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Mapping cardiac-induced lung motion using high-resolution time-resolved phase-contrast synchrotron computed tomography

OBJECTIVE. The aim of this study was to quantitatively assess hyaline cartilage and subchondral bone conditions in a fully preserved cadaveric human knee joint using high-resolution x-ray propagation-based phase-contrast imaging (PBI) CT and to compare the performance of the new technique with conventional CT and MRI. MATERIALS AND METHODS. A cadaveric human knee was examined using an x-ray beam of 60 keV, a detector with a 90-mm 2 FOV, and a pixel size of 46 × 46 µm 2 . PBI CT images were reconstructed with both the filtered back projection algorithm and the equally sloped tomography method. Conventional 3-T MRI and CT were also performed. Measurements of cartilage thickness, cartilage lesions, International Cartilage Repair Society scoring, and detection of subchondral bone changes were evaluated. Visual inspection of the specimen akin to arthroscopy was conducted and served as a standard of reference for lesion detection. RESULTS. Loss of cartilage height was visible on PBI CT and MRI. Quantification of cartilage thickness showed a strong correlation between the two modalities. Cartilage lesions appeared darker than the adjacent cartilage on PBI CT. PBI CT showed similar agreement to MRI for depicting cartilage substance defects or lesions compared with the visual inspection. The assessment of subchondral bone cysts showed moderate to strong agreement between PBI CT and CT. CONCLUSION. In contrast to the standard clinical methods of MRI and CT, PBI CT is able to simultaneously depict cartilage and bony changes at high resolution. Though still an experimental technique, PBI CT is a promising high-resolution imaging method to evaluate comprehensive changes of osteoarthritic disease in a clinical setting.

International audience; Theranostics is an innovative research field that aims to develop high target specificity cancer treatments by administering small metal-based nanoparticles (NPs). This new generation of compounds exhibits diagnostic and therapeutic properties due to the high atomic number of their metal component. In the framework of a combined research program on low dose X-ray imaging and theranostic NPs, X-ray Phase Contrast Tomography (XPCT) was performed at ESRF using a 3 μm pixel optical system on two samples: a mouse brain bearing melanoma metastases injected with gadolinium NPs and, a mouse liver injected with gold NPs. XPCT is a non-destructive technique suitable to achieve the 3D reconstruction of a specimen and, widely used at micro-scale to detect abnormalities of the vessels, which are associated to the tumor growth or to the development of neurodegenerative diseases. Moreover, XPCT represents a promising and complementary tool to study the biodistribution of theranostic NPs in biological materials, thanks to the strong contrast with respect to soft tissues that metal-based NPs provide in radiological images. This work is relied on an original imaging approach based on the evaluation of the contrast differences between the images acquired below and above K-edge energies, as a proof of the certain localization of NPs. We will present different methods aiming to enhance the localization of NPs and a 3D map of their distribution in large volume of tissues.

International audience; The word "theranostic" derives from the fusion of two terms: therapeutic and diagnostic. It is a promising research field that aims to develop innovative therapies with high target specificity by exploiting the therapeutic and diagnostic properties, in particular for metal-based nanoparticles (NPs) developed to erase cancer. In the framework of a combined research program on low dose X-ray imaging and theranostic nanoparticles (NPs), high resolution Phase-Contrast Tomography images of mice organs injected with gadolinium and gold-NPs were acquired at the European Synchrotron Radiation Facility (ESRF). Both compounds are good X-ray contrast agents due to their high attenuation coefficient with respect to biological tissues, especially immediately above K-edge energy. X-ray tomography is a powerful non-invasive technique to image the 3D vasculature network in order to detect abnormalities. Phase contrast methods provide more detailed anatomical information with higher discrimination among soft tissues. We present the images of mice liver and brain injected with gold and gadolinium NPs, respectively. We discuss different image processing methods used aiming at enhancing the accuracy on localizing nanoparticles.

Phase-contrast imaging (PCI) on synchrotron radiation (SR) light source has become a paradigm in X-ray biomedical imaging. In vitro and in vivo biomedical research has attracted high attention thanks to its capability of providing high diagnostic significant images in a wide range of organs or viscera, including the breast, joints, cartilage, lung, eyes, vasculature, brain and central nervous system. In this chapter, the basic principle, main phase-contrast imaging methods and their bio-medical applications are introduced. Various imaging methods are described and evaluated. The prospect and limitations of synchrotron-based medical imaging are briefly discussed as well.

Thanks to their high detection efficiency and low intrinsic noise, direct conversion X-ray Photon Counting Detectors (XPCDs) are particularly suitable for low dose imaging applications such as mammography. The photon counting technology can implement also two or more acquisition thresholds to perform single-shot spectral imaging with one polychromatic source. However, XPCDs with thick high Z crystal sensor and small pixel size are affected by the charge sharing effect. This issue can induce multiple counts from a single interaction reducing both spectral and spatial resolutions. In a pure counting mode, multiple counts from charge sharing can be partially or totally removed by increasing the acquisition threshold at the cost of a loss of efficiency. Thus, the performances of XPCDs can be threshold-dependent. New generation XPCDs implement solutions to cope with charge sharing issue. If the charge sharing is properly corrected, no multiple counts are recorded and the performances (detection efficiency, spectral and spatial resolutions) of the acquisition system are expected to be independent from the acquisition threshold. This work presents a study of a Pixirad-1 detection system based on a CdTe Schottky sensor and PIXIE-III readout system. This chip can be configured in three different operation modes, two of which implement solutions to remove multiple counts. Using monochromatic radiation, the performances of these different operation modes have been compared trough a measure of the integral spectra and the Signal to Noise Ratio (SNR) as function of the acquisition threshold.

