projected area of inflated lung parenchyma was found after a pneumothorax was induced. Therefore, the detection of pneumothoraces in x-ray dark-field radiography was facilitated compared to transmission imaging in a large animal model.

Contains fulltext : 196944.pdf (Publisher’s version ) (Open Access) Disorders of the lungs such as chronic obstructive pulmonary disease (COPD) are a major cause of chronic morbidity and mortality and the third leading cause of death in the world. The absence of sensitive diagnostic tests for early disease stages of COPD results in under-diagnosis of this treatable disease in an estimated 60-85% of the patients. In recent years a grating-based approach to X-ray dark-field contrast imaging has shown to be very sensitive for the detection and quantification of pulmonary emphysema in small animal models. However, translation of this technique to imaging systems suitable for humans remains challenging and has not yet been reported. In this manuscript, we present the first X-ray dark-field images of in-situ human lungs in a deceased body, demonstrating the feasibility of X-ray dark-field chest radiography on a human scale. Results were correlated with findings of computed tomography imaging and autopsy. The performance of the experimental radiography setup allows acquisition of multi-contrast chest X-ray images within clinical boundary conditions, including radiation dose. Upcoming clinical studies will have to demonstrate that this technology has the potential to improve early diagnosis of COPD and pulmonary diseases in general.

X-ray chest radiography is an inexpensive and broadly available tool for initial assessment of the lung in clinical routine, but typically lacks diagnostic sensitivity for detection of pulmonary diseases in their early stages. Recent X-ray dark-field (XDF) imaging studies on mice have shown significant improvements in imaging-based lung diagnostics. Especially in the case of early diagnosis of chronic obstructive pulmonary disease (COPD), XDF imaging clearly outperforms conventional radiography. However, a translation of this technique towards the investigation of larger mammals and finally humans has not yet been achieved. In this letter, we present the first in-vivo XDF full-field chest radiographs (32 × 35 cm2) of a living pig, acquired with clinically compatible parameters (40 s scan time, approx. 80 µSv dose). For imaging, we developed a novel high-energy XDF system that overcomes the limitations of currently established setups. Our XDF radiographs yield sufficiently high image quality to enable radiographic evaluation of the lungs. We consider this a milestone in the bench-to-bedside translation of XDF imaging and expect XDF imaging to become an invaluable tool in clinical practice, both as a general chest X-ray modality and as a dedicated tool for high-risk patients affected by smoking, industrial work and indoor cooking.

Purpose: To evaluate the performance of an experimental X-ray dark-field radiography system for chest imaging in humans and to compare with conventional diagnostic imaging. Materials and Methods: The study was institutional review board (IRB) approved. A single human cadaver (52 years, female, height: 173 cm, weight: 84 kg, chest circumference: 97 cm) was imaged within 24 hours post mortem on the experimental x-ray dark-field system. In addition, the cadaver was imaged on a clinical CT system to obtain a reference scan. The grating-based dark-field radiography setup was equipped with a set of three gratings to enable grating-based dark-field contrast x-ray imaging. The prototype operates at an acceleration voltage of up to 70 kVp and with a field-of-view large enough for clinical chest x-ray (>35 x 35 cm2). Results: It was feasible to extract x-ray dark-field signal of the whole human thorax, clearly demonstrating that human x-ray dark-field chest radiography is feasible. Lung tissue produced strong scattering, reflected in a pronounced x-ray dark-field signal. The ribcage and the backbone are less prominent than the lung but are also distinguishable. Finally, the soft tissue is not present in the dark-field radiography. The regions of the lungs affected by edema, as verified by CT, showed less dark-field signal compared to healthy lung tissue. Conclusion: Our results reveal the current status of translating dark-field imaging from a micro (small animal) scale to a macro (patient) scale. The performance of the experimental x-ray dark-field radiography setup offers, for the first time, obtaining multi-contrast chest x-ray images (attenuation and dark-field signal) from a human cadaver.

X-ray grating-based interferometry promises unique new diagnostic possibilities in medical imaging and materials analysis. To transfer this method from scientific laboratories or small-animal applications to clinical radiography applications, compact setups with a large field of view (FoV) are required. Currently the FoV is limited by the grating area, which is restricted due to the complex manufacturing process. One possibility to increase the FoV is tiling individual grating tiles to create one large area grating mounted on a carrier substrate. We investigate theoretically the accuracy needed for a tiling process in all degrees of freedom by applying a simulation approach. We show how the resulting precision requirements can be met using a custom-built frame for exact positioning. Precise alignment is achieved by comparing the fringe patterns of two neighboring grating tiles in a grating interferometer. With this method, the FoV can be extended to practically any desired length in one dimension. First results of a phase-contrast scanning setup with a full FoV of 384 mm × 24 mm show the suitability of this method.

