Dose profiles and x-ray energy optimization for microbeam radiation therapy by high-dose, high resolution dosimetry using Sm-doped fluoroaluminate glass plates and Monte Carlo transport simulation.

Microbeam radiation therapy (MRT) utilizes highly collimated synchrotron generated x-rays to create narrow planes of high dose radiation for the treatment of tumors. Individual microbeams have a typical width of 30-50 µm and are separated by a distance of 200-500 µm. The dose delivered at the center of the beam is lethal to cells in the microbeam path, on the order of hundreds of Grays (Gy). The tissue between each microbeam is spared and helps aid in the repair of adjacent damaged tissue. Radiation interactions within the peak of the microbeam, such as the photoelectric effect and incoherent (atomic Compton) scattering, cause some dose to be delivered to the valley areas adjacent to the microbeams. As the incident x-ray energy is modified, radiation interactions within a material change and affect the probability of interactions, as well as the directionality and energy of ionizing particles (electrons) that deposit energy in the valley regions surrounding the microbeam peaks. It is crucial that the valley dose between microbeams be minimal to maintain the effectiveness of MRT. Using a monochromatic x-ray source with x-ray energies ranging from 30 to 150 keV, a detailed investigation into the effect of incident x-ray energy on the dose profiles of microbeams was performed using samarium doped fluoroaluminate (FA) glass as the medium. All dosimetric measurements were carried out using a purpose-built fluorescence confocal microscope dosimetric technique that used Sm-doped FA glass plates as the irradiated medium. Dose profiles are measured over a very a wide range of x-ray energies at micrometer resolution and dose distribution in the microbeam are mapped. The measured microbeam profiles at different energies are compared with the MCNP6 radiation transport code, a general transport code which can calculate the energy deposition of electrons as they pass through a given material. The experimentally measured distributions can be used to validate the results for electron energy deposition in fluoroaluminate glass. Code validation is necessary for using transport codes in future treatment planning for MRT and other radiation therapies. It is shown that simulated and measured micro beam-profiles are in good agreement, and micrometer level changes can be observed using this high-resolution dosimetry technique. Full width at 10% of the maximum peak (FW@10%) was used to quantify the microbeam width. Experimental measurements on FA glasses and simulations on the dependence of the FW@10% at various energies are in good agreement. Simulations on energy deposited in water indicate that FW@10% reaches a local minimum around energies 140 keV. In addition, variable slit width experiments were carried out at an incident x-ray energy of 100 keV in order to determine the effect of the narrowing slit width on the delivered peak dose. The microbeam width affects the peak dose, which decreases with the width of the microbeam. Experiments suggest that a typical microbeam width for MRT is likely to be between 20-50 µm based on this work.

Bubbles in noodle dough: Characterization by X-ray microtomography.

Bubbles, found in a huge variety of food products, are known to afford desirable quality attributes, especially those related to texture, mouthfeel and taste. However, the presence of bubbles and their effects on wheat flour noodles is an aspect that has been, until now, largely overlooked, despite the positive and negative connotations of bubbly inclusions on Asian noodle quality. X-rays from a synchrotron source (Biomedical Imaging and Therapy facility at the Canadian Light Source) were used to rapidly and non-destructively acquire tomographic images of noodle dough. Appropriate image analysis protocols were used to determine the bubble size distribution, the orientation of bubbles, and their position within the dough sheet. The effect of processing (one or multiple lamination steps) on bubble properties in the dough that was subsequently sheeted (gradual elongation and reduction in thickness) was investigated. Bubble size distributions, well captured by lognormal distribution function, showed that the lamination process induced bubble entrapment and reduction in bubble size. Bubbles were found to be flat, elongated and oriented in the sheeting direction, this effect being less for doughs laminated ten times (90° rotations between lamination steps). Interestingly, a gradient in concentration of bubbles within the dough sheet was found from the noodle core to the sheet edges. Aging effects were also apparent. This first non-destructive study of bubbles in wheat-flour noodle dough provides a more complete knowledge of the dough sheet's internal structure, and how it originates via processing, and this has repercussions on the overall quality of Asian noodles.

Multiple image x-radiography for functional lung imaging.