Regarding the basics of ear structure-function relationships in fish, the actual motion of the solid otolith relative to the underlying sensory epithelium has rarely been investigated. Otolith motion has been characterized based on a few experimental studies and on approaches using mathematical modeling, which have yielded partially conflicting results. Those studies either predicted a simple back-and-forth motion of the otolith or a shape-dependent, more complex motion. Our study was designed to develop and test a new set-up to generate experimental data on fish otolith motion in-situ. Investigating the basic parameters of otolith motion requires an approach with high spatial and temporal resolution. We therefore used hard X-ray phase contrast imaging (XPCI). We compared two anatomically well-studied cichlid species, Steatocranus tinanti and Etroplus maculatus, which, among other features, differ in the 3D shape of their otoliths. In a water-filled tank, we presented a pure tone of 200 Hz to 1) isolated otoliths embedded in agarose serving as a simple model or 2) to a fish (otoliths in-situ). Our new set-up successfully visualized the motion of otoliths in-situ and therefore paves the way for future studies evaluating the principles of otolith motion.

CONTENTS 50.1 Introduction 50.2 General Considerations 50.3 Analyzer-Based Imaging 50.3.1 The Rocking Curve 50.3.2 A Simple Model of AB Image Formation 50.3.2.1 The Sample Introduces Refraction, But No USAXS 50.3.2.2 The Sample Introduces USAXS, But No Refraction 50.3.2.3 The Sample Introduces Both Refraction and USAXS 50.3.3 Phase Retrieval 50.3.3.1 The Sample Introduces Refraction, But No USAXS 50.3.3.2 The Sample Introduces USAXS, But No Refraction 50.3.3.3 The Sample Introduces Both Refraction and USAXS 50.3.3.4 Other Approaches to Phase Retrieval 50.3.4 Requirements 50.4 Edge Illumination 50.4.1 The Illumination Curve 50.4.2 Phase Retrieval and Sensitivity 50.4.3 Coherence Requirements 50.5 Computed Tomography 50.6 Applications to Biomedical Imaging 50.6.1 Breast 50.6.2 Musculoskeletal Phase-Contrast Imaging 50.6.3 Lung 50.6.4 Neuroimaging 50.6.5 Vasculature, Circulation, and Other Tissues 50.7 Conclusion References

International audience; Introduction: Novel X-ray–based high-resolution propagation-based phase-contrast imaging computed tomography (PBI-CT) is a technique utilizing the dual property of X-rays passing through tissue. It provides contrast information about tissue architecture by using the proportional larger refraction signal by phase shifts that arise at tissue borders, even when its absorption contrast differences are imperceptible. Given this ability, the goal of our study was to evaluate the feasibility of PCI-CT in depicting hyaline cartilage in guinea pig knee joints of different age groups and compare it with micro-CT.Materials and Methods: We examined the ex vivo knee joint of three guinea pigs (Hartley strain) ages 9, 15, and 21 months using PBI-CT at the European Synchrotron Radiation Facility in Grenoble, France (biomedical beamline ID17, collimated X-ray beam 52 keV, field of view 60 mm2, resolution 46 × 46 µm2) and a conventional absorption-based micro-CT, typically used for small animal CT imaging (GE, Phoenix X-ray; same resolution of 46 × 46 µm2). Phase retrieved PBI-CT images were reconstructed sagittally by using the filtered back projection algorithm and equally sloped tomography and compared with corresponding conventional micro-CT data sets. The femoral and tibial cartilage were manually segmented and color coded for improved visualization.Results: PBI-CT shows superior visualization of the guinea pig femoral and tibial cartilage layers compared with the absorption-based conventional micro-CT that was acquired with the same resolution. The original data sets show no differences between the cartilage plates of the guinea pigs of different age groups. However, after application of a color map, differences in electron densities of the cartilage plates of the different age groups were depictable.Conclusion: PBI-CT provides improved cartilage depiction compared with conventional absorption-based micro-CT. Color mapping enables highlighting differences in the cartilage structure of aging cartilage in a small animal model such as in guinea pigs. Given this ability of PCI-CT in depicting differences in such small structures, it may be a promising technique for future cartilage imaging studies in small animal models.

Purpose Experimental neuroimaging provides a wide range of methods for the visualization of brain anatomic morphology down to subcellular detail. Still, each technique-specific detection mechanism presents compromises among the achievable field-of-view size, spatial resolution, and nervous tissue sensitivity, leading to partial sample coverage, unresolved morphologic structures, or sparse labeling of neuronal populations and often also to obligatory sample dissection or other sample invasive manipulations. X-ray phase-contrast imaging computed tomography (PCI-CT) is an experimental imaging method that simultaneously provides micrometric spatial resolution, high soft-tissue sensitivity, and exvivo full organ rodent brain coverage without any need for sample dissection, staining or labeling, or contrast agent injection. In the present study, we explored the benefits and limitations of PCI-CT use for invitro imaging of normal and cancerous brain neuromorphology after invivo treatment with synchrotron-generated x-ray microbeam radiation therapy (MRT), a spatially fractionated experimental high-dose radiosurgery. The goals were visualization of the MRT effects on nervous tissue and a qualitative comparison of the results to the histologic and high-field magnetic resonance imaging findings. Methods and Materials MRT was administered invivo to the brain of both healthy and cancer-bearing rats. At 45days after treatment, the brain was dissected out and imaged exvivo using propagation-based PCI-CT. Results PCI-CT visualizes the brain anatomy and microvasculature in 3 dimensions and distinguishes cancerous tissue morphology, necrosis, and intratumor accumulation of iron and calcium deposits. Moreover, PCI-CT detects the effects of MRT throughout the treatment target areas (eg, the formation of micrometer-thick radiation-induced tissue ablation). The observed neurostructures were confirmed by histologic and immunohistochemistry examination and related to the micro-magnetic resonance imaging data. Conclusions PCI-CT enabled a unique 3D neuroimaging approach for exvivo studies on small animal models in that it concurrently delivers high-resolution insight of local brain tissue morphology in both normal and cancerous micro-milieu, localizes radiosurgical damage, and highlights the deep microvasculature. This method could assist experimental small animal neurology studies in the postmortem evaluation of neuropathology or treatment effects. &nbsp

Conventional chemotherapy and radiation treatment are two cornerstones of cancer treatment but efforts are required to improve their "therapeutic window". The development of metal complexes, including platinum, has had an enormous impact on current cancer chemotherapy. However, these chemotherapeutic drugs can be employed only in the management of a limited number of cancers and, furthermore, their use causes significant side effects. Research over the past 10 years has produced new complexes containing heavy atoms other than platinum, such as iron, cobalt, or gold, which have been used in phase I and phase II trials. Recent preclinical research has shown promising results also using titanium, ruthenium, copper and silver. The anticancer activity of metal-based compounds and nanoparticles (gold and gadolinium in particular) is presently under evaluation in several laboratories in combination with or without X-ray therapy. In fact, if present in sufficiently high concentrations in the tumors, metals can act as a radiotherapy adjuvant: they possess an increased capability to absorb the X-ray radiation with respect to the water-based tissues. Low energy electrons will be then released close to the metal and, therefore, determine a local dose enhancement. This review will focus on the anticancer properties of new drugs and on the rationale for testing their usefulness in combined treatment.

