<p>The development of digital detectors for X-ray imaging in medical diagnostics receives an increasing amount of attention. The detector under development at the Department of Radiation Sciences at Uppsala University is a hybrid pixel detector, which consists of a semiconductor sensor mounted onto a readout chip. The readout chip is capable of performing photon counting and has an externally adjustable threshold.</p><p>A simulation tool for the detector and a model applying the linear-systems transfer theory to X-ray hybrid pixel detectors have been developed. Also a characterization of the readout chip has been done. In order to estimate the potential of the detector for diagnostic radiology, we investigate the image quality using the spatial frequency dependent detective quantum efficiency (DQE). By means of the detector simulations, the influence of threshold setting, noise sources, level of exposure and charge sharing on the DQE have been studied. By means of the linear-systems theory, a single analytical expression is provided to obtain the DQE of a hybrid pixel detector.</p><p>The method developed in this thesis will make it possible to optimize a detector design according to a particular medical application. It will also permit modifications and new features to be included without having to construct a full detector system.</p>

<p>Medical X-ray imaging is an important tool in diagnostic radiology. The ionising-radiation dose to the patient is justified by the clinical benefit of the examination. Nonetheless, detectors that operate at even lower doses and provide more information to the radiologist are desired. A hybrid pixel detector has the potential to provide a leap in detector technology as it incorporates a more advanced signal-processing capability than currently used detectors.</p><p>The DIXI digital detector is a hybrid pixel detector developed for X-ray imaging. It consists of a readout chip and a semiconductor sensor. The division in two parts makes it possible to optimise each part individually. The detector is divided into square pixels with a size of 270 x 270 μm2. DIXI has the ability to count single photons and every readout pixel has two embedded counters to allow the acquisition of two images close in time. A discriminator enables the selection of photons with energies above a preset threshold level.</p><p>The readout chip Angie has been developed and its performance has been evaluated in terms of noise, threshold variation and capability to perform energy weighted counting. Silicon sensors have been fabricated, and a control system for DIXI has been designed and built. An electroless process for deposition of Ni/Au bumps on the chip and sensor has been optimised as a preparation for the assembly of a complete detector, which is being assembled by flip-chip bonding using anisotropic conductive film.</p><p>A simulation library for the DIXI detector has been set up and results on the image quality are reported for different exposures and working conditions. A theoretical model for hybrid pixel detectors based on the cascaded linear system theory has been developed. The model can be used to investigate and optimise the detector for different detector configurations and operating conditions.</p>

<p> Two-pion production reactions in proton-proton collisions have been studied using the PROMICE/WASA detector and an internal cluster gas-jet target at the CELSIUS storage ring in Uppsala. Three out of the four isospin-independent reaction channels have been measured at several energies in the intermediate and near threshold energy region. Important parts of the analysis include the identification of neutral pions from the invariant mass of the decay gammas, the identification of positive pions with the delayed pulse technique and the use of Monte Carlo simulations to understand the detector response. The total cross sections for the pp®ppπ⁺π^-, the pp®ppπ⁰π⁰ and the pp®pnπ⁺π⁰ reactions are presented at beam energies ranging from 650 to 775 MeV. </p><p>The production mechanism for two-pion production near threshold seems to be dominated by resonance production. The contribution from the non-resonant terms alone can not reproduce the total cross sections. In most models, two-pion production is governed by the δ and the <i>N</i>^* resonances in either one or both of the participating nucleons. </p><p>The <i>N</i>^*(1440)®N(πp)^T=0_S−<i>wave</i> transition has been suggested as the dominating production mechanism for two-pion production in proton-proton collisions. However, the total cross sections presented in this thesis show that other production mechanisms also must give large contributions. </p>

The increasing demand for characterization of nuclear fuel, both from an operator and authority point of view, motivates the development of new experimental and, preferable, non-destructive methods. In this thesis, some methods based on nuclear spectroscopic techniques are presented. Various parameters of irradiated fuel are shown to be determined with high accuracy and confidence by utilizing gamma-ray scanning, tomography and passive neutron assay. Specifically, fuel parameