Microbeams have been used for radiation biology research since their introduction in the 1950s. A goal since their inception has been to irradiate individual cells and sub-cellular components with individual charged particles. These two criteria have been simultaneously achievable only within the last decade thanks to new technologies capable of producing very thin materials. The McMaster Microbeam Laboratory wishes to conduct such experiments using a proton beam. However, there are presently no commercially available detectors for this application, which necessitates the need for a new detector. Following literature research, a 10 μm thin Schottky diode detector was selected as the most appropriate type of detector for the setup at McMaster. The design of the detector and detection system geometries were optimized to reduce beam scattering and broadening with the aid of TRIM and MCNP simulations. Two detectors were fully constructed. However, a stable response to radiation was not achieved. One of the detectors appeared to function as a radiation detector very briefly but this result was not reproducible. The I-V curve of the detectors proved that they functioned as expected as diodes. However, without a radiation response no further characterization could be completed. Although problem solving efforts to overcome this issue were unsuccessful, a large silicon dopant concentration is suspected to be a possible cause. / Thesis / Master of Science (MSc)

Current radiotherapy techniques are focused on delivering effective treatments while sparing surrounding healthy tissues. As a result, radiotherapy treatments are using narrower and more tightly conforming therapy techniques. For these treatments to be effective an accurate measure of the dose delivered by these very narrow radiotherapy beams, both in and around the target volume, is required. It is a challenging task for the conventional type dosimeters to determine dose distribution in such small fields. The best example of such fields is microbeam beam radiotherapy (MRT), a developing treatment technique that takes this requirement even further. MRT delivers an array of micrometre size radiotherapy beams to the target. MRT has been shown to be highly effective, but reliable dosimetry of MRT is challenging due to the micrometre scales involved. Attempts to determine the MRT dose distribution have been documented for using special type dosimeters such as radioch romic film and MOSFET detectors, as well as Monte Carlo simulations. This thesis investigates polymer gels as a dosimeter for dose distribution measurements of small radiotherapy fields and microbeams. Polymer gel dosimetry is a technique which uses a tissue-equivalent gel to act as both a three-dimensional dosimeter and a phantom at the same time. These gels polymerise when exposed to ionising radiation and the response is locally dose dependent linearly. This thesis investigates the use of polymer gels for the dosimetry of small sub-centimetre (down to 3 × 3 mm2) and micrometre radiotherapy fields. A high resolution imaging technique is also required for such small beam dosimetry. This work used special high strength MRI scanners to analyse polymer gels at high resolution. This work explores the feasibility of polymer gels irradiated by microbeams and analysed using Raman spectroscopy as a dosimeter for synchrotron generated microbeams. MRT is characterised by very high doses, and special high-dose resistive types of gel were developed as part of this work. It is shown that polymer gels imagined using Raman spectroscopy techniques are capable of measuring the dose distribution of microbeam radiation techniques. This thesis also investigates the use of polymer gels to measure dose perturbations caused by metallic artefacts. Metallic artefacts, such as a surgical aneurysm clip, can be left in a patient and cause dose perturbations during radiotherapy procedures. Polymer gels were used to determine the degree of dose enhancement induced by an aneurysm clip placed inside when irradiated with a typical stereotactic radiotherapy procedure. In addition, this thesis used gels in several other innovative applications. Photonuclear interactions generated in gel by high energy x-ray beams were measured via secondary neutrons. Special clear-type gels that do not change colour with irradiation were developed. Polymer gels were investigated for dosimetry of an extremely high dose rate capacitor type linear accelerator. And polymer gels were for measurement of a high energy proton beam.

This thesis presents interdisciplinary, collaborative research in the field of synchrotron microbeam radiation therapy (MRT). Synchrotron MRT is an experimental radiotherapy technique under consideration for clinical use, following demonstration of efficacy in tumour-bearing rodent models with remarkable sparing of normal tissue. A high flux, X-ray beam from a synchrotron is segmented into micro-planar arrays of narrow beams, typically 25 μm wide and with peak-to-peak separations of 200 μm. The radiobiological effect of MRT and the underlying cellular mechanisms are poorly understood. The ratio between dose in the ‘peaks’of the microbeams to the dose in the ‘valleys’, between the microbeams, has strong biological significance. However, there are difficulties in accurately measuring the dose distribution for MRT. The aim of this thesis is to address elements of both the dosimetric and radiobiological gaps that exist in the field of synchrotron MRT. A method of film dosimetry and microdensitometry was adapted in order to measure the peak-to-valley dose ratios for synchrotron MRT. Two types of radiochromic film were irradiated in a phantom and also flush against a microbeam collimator on beamline BL28B2 at the SPring-8 synchrotron. The HD-810 and EBT varieties of radiochromic film were used to record peak dose and valley dose respectively. In other experiments, a dose build-up effect was investigated and the half value layer of the beam with and without the microbeam collimator was measured to investigate the effect of the collimator on the beam quality. The valley dose obtained for films placed flush against the collimator was approximately 0.25% of the peak dose. Within the water phantom, the valley dose had increased to between 0.7–1.8% of the peak dose, depending on the depth in the phantom. We also demonstrated, experimentally and by Monte Carlo simulation, that the dose is not maximal on the surface and that there is a dose build-up effect. The microbeam collimator did not make an appreciable difference to the beam quality. The measured values of peak-to-valley dose ratio were higher than those predicted by previously published Monte Carlo simulation papers. For the radiobiological studies, planar (560 Gy) or cross-planar (2 x 280 Gy or 2 x 560 Gy) irradiations were delivered to mice inoculated with mammary tumours in their leg, on beamline BL28B2 at the SPring-8 synchrotron. Immunohistochemical staining for DNA double strand breaks, proliferation and apoptosis was performed on irradiated tissue sections. The MRT response was compared to conventional radiotherapy at 11, 22 or 44 Gy. The results of the study provides the first evidence for a differential tissue response at a cellular level between normal and tumour tissues following synchrotron MRT. Within 24 hours of MRT to tumour, obvious cell migration had occurred into and out of irradiated zones. MRT-irradiated tumours showed significantly less proliferative capacity by 24 hours post-irradiation (P = 0.002). Median survival times for EMT-6.5 and 67NR tumour-bearing mice following MRT (2 x 560 Gy) and conventional radiotherapy (22 Gy) increased significantly compared to unirradiated controls (P < 0.0005). However, there was markedly less normal tissue damage from MRT than from conventional radiotherapy. MRT-treated normal skin mounts a more coordinated repair response than tumours. Cell-cell communication of death signals from directly irradiated, migrating cells, may explain why tumours are less resistant to high dose MRT than normal tissue.

Radiation induced bystander effects have changed our understanding of the biological effects of ionizing radiations. The original assumption was that biological effects require direct damage to DNA. The bystander effect eliminated that requirement and has become one main stream in radiation research ever since first reported over 20 years ago. Most bystander studies to date have been carried out by using conventional single cell in vitro systems , 2D cell array and 3D tissue samples, which are useful tools to characterize basic cellular and molecular responses. But to reveal the complexity of radiation responses and cellular communication, live animal models have many advantages. In recent years, models such as C. elegans and Zebrafish have been utilized in bystander effects research. In the Loma Linda/TAMU experiment, a L1 larva C. elegans model was devloped to study the radiation bystander effects by irradiating single intestine cell nuclei with a microbeam of protons. Due to the stochastic nature of particle interactions with matter and changing stopping power when protons slow down, precise dosimetry in the target nucleus is a difficult problem. This research was undertaken to provide a detailed description of the energy deposition in the targeted and surrounding non-targeted cell nuclei, and to evaluate the probabilities of the non-targeted cell nucleus being irradiated. A low probability is required to exclude the possibility of radiation biological an effect in non-targeted cells is caused by scattered particles. Mathematical models of the microbeam system and the worm body were constructed in this research. Performing Monte Carlo simulations with computer code, Geant 4, this research provided dosimetry data in cell nuclei in different positions and Geant 4, this research provided dosimetry data in cell nuclei in different positions and probabilities of scattering to non-targeted cell nuclei in various microbeam collima- tor configurations. The data provided will be useful for future collimated microbeam design.

