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Dark-field radiography of the human chest is a promising novel imaging technique with the potential of becoming a valuable tool for the early diagnosis of chronic obstructive pulmonary disease and other diseases of the lung. The large field-of-view needed for clinical purposes could recently be achieved by a scanning system. While this approach overcomes the limited availability of large area grating structures, it also results in a prolonged image acquisition time, leading to concomitant motion artifacts caused by intrathoracic movements (e.g. the heartbeat). Here we report on a motion artifact reduction algorithm for a dark-field X-ray scanning system, and its successful evaluation in a simulated chest phantom and human in vivo chest X-ray dark-field data. By partitioning the acquired data into virtual scans with shortened acquisition time, such motion artifacts may be reduced or even fully avoided. Our results demonstrate that motion artifacts (e.g. induced by cardiac motion or diaphragmatic movements) can effectively be reduced, thus significantly improving the image quality of dark-field chest radiographs.

Objectives To compare the visibility of anatomical structures and overall quality of the attenuation images obtained with a dark-field X-ray radiography prototype with those from a commercial radiography system. Methods Each of the 65 patients recruited for this study obtained a thorax radiograph at the prototype and a reference radiograph at the commercial system. Five radiologists independently assessed the visibility of anatomical structures, the level of motion artifacts, and the overall image quality of all attenuation images on a five-point scale, with 5 points being the highest rating. The average scores were compared between the two image types. The differences were evaluated using an area under the curve (AUC) based z-test with a significance level of p ≤ 0.05. To assess the variability among the images, the distributions of the average scores per image were compared between the systems. Results The overall image quality was rated high for both devices, 4.2 for the prototype and 4.6 for the commercial system. The rating scores varied only slightly between both image types, especially for structures relevant to lung assessment, where the images from the commercial system were graded slightly higher. The differences were statistically significant for all criteria except for the bronchial structures, the cardiophrenic recess, and the carina. Conclusions The attenuation images acquired with the prototype were assigned a high diagnostic quality despite a lower resolution and the presence of motion artifacts. Thus, the attenuation-based radiographs from the prototype can be used for diagnosis, eliminating the need for an additional conventional radiograph. Key Points • Despite a low tube voltage (70 kVp) and comparably long acquisition time, the attenuation images from the dark-field chest radiography system achieved diagnostic quality for lung assessment. • Commercial chest radiographs obtained a mean rating score regarding their diagnostic quality of 4.6 out of 5, and the grating-based images had a slightly lower mean rating score of 4.2 out of 5. • The difference in rating scores for anatomical structures relevant to lung assessment is below 5%.

Resubmitted for review at IEEE TMI on February 7th, 2023.

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.

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.

Background Dark-field chest radiography allows for assessment of lung alveolar structure by exploiting wave optical properties of x-rays. Purpose To evaluate the qualitative and quantitative features of dark-field chest radiography in participants with pulmonary emphysema as compared with those in healthy control subjects. Materials and Methods In this prospective study conducted from October 2018 to October 2020, participants aged at least 18 years who underwent clinically indicated chest CT were screened for participation. Inclusion criteria were an ability to consent to the procedure and stand upright without help. Exclusion criteria were pregnancy, serious medical conditions, and any lung condition besides emphysema that was visible on CT images. Participants were examined with a clinical dark-field chest radiography prototype that simultaneously acquired both attenuation-based radiographs and dark-field chest radiographs. Dark-field coefficients were tested for correlation with each participant's CT-based emphysema index using the Spearman correlation test. Dark-field coefficients of adjacent groups in the semiquantitative Fleischner Society emphysema grading system were compared using a Wilcoxon Mann-Whitney

Phase-contrast imaging is one of the standard X-ray imaging methods at synchrotron beamlines and has already proven to be beneficial for soft-tissue visualization. However, most implementations use single-distance inline phase-contrast techniques, and are thus not able to provide quantitative information. To access these, grating-based imaging (GBI) setups or, rather recently, speckle-based imaging (SBI) methods can be used. We built a new grating-based setup at the beamline P05 operated by HZG at the storage ring PETRA III / DESY. This new setup overcomes the previously reported limitations in spatial resolution compared to inline phase-contrast imaging. Furthermore, it allows for accurate quantitative phase contrast micro computed tomography of biological soft tissue. We replaced the typically used sandpaper by a 2D phase-grating as a wavefront marker, which increased the visibility and allowed for using fewer phase steps. Combined with an existing SBI phase-retrieval algorithm, the so-called Unified Modulated Pattern Analysis (UMPA) and an optimized scan protocol, we reached a resolution below 4 microns in scan times less than two hours. We investigated stained and unstained tissue samples, to quantify the staining process of different tissue types and were able to observe an increase in electron density, dependent on the stain and tissue type. By this, we could show the successful operation of our setup to quantitatively investigate samples on a micro meter scale at the beamline P05.

