Multivariate calibration of energy-dispersive X-ray diffraction data for predicting the composition of pharmaceutical tablets in packaging.

A system using energy-dispersive X-ray diffraction (EDXRD) has been developed and tested using multivariate calibration for the quantitative analysis of tablet-form mixtures of common pharmaceutical ingredients. A principal advantage of EDXRD over the more traditional and common angular dispersive X-ray diffraction technique (ADXRD) is the potential of EDXRD to analyse tablets within their packaging, due to the higher energy X-rays used. In the experiment, a series of caffeine, paracetamol and microcrystalline cellulose mixtures were prepared and pressed into tablets. EDXRD profiles were recorded on each sample and a principal component analysis (PCA) was carried out in both unpackaged and packaged scenarios. In both cases the first two principal components explained >98% of the between-sample variance. The PCA projected the sample profiles into two dimensional principal component space in close accordance to their ternary mixture design, demonstrating the discriminating potential of the EDXRD system. A partial least squares regression (PLSR) model was built with the samples and was validated using leave-one-out cross-validation. Low prediction errors of between 2% and 4% for both unpackaged and packaged tablets were obtained for all three chemical compounds. The prediction capability through packaging demonstrates a truly non-destructive method for quantifying tablet composition and demonstrates good potential for EDXRD to be applied in the field of counterfeit medicine screening and pharmaceutical quality control.

Correlation of X-ray diffraction signatures of breast tissue and their histopathological classification.

This pilot study examines the correlation of X-ray diffraction (XRD) measurements with the histopathological analysis of breast tissue. Eight breast cancer samples were investigated. Each sample contained a mixture of normal and cancerous tissues. In total, 522 separate XRD measurements were made at different locations across the samples (8 in total). The resulting XRD spectra were subjected to principal component analysis (PCA) in order to determine if there were any distinguishing features that could be used to identify different tissue components. 99.0% of the variation between the spectra were described by the first two principal components (PC). Comparing the location of points in PC space with the classification determined by histopathology indicated correlation between the shape/magnitude of the XRD spectra and the tissue type. These results are encouraging and suggest that XRD could be used for the intraoperative or postoperative classification of bulk tissue samples.

Phase-contrast microscopy at high x-ray energy with a laboratory setup.

We report on the design and realization of an x-ray imaging system for quantitative phase-contrast microscopy at high x-ray energy with laboratory-scale instrumentation. Phase and amplitude were separated quantitatively at x-ray energies up to 80 keV with micrometric spatial resolution. The accuracy of the results was tested against numerical simulations, and the spatial resolution was experimentally quantified by measuring a Siemens star phase object. This simple setup should find broad application in those areas of x-ray imaging where high energy and spatial resolution are simultaneously required and in those difficult cases where the sample contains materials with similar x-ray absorption.

Proof-of-concept demonstration of edge-illumination x-ray phase contrast imaging combined with tomosynthesis.

In this note we present the first proof-of-concept results on the potential effectiveness of the edge-illumination x-ray phase contrast method (in its 'coded-aperture' based lab implementation) combined with tomosynthesis. We believe that, albeit admittedly preliminary (e.g. we only present phantom work), these results deserve early publication in a note primarily for four reasons. First, we fully modelled the imaging acquisition method, and validated the simulation directly with experimental results. This shows that the implementation of the method in the new geometry is understood, and thus that it will be possible to use the model to simulate more complex scenarios in the future. Secondly, we show that a strong phase contrast signal is preserved in the reconstructed tomosynthesis slices: this was a concern, as the high spatial frequency nature of the signal makes it sensitive to any filtration-related procedure. Third, we show that, despite the non-optimized nature of the imaging prototype used, we can perform a full angular scan at acceptable dose levels and with exposure times not excessively distant from what is required by clinical practice. Finally, we discuss how the proposed phase contrast method, unlike other approaches apart from free-space propagation (which however requires a smaller focal spot, thus reducing the flux and increasing exposure times), can be easily implemented in a tomosynthesis geometry suitable for clinical use. In summary, we find that these technical results indicate a high potential for the combination of the two methods. Combining slice separation with detail enhancement provided by phase effects would substantially increase the detectability of small lesions and/or calcifications, which we aim to demonstrate in the next steps of this study.