Purpose: The purpose of the present study was to evaluate if x-ray dark-field imaging can help to visualize lung cancer in mice. Materials and Methods: The experiments were performed using mutant mice with high-grade adenocarcinomas. Eight animals with pulmonary carcinoma and eight control animals were imaged in radiography mode using a prototype small-animal x-ray dark-field scanner and three of the cancerous ones additionally in CT mode. After imaging, the lungs were harvested for histological analysis. To determine their diagnostic value, x-ray dark-field and conventional attenuation images were analyzed by three experienced readers in a blind assessment. Results radiographic imaging: The lung nodules were much clearer visualized on the dark-field radiographs compared to conventional radiographs. The loss of air-tissue interfaces in the tumor leads to a significant loss of x-ray scattering, reflected in a strong dark-field signal change. The difference between tumor and healthy tissue in terms of x-ray attenuation is significantly less pronounced. Furthermore, the signal from the overlaying structures on conventional radiographs complicates the detection of pulmonary carcinoma. Results CT imaging: The very first in-vivo CT-imaging results are quite promising as smaller tumors are often better visible in the dark-field images. However the imaging quality is still quite low, especially in the attenuation images due to un-optimized scanning parameters. Conclusion: We found a superior diagnostic performance of dark-field imaging compared to conventional attenuation based imaging, especially when it comes to the detection of small lung nodules. These results support the motivation to further develop this technique and translate it towards a clinical environment.

To test the hypothesis that the joint distribution of x-ray transmission and dark-field signals obtained with a compact cone-beam preclinical scanner with a polychromatic source can be used to diagnose pulmonary emphysema in ex vivo murine lungs.The animal care committee approved this study. Three excised murine lungs with pulmonary emphysema and three excised murine control lungs were imaged ex vivo by using a grating-based micro-computed tomographic (CT) scanner. To evaluate the diagnostic value, the natural logarithm of relative transmission and the natural logarithm of dark-field scatter signal were plotted on a per-pixel basis on a scatterplot. Probability density function was fit to the joint distribution by using principle component analysis. An emphysema map was calculated based on the fitted probability density function.The two-dimensional scatterplot showed a characteristic difference between control and emphysematous lungs. Control lungs had lower average median logarithmic transmission (-0.29 vs -0.18, P = .1) and lower average dark-field signal (-0.54 vs -0.37, P = .1) than emphysematous lungs. The angle to the vertical axis of the fitted regions also varied significantly (7.8° for control lungs vs 15.9° for emphysematous lungs). The calculated emphysema distribution map showed good agreement with histologic findings.X-ray dark-field scatter images of murine lungs obtained with a preclinical scanner can be used in the diagnosis of pulmonary emphysema.http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.13122413/-/DC1.

In clinically established-absorption-based-biomedical x-ray imaging, contrast agents with high atomic numbers (e.g. iodine) are commonly used for contrast enhancement. The development of novel x-ray contrast modalities such as phase contrast and dark-field contrast opens up the possible use of alternative contrast media in x-ray imaging. We investigate using ultrasound contrast agents, which unlike iodine-based contrast agents can also be administered to patients with renal impairment and thyroid dysfunction, for application with a recently developed novel x-ray dark-field imaging modality. To produce contrast from these microbubble-based contrast agents, our method exploits ultra-small-angle coherent x-ray scattering. Such scattering dark-field x-ray images can be obtained with a grating-based x-ray imaging setup, together with refraction-based differential phase-contrast and the conventional attenuation contrast images. In this work we specifically show that ultrasound contrast agents based on microbubbles can be used to produce strongly enhanced dark-field contrast, with superior contrast-to-noise ratio compared to the attenuation signal. We also demonstrate that this method works well with an x-ray tube-based setup and that the relative contrast gain even increases when the pixel size is increased from tenths of microns to clinically compatible detector resolutions about up to a millimetre.