We present an ultra-thin transmission-type radiation detector developed for counting microbeam alpha particles. The ∆E alpha detector is a single crystal chemical vapor deposited diamond (ScCVDD) and will be installed between the microbeam accelerator window and a biologic sample. The commercially available optical grade ScCVDD sample (3 mm × 3 mm × 50 µm) was etched down to a few µm thickness which allows alpha particles to penetrate, and then it was followed by the surface cleaning, electrical contact deposition and post-metallization annealing. SRIM code and MCNP6 were used for energy loss calculation of alpha particles in electrodes and diamond and pulse height spectra prediction. In order to evaluate the performance of the ultra-thin ScCVDD detector, a ∆E-E detectors system was setup using a calibration source, the ScCVD detector and a silicon surface barrier detector (SBD). The absolute and intrinsic totally efficiency were determined as 0.3 % and 16 % respectively. Alpha and gamma peaks were observed while the peak resolution is not quite promised. The transmission ability of the ScCVDD detector was verified by applying coincidence operation with 0.22 µs time window. The thickness of the ultra-thin diamond sample was reassessed to be 8.315±0.690 µm from ∆E-E spectrometery. / Thesis / Master of Science (MSc)

Microbeam radiation therapy (MRT) is a potential cancer therapy technique that uses an intense X-ray beam produced by a synchrotron. In MRT, an array of microplanar beams, called a microbeam, is delivered to a tumour. The dose at each centre of planar beams is extremely large (several hundred grays) while dose level in the valley between the peaks is below several tens of gray. Moreover, the width of each planar beam is typically 20 - 50 µm, and the distance from a centre of planar-beam to that of adjacent beam is 200 - 400 µm. For the latter reasons, the fundamental requirements for the dosimetry technique in MRT are (1) a micrometer-scale spatial resolution and (2) detection sensitivity at large doses (5 - 1000 Gy). No existing detectors can satisfy those two requirements together. The objective of the Ph.D. research is to develop a prototype dosimetry technique which fulfils the requirements for measuring the dose profile in the microbeam. The currently used approach relies on the indirect detection of X-rays; in which the X-ray dose is recorded on a detector plate, and then the recorded signals are digitized using a reader. Our proposed approach utilizes Sm3+-doped polycrystallites, glasses, and/or suitable glass-ceramics (though our approach is not limited to the use of Sm ion) for the detector plate, in which a valence reduction of Sm3+, that is the conversion of Sm3+ to Sm2+, takes place upon irradiation of X-rays. The extent of reduction is further read out using confocal fluorescence microscopy via the photoluminescence (PL) signals of Sm3+ and Sm2+. The work carried out throughout the course of the research includes the construction of confocal fluorescence microscopy, synthesis and characterizations of dosimeter materials, as well as application tests of our approach for measuring the dose profile of a microbeam used at synchrotron facilities -- Canadian Light Source (CLS), Saskatoon, Canada, European Synchrotron Radiation Facility (ESRF), Grenoble, France, and SPring-8, Hyogo, Japan. Further, the research has shown that 1 % Sm-doped fluoroaluminate glass is one of the best candidates for the type of dosimetric application. It has the dynamic range of ~1 to over 1000 Gy which covers the dose range used in MRT, excellent signal-to-noise ratio (large extent of Sm3+ → Sm2+ change), and excellent stability of recorded signal over time. The recorded signal in the detector is erasable by heating or exposing to light such as UV. Furthermore, with a use of confocal microscope, it has ability to measure the distribution pattern of dose over the cross-section of microbeam. Therefore, we believe that our approach is one of the most promising techniques available.