Microbeam radiation therapy (MRT) is an irradiation modality for therapeutic purposes which uses arrays of collimated quasi parallel microbeams, each up to 100 mm wide, to deliver high radiation doses. Several studies have reported the extraordinary tolerance of normal tissues to MRT irradiation; conversely, MRT has been shown to be highly efficient on tumor growth control. The original and most widely developed application of MRT, yet in the preclinical phase, consists in using spatially fractionated X-ray beams issued from a synchrotron radiation source in the treatment of brain tumors. More recently, MRT has been tested in successful pioneering assays to reduce or interrupt seizures in preclinical models of epilepsy. The MRT concept has also been extended to proton therapy. The development of MRT towards its clinical implementation is presently driven by an EU-supported consortium of laboratories from 16 countries within the COST Action TD1205 (SYRA3). The results of the first SYRA3 workshop on "Radiation Therapy with Synchrotron Radiation: Achievements and Challenges" held in Krakow (Poland) during March 25-26 2014 are summarized in this issue with an overview presented in this paper. The papers reflect the multidisciplinary international activities of SYRA3. The topics covered in this focus issue include medical physics aspects, pre-clinical studies, clinical applications, and an industrial perspective; finally an outlook towards future prospects of compact sources and proton microbeams. (C) 2015 Published by Elsevier Ltd on behalf of Associazione Italiana di Fisica Medica.

The refractive-index gradient vector field approach establishes a connection between a tomographic data set of differential phase contrast images and the distribution of the partial spatial derivatives of the refractive index in an object. The reconstruction of the refractive index in a plane requires the integration of its gradient field. This work shows how this integration can be efficiently performed by converting the problem to the Poisson equation, which can be accurately solved even in the case of noisy and large datasets. The performance of the suggested method is discussed and demonstrated experimentally by computing the refractive index distribution in both a simple plastic phantom and a complex biological sample. The quality of the reconstruction is evaluated through the direct comparison with other commonly used methods. To this end, the refractive index is retrieved from the same data set using also (1) the filtered backprojection algorithm for gradient projections, and (2) the regularized phase-retrieval procedure. Results show that the gradient vector field approach combined with the developed integration technique provides a very accurate depiction of the sample internal structure. Contrary to the two other techniques, the considered method does not require a preliminary phase-retrieval and can be implemented with any advanced computer tomography algorithm. In this work, analyzer-based phase contrast images are used for demonstration. Results, however, are generally valid and can be applied for processing differential phase-contrast tomographic data sets obtained with other phase-contrast imaging techniques.

Medical imaging and radiation therapy are widely used synchrotron-based techniques which have one thing in common: a significant dose delivery to typically biological samples. Among the ways to provide the experimenters with image guidance techniques indicating optimization strategies, Monte Carlo simulation has become the gold standard for accurately predicting radiation dose levels under specific irradiation conditions. A highly important hampering factor of this method is, however, its slow statistical convergence. A track length estimator (TLE) module has been coded and implemented for the first time in the open-source Monte Carlo codeGATE/Geant4. Results obtained with the module and the procedures used to validate them are presented. A database of energy-absorption coefficients was also generated, which is used by the TLE calculations and is now also included inGATE/Geant4. The validation was carried out by comparing the TLE-simulated doses with experimental data in a synchrotron radiation computed tomography experiment. The TLE technique shows good agreementversusboth experimental measurements and the results of a classical Monte Carlo simulation. Compared with the latter, it is possible to reach a pre-defined statistical uncertainty in about two to three orders of magnitude less time for complex geometries without loss of accuracy.

Objectives: Positive pressure ventilation exposes the lung to mechanical stresses that can exacerbate injury. The exact mechanism of this pathologic process remains elusive. The goal of this study was to describe recruitment/derecruitment at acinar length scales over short-time frames and test the hypothesis that mechanical interdependence between neighboring lung units determines the spatial and temporal distributions of recruitment/derecruitment, using a computational model. Design: Experimental animal study. Setting: International synchrotron radiation laboratory. Subjects: Four anesthetized rabbits, ventilated in pressure controlled mode. Interventions: The lung was consecutively imaged at ∼ 1.5-minute intervals using phase-contrast synchrotron imaging, at positive end-expiratory pressures of 12, 9, 6, 3, and 0 cm H2O before and after lavage and mechanical ventilation induced injury. The extent and spatial distribution of recruitment/derecruitment was analyzed by subtracting subsequent images. In a realistic lung structure, we implemented a mechanistic model in which each unit has individual pressures and speeds of opening and closing. Derecruited and recruited lung fractions (Fderecruited, Frecruited) were computed based on the comparison of the aerated volumes at successive time points. Measurements and Main Results: Alternative recruitment/derecruitment occurred in neighboring alveoli over short-time scales in all tested positive end-expiratory pressure levels and despite stable pressure controlled mode. The computational model reproduced this behavior only when parenchymal interdependence between neighboring acini was accounted for. Simulations closely mimicked the experimental magnitude of Fderecruited and Frecruited when mechanical interdependence was included, while its exclusion gave Frecruited values of zero at positive end-expiratory pressure greater than or equal to 3 cm H2O. Conclusions: These findings give further insight into the microscopic behavior of the injured lung and provide a means of testing protective-ventilation strategies to prevent recruitment/derecruitment and subsequent lung damage. Copyright © 2017 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

The degenerative effects of multiple sclerosis at the level of the vascular and neuronal networks in the central nervous system are currently the object of intensive investigation. Preclinical studies have demonstrated the efficacy of mesenchymal stem cell (MSC) therapy in experimental autoimmune encephalomyelitis (EAE), the animal model for multiple sclerosis, but the neuropathology of specific lesions in EAE and the effects of MSC treatment are under debate. Because conventional imaging techniques entail protocols that alter the tissues, limiting the reliability of the results, we have used non-invasive X-ray phase-contrast tomography to obtain an unprecedented direct 3D characterization of EAE lesions at micro-to-nano scales, with simultaneous imaging of the vascular and neuronal networks. We reveal EAE-mediated alterations down to the capillary network. Our findings shed light on how the disease and MSC treatment affect the tissues, and promote X-ray phase-contrast tomography as a powerful tool for studying neurovascular diseases and monitoring advanced therapies.

The detection system is a key part of any imaging station. Here the performance of the novel sCMOS-based detection system installed at the ID17 biomedical beamline of the European Synchrotron Radiation Facility and dedicated to high-resolution computed-tomography imaging is analysed. The system consists of an X-ray-visible-light converter, a visible-light optics and a PCO.Edge5.5 sCMOS detector. Measurements of the optical characteristics, the linearity of the system, the detection lag, the modulation transfer function, the normalized power spectrum, the detective quantum efficiency and the photon transfer curve are presented and discussed. The study was carried out at two different X-ray energies (35 and 50keV) using both 2× and 1× optical magnification systems. The final pixel size resulted in 3.1 and 6.2μm, respectively. The measured characteristic parameters of the PCO.Edge5.5 are in good agreement with the manufacturer specifications. Fast imaging can be achieved using this detection system, but at the price of unavoidable losses in terms of image quality. The way in which the X-ray beam inhomogeneity limited some of the performances of the system is also discussed.The detection system is a key part of any imaging station. Here the performance of the novel sCMOS-based detection system installed at the ID17 biomedical beamline of the European Synchrotron Radiation Facility and dedicated to high-resolution computed-tomography imaging is analysed.

Quality of a refractive compound X-ray lens can be limited by imperfections in surfaces of unit lenses and stacking precision. In general case both the lens transmission and optical aberrations define properties of a beam in the lens exit plane; together they can be expressed in terms of the generalized pupil function. In this work we measure this function for a diamond single crystal compound refractive lens. Consequently, we apply the pupil function to evaluate the performance of the examined compound refractive X-ray lens. A number of practically important conclusions can be drawn from such analysis. © 2017 Optical Society of America.

The investigation of the neuronal network in mouse spinal cord models represents the basis for the research on neurodegenerative diseases. In this framework, the quantitative analysis of the single elements in different districts is a crucial task. However, conventional 3D imaging techniques do not have enough spatial resolution and contrast to allow for a quantitative investigation of the neuronal network. Exploiting the high coherence and the high flux of synchrotron sources, X-ray Phase-Contrast multiscale-Tomography allows for the 3D investigation of the neuronal microanatomy without any aggressive sample preparation or sectioning. We investigated healthy-mouse neuronal architecture by imaging the 3D distribution of the neuronal-network with a spatial resolution of 640 nm. The high quality of the obtained images enables a quantitative study of the neuronal structure on a subject-by-subject basis. We developed and applied a spatial statistical analysis on the motor neurons to obtain quantitative information on their 3D arrangement in the healthy-mice spinal cord. Then, we compared the obtained results with a mouse model of multiple sclerosis. Our approach paves the way to the creation of a “database” for the characterization of the neuronal network main features for a comparative investigation of neurodegenerative diseases and therapies.

A collection of more than 1800 carbonized papyri, discovered in the Roman ‘Villa dei Papiri’ at Herculaneum is the unique classical library survived from antiquity. These papyri were charred during 79 A.D. Vesuvius eruption, a circumstance which providentially preserved them until now. This magnificent collection contains an impressive amount of treatises by Greek philosophers and, especially, Philodemus of Gadara, an Epicurean thinker of 1st century BC. We read many portions of text hidden inside carbonized Herculaneum papyri using enhanced X-ray phase-contrast tomography non-destructive technique and a new set of numerical algorithms for ‘virtual-unrolling’. Our success lies in revealing the largest portion of Greek text ever detected so far inside unopened scrolls, with unprecedented spatial resolution and contrast, all without damaging these precious historical manuscripts. Parts of text have been decoded and the ‘voice’ of the Epicurean philosopher Philodemus is brought back again after 2000 years from Herculaneum papyri.

International audience

A collection of more than 1800 carbonized papyri, discovered in the Roman ‘Villa dei Papiri’ at Herculaneum is the unique classical library survived from antiquity. These papyri were charred during 79 A.D. Vesuvius eruption, a circumstance which providentially preserved them until now. This magnificent collection contains an impressive amount of treatises by Greek philosophers and, especially, Philodemus of Gadara, an Epicurean thinker of 1st century BC. We read many portions of text hidden inside carbonized Herculaneum papyri using enhanced X-ray phase-contrast tomography non-destructive technique and a new set of numerical algorithms for ‘virtual-unrolling’. Our success lies in revealing the largest portion of Greek text ever detected so far inside unopened scrolls, with unprecedented spatial resolution and contrast, all without damaging these precious historical manuscripts. Parts of text have been decoded and the ‘voice’ of the Epicurean philosopher Philodemus is brought back again after 2000 years from Herculaneum papyri.

Objectives Neoadjuvant chemotherapy is the state-of-the-art treatment in advanced breast cancer. A correct visualization of the post-therapeutic tumor size is of high prognostic relevance. X-ray phase-contrast computed tomography (PC-CT) has been shown to provide improved soft-tissue contrast at a resolution formerly restricted to histopathology, at low doses. This study aimed at assessing ex-vivo the potential use of PC-CT for visualizing the effects of neoadjuvant chemotherapy on breast carcinoma. Materials and Methods The analysis was performed on two ex-vivo formalin-fixed mastectomy samples containing an invasive carcinoma removed from two patients treated with neoadjuvant chemotherapy. Images were matched with corresponding histological slices. The visibility of typical post-therapeutic tissue changes was assessed and compared to results obtained with conventional clinical imaging modalities. Results PC-CT depicted the different tissue types with an excellent correlation to histopathology. Post-therapeutic tissue changes were correctly visualized and the residual tumor mass could be detected. PC-CT outperformed clinical imaging modalities in the detection of chemotherapy-induced tissue alterations including post-therapeutic tumor size. Conclusions PC-CT might become a unique diagnostic tool in the prediction of tumor response to neoadjuvant chemotherapy. PC-CT might be used to assist during histopathological diagnosis, offering a high-resolution and high-contrast virtual histological tool for the accurate delineation of tumor boundaries.

