K-edge subtraction synchrotron X-ray imaging in bio-medical research.

High contrast in X-ray medical imaging, while maintaining acceptable radiation dose levels to the patient, has long been a goal. One of the most promising methods is that of K-edge subtraction imaging. This technique, first advanced as long ago as 1953 by B. Jacobson, uses the large difference in the absorption coefficient of elements at energies above and below the K-edge. Two images, one taken above the edge and one below the edge, are subtracted leaving, ideally, only the image of the distribution of the target element. This paper reviews the development of the KES techniques and technology as applied to bio-medical imaging from the early low-power tube sources of X-rays to the latest high-power synchrotron sources. Applications to coronary angiography, functional lung imaging and bone growth are highlighted. A vision of possible imaging with new compact sources is presented.

Quantitative Imaging of Regional Aerosol Deposition, Lung Ventilation and Morphology by Synchrotron Radiation CT.

To understand the determinants of inhaled aerosol particle distribution and targeting in the lung, knowledge of regional deposition, lung morphology and regional ventilation, is crucial. No single imaging modality allows the acquisition of all such data together. Here we assessed the feasibility of dual-energy synchrotron radiation imaging to this end in anesthetized rabbits; both in normal lung (n = 6) and following methacholine (MCH)-induced bronchoconstriction (n = 6), a model of asthma. We used K-edge subtraction CT (KES) imaging to quantitatively map the regional deposition of iodine-containing aerosol particles. Morphological and regional ventilation images were obtained, followed by quantitative regional iodine deposition maps, after 5 and 10 minutes of aerosol administration. Iodine deposition was markedly inhomogeneous both in normal lung and after induced bronchoconstrition. Deposition was significantly reduced in the MCH group at both time points, with a strong dependency on inspiratory flow in both conditions (R2 = 0.71; p < 0.0001). We demonstrate for the first time, the feasibility of KES CT for quantitative imaging of lung deposition of aerosol particles, regional ventilation and morphology. Since these are among the main factors determining lung aerosol deposition, we expect this imaging approach to bring new contributions to the understanding of lung aerosol delivery, targeting, and ultimately biological efficacy.

Radiation dose and image quality in K-edge subtraction computed tomography of lung in vivo.

K-edge subtraction computed tomography (KES-CT) allows simultaneous imaging of both structural features and regional distribution of contrast elements inside an organ. Using this technique, regional lung ventilation and blood volume distributions can be measured experimentally in vivo. In order for this imaging technology to be applicable in humans, it is crucial to minimize exposure to ionizing radiation with little compromise in image quality. The goal of this study was to assess the changes in signal-to-noise ratio (SNR) of KES-CT lung images as a function of radiation dose. The experiments were performed in anesthetized and ventilated rabbits using inhaled xenon gas in O2 at two concentrations: 20% and 70%. Radiation dose, defined as air kerma (Ka), was measured free-in-air and in a 16 cm polymethyl methacrylate phantom with a cylindrical ionization chamber. The dose free-in-air was varied from 2.7 mGy to 8.0 Gy. SNR in the images of xenon in air spaces was above the Rose criterion (SNR > 5) when Ka was over 400 mGy with 20% xenon, and over 40 mGy with 70% xenon. Although in human thorax attenuation is higher, based on these findings it is estimated that, by optimizing the imaging sequence and reconstruction algorithms, the radiation dose could be further reduced to clinically acceptable levels.

Quantitative functional imaging and kinetic studies with high-Z contrast agents using synchrotron radiation computed tomography.

1. There is an increasing demand in diagnostic radiology for extracting additional morphological and functional quantitative parameters from three-dimensional computed tomography (CT) images. Synchrotron radiation computed tomography (SRCT) is the state-of-the-art method in preclinical X-ray CT, because its performance is close to the theoretical limits in terms of accuracy and precision. 2. The SRCT method with monochromatic X-ray beams yields absolute high-Z element contrast agent concentrations, without errors arising from beam hardening or scatter artefacts, by using digital subtraction techniques of the sinograms. Each pixel of the reconstructed difference images provides a quantitative concentration versus time curve of inhaled or injected high-Z contrast agents (xenon or iodine) with a high sensitivity. This is the key point of two functional imaging techniques that were developed at the European Synchrotron Radiation Facility: brain perfusion and lung function (ventilation and perfusion). 3. These two imaging techniques provide parametric images expressed in absolute perfusion parameters (blood volume, blood flow, mean transit time and capillary permeability) or ventilation parameters (lung volume, regional lung ventilation, bronchial lumen size, regional airway and lung compliance) with a high accuracy and precision. 4. The aim of the present brief review is to give a snapshot of the status and perspectives of these two imaging techniques, with emphasis on the performances and interests for functional imaging. Two separate sections will then describe the results obtained so far using SRCT as an in vivo functional imaging tool for measuring changes in haemodynamics and ventilation, in the investigation of experimental pathophysiology and in the effects of therapeutic intervention.