A quantitative, non-interferometric X-ray phase contrast imaging technique.

We present a quantitative, non-interferometric, X-ray differential phase contrast imaging technique based on the edge illumination principle. We derive a novel phase retrieval algorithm which requires only two images to be acquired and verify the technique experimentally using synchrotron radiation. The technique is useful for planar imaging but is expected to be important for quantitative phase tomography also. The properties and limitations of the technique are studied in detail.

Phase and absorption retrieval using incoherent X-ray sources.

X-ray phase contrast imaging has overcome the limitations of X-ray absorption imaging in many fields. Particular effort has been directed towards developing phase retrieval methods: These reveal quantitative information about a sample, which is a requirement for performing X-ray phase tomography, allows material identification and better distinction between tissue types, etc. Phase retrieval seems impossible with conventional X-ray sources due to their low spatial coherence. In the only previous example where conventional sources have been used, collimators were employed to produce spatially coherent secondary sources. We present a truly incoherent phase retrieval method, which removes the spatial coherence constraints and employs a conventional source without aperturing, collimation, or filtering. This is possible because our technique, based on the pixel edge illumination principle, is neither interferometric nor crystal based. Beams created by an X-ray mask to image the sample are smeared due to the incoherence of the source, yet we show that their displacements can still be measured accurately, obtaining strong phase contrast. Quantitative information is extracted from only two images rather than a sequence as required by several coherent methods. Our technique makes quantitative phase imaging and phase tomography possible in applications where exposure time and radiation dose are critical. The technique employs masks which are currently commercially available with linear dimensions in the tens of centimeters thus allowing for a large field of view. The technique works at high photon energy and thus promises to deliver much safer quantitative phase imaging and phase tomography in the future.

Technical Note: modification of the standard gain correction algorithm to compensate for the number of used reference flat frames in detector performance studies.

PURPOSE: The x-ray performance evaluation of digital x-ray detectors is based on the calculation of the modulation transfer function (MTF), the noise power spectrum (NPS), and the resultant detective quantum efficiency (DQE). The flat images used for the extraction of the NPS should not contain any fixed pattern noise (FPN) to avoid contamination from nonstochastic processes. The "gold standard" method used for the reduction of the FPN (i.e., the different gain between pixels) in linear x-ray detectors is based on normalization with an average reference flat-field. However, the noise in the corrected image depends on the number of flat frames used for the average flat image. The aim of this study is to modify the standard gain correction algorithm to make it independent on the used reference flat frames. METHODS: Many publications suggest the use of 10-16 reference flat frames, while other studies use higher numbers (e.g., 48 frames) to reduce the propagated noise from the average flat image. This study quantifies experimentally the effect of the number of used reference flat frames on the NPS and DQE values and appropriately modifies the gain correction algorithm to compensate for this effect. RESULTS: It is shown that using the suggested gain correction algorithm a minimum number of reference flat frames (i.e., down to one frame) can be used to eliminate the FPN from the raw flat image. This saves computer memory and time during the x-ray performance evaluation. CONCLUSIONS: The authors show that the method presented in the study (a) leads to the maximum DQE value that one would have by using the conventional method and very large number of frames and (b) has been compared to an independent gain correction method based on the subtraction of flat-field images, leading to identical DQE values. They believe this provides robust validation of the proposed method.

Technical note: further development of a resolution modification routine for the simulation of the modulation transfer function of digital x-ray detectors.