OBJECTIVE: The aim of this study was to evaluate the diagnostic value of x-ray dark-field imaging in projection radiography-based depiction of pneumothoraces in the neonatal murine lung, a potentially life-threatening medical condition that requires a timely and correct diagnosis. MATERIALS AND METHODS: By the use of a unique preclinical model, 7-day-old C57Bl/6N mice received mechanical ventilation for 2 or 8 hours with oxygen-rich gas (FIO2 = 0.4; n = 24). Unventilated mice either spontaneously breathed oxygen-rich gas (FIO2 = 0.4) for 2 or 8 hours or room air (n = 22). At the end of the experiment, lungs were inflated with a standardized volume of air after a lethal dose of pentobarbital was administered to the pups. All lungs were imaged with a prototype grating-based small-animal scanner to acquire x-ray transmission and dark-field radiographs. Image contrast between the air-filled pleural space and lung tissue was quantified for both transmission and dark-field radiograms. After the independent expert's assessment, 2 blinded readers evaluated all dark-field and transmission images for the presence or absence of pneumothoraces. Contrast ratios, diagnostic accuracy, as well as reader's confidence and interreader agreement were recorded for both imaging modalities. RESULTS: Evaluation of both x-ray transmission and dark-field radiographs by independent experts revealed the development of a total of 10 pneumothoraces in 8 mice. Here, the contrast ratio between the air-filled pleural space of the pneumothoraces and the lung tissue was significantly higher in the dark field (8.4 ± 3.5) when compared with the transmission images (5.1 ± 2.8; P < 0.05). Accordingly, the readers' diagnostic confidence for the diagnosis of pneumothoraces was significantly higher for dark-field compared with transmission images (P = 0.001). Interreader agreement improved from moderate for the analysis of transmission images alone (κ = 0.41) to very good when analyzing dark-field images alone (κ = 0.90) or in combination with transmission images (κ = 0.88). Diagnostic accuracy significantly improved for the analysis of dark-field images alone (P = 0.04) or in combination with transmission images (P = 0.02), compared with the analysis of transmission radiographs only. CONCLUSIONS: The significant improvement in contrast ratios between lung parenchyma and free air in the dark-field images allows the facilitated detection of pneumothoraces in the newborn mouse. These preclinical experiments indicate the potential of the technique for future clinical applications.

Background: Mechanical ventilation (MV) and the supplementation of oxygen-rich gas, often needed in postnatal resuscitation procedures, are known to be main risk factors for impaired pulmonary development in the preterm and term neonates. We analyzed whether the advance from conventional x-ray technology to x-ray dark-field radiography can improve visualization of early lung injury induced by MV and hyperoxia in neonatal mice. Methods: 5-7-day-old wild type C57BL/6 mice were mechanically ventilated with oxygen-enriched gas (MV-O 2 ; FiO 2 0.4) for 2 or 8 hours. Unventilated, spontaneously breathing littermates were kept in FiO 2 0.4 for 2 and 8 hours or in room air. After pulmonary function testing, the animals were imaged using a prototype small-animal x-ray dark-field scanner before standardized fixation for histologic analysis. Results: X-ray dark field of neonatal mice undergoing hyperoxia and MV-O2 revealed increasing loss of x-ray small-angle scattering when compared to the images obtained from animals kept in room air. The observed changes assessed by imaging correlated well with results of histologic analysis and were found to yield superior differentiation than lung function testing. Conclusion: The present study was able to show, that X-ray dark-field radiography acquired with a grating interferometer visualizes already minor changes in the morphology of the developing lung, caused by hyperoxia or MV-O 2 . In the future, this imaging technique can be applied to provide early diagnosis and monitor treatment regimen in neonatal lung injury by appropriate surveillance protocols.

The aim of this study was to evaluate whether diagnosing pulmonary fibrosis with projection radiography can be improved by using X-ray dark-field radiograms. Pulmonary X-ray transmission and dark-field images of C57Bl/6N mice, either treated with bleomycin to induce pulmonary fibrosis or PBS to serve as controls, were acquired with a prototype grating-based small-animal scanner. Two blinded readers, both experienced radiologists and familiar with dark-field imaging, had to assess dark-field and transmission images for the absence or presence of fibrosis. Furthermore readers were asked to grade their stage of diagnostic confidence. Histological evaluation of the lungs served as the standard of reference in this study. Both readers showed a notably higher diagnostic confidence when analyzing the dark-field radiographs (p