Purpose Edge illumination (EI) X-ray phase-contrast imaging (XPCI) has been under development at University College London in recent years, and has shown great potential for both laboratory and synchrotron applications. In this work, we propose a new acquisition and processing scheme. Contrary to existing retrieval methods for EI, which require as input two images acquired in different setup configurations, the proposed approach can retrieve an approximate map of the X-ray phase from a single image, thus significantly simplifying the acquisition procedure and reducing data collection times. Methods The retrieval method is analytically derived, based on the assumption of a quasi-homogeneous object, i.e. an object featuring a constant ratio between refractive index and absorption coefficient. The noise properties of the input and retrieved images are also theoretically analyzed under the developed formalism. The method is applied to experimental synchrotron images of a biological object. Results The experimental results show that the method can provide high-quality images, where the “edge” signal typical of XPCI images is transformed to an “area” contrast that enables an easier interpretation of the sample geometry. Moreover, the retrieved images confirm that the method is highly stable against noise. Conclusions We anticipate that the developed approach will become the method of choice for a variety of applications of EI XPCI, thanks to its ability to simplify the acquisition procedure and reduce acquisitions time and dose to the sample. Future work will focus on the adaptation of the method to computed tomography and to polychromatic radiation from X-ray tubes.

We report results of the computed tomography reconstruction of the index of refraction in a whole rabbit knee joint examined at the photon energy of 51 keV. Refraction based images make it possible to delineate the bone, cartilage, and soft tissues without adjusting the contrast window width and level. Density variations, which are related to tissue composition and are not visible in absorption X-ray images, are detected in the obtained refraction based images. We discuss why refraction-based images provide better detectability of low contrast features than absorption images.

Mammography is the primary imaging tool for screening and diagnosis of human breast cancers, but ∼10–20% of palpable tumors are not detectable on mammograms and only about 40% of biopsied lesions are malignant. Here we report a high-resolution, low-dose phase contrast X-ray tomographic method for 3D diagnosis of human breast cancers. By combining phase contrast X-ray imaging with an image reconstruction method known as equally sloped tomography, we imaged a human breast in three dimensions and identified a malignant cancer with a pixel size of 92 μm and a radiation dose less than that of dual-view mammography. According to a blind evaluation by five independent radiologists, our method can reduce the radiation dose and acquisition time by ∼74% relative to conventional phase contrast X-ray tomography, while maintaining high image resolution and image contrast. These results demonstrate that high-resolution 3D diagnostic imaging of human breast cancers can, in principle, be performed at clinical compatible doses.

Synchrotron-generated X-ray microplanar beams (microbeams) are characterized by peculiar biological properties such as a remarkable tissue-sparing effect in healthy tissues including the central nervous system (CNS) and, as a direct consequence, the ability to deliver extremely high doses without induction of radionecrosis. Growing experimental evidence is showing remarkable tolerance of brain and spinal cord to irradiation with microbeam arrays delivering doses up to 400 Gy with a beam width up to 0·7 mm. Submillimetric beams can be delivered following a stereotactic design bringing to the target doses in the range of hundreds of Gray without harm to the surrounding tissues. Microbeam arrays can be used to generate cortical transections or subcortical lesions, thus enabling the non-invasive modulation of brain networks. This novel microradiosurgical approach is of great interest for the treatment of a variety of brain disorders, including functional diseases such as epilepsy and movement disorders.

High-resolution analyser-based X-ray imaging computed tomography (HR ABI-CT) findings on in vitro human breast cancer are compared with histopathology, mammography, computed tomography (CT) and magnetic resonance imaging. The HR ABI-CT images provided significantly better low-contrast visibility compared with the standard radiological images. Fine cancer structures indistinguishable and superimposed in mammograms were seen, and could be matched with the histopathological results. The mean glandular dose was less than 1 mGy in mammography and 12-13 mGy in CT and ABI-CT. The excellent visibility of in vitro breast cancer suggests that HR ABI-CT may have a valuable role in the future as an adjunct or even alternative to current breast diagnostics, when radiation dose is further decreased, and compact synchrotron radiation sources become available.

Diffraction enhanced imaging (DEI), also called analyzer-based imaging (ABI), cultivated within the synchrotron community, has the potential to revolutionize medical imaging through reduced dose and enhanced contrast imaging.

Purpose: An adequate dosimetry protocol for synchrotron radiation and the specific features of the ID17 Biomedical Beamline at the European Synchrotron Radiation Facility are essential for the preparation of the forthcoming clinical trials in the synchrotron stereotactic radiation therapy (SSRT). The main aim of this work is the definition of a suitable protocol based on standards of dose absorbed to water. It must allow measuring the absolute dose with an uncertainty within the recommended limits for patient treatment of 2%-5%. Methods: Absolute dosimetry is performed with a thimble ionization chamber (PTW semiflex 31002) whose center is positioned at 2 g cm{sup -2} equivalent depth in water. Since the available synchrotron beam at the ESRF Biomedical Beamline has a maximum height of 3 mm, a scanning method was employed to mimic a uniform exposition of the ionization chamber. The scanning method has been shown to be equivalent to a broad beam irradiation. Different correction factors have been assessed by using Monte Carlo simulations. Results: The absolute dose absorbed to water at 80 keV was measured in reference conditions with a 2% global uncertainty, within the recommended limits. The dose rate was determined to be in the range between 14 and 18more » Gy/min, that is to say, a factor two to three times higher than the 6 Gy/min achievable in RapidArc or VMAT machines. The dose absorbed to water was also measured in a RW3 solid water phantom. This phantom is suitable for quality assurance purposes since less than 2% average difference with respect to the water phantom measurements was found. In addition, output factors were assessed for different field sizes. Conclusions: A dosimetry protocol adequate for the specific features of the SSRT technique has been developed. This protocol allows measuring the absolute dose absorbed to water with an accuracy of 2%. It is therefore satisfactory for patient treatment.« less