PURPOSE: This paper proposes the further development of a resolution modification routine which is used to simulate the presampling modulation transfer function (pMTF) of digital x-ray detectors. METHODS: It suggests a method to reconstruct anisotropic two dimensional (2D) pMTF matrices from the experimentally measured horizontal and vertical 1D pMTFs. In this study, the horizontal dimension of the detector is 17.3 cm, while the vertical one is 24 cm. This matrix is multiplied with the 2D Fourier transform of the super-sampled ideal input image to simulate blurring. Then, the restored image is sampled to form the pixels of the digital image. The authors suggest convolution with the comb function instead of the rectangular function to avoid the correction with the sinc function required by the latter. It is demonstrated that this correction is avoided when the comb function is used. Moreover, this study suggests a way to effectively sample the images in the case when the ratio between the "analog" pitch of the super-sampled input image and the pixel pitch of the digital x-ray detector is a semi-integer. RESULTS: The validation of the simulation algorithm demonstrated that when the comb function was used the average absolute difference between the pMTF measured from the output images and the input ones was less than 1%, while this was of 13% when the rectangular function was used. When a sinc correction was applied in the latter case the difference decreased again to less than 1%. CONCLUSIONS: The developed modification routine provides the means to simulate the spatial resolution of digital x-ray detectors under a wider range of conditions.

Noninterferometric phase-contrast images obtained with incoherent x-ray sources.

We report on what are believed to be the first full-scale images obtained with the coded aperture concept, which uses conventional x-ray sources without the need to collimate/aperture their output. We discuss the differences in the underpinning physical principles with respect to other methods, and explain why these might lead to a more efficient use of the source. In particular, we discuss how the evaluation of the first imaging system provided promising indications on the method's potential to detect details invisible to conventional absorption methods, use an increased average x-ray energy, and reduce exposure times-all important aspects with regards to real-world implementations.

A New Generation of X-ray Baggage Scanners Based on a Different Physical Principle.

X-ray baggage scanners play a basic role in the protection of airports, customs, and other strategically important buildings and infrastructures. The current technology of baggage scanners is based on x-ray attenuation, meaning that the detection of threat objects relies on how various objects differently attenuate the x-ray beams going through them. This capability is enhanced by the use of dual-energy x-ray scanners, which make the determination of the x-ray attenuation characteristics of a material more precise by taking images with different x-ray spectra, and combining the information appropriately. However, this still has limitations whenever objects with similar attenuation characteristics have to be distinguished. We describe an alternative approach based on a different x-ray interaction phenomenon, x-ray refraction. Refraction is a familiar phenomenon in visible light (e.g., what makes a straw half immersed in a glass of water appear bent), which also takes place in the x-ray regime, only causing deviations at much smaller angles. Typically, these deviations occur at the boundaries of all objects. We have developed a system that, like other "phase contrast" based instruments, is capable of detecting such deviations, and therefore of creating precise images of the contours of all objects. This complements the material-related information provided by x-ray attenuation, and helps contextualizing the nature of the individual objects, therefore resulting in an increase of both sensitivity (increased detection rate) and specificity (reduced rate of false positives) of baggage scanners.

Source size and temporal coherence requirements of coded aperture type x-ray phase contrast imaging systems.

There is currently much interest in developing X-ray Phase Contrast Imaging (XPCI) systems which employ laboratory sources in order to deploy the technique in real world applications. The challenge faced by nearly all XPCI techniques is that of efficiently utilising the x-ray flux emitted by an x-ray tube which is polychromatic and possesses only partial spatial coherence. Techniques have, however, been developed which overcome these limitations. Such a technique, known as coded aperture XPCI, has been under development in our laboratories in recent years for application principally in medical imaging and security screening. In this paper we derive limitations imposed upon source polychromaticity and spatial extent by the coded aperture system. We also show that although other grating XPCI techniques employ a different physical principle, they satisfy design constraints similar to those of the coded aperture XPCI.

Design of a novel phase contrast x-ray imaging system for mammography.

It is hoped that x-ray phase contrast imaging (XPCi) will provide a generational improvement in the effectiveness of mammography. XPCi is sensitive to the refraction which x-rays undergo as a result of the variation in x-ray propagation speeds within an object. XPCi is, however, seldom used in clinical applications owing mainly to a lack of suitable systems. The radiation physics group at UCL has previously designed and built an XPCi system sensitive to phase gradients in one dimension for application in security inspection. We present here the design methodology and final design of a prototype XPCi system sensitive to phase gradients in two directions for use in mammography. The technique makes efficient use of the flux available from a laboratory x-ray source, thus making it suitable for clinical use.

Limitations imposed by specimen phase gradients on the design of grating based x-ray phase contrast imaging systems.