The radiotherapy clinical trials projects at the ESRF: technical aspects.

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.

USAXS and SAXS from cancer-bearing breast tissue samples.

USAXS and SAXS patterns from cancer-bearing human breast tissue samples were recorded at beamline ID02 of the ESRF using a Bonse-Hart camera and a pinhole camera. The samples were classified as being ductal carcinoma, grade II, and ductal carcinoma in situ, partly invasive. The samples included areas of healthy collagen, invaded collagen, necrotic ducts with calcifications, and adipose tissue. The scattering patterns were analyzed in different ways to separate the scattering contribution and the direct beam from the observed rocking curve (RC) of the analyzer. It was found that USAXS from all tissues was weak, and the effects on the analyzer RC were observed only in the low-intensity tails of the patterns. The intrinsic RC was convolved with different model functions for the impulse response of the sample, and the best fit with experiment was obtained by the Pearson VII function. Significantly different distributions for the Pearson exponent m were obtained in benign and malignant regions of the samples. For a comparison with analyzer-based imaging (ABI) or diffraction enhanced imaging (DEI) a "long-slit" integration of the patterns was performed, and this emphasized the scattering contribution in the tails of the rocking curve.

Simultaneous in vivo synchrotron radiation computed tomography of regional ventilation and blood volume in rabbit lung using combined K-edge and temporal subtraction.

In K-edge subtraction (KES) imaging with synchrotron radiation computed tomography (SRCT), two images are taken simultaneously using energies above and below the K-absorption edge of a contrast agent. A logarithmic difference image reveals the contrast agent concentration with good accuracy. Similarly, in temporal subtraction imaging (TSI) the reference image is taken before the introduction of the contrast agent. Quantitative comparisons of in vivo images of rabbit lung indicated that similar results for concentrations of iodine in blood vessels and xenon in airways are obtained by KES and TSI, but the level of noise and artifacts was higher in the latter. A linear fit showed that in the lung parenchyma rho(TSI) = (0.97 +/- 0.03)rho(KES) + (0.00 +/- 0.05) for xenon and rho(TSI) = (1.21 +/- 0.15)rho(KES) + (0.0 +/- 0.1) for iodine. For xenon the calculation of time constant of ventilation gave compatible values for both of the methods. The two methods are combined for the simultaneous determination of the xenon concentration (by KES) and the iodine concentration (by TSI) in lung imaging, which will allow simultaneous in vivo determination of ventilation and perfusion.

Performance of a dispersion-compensating scanning X-ray spectrometer for Compton profile measurements.

A new X-ray spectrometer has been constructed for Compton profile measurements at beamline ID15B of the ESRF. The spectrometer is based on a novel idea, dispersion compensation, which was proposed earlier. A cylindrically bent Laue monochromator focuses approximately 90 keV synchrotron radiation at about 0.7 m before the sample, and produces a well defined energy or wavelength gradient on the sample. A cylindrically bent Laue analyser almost perfectly compensates this wavelength gradient. Using an Al sample, it has been confirmed that the new spectrometer improves the counting rate by a factor of two compared with the previously constructed 30 keV and 60 keV spectrometers, with a comparable momentum resolution. Because of reduced absorption owing to use of high-energy X-rays, the enhancement of the counting rate is spectacular for heavy-element materials.

Imaging lobular breast carcinoma: comparison of synchrotron radiation DEI-CT technique with clinical CT, mammography and histology.

Different modalities for imaging cancer-bearing breast tissue samples are described and compared. The images include clinical mammograms and computed tomography (CT) images, CT images with partly coherent synchrotron radiation (SR), and CT and radiography images taken with SR using the diffraction enhanced imaging (DEI) method. The images are evaluated by a radiologist and compared with histopathological examination of the samples. Two cases of lobular carcinoma are studied in detail. The indications of cancer are very weak or invisible in the conventional images, but the morphological changes due to invasion of cancer become pronounced in the images taken by the DEI method. The strands penetrating adipose tissue are seen clearly in the DEI-CT images, and the histopathology confirms that some strands contain the so-called 'Indian file' formations of cancer cells. The radiation dose is carefully measured for each of the imaging modalities. The mean glandular dose (MGD) for 50% glandular breast tissue is about 1 mGy in conventional mammography and less than 0.25 mGy in projection DEI, while in the clinical CT imaging the MGD is very high, about 45 mGy. The entrance dose of 95 mGy in DEI-CT imaging gives rise to an MGD of 40 mGy, but the dose may be reduced by an order of magnitude, because the contrast is very large in most images.

Effect of tidal volume on distribution of ventilation assessed by synchrotron radiation CT in rabbit.