Over the last two decades phase contrast x-ray imaging techniques have been extensively studied for applications in the biomedical field. Published results demonstrate the high capability of these imaging modalities of improving the image contrast of biological samples with respect to standard absorption-based radiography and routinely used clinical imaging techniques. A clear depiction of the anatomic structures and a more accurate disease diagnosis may be provided by using radiation doses comparable to or lower than those used in current clinical methods. In the literature many works show images of phantoms and excised biological samples proving the high sensitivity of the phase contrast imaging methods for in vitro investigations. In this scenario, the applications of the so-called analyzer-based x-ray imaging (ABI) phase contrast technique are particularly noteworthy. The objective of this work is to demonstrate the feasibility of in vivo x-ray ABI phase contrast imaging for biomedical applications and in particular with respect to joint anatomic depiction and osteoarthritis detection. ABI in planar and tomographic modes was performed in vivo on articular joints of guinea pigs in order to investigate the animals with respect to osteoarthritis by using highlymonochromatic x-rays of 52 keV and a low noise detector with a pixel size of 47 × 47 μm2. Images give strong evidence of the ability of ABI in depicting both anatomic structures in complex systems as living organisms and all known signs of osteoarthritis with high contrast, high spatial resolution and with an acceptable radiation dose. This paper presents the first proof of principle study of in vivo application ofABI. The technical challenges encountered when imaging an animal in vivo are discussed. This experimental study is an important step toward the study of clinical applications of phase contrast x-ray imaging techniques. © 2010 Institute of Physics and Engineering in Medicine.

In x-ray phase-contrast analyzer-based imaging, the contrast is provided by a combination of absorption, refraction and scattering effects. Several extraction algorithms, which attempt to separate and quantify these different physical contributions, have been proposed and applied. In a previous work, we presented a quantitative comparison of five among the most well-known extraction algorithms based on the geometrical optics approximation applied to planar images: diffraction-enhanced imaging (DEI), extended diffraction-enhanced imaging (E-DEI), generalized diffraction-enhanced imaging (G-DEI), multiple-image radiography (MIR) and Gaussian curve fitting (GCF). In this paper, we compare these algorithms in the case of the computed tomography (CT) modality. The extraction algorithms are applied to analyzer-based CT images of both plastic phantoms and biological samples (cartilage-on-bone cylinders). Absorption, refraction and scattering signals are derived. Results obtained with the different algorithms may vary greatly, especially in the case of large refraction angles. We show that ABI-CT extraction algorithms can provide an excellent tool to enhance the visualization of cartilage internal structures, which may find applications in a clinical context. Besides, by using the refraction images, the refractive index decrements for both the cartilage matrix and the cartilage cells have been estimated.

When an X-ray wave traverses an object, its amplitude and phase change, resulting in attenuation, interference, and refraction, and in phase-contrast X-ray imaging (PCI) these are converted to intensity changes. The relative change of the X-ray phase per unit path length is even orders of magnitude larger than that of the X-ray amplitude, so that the image contrast based on variation of the X-ray phase is potentially much stronger than the contrast based on X-ray amplitude (absorption contrast). An important medical application of PCI methods is soft-tissue imaging, where the absorption contrast is inherently weak. It is shown by in vitro examples that signs of malignant human breast tumor are enhanced in PCI images. Owing to the strong contrast, the radiation dose can be greatly reduced, so that a high-resolution phase-contrast X-ray tomography of the breast is possible with about 1 mGy mean glandular dose. Scattered radiation carries essential information on the atomic and molecular structure of the object, and particularly small-angle X-ray scattering can be used to trace cancer. The imaging methods developed at the synchrotron radiation facilities will become available in the clinical environment with the ongoing development of compact radiation sources, which produce intense X-ray beams of sufficient coherence. Several developments that are under way are described here.

Here we review our recent progress in the field of X-ray dark-field and phase-contrast imaging using a grating interferometer. We describe the basic imaging principles of grating-based phase-contrast and dark-field radiography and present some exemplary results obtained for simple test objects and biological specimens. Furthermore, we discuss how phase-contrast and dark-field radiography can be combined with the concept of computed tomography, and yield highly detailed three-dimensional insights into biomedical sample. Exemplary results obtained with standard X-ray tube sources and highly brilliant synchrotron sources are presented.

International audience; To analyze the effects of the microbeam width (25, 50 and 75 microm) on the survival of 9L gliosarcoma tumor-bearing rats and on toxicity in normal tissues in normal rats after microbeam radiation therapy (MRT), 9L gliosarcomas implanted in rat brains, as well as in normal rat brains, were irradiated in the MRT mode. Three configurations (MRT25, MRT50, MRT75), each using two orthogonally intersecting arrays of either 25, 50 or 75 microm wide microbeams, all spaced 211 microm on center, were tested. For each configuration, peak entrance doses of 860, 480 and 320 Gy, respectively, were calculated to produce an identical valley dose of 18 Gy per individual array at the center of the tumor. Two, 7 and 14 days after radiation treatment, 42 rats were killed to evaluate histopathologically the extent of tumor necrosis, and the presence of proliferating tumors cells and tumor vessels. The median survival times of the normal rats were 4.5, 68 and 48 days for MRT25, 50 and 75, respectively. The combination of the highest entrance doses (860 Gy per array) with 25 microm wide beams (MRT25) resulted in a cumulative valley dose of 36 Gy and was excessively toxic, as it led to early death of all normal rats and of approximately 50% of tumor-bearing rats. The short survival times, particularly of rats in the MRT25 group, restricted adequate observance of the therapeutic effect of the method on tumor-bearing rats. However, microbeams of 50 microm width led to the best median survival time after 9L gliosarcoma MRT treatment and appeared as the better compromise between tumor control and normal brain toxicity compared with 75 microm or 25 microm widths when used with a 211 microm on-center distance. Despite very high radiation doses, the tumors were not sterilized; viable proliferating tumor cells remained present at the tumor margin. This study shows that microbeam width and peak entrance doses strongly influence tumor responses and normal brain toxicity, even if valley doses are kept constant in all groups. The use of 50 microm wide microbeams combined with moderate peak doses resulted in a higher therapeutic ratio.