Recent work using low-doses of ionising radiations, both in vitro and in ViVO, has suggested that the responses of biological systems in the region of less than 1 Gray may not be predicted by simple extrapolation from the responses at higher doses. Additional experiments, using high-LET radiations at doses of much less than one alpha particle traversal per cell nucleus, have shown responses in a greater number of cells than have received a radiation dose. These findings, and increased concern over the effects of the exposure of the general population to low-levels of background radiation, for example due to radon daughters in the lungs, have stimulated the investigation of the response of mammalian cells to ionising radiations in the extreme low-dose region. In all broad field exposures to particulate radiations at low-dose levels an inherent dose uncertainty exists due to random counting statistics. This dose variation produces a range of values for the measured biological effect within the irradiated population, therefore making the elucidation of the dose-effect relationship extremely difficult. The use of the microbeam irradiation technique will allow the delivery of a controlled number of particles to specific targets within an individual cell with a high degree of accuracy. This approach will considerably reduce the level of variation of biological effect within the irradiated cell population and will allow low-dose responses of cellular systems to be determined. In addition, the proposed high spatial resolution of the microbeam developed will allow the investigation of the distribution of radiation sensitivity within the cell, to provide a better understanding of the mechanisms of radiation action. The target parameters for the microbeam at the Gray Laboratory are a spatial resolution of less than 1 urn and a detection efficiency of better than 99 %. The work of this thesis was to develop a method of collimation, in order to produce a microbeam of 3.5 MeV protons, and to develop a detector to be used in conjunction with the collimation system. In order to determine the optimum design of collimator necessary to produce a proton microbeam, a computer simulation based upon a Monte-Carlo simulation code, written by Dr S J Watts, was developed. This programme was then used to determine the optimum collimator length and the effects of misalignment and divergence of the incident proton beam upon the quality of the collimated beam produced. Designs for silicon collimators were produced, based upon the results of these simulations, and collimators were subsequently produced for us using techniques of micro-manufacturing developed in the semiconductor industry. Other collimator designs were also produced both in-house and commercially, using a range of materials. These collimators were tested to determine both the energy and spatial resolutions of the transmitted proton beam produced. The best results were obtained using 1.6 mm lengths of 1.5 µm diameter bore fused silica tubing. This system produced a collimated beam having a spatial resolution with 90 % of the transmitted beam lying within a diameter of 2.3 ± 0.9 µm and with an energy spectrum having 75 % of the transmitted protons within a Gaussian fit to the full-energy peak. Detection of the transmitted protons was achieved by the use of a scintillation transmission detector mounted over the exit aperture of the collimator. An approximately 10 urn thick ZnS(Ag) crystal was mounted between two 30 urn diameter optical fibres and the light emitted from the crystal transmitted along the fibres to two photomultiplier tubes. The signals from the tubes were analyzed, using coincidence counting techniques, by means of electronics designed by Dr B Vojnovic. The lowest counting inefficiencies obtained using this approach were a false positive count level of 0.8 ± 0.1 % and an uncounted proton level of 0.9 ± 0.3 %. The elements of collimation and detection were then combined in a rugged microbeam assembly, using a fused silica collimator having a bore diameter of 5 urn and a scintillator crystal having a thickness of - 15 µm. The microbeam produced by this initial assembly had a spatial resolution with 90 % of the transmitted protons lying within a diameter of 5.8 ± 1.6 µm, and counting inefficiencies of 0.27 ± 0.22 % and 1.7 ± 0.4 % for the levels of false positive and missed counts respectively. The detector system in this assembly achieves the design parameter of 99 % efficiency, however, the spatial resolution of the beam is not at the desired I urn level. The diameter of the microbeam beam produced is less than the nuclear diameter of many cell lines and so the beam may be used to good effect in the low-dose irradiation of single cells. In order to investigate the variation in sensitivity within a cell the spatial resolution of the beam would require improvement. Proposed methods by which this may be achieved are described.

Neste trabalho, descrevemos o crescimento controlado e alinhado de nanofios de óxido de zinco (ZnO), bem como a análise das propriedades de emissão de campo (Field Emission) destes nanomateriais. Diferentes estratégias de síntese e posicionamento dos nanofios foram utilizadas para a otimização da emissão de elétrons por campo. Utilizamos diferentes técnicas de litografia no processo de crescimento de nanofios em regiões pré-definidas. Como resultado, são apresentadas diferentes condições para o crescimento de nanofios de ZnO. As caracterizações estruturais comprovam a qualidade cristalina dos fios. As emissões de elétrons por campo foram caracterizadas e seguem, em média, as previsões da teoria de Fowler-Nordheim. A amostra com melhor desempenho apresenta emissão de 50 A em um campo aplicado de ~2.6 V/μm. Os fios iniciam a emissão em 1.6 V/μm, considerando uma corrente inicial de 10-6 A. Tal investigação visa contribuir para o uso destes materiais nas tecnologias de mostradores planos (Field Emission Display - FED), de alta resolução. / In this work, we report on the controlled growth of vertically aligned zinc oxide (ZnO) nanowires, as well as their field emission properties. Different syntheses and positioning strategies concerning nanowires growth were proposed with the purpose of optimizing its electron field emission. Different lithography techniques were used in order to grow the wires on specific locations on the substrate. As result we present several conditions for the ZnO nanowires growth. The structural characterizations show the high crystal quality obtained. The field emission behavior of the wires was investigated showing that it follows the Fowler-Nordheim theory predictions. The best sample showed an emission of 50 A at ~2.6 V/μm of applied electric field. The emission threshold field was 1.6 V/μm for a current of 10-6 A. This research aims to contribute for the use of these materials in the high resolution flat panel displays technology (Field Emission Display - FED).