A respiration-gated synchrotron radiation computed tomography (SRCT) technique, which allows visualization and direct quantification of inhaled stable xenon gas, was used to study the effect of tidal volume (Vt) on regional lung ventilation. High-resolution maps (pixel size 0.35 x 0.35 mm) of local washin time constants (tau) and regional specific ventilation were obtained in five anesthetized, paralyzed, and mechanically ventilated rabbits in upright body position at the fourth, sixth, and eighth dorsal vertebral levels with a Vt from 4.9 +/- 0.3 to 7.9 +/- 0.4 ml/kg (means +/- SE). Increasing Vt without an increase in minute ventilation resulted in a proportional increase of mean specific ventilation up to 65% in all studied lung levels and reduced the scattering of washin tau values. The tau values had log-normal distributions. The results indicate that an increase in Vt decreases nonuniformity of intraregional ventilatory gas exchange. The findings suggest that (SRCT) provides a new quantitative tool with high spatial discrimination ability for assessment of changes in peripheral pulmonary gas distribution during mechanical ventilation.

Medical applications of synchrotron radiation.

The medical imaging and therapeutic technologies that are based on the use of radiation are reviewed briefly, with special emphasis on the recent developments of synchrotron radiation (SR) methods. New results have been achieved in all of these areas since the last comprehensive reviews were written in this field. This topical review is intended to make the latest possible results and complete set of references available. The different contrast mechanisms in imaging by x-rays are described. The applications range from whole-body imaging to studies of atomic and molecular structures. The SR imaging applications include coronary angiography, bronchography, mammography, computed tomography, x-ray microscopy and imaging by scattering. The therapy applications include photon activation therapy and microbeam radiation therapy.

Small-angle x-ray scattering studies of human breast tissue samples.

Small-angle x-ray scattering (SAXS) patterns are recorded from thin breast tissue samples containing healthy and cancerous regions. The SAXS patterns are compared with histo-pathological observations. The information available from SAXS is reviewed, and a model for scattering from collagen is presented. Scattering patterns of collagen at regions far from the tumours are essentially different from those at tumours. The axial period of collagen fibrils is 65.0 +/- 0.1 nm in healthy regions, and 0.3 nm larger in cancer-invaded regions. The average intensity of scattering from cancerous regions is an order of magnitude higher than the intensity from healthy regions. This is interpreted to arise from an increase of the specific surface area of the scatterers, which is due to a disruption of the molecular and supra-molecular structures in cancerous regions and invasion of new types of cells. The differences of the SAXS patterns are large and distinctive enough to suggest that these phenomena may be utilized in mammography.

Quantitative functional lung imaging with synchrotron radiation using inhaled xenon as contrast agent.

Small airways play a key role in the distribution of ventilation and in the matching of ventilation to perfusion. The purpose of this study was to introduce an imaging method that allows measurement of regional lung ventilation and evaluation of the function of airways with a small diameter. The experiments were performed at the Medical Beamline of the European Synchrotron Radiation Facility. Monochromatic synchrotron radiation beams were used to obtain quantitative respiration-gated images of lungs and airways in two anaesthetized and mechanically ventilated rabbits using inhaled stable xenon (Xe) gas as a contrast agent. Two simultaneous images were acquired at two different energies, above and below the K-edge of Xe. Logarithmic subtraction of the two images yields absolute Xe concentrations. This technique is known as K-edge subtraction (KES) radiography. Two-dimensional planar and CT images were obtained showing spatial distribution of Xe concentrations within the airspaces, as well as the dynamics of filling with Xe. Bronchi down to 1 mm in diameter were visible both in the subtraction radiographs and in tomographic images. Absolute concentrations of Xe gas were calculated within the tube carrying the inhaled gas mixture, small and large bronchi, and lung tissue. Local time constants of ventilation with Xe were obtained by following the evolution of gas concentration in sequential computed tomography images. The results of this first animal study indicate that KES imaging of lungs with Xe gas as a contrast agent has great potential in studies of the distribution of ventilation within the lungs and of airway function, including airways with a small diameter.

First human transvenous coronary angiography at the European Synchrotron Radiation Facility.

The first operation of the European Synchrotron Radiation Facility (ESRF) medical beamline is reported in this paper. The goal of the angiography project is to develop a reduced risk imaging technique, which can be used to follow up patients after coronary intervention. After the intravenous injection of a contrast agent (iodine) two images are produced with monochromatic beams, bracketing the iodine K-edge. The logarithmic subtraction of the two measurements results in an iodine enhanced image, which can be precisely quantified. A research protocol has been designed to evaluate the performances of this method in comparison with the conventional technique. Patients included in the protocol have previously undergone angioplasty. If a re-stenosis is suspected, the patient is imaged both at the ESRF and at the hospital with the conventional technique, within the next few days. This paper reports the results obtained with the first patients. To date, eight patients have been imaged and excellent image quality was obtained.