Thomson scattering x-ray sources can provide spectral distributions that are ideally suited for mammography with sufficient fluence rates. In this article, the authors investigate the effects of different spectral distributions on the image quality in simulated images of a breast mammographic phantom containing details of different compositions and thicknesses. They simulated monochromatic, quasimonochromatic, and polychromatic x-ray sources in order to define the energy for maximum figure of merit (signal-difference-to-noise ratio squared/mean glandular dose), the effect of an energy spread, and the effect of the presence of higher-order harmonics. The advantages of these sources with respect to conventional polychromatic sources as a function of phantom and detail thickness were also investigated. The results show that the energy for the figure of merit peak is between 16 and 27.4 keV, depending on the phantom thickness and detail composition and thickness. An energy spread of about 1 keV standard deviation, easily achievable with compact x-ray sources, does not appreciably affect the image quality.

Purpose: The purpose of this work is to assess which energy in minibeam radiation therapy provides the best compromise between the deposited dose in the tumor and the sparing of the healthy tissues. Methods: Monte Carlo simulations (PENELOPE 2006) have been used as a method to calculate the ratio of the peak-to-valley doses (PVDR) in the healthy tissues and in the tumor for different beam energies. The maximization of the ratio of PVDR in the healthy tissues and in the tumor has been used as a criterion. Results: The main result of this work is that, for the parameters being used in preclinical trials (minibeam sizes of 600 {mu}m and 1200 {mu}m center-to-center separation), the optimum beam energy is 375 keV. Conclusions: The conclusion is that this is the energy of minibeams that should be used in the preclinical studies.

An imaging method is discussed that allows for the differentiated imaging of lead white and vermilion in a painting. These noninvasive experiments were performed at the biomedical beamline ID17 of the Synchrotron Radiation Facility in Grenoble. This was done to gain a better understanding of original painting technique. In particular the use of vermilion and lead white for portrait painting is significant; the relevance is indicated for technical art history, as well as for problems of conservation. The method is demonstrated here in the study of a portrait by the 17th century master Carel Fabritius. Monochromatic synchrotron radiation beams were used to obtain quantitative images of different paint layers. The facilities allow for differentiation of pigments with elements greater than 20 keV. Two simultaneous images were acquired, each at two different energies, above and below the K-edges of lead and mercury. Logarithmic subtraction of the two images yields relevant distribution images. This tec...

Microbeam radiation therapy(MRT) is an innovative technique to treat braintumors. The synchrotron generated x-ray beam, used for the treatment, is collimated and delivered in an array of narrow micrometer-sized planar rectangular fields. Several preclinical experiments performed at the Brookhaven National Laboratory (BNL) and at the European Synchrotron Radiation Facility (ESRF) have shown the sparing effect of the healthy tissue and the ablation of tumors in several animal models. It has also been determined that MRT yields a higher therapeutic index than nonsegmented beams of the same energy. This therapeutic index could be greatly improved by loading the tumor with high atomic number ( Z ) contrast agents. In this work, the dose enhancement factors and the peak to valley dose ratios (PVDRs) are assessed for different gadolinium ( Z = 64 ) concentrations in the tumor and different microbeam energies by using Monte Carlo simulations (PENELOPE 2006 code). A significant decrease in the PVDR values in the tumor, and therefore a relevant increase in the dose deposition, is found in the presence of gadolinium. The optimum energy for the dose deposition in the tumor while keeping a high PVDR in the healthy tissues, which guaranties their sparing, has been investigated.

International audience; The technical feasibility of temporal and spatial fractionations of the radiation dose has been evaluated using synchrotron microbeam radiation therapy for brain tumors in rats. A significant increase in lifespan (216%, p < 0.0001) resulted when three fractions of microbeam irradiation were applied to the tumor through three different ports, orthogonal to each other, at 24 h intervals. However, there were no long-term survivors, and immunohistological studies revealed that 9 L tumors were not entirely ablated.

Several synchrotrons around the world are currently developing innovative radiotherapy techniques with the aim of palliating and possibly curing human brain tumors. Amongst them, microbeam radiation therapy (MRT) and, more recently, minibeam radiation therapy (MBRT) have shown promising results. In MBRT the beam thickness ranges from 500 to 700 microm with a separation between two adjacent minibeams of the same value, whilst in MRT the thickness is of the order of 25-50 microm with a distance between adjacent microbeams of the order of 200 microm. An original method has been developed and tested at the ESRF ID17 biomedical beamline to produce the minibeam patterns. It utilizes a specially developed high-energy white-beam chopper whose action is synchronized with the vertical motion of the target moving at constant speed. Each opening of the chopper generates a horizontal beam print. The method described here has the advantage of being simple and reliable, and it allows for an easy control of the patient safety in future clinical trials. To study the feasibility of the method, dosimetric measurements have been performed using Gafchromic HD-810 films and compared with Monte Carlo simulations. The results of this comparison are discussed.

Synchrotron radiation is an innovative tool for the treatment of brain tumors. In the stereotactic synchrotron radiation therapy (SSRT) technique a radiation dose enhancement specific to the tumor is obtained. The tumor is loaded with a high atomic number (Z) element and it is irradiated in stereotactic conditions from several entrance angles. The aim of this work was to assess dosimetric properties of the SSRT for preparing clinical trials at the European Synchrotron Radiation Facility (ESRF). To estimate the possible risks, the doses received by the tumor and healthy tissues in the future clinical conditions have been calculated by using Monte Carlo simulations (PENELOPE code). The dose enhancement factors have been determined for different iodine concentrations in the tumor, several tumor positions, tumor sizes, and different beam sizes. A scheme for the dose escalation in the various phases of the clinical trials has been proposed. The biological equivalent doses and the normalized total doses received by the skull have been calculated in order to assure that the tolerance values are not reached.