Detection and visualization of lung tissue structures is impaired by predominance of air. However, by using synchrotron x-rays, refraction of x-rays at the interface of tissue and air can be utilized to generate contrast which may in turn enable quantification of lung optical properties. We utilized multiple image radiography, a variant of diffraction enhanced imaging, at the Canadian light source to quantify changes in unique x-ray optical properties of lungs, namely attenuation, refraction and ultra small-angle scatter (USAXS or width) contrast ratios as a function of lung orientation in free-breathing or respiratory-gated mice before and after intra-nasal bacterial endotoxin (lipopolysaccharide) instillation. The lung ultra small-angle scatter and attenuation contrast ratios were significantly higher 9 h post lipopolysaccharide instillation compared to saline treatment whereas the refraction contrast decreased in magnitude. In ventilated mice, end-expiratory pressures result in an increase in ultra small-angle scatter contrast ratio when compared to end-inspiratory pressures. There were no detectable changes in lung attenuation or refraction contrast ratio with change in lung pressure alone. In effect, multiple image radiography can be applied towards following optical properties of lung air-tissue barrier over time during pathologies such as acute lung injury.

Respiratory-gated KES imaging of a rat model of acute lung injury at the Canadian Light Source.

In this study, contrast-enhanced X-ray tomographic imaging for monitoring and quantifying respiratory disease in preclinical rodent models is proposed. A K-edge imaging method has been developed at the Canadian Light Source to very accurately obtain measurements of the concentration of iodinated contrast agent in the pulmonary vasculature and inhaled xenon in the airspaces of rats. To compare the iodine and xenon concentration maps, a scout projection image was acquired to define the region of interest within the thorax for imaging and to ensure the same locations were imaged in each K-edge subtraction (KES) acquisition. A method for triggering image acquisition based on the real-time measurements of respiration was also developed to obtain images during end expiration when the lungs are stationary, in contrast to other previously published studies that alter the respiration to accommodate the image acquisition. In this study, images were obtained in mechanically ventilated animals using physiological parameters at the iodine K-edge in vivo and at the xenon K-edge post mortem (but still under mechanical ventilation). The imaging techniques were performed in healthy Brown Norway rats and in age-matched littermates that had an induced lung injury to demonstrate feasibility of the imaging procedures and the ability to correlate the lung injury and the quantitative measurements of contrast agent concentrations between the two KES images. The respiratory-gated KES imaging protocol can be easily adapted to image during any respiratory phase and is feasible for imaging disease models with compromised lung function.

Multiple energy synchrotron biomedical imaging system.

A multiple energy imaging system that can extract multiple endogenous or induced contrast materials as well as water and bone images would be ideal for imaging of biological subjects. The continuous spectrum available from synchrotron light facilities provides a nearly perfect source for multiple energy x-ray imaging. A novel multiple energy x-ray imaging system, which prepares a horizontally focused polychromatic x-ray beam, has been developed at the BioMedical Imaging and Therapy bend magnet beamline at the Canadian Light Source. The imaging system is made up of a cylindrically bent Laue single silicon (5,1,1) crystal monochromator, scanning and positioning stages for the subjects, flat panel (area) detector, and a data acquisition and control system. Depending on the crystal's bent radius, reflection type, and the horizontal beam width of the filtered synchrotron radiation (20-50 keV) used, the size and spectral energy range of the focused beam prepared varied. For example, with a bent radius of 95 cm, a (1,1,1) type reflection and a 50 mm wide beam, a 0.5 mm wide focused beam of spectral energy range 27 keV-43 keV was obtained. This spectral energy range covers the K-edges of iodine (33.17 keV), xenon (34.56 keV), cesium (35.99 keV), and barium (37.44 keV); some of these elements are used as biomedical and clinical contrast agents. Using the developed imaging system, a test subject composed of iodine, xenon, cesium, and barium along with water and bone were imaged and their projected concentrations successfully extracted. The estimated dose rate to test subjects imaged at a ring current of 200 mA is 8.7 mGy s-1, corresponding to a cumulative dose of 1.3 Gy and a dose of 26.1 mGy per image. Potential biomedical applications of the imaging system will include projection imaging that requires any of the extracted elements as a contrast agent and multi-contrast K-edge imaging.

BMIT facility at the Canadian Light Source: Advances in X-ray phase-sensitive imaging.

The BioMedical Imaging and Therapy (BMIT) facility [1,2] located at the Canadian Light Source, provides synchrotron-specific imaging and radiation therapy capabilities. There are two separate beamlines used for experiments: the bending magnet (05B1-1) and the insertion device (05ID-2) beamline. The bending magnet beamline provides access to monochromatic beam spanning a spectral range of 15-40keV, and the beam is 240mm wide in the POE-2 experimental hutch. Users can also perform experiments with polychromatic (pink) beam. The insertion device beamline was officially opened for general user program in 2015. The source for the ID beamline is a multi-pole, superconducting 4.3T wiggler. The high field gives a critical energy over 20keV. The optics hutches prepare a beam that is 220mm wide in the last experimental hutch SOE-1. The monochromatic spectral range spans 25-150+keV. Several different X-ray detectors are available for both beamlines, with resolutions ranging from 2µm to 200µm. BMIT provides a number of imaging techniques including standard absorption X-ray imaging, K-edge subtraction imaging (KES), in-line phase contrast imaging (also known as propagation based imaging, PBI) and Diffraction Enhanced Imaging/Analyzer Based Imaging (DEI/ABI), all in either projection or CT mode. PBI and DEI/ABI are particularly important tools for BMIT users since these techniques enable visualization of soft tissue and allow for low dose imaging.