Accounting for about 1.5 million deaths annually, lung cancer is the prevailing cause of cancer deaths worldwide, mostly associated with long-term smoking effects. Numerous small-animal studies are performed currently in order to better understand the pathogenesis of the disease and to develop treatment strategies. Within this letter, we propose to exploit X-ray dark-field imaging as a novel diagnostic tool for the detection of lung cancer on projection radiographs. Here, we demonstrate in living mice bearing lung tumors, that X-ray dark-field radiography provides significantly improved lung tumor detection rates without increasing the number of false-positives, especially in the case of small and superimposed nodules, when compared to conventional absorption-based imaging. While this method still needs to be adapted to larger mammals and finally humans, the technique presented here can already serve as a valuable tool in evaluating novel lung cancer therapies, tested in mice and other small animal models.

In the field of biomedical X-ray imaging, novel techniques, such as phase-contrast and dark-field imaging, have the potential to enhance the contrast and provide complementary structural information about a specimen. In this paper, a first prototype of a preclinical X-ray phase-contrast CT scanner based on a Talbot-Lau interferometer is characterized. We present a study of the contrast-to-noise ratios for attenuation and phase-contrast images acquired with the prototype scanner. The shown results are based on a series of projection images and tomographic data sets of a plastic phantom in phase and attenuation-contrast recorded with varying acquisition settings. Subsequently, the signal and noise distribution of different regions in the phantom were determined. We present a novel method for estimation of contrast-to-noise ratios for projection images based on the cylindrical geometry of the phantom. Analytical functions, representing the expected signal in phase and attenuation-contrast for a circular object, are fitted to individual line profiles of the projection data. The free parameter of the fit function is used to estimate the contrast and the goodness of the fit is determined to assess the noise in the respective signal. The results depict the dependence of the contrast-to-noise ratios on the applied source voltages, the number of steps of the phase stepping routine, and the exposure times for an individual step. Moreover, the influence of the number of projection angles on the image quality of CT slices is investigated. Finally, the implications for future imaging purposes with the scanner are discussed.

X-ray computed tomography of small animals and their organs is an essential tool in basic and preclinical biomedical research. In both phase-contrast and absorption tomography high spatial resolution and short exposure times are of key importance. However, the observable spatial resolutions and achievable exposure times are presently limited by system parameters rather than more fundamental constraints like, e.g., dose. Here we demonstrate laboratory tomography with few-ten μm spatial resolution and few-minute exposure time at an acceptable dose for small-animal imaging, both with absorption contrast and phase contrast. The method relies on a magnifying imaging scheme in combination with a high-power small-spot liquid-metal-jet electron-impact source. The tomographic imaging is demonstrated on intact mouse, phantoms and excised lungs, both healthy and with pulmonary emphysema.

Changes in x-ray attenuating tissue caused by lung disorders like emphysema or fibrosis are subtle and thus only resolved by high-resolution computed tomography (CT). The structural reorganization, however, is of strong influence for lung function. Dark-field CT (DFCT), based on small-angle scattering of x-rays, reveals such structural changes even at resolutions coarser than the pulmonary network and thus provides access to their anatomical distribution. In this proof-of-concept study we present x-ray in vivo DFCTs of lungs of a healthy, an emphysematous and a fibrotic mouse. The tomographies show excellent depiction of the distribution of structural – and thus indirectly functional – changes in lung parenchyma, on single-modality slices in dark field as well as on multimodal fusion images. Therefore, we anticipate numerous applications of DFCT in diagnostic lung imaging. We introduce a scatter-based Hounsfield Unit (sHU) scale to facilitate comparability of scans. In this newly defined sHU scale, the pathophysiological changes by emphysema and fibrosis cause a shift towards lower numbers, compared to healthy lung tissue., Highlights • We present so far unreported x-ray scatter dark-field CT scans of living mice performed with a Talbot–Lau interferometer. • Dark field gives access to structural information not provided by attenuation CT at scales below the detector pixel size. • Changes of lung alveoli structure are clearly visualized by dark-field CT for emphysema and fibrosis. Lung diseases pose one of the leading causes of death worldwide. They are often difficult to diagnose at an early stage due to low sensitivity of conventional medical imaging systems towards structural changes of the lung tissue. With dark-field imaging based on scattering of x-rays such structural changes can be visualized even at imaging system resolutions coarser than the lung alveoli, as opposed to conventional x-ray imaging based on attenuation. By overcoming experimental scan time and dose issues, we report the first dark-field computed tomography scans on living mice, demonstrating excellent depiction of the anatomical distribution of pathological lung changes.