Research at the European Synchrotron Radiation Facility medical beamline.

The application of synchrotron radiation in medical research has become a mature field of research at synchrotron facilities worldwide. In the relatively short time that synchrotrons have been available to the scientific community, their characteristic beams of UV and X-ray radiation have been applied to virtually all areas of medical science which use ionizing radiation. The ability to tune intense monochromatic beams over wide energy ranges differentiates these sources from standard clinical and research tools. At the European Synchrotron Radiation Facility (Grenoble, France), a major research facility is operational on an advanced wiggler radiation beamport, ID17. The beamport is designed to carry out a broad range of research ranging from cell radiation biology to in vivo human studies. Medical imaging programs at ID17 include transvenous coronary angiography, computed tomography, mammography and bronchography. In addition, a major research program on microbeam radiation therapy is progressing. This paper will present a very brief overview of the beamline and the imaging and therapy programs.

In vivo K-edge imaging with synchrotron radiation.

We present in this paper two imaging techniques using contrast agents assessed with in vivo experiments. Both methods are based on the same physical principle, and were implemented at the European Synchrotron Radiation Facility medical beamline. The first one is intravenous coronary angiography using synchrotron radiation X-rays. This imaging technique has been planned for human studies in the near future. We describe the first experiments that were carried out with pigs at the ESRF. The second imaging mode is computed tomography using synchrotron radiation on rats bearing brain tumors. Owing to synchrotron radiation physical properties, these new imaging methods provide additional information compared to conventional techniques. After infusion of the contrast agent, it is possible to derive from the images the concentration of the contrast agent in the tumor area for the computed tomography and in any visible vessel for the angiography method.

Fixed-exit monochromator for computed tomography with synchrotron radiation at energies 18-90 keV.

A fixed-exit monochromator has been constructed for computed tomography (CT) studies at the Medical Beamline of the European Synchrotron Radiation Facility. A non-dispersive pair of bent Laue-type crystals is used, and the first crystal is water-cooled. The monochromator operates at energies from 18 to 90 keV, and the maximum width of the beam is 150 mm. The performance of the monochromator is studied with respect to the beam intensity and energy distributions, and a close agreement is found between the calculated and experimental results. The intensity is between 10(9) and 10(10) photons s(-1) mm(-2) under typical operating conditions. The harmonic content of a 25 keV beam is about 30% at the minimum wiggler gap of 25 mm (field 1.57 T) and decreases by an order of magnitude when the gap is increased to 60 mm (field 0.62 T). The experimental set-up for CT studies includes dose monitors, goniometers and translation stages for positioning and scanning the object, and a 432-element linear-array Ge detector. Examples from phantom studies and in vivo animal experiments are shown to illustrate the spatial resolution and contrast of the reconstructed images.

Feasibility study of x-ray diffraction computed tomography for medical imaging.

A feasibility study of soft-tissue imaging based on x-ray wide-angle diffraction contrast has been performed at the medical beamline of the European Synchrotron Radiation Facility (ESRF). The technique employs computed-tomography algorithms to reconstruct from one data set the spatial distribution of several tissues differentiated by their diffraction properties. Radial diffraction profiles are measured in parallel projections from the sample and decomposed into material-selective weighting factors, which form the sinograms for the reconstructions. Attenuation effects--inherent in imaging techniques using scattered radiation--are efficiently corrected for by a ray-tracing method applied to the corresponding absorption image. Images of 7 cm diameter samples composed of fat, bone and muscle were generated at 60 and 80 keV x-ray energy. The highest surface-absorbed dose was 24 mGy, but substantial contrast could still be obtained at 7 mGy, indicating potential applicability in medical imaging. The dominant noise contribution in the images stems from the detection system, pointing to a possible decrease in the surface-absorbed dose for an optimized system of more than a factor of 2.

Experiments with very high energy synchrotron radiation.

The use of synchrotron radiation with very high photon energies has become possible only with the latest generation of storage rings. All high-electron-energy synchrotron sources will have a dedicated program for the use of very high photon energies. The high-energy beamline ID15 at the ESRF was the first beamline built and dedicated to this purpose, and it has now been in user operation for more than three years. The useful energy range of this beamline is 30-1000 keV and the superconducting insertion device for producing the highest attainable photon energies is described in detail. The techniques most often used today are diffraction and Compton scattering; an overview of the most important experiments is given. Both techniques have been used in the investigation of magnetic systems, and, additionally, the high resolution in reciprocal space, which can be achieved in diffraction, has led to a series of applications. Other fields of research are addressed, and attempts to indicate possible future research areas of high-energy synchrotron radiation are made.