In vivo imaging of rat cortical bone porosity by synchrotron phase contrast micro computed tomography.

Cortical bone is a dynamic tissue which undergoes adaptive and pathological changes throughout life. Direct longitudinal tracking of this remodeling process holds great promise for improving our understanding of bone development, maintenance and senescence. The application of in vivo micro-computed tomography (micro-CT) has enabled longitudinal tracking of trabecular bone microarchitecture with commercially available scanners generally operating in the 10-20 µm voxel range with absorbed doses reported between 0.5 and 1 Gy. Imaging of cortical bone microarchitecture (porosity) requires higher resolution and thus in vivo imaging of these structures has not been achieved due to excessive radiation dose. In this study we tested the hypothesis that synchrotron propagation phase contrast micro-CT can enable in vivo imaging of cortical porosity in rats at doses comparable to those currently employed for trabecular bone imaging. Synchrotron imaging experiments were conducted at the Canadian Light Source using the bending magnet beamline of the BioMedical Imaging and Therapy (BMIT) facility. Protocol optimization (propagation distance, projection number) was conducted ex vivo on rat (Sprague-Dawley) forelimbs with dose determined by ion chamber and lithium fluoride crystal thermoluminescent dosimeters. Comparative ex vivo imaging was performed using laboratory in vivo scanning systems, identifying a range of doses between 1.2-3.6 Gy for common protocols. A final in vivo synchrotron protocol involving a 2.5 Gy dose was implemented with live rats. The resulting images demonstrated improved delineation of cortical porosity through the improved edge enhancement effect of phase contrast, opening the door to novel experimental studies involving the longitudinal tracking of remodeling.

Spectral K-edge subtraction imaging.

We describe a spectral x-ray transmission method to provide images of independent material components of an object using a synchrotron x-ray source. The imaging system and process is similar to K-edge subtraction (KES) imaging where two imaging energies are prepared above and below the K-absorption edge of a contrast element and a quantifiable image of the contrast element and a water equivalent image are obtained. The spectral method, termed 'spectral-KES' employs a continuous spectrum encompassing an absorption edge of an element within the object. The spectrum is prepared by a bent Laue monochromator with good focal and energy dispersive properties. The monochromator focuses the spectral beam at the object location, which then diverges onto an area detector such that one dimension in the detector is an energy axis. A least-squares method is used to interpret the transmitted spectral data with fits to either measured and/or calculated absorption of the contrast and matrix material-water. The spectral-KES system is very simple to implement and is comprised of a bent Laue monochromator, a stage for sample manipulation for projection and computed tomography imaging, and a pixelated area detector. The imaging system and examples of its applications to biological imaging are presented. The system is particularly well suited for a synchrotron bend magnet beamline with white beam access.

Individual results of treatment of COPD with low doses of fenoterol compared with treatment with ipratropium bromide.

We compared the effects of 30-day treatments with fenoterol in low doses (4 x 100 mcg) and ipratropium bromide (4 x 40 mcg) on the lung function parameters (LFP), dyspnea and physical capacity of patients with severe chronic obstructive pulmonary disease (COPD) (FEV1 < 35% pred.) and analysed the individual response of patients to the administered therapy. The study included two groups of patients treated with fenoterol (n = 22) and ipratropium bromide (n = 22). The patients were matched by functional characteristics (age: 60 +/- 7 and 57 +/- 9 years; ATS Dyspnea Scale: 2.7 +/- 0.8 and 2.4 +/- 0.9; FEV1%: 25 +/- 7% and 23 +/- 6%; pO2: 62.4 +/- 5.3 mm Hg and 61.0 +/- 9.5 mm Hg; all values mean +/- SD). After 30 days of treatment we measured the lung function parameters (FEV1, FVC), dyspnea indices (ATS dyspnea scale, Borg scale) and the physical capacity of the patients (6-minute walking distance test). The results showed that in an open experiment fenoterol (4 x 100 mcg daily), unlike ipratropium bromide (4 x 40 mcg daily), cannot improve statistically and clinically significantly the lung function parameters, dyspnea and the physical capacity of the group as a whole. However, when the findings were assessed for each patient individually, 32% of the patients proved to have responded positively to the treatment. Therefore efficaciousness of fenoterol in low doses should be determined by assessing the lung function parameters, dyspnea and the physical capacity individually for each patient.