Neste trabalho, descrevemos o crescimento controlado e alinhado de nanofios de óxido de zinco (ZnO), bem como a análise das propriedades de emissão de campo (Field Emission) destes nanomateriais. Diferentes estratégias de síntese e posicionamento dos nanofios foram utilizadas para a otimização da emissão de elétrons por campo. Utilizamos diferentes técnicas de litografia no processo de crescimento de nanofios em regiões pré-definidas. Como resultado, são apresentadas diferentes condições para o crescimento de nanofios de ZnO. As caracterizações estruturais comprovam a qualidade cristalina dos fios. As emissões de elétrons por campo foram caracterizadas e seguem, em média, as previsões da teoria de Fowler-Nordheim. A amostra com melhor desempenho apresenta emissão de 50 A em um campo aplicado de ~2.6 V/μm. Os fios iniciam a emissão em 1.6 V/μm, considerando uma corrente inicial de 10-6 A. Tal investigação visa contribuir para o uso destes materiais nas tecnologias de mostradores planos (Field Emission Display - FED), de alta resolução. / In this work, we report on the controlled growth of vertically aligned zinc oxide (ZnO) nanowires, as well as their field emission properties. Different syntheses and positioning strategies concerning nanowires growth were proposed with the purpose of optimizing its electron field emission. Different lithography techniques were used in order to grow the wires on specific locations on the substrate. As result we present several conditions for the ZnO nanowires growth. The structural characterizations show the high crystal quality obtained. The field emission behavior of the wires was investigated showing that it follows the Fowler-Nordheim theory predictions. The best sample showed an emission of 50 A at ~2.6 V/μm of applied electric field. The emission threshold field was 1.6 V/μm for a current of 10-6 A. This research aims to contribute for the use of these materials in the high resolution flat panel displays technology (Field Emission Display - FED).

Neste trabalho, descrevemos o crescimento controlado e alinhado de nanofios de óxido de zinco (ZnO), bem como a análise das propriedades de emissão de campo (Field Emission) destes nanomateriais. Diferentes estratégias de síntese e posicionamento dos nanofios foram utilizadas para a otimização da emissão de elétrons por campo. Utilizamos diferentes técnicas de litografia no processo de crescimento de nanofios em regiões pré-definidas. Como resultado, são apresentadas diferentes condições para o crescimento de nanofios de ZnO. As caracterizações estruturais comprovam a qualidade cristalina dos fios. As emissões de elétrons por campo foram caracterizadas e seguem, em média, as previsões da teoria de Fowler-Nordheim. A amostra com melhor desempenho apresenta emissão de 50 A em um campo aplicado de ~2.6 V/μm. Os fios iniciam a emissão em 1.6 V/μm, considerando uma corrente inicial de 10-6 A. Tal investigação visa contribuir para o uso destes materiais nas tecnologias de mostradores planos (Field Emission Display - FED), de alta resolução. / In this work, we report on the controlled growth of vertically aligned zinc oxide (ZnO) nanowires, as well as their field emission properties. Different syntheses and positioning strategies concerning nanowires growth were proposed with the purpose of optimizing its electron field emission. Different lithography techniques were used in order to grow the wires on specific locations on the substrate. As result we present several conditions for the ZnO nanowires growth. The structural characterizations show the high crystal quality obtained. The field emission behavior of the wires was investigated showing that it follows the Fowler-Nordheim theory predictions. The best sample showed an emission of 50 A at ~2.6 V/μm of applied electric field. The emission threshold field was 1.6 V/μm for a current of 10-6 A. This research aims to contribute for the use of these materials in the high resolution flat panel displays technology (Field Emission Display - FED).