X-ray grating interferometry requires gratings with periods in the micrometer range and allows the acquisition of the dark-field contrast. The analyzer grating is designed to match the period of the interference pattern in order to translate it into a measurable intensity modulation. In this study, we explore the influence of a sample-induced mismatch between the interference pattern and the analyzer grating on the dark-field contrast. We propose a formula for the calculation of the signal due to a period mismatch and present estimations varying periods and detector pixel size. Furthermore, numerical simulations of the X-ray wave-front demonstrate that the wave-front curvature, described by the lens-term, e.g. behind a parabolic lens or edges of a sample can change the period of the interference pattern. Our results give a concrete explanation for the formation of a dark-field contrast from object edges and thus allow a better understanding of the dark-field signal obtained with a grating interferometer.

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive lung disease with a median life expectancy of 4-5 years after initial diagnosis. Early diagnosis and accurate monitoring of IPF are limited by a lack of sensitive imaging techniques that are able to visualize early fibrotic changes at the epithelial-mesenchymal interface. Here, we report a new x-ray imaging approach that directly visualizes the air-tissue interfaces in mice in vivo. This imaging method is based on the detection of small-angle x-ray scattering that occurs at the air-tissue interfaces in the lung. Small-angle scattering is detected with a Talbot-Lau interferometer, which provides the so-called x-ray dark-field signal. Using this imaging modality, we demonstrate-for the first time-the quantification of early pathogenic changes and their correlation with histological changes, as assessed by stereological morphometry. The presented radiography method is significantly more sensitive in detecting morphological changes compared with conventional x-ray imaging, and exhibits a significantly lower radiation dose than conventional x-ray CT. As a result of the improved imaging sensitivity, this new imaging modality could be used in future to reduce the number of animals required for pulmonary research studies.

Grating-based X-ray dark-field contrast is an emerging new imaging modality that is demonstrating particularly high potential for radiography. The signal in dark-field X-ray imaging is determined by small-angle X-ray scattering at structures typically below the spatial resolution of the imaging setup. Thus, this technique not only yields complementary information but also visualizes information that lies under the resolution limit for conventional, absorption-based radiography. Grating-based X-ray dark-field imaging has been shown to be feasible with both synchrotron radiation and conventional X-ray tubes. Lung, breast, and bone imaging have been identified as the applications promising the main impact, but other applications are on the horizon. Specifically, dark-field radiography has been used to detect pulmonary emphysema and assesses its regional distribution in mice and holds promise to improve the visualization of micro-calcifications in mammography and yields information about bone microstructure. Further technical developments are required to make the technique suitable for clinical use.

The main shortcoming of conventional biomedical x-ray imaging is the weak soft-tissue contrast caused by the small differences in the absorption coefficients between different materials. This issue can be addressed by x-ray phasesensitive imaging approaches, e.g. x-ray Talbot-Lau grating interferometry. The advantage of the three-grating Talbot-Lau approach is that it allows to acquire x-ray phase-contrast and dark-field images with a conventional lab source. However, through the introduction of the grating interferometer some constraints are imposed on the setup geometry. In general, the grating pitch and the mean x-ray energy determine the setup dimensions. The minimal length of the setup increases linearly with energy and is proportional to p2, where p is the grating pitch. Thus, a high-energy (100 keV) compact grating-based setup for x-ray imaging can be realized only if gratings with aspect-ratio of approximately 300 and a pitch of 1-2 μm were available. However, production challenges limit the availability of such gratings. In this study we consider the use of non-binary phase-gratings as means of designing a more compact grating interferometer for phase-contrast imaging. We present simulation and experimental data for both monochromatic and polychromatic case. The results reveal that phase-gratings with triangular-shaped structures yield visibilities that can be used for imaging purposes at significantly shorter distances than binary gratings. This opens the possibility to design a high-energy compact setup for x-ray phase-contrast imaging. Furthermore, we discuss different techniques to achieve triangular-shaped phase-shifting structures.

X-ray imaging using a Talbot-Lau interferometer, consisting of three binary gratings, is a well-established approach to acquire x-ray phase-contrast and dark-field images with a polychromatic source. However, challenges in the production of high aspect ratio gratings limit the construction of a compact setup for high x-ray energies. In this study we consider the use of phase gratings with triangular-shaped structures in an x-ray interferometer and show that such gratings can yield high visibilities for significantly shorter propagation distances than conventional gratings with binary structures. The findings are supported by simulation and experimental results for both cases of a monochromatic and a polychromatic source.