The radiotherapy clinical trials projects, both aiming at treating aggressive brain tumors, require several major modifications and new constructions at the ESRF ID17 Biomedical beamline. The application of the Stereotactic Synchrotron Radiation Therapy (SSRT) technique mainly necessitates an upgrade of the existing patient positioning system, which was formerly used for the angiography program. It will allow for accurate positioning, translation and rotation of the patient during the treatment. For the Microbeam Radiation Therapy (MRT) clinical trials project, a new white beam hutch will be constructed to accommodate a dedicated patient positioning system. Consequently, the existing control hutches and the related installations will also be completely refurbished. Furthermore, the foreseen installation of a second X-ray source, which will allow doubling the currently available photon flux at high energies, requires a redesign of most optical components to handle the increased power and power densities. Starting from the current ID17 Biomedical beamline layout, the paper will present an update of the different modification/construction projects, including the general organization and planning.

Monitoring the progression of osteoarthritis (OA) and the effects of therapy during clinical trials is still a challenge for present clinical imaging techniques since they present intrinsic limitations and can be sensitive only in case of advanced OA stages. In very severe cases, partial or complete joint replacement surgery is the only solution for reducing pain and restoring the joint functions. Poor imaging quality in practically all medical imaging technologies with respect to joint surfaces and to metal implant imaging calls for the development of new techniques that are sensitive to stages preceding the point of irreversible damage of the cartilage tissue. In this scenario, X-ray phase contrast modalities could play an important role since they can provide improved contrast compared to conventional absorption radiography, with a similar or even reduced tissue radiation dose. In this study, the analyzer-based imaging (ABI), a technique sensitive to the X-ray refraction and permitting a high scatter rejection, has been successfully applied in vitro on excised human synovial joints and sheep implants. Pathological and healthy joints as well as metal implants have been imaged in projection and computed tomography ABI mode at high resolution and clinically compatible doses (

Microbeam radiation therapy (MRT) is a form of radiosurgery first dedicated to the treatment of brain tumors. It uses arrays of synchrotron generated X-rays microbeams of very high doses (typically 625 Gy). Microbeams are typically few micrometers large (25 microm) and few hundred micrometers spaced (200 microm). Previous experiments have shown that despite a good tumor eradication rate (5/11), a 100-microm spacing unidirectional irradiation (skin dose 625 Gy, width 25 microm) was too invasive for normal tissue. On the contrary, a 200-microm spacing unidirectional irradiation preserved healthy tissue with a low tumor eradication rate (2/32). The purpose of this study was to enhance the potential of the 200 microm spacing irradiation protocol. After diagnosis of the tumor by MRI, 9L tumor-bearing rats were laterally irradiated with 51 microbeams (625 Gy, 25 microm, 200 microm) 14 days after implantation. Three drugs (Gd-DTPA, CisPt, temozolomide) were tested, after intratumoral injection at the theoretical center of the tumor. Control rats displayed a median survival time of 19 days. There was no significant difference between drug-treated rats and control group. Irradiated animals showed an increase in life span (ILS) of 60.5%. Interestingly, the ILS increased to 131.6% and 1/6 rat survived more than 1 year in case of MRT combined with gadolinium injection. These results showed that the synergy between gadolinium injection (acting as a dose enhancer) and MRT improved significantly the life span of tumor bearing rats (more than a factor 2).

The first practical application of X-rays, more than 100 years ago, was for biomedical imaging. Although not central to the initial development of 3 rd generation synchrotron light sources, imaging techniques have today established themselves as a core element of the research program at all major light sources, including the ESRF, where X-ray imaging has been identified as one of five main themes for its Upgrade Programme [1].

The purpose of this work was the understanding of microbeam radiation therapy at the ESRF in order to find the best compromise between curing of tumors and sparing of normal tissues, to obtain a better understanding of survival curves and to report its efficiency. This method uses synchrotron-generated x-ray microbeams. Rats were implanted with 9L gliosarcomas and the tumors were diagnosed by MRI. They were irradiated 14 days after implantation by arrays of 25 microm wide microbeams in unidirectional mode, with a skin entrance dose of 625 Gy. The effect of using 200 or 100 microm center-to-center spacing between the microbeams was compared. The median survival time (post-implantation) was 40 and 67 days at 200 and 100 microm spacing, respectively. However, 72% of rats irradiated at 100 microm spacing showed abnormal clinical signs and weight patterns, whereas only 12% of rats were affected at 200 microm spacing. In parallel, histological lesions of the normal brain were found in the 100 microm series only. Although the increase in lifespan was equal to 273% and 102% for the 100 and 200 microm series, respectively, the 200 microm spacing protocol provides a better sparing of healthy tissue and may prove useful in combination with other radiation modalities or additional drugs.

We present here the latest results from tests performed at the ESRF ID17 and ID21 beamlines for the characterization of novel beam monitors for Microbeam Radiation Therapy (MRT), which is currently being implemented at ID17. MRT aims at treating solid tumors by exploiting an array of evenly spaced microbeams, having an energy spectrum distributed between 27 and 600 keV and peaking at 100 keV. Given the high instantaneous dose delivered (up to 20 kGy/s), the position and the intensity of the microbeams has to be precisely and instantly monitored. For this purpose, we developed dedicated silicon microstrip beam monitors. We have successfully characterized them, both with a microbeam array at ID17, and a submicron scanning beam at ID21. We present here the latest results obtained in recent tests along with an outlook on future developments.

Among the new emerging cancer therapies, Microbeam Radiation Therapy (MRT) is currently showing very promising results in terms of limiting or decreasing tumor growth while keeping the damage to healthy tissue to a minimum. The MRT is able to deliver unprecedented dose rates of up to 20 kGy/s, posing important questions in terms of treatment planning and patient safety during treatment. For this reason, a beam monitoring system must be built, in which a detector acquires the microbeam array profile in real-time. In case of anomalies detection, the detector signals the beam-line to close the shutter as an emergency safety measure. Many sensors technologies for beam monitoring are currently being considered and silicon strip detectors seem to be very promising candidates. In this study the characterisation in full MRT conditions of a novel silicon strip detector is reported explaining strengths and weaknesses of the devices. Modifications to the sensor layout are also suggested in this study.