Background X-ray dark-field radiography takes advantage of the wave properties of x-rays, with a relatively high signal in the lungs due to the many air-tissue interfaces in the alveoli. Purpose To describe the qualitative and quantitative characteristics of x-ray dark-field images in healthy human subjects. Materials and Methods Between October 2018 and January 2020, patients of legal age who underwent chest CT as part of their diagnostic work-up were screened for study participation. Inclusion criteria were a normal chest CT scan, the ability to consent, and the ability to stand upright without help. Exclusion criteria were pregnancy, serious medical conditions, and changes in the lung tissue, such as those due to cancer, pleural effusion, atelectasis, emphysema, infiltrates, ground-glass opacities, or pneumothorax. Images of study participants were obtained by using a clinical x-ray dark-field prototype, recently constructed and commissioned at the authors' institution, to simultaneously acquire both attenuation-based and dark-field thorax radiographs. Each subject's total dark-field signal was correlated with his or her lung volume, and the dark-field coefficient was correlated with age, sex, weight, and height. Results Overall, 40 subjects were included in this study (average age, 62 years ± 13 [standard deviation]; 26 men, 14 women). Normal human lungs have high signal, while the surrounding osseous structures and soft tissue have very low and no signal, respectively. The average dark-field signal was 2.5 m-1 ± 0.4 of examined lung tissue. There was a correlation between the total dark-field signal and the lung volume (r = 0.61, P < .001). No difference was found between men and women (P = .78). Also, age (r = -0.18, P = .26), weight (r = 0.24, P = .13), and height (r = 0.01, P = .96) did not influence dark-field signal. Conclusion This study introduces qualitative and quantitative values for x-ray dark-field imaging in healthy human subjects. The quantitative x-ray dark-field coefficient is independent from demographic subject parameters, emphasizing its potential in diagnostic assessment of the lung. ©RSNA, 2021 See also the editorial by Hatabu and Madore in this issue.

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.

Optica 8(12), 1588 - 1595 (2021). doi:10.1364/OPTICA.441004, Two-dimensional (2D) Talbot array illuminators (TAIs) were designed, fabricated, and evaluated for high-resolution high-contrast x-ray phase imaging of soft tissue at 10���20 keV. The TAIs create intensity modulations with a high compression ratio on the micrometer scale at short propagation distances. Their performance was compared with various other wavefront markers in terms of period, visibility, flux efficiency, and flexibility to be adapted for limited beam coherence and detector resolution. Differential x-ray phase contrast and dark-field imaging were demonstrated with a one-dimensional, linear phase stepping approach yielding 2D phase sensitivity using unified modulated pattern analysis (UMPA) for phase retrieval. The method was employed for x-ray phase computed tomography reaching a resolution of 3 ��m on an unstained murine artery. It opens new possibilities for three-dimensional, non-destructive, and quantitative imaging of soft matter such as virtual histology. The phase modulators can also be used for various other x-ray applications such as dynamic phase imaging, super-resolution structured illumination microscopy, or wavefront sensing., Published by OSA, Washington, DC

In this article, we report on a novel acquisition scheme for time- and dose-saving retrieval of dark-field data in grating-based phase-contrast imaging. In comparison to currently available techniques, the proposed approach only requires two phase steps. More importantly, our method is capable of accurately retrieving the dark-field signal where conventional approaches fail, for instance in the case of very low photon statistics. Finally, we successfully extend two-shot dark-field imaging to tomographic investigations, by implementing an iterative reconstruction with appropriate weights. Our results indicate an important progression towards the clinical feasibility of dark-field tomography.

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.

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.

Background Spirometry and conventional chest x-ray have limitations in investigating early emphysema, while computed tomography, the reference imaging method in this context, is not part of routine patient care due to its higher radiation dose. In this work, we investigated a novel low-dose imaging modality, dark-field chest x-ray, for the evaluation of emphysema in patients with alpha1-antitrypsin deficiency. Methods By exploiting wave properties of x-rays for contrast formation, dark-field chest x-ray visualises the structural integrity of the alveoli, represented by a high signal over the lungs in the dark-field image. We investigated four patients with alpha1-antitrypsin deficiency with a novel dark-field x-ray prototype and simultaneous conventional chest x-ray. The extent of pulmonary function impairment was assessed by pulmonary function measurement and regional emphysema distribution was compared with CT in one patient. Results We show that dark-field chest x-ray visualises the extent of pulmonary emphysema displaying severity and regional differences. Areas with low dark-field signal correlate with emphysematous changes detected by computed tomography using a threshold of -950 Hounsfield units. The airway parameters obtained by whole-body plethysmography and single breath diffusing capacity of the lungs for carbon monoxide demonstrated typical changes of advanced emphysema. Conclusions Dark-field chest x-ray directly visualised the severity and regional distribution of pulmonary emphysema compared to conventional chest x-ray in patients with alpha1-antitrypsin deficiency. Due to the ultra-low radiation dose in comparison to computed tomography, dark-field chest x-ray could be beneficial for long-term follow-up in these patients.