OBJECTIVES: The purpose of this study was to assess whether the recently developed method of grating-based x-ray dark-field radiography can improve the diagnosis of pulmonary emphysema in vivo. MATERIALS AND METHODS: Pulmonary emphysema was induced in female C57BL/6N mice using endotracheal instillation of porcine pancreatic elastase and confirmed by in vivo pulmonary function tests, histopathology, and quantitative morphometry. The mice were anesthetized but breathing freely during imaging. Experiments were performed using a prototype small-animal x-ray dark-field scanner that was operated at 35 kilovolt (peak) with an exposure time of 5 seconds for each of the 10 grating steps. Images were compared visually. For quantitative comparison of signal characteristics, regions of interest were placed in the upper, middle, and lower zones of each lung. Receiver-operating-characteristic statistics were performed to compare the effectiveness of transmission and dark-field signal intensities and the combined parameter "normalized scatter" to differentiate between healthy and emphysematous lungs. RESULTS: A clear visual difference between healthy and emphysematous mice was found for the dark-field images. Quantitative measurements of x-ray dark-field signal and normalized scatter were significantly different between the mice with pulmonary emphysema and the control mice and showed good agreement with pulmonary function tests and quantitative histology. The normalized scatter showed a significantly higher discriminatory power (area under the receiver-operating-characteristic curve [AUC], 0.99) than dark-field (AUC, 0.90; P = 0.01) or transmission signal (AUC, 0.69; P < 0.001) alone did, allowing for an excellent discrimination of healthy and emphysematous lung regions. CONCLUSIONS: In a murine model, x-ray dark-field radiography is technically feasible in vivo and represents a substantial improvement over conventional transmission-based x-ray imaging for the diagnosis of pulmonary emphysema.

Purpose: The purpose of this study was to assess whether grating-based X-ray imaging may have a role in imaging of pulmonary nodules on radiographs. Materials and methods: A mouse lung containing multiple lung tumors was imaged using a small-animal scanner with a conventional X-ray source and a grating interferometer for phase-contrast imaging. We qualitatively compared the signal characteristics of lung nodules on transmission, dark-field and phase-contrast images. Furthermore, we quantitatively compared signal characteristics of lung tumors and the adjacent lung tissue and calculated the corresponding contrast-to-noise ratios. Results: Of the 5 tumors visualized on the transmission image, 3/5 tumors were clearly visualized and 1 tumor was faintly visualized in the dark-field image as areas of decreased small angle scattering. In the phase-contrast images, 3/5 tumors were clearly visualized, while the remaining 2 tumors were faintly visualized by the phase-shift occurring at their edges. No additional tumors were visualized in either the dark-field or phase-contrast images. Compared to the adjacent lung tissue, lung tumors were characterized by a significant decrease in transmission signal (median 0.86 vs. 0.91, p = 0.04) and increase in dark-field signal (median 0.71 vs. 0.65, p = 0.04). Median contrast-to-noise ratios for the visualization of lung nodules were 4.4 for transmission images and 1.7 for dark-field images (p = 0.04). Conclusion: Lung nodules can be visualized on all three radiograph modalities derived from grating-based X-ray imaging. However, our initial data suggest that grating-based multimodal X-ray imaging does not increase the sensitivity of chest radiographs for the detection of lung nodules. (C) 2013 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved. (Less)

Pulmonary emphysema is a widespread disorder characterized by irreversible destruction of alveolar walls. The spatial distribution of the disease, so far, could only be obtained using an X-ray CT scan, implying a high patient dose. X-ray scattering on alveolar structures is measured in the dark-field signal. The signal is dependent on the size of alveoli and therefore, a combination of absorption and darkfield signal is explored for mapping the distribution of emphysema in the lung on x-ray projection images. In this study three excised murine lungs with pulmonary emphysema and three control samples were imaged using a compact, cone-beam, small-animal x-ray dark-field scanner with a polychromatic source. Statistical analysis of the results, based on a combination of transmission and darkfield signals, revealed a distinct difference between emphysematous and control samples. Subsequently, the distribution of emphysema was mapped out per-pixel for the lungs and showed good agreement with histological findings.