X-ray phase contrast imaging is a very promising technique that may lead to significant advancements in a variety of fields, perhaps most notably, medical imaging. The radiation physics group at University College London is currently developing an x-ray phase contrast imaging technique that works with laboratory x-ray sources. This system essentially measures the degree to which photons are refracted by regions of an imaged object. The amount of refraction that may be expected to be encountered in practice impacts strongly upon the design of the imaging system. In this paper, we derive an approximate expression between the properties of archetypal imaged objects encountered in practice and the resulting distribution of refracted photons. This is used to derive constraints governing the design of the system.

The relationship between wave and geometrical optics models of coded aperture type x-ray phase contrast imaging systems.

X-ray phase contrast imaging is a very promising technique which may lead to significant advancements in medical imaging. One of the impediments to the clinical implementation of the technique is the general requirement to have an x-ray source of high coherence. The radiation physics group at UCL is currently developing an x-ray phase contrast imaging technique which works with laboratory x-ray sources. Validation of the system requires extensive modelling of relatively large samples of tissue. To aid this, we have undertaken a study of when geometrical optics may be employed to model the system in order to avoid the need to perform a computationally expensive wave optics calculation. In this paper, we derive the relationship between the geometrical and wave optics model for our system imaging an infinite cylinder. From this model we are able to draw conclusions regarding the general applicability of the geometrical optics approximation.

An active pixel sensor x-ray diffraction (APXRD) system for breast cancer diagnosis.

This paper describes the potential application of an active pixel sensor-based x-ray diffraction (APXRD) system in the field of breast cancer diagnosis. The design and initial testing of the system was reported previously (Bohndiek et al 2008b Phys. Med. Biol. 53 655-72). The system has potential both as a 'diffraction enhanced breast imager' (DEBI) and as a probe for quantitative analysis of breast biopsy samples. The resolution of the system in a DEBI arrangement is 1 mm and the contrast available using a material-specific x-ray diffraction image was found to be up to seven times greater than that of a transmission image. Scatter signatures from a series of biopsy-equivalent samples, ranging in composition from 100% fat to 100% fibrous tissue, were acquired with the APXRD system. Multivariate data analysis was used to produce a partial least squares (PLS) model sensitive to sample fat content. The final model is able to accurately predict the fat content of a series of unknown samples and is robust to significant added noise. This suggests that the APXRD system could provide a simple, semi-automated, quantitative measurement system for analysis of breast biopsy samples. Training on a range of scatter signatures from real breast biopsy samples covering various stages of disease is now needed to test this hypothesis.

A CMOS active pixel sensor system for laboratory- based x-ray diffraction studies of biological tissue.

X-ray diffraction studies give material-specific information about biological tissue. Ideally, a large area, low noise, wide dynamic range digital x-ray detector is required for laboratory-based x-ray diffraction studies. The goal of this work is to introduce a novel imaging technology, the CMOS active pixel sensor (APS) that has the potential to fulfil all these requirements, and demonstrate its feasibility for coherent scatter imaging. A prototype CMOS APS has been included in an x-ray diffraction demonstration system. An industrial x-ray source with appropriate beam filtration is used to perform angle dispersive x-ray diffraction (ADXRD). Optimization of the experimental set-up is detailed including collimator options and detector operating parameters. Scatter signatures are measured for 11 different materials, covering three medical applications: breast cancer diagnosis, kidney stone identification and bone mineral density calculations. Scatter signatures are also recorded for three mixed samples of known composition. Results are verified using two independent models for predicting the APS scatter signature: (1) a linear systems model of the APS and (2) a linear superposition integral combining known monochromatic scatter signatures with the input polychromatic spectrum used in this case. Cross validation of experimental, modelled and literature results proves that APS are able to record biologically relevant scatter signatures. Coherent scatter signatures are sensitive to multiple materials present in a sample and provide a means to quantify composition. In the future, production of a bespoke APS imager for x-ray diffraction studies could enable simultaneous collection of the transmitted beam and scattered radiation in a laboratory-based coherent scatter system, making clinical transfer of the technique attainable.