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).

We have developed a compact grating-based in-vivo phase-contrast micro-CT system with a rotating gantry. The 50 W microfocus x-ray source operates with 20 to 50 kV peak energy. The length of the rotating interferometer is around 47 cm. Pixel size in the object is 30 micron; the field of view is approx. 35 mm in diameter, suited to image a mouse. The interferometer consists of three gratings: an absorption grating close to the x-ray source, a phase grating to introduce a π/2 phase shift and an absorption analyzer grating positioned at the first fractional Talbot distance. Numerous drives and actuators are used to provide angular and linear grating alignment, phase stepping and object/gantry precision positioning. Phantom studies were conducted to investigate performance, accuracy and stability of the scanner. In particular, the influences of gantry rotation and of temperature fluctuations on the interferometric image acquisition were characterized. Also dose measurements were performed. The first imaging results obtained with the system show the complementary nature of phase-contrast micro-CT images with respect to absorption-based micro-CT. Future improvements, necessary to optimize the scanner for in-vivo small-animal CT scanning on a regular and easy-to-use basis, are also discussed.

After successful demonstrations of soft-tissue phase-contrast imaging with grating interferometers at synchrotron radiation sources and at laboratory based x-ray tubes, a first preclinical CT scanner with grating based phase contrast imaging modality has been constructed. The rotating gantry is equipped with a three-grating interferometer, a 50 watt tungsten anode source and a Hamamatsu flat panel detector. The total length of the interferometer is 45 cm, and the bed of the scanner is optimized for mice, with a scanning diameter of 35 mm. From one single scan both phase-contrast and standard attenuation based tomography can be attained, providing an overall gain in image contrast.

The dark-field signal obtained with X-ray grating interferometry combines the object's small-angle scattering auto-correlation function with an imaging modality. Here we report on the measurement of such correlation functions with a laboratory X-ray system. By fitting a theoretical model to the data we are able to determine the size and short-range order of the scattering structures. Thus, a quantitative interpretation of the dark-field signal is also possible with a polychromatic and divergent beam. We further show how the microscopic information is obtained for mesoscale objects and can be represented in order to overlay the microstructural information on top of the macrostructure. The quantitative real-space information on the form and structure factor makes this technique highly attractive for materials science as it allows one to study these properties in the laboratory.

PURPOSE The purpose of this study was to evaluate the dose characteristic for patient examinations at the first clinical X-ray dark-field chest radiography system and to determine whether the effective patient dose is within a clinically acceptable dose range. METHODS A clinical setup for grating-based dark-field chest radiography was constructed and commissioned, operating at a tube voltage of 70 kVp. Thermoluminescent dosimeter (TLD) measurements were conducted using an anthropomorphic phantom modeling the reference person to obtain a conversion coefficient relating dose area product (DAP) to effective patient dose at the dark-field system. For 92 patients, the DAP values for posterior-anterior measurements were collected at the dark-field system. Using the previously determined conversion coefficient, the effective dose was calculated. RESULTS A reference person, modeled by an anthropomorphic phantom, receives an effective dose of 35 µSv. For the examined patients, a mean effective dose of 39 µSv was found. CONCLUSIONS The effective dose at the clinical dark-field radiography system, generating both attenuation and dark-field images, is within the range of reported standard dose values for chest radiography.

The aim of this study was to evaluate the feasibility of early stage imaging of acute lung inflammation in mice using grating-based X-ray dark-field imaging in vivo. Acute lung inflammation was induced in mice by orotracheal instillation of porcine pancreatic elastase. Control mice received orotracheal instillation of PBS. Mice were imaged immediately before and 1 day after the application of elastase or PBS to assess acute changes in pulmonary structure due to lung inflammation. Subsequently, 6 mice from each group were sacrificed and their lungs were lavaged and explanted for histological analysis. A further 7, 14 and 21 days later the remaining mice were imaged again. All images were acquired with a prototype grating-based small-animal scanner to generate dark-field and transmission radiographs. Lavage confirmed that mice in the experimental group had developed acute lung inflammation one day after administration of elastase. Acute lung inflammation was visible as a striking decrease in signal intensity of the pulmonary parenchyma on dark-field images at day 1. Quantitative analysis confirmed that dark-field signal intensity at day 1 was significantly lower than signal intensities measured at the remaining timepoints, confirming that acute lung inflammation can be depicted in vivo with dark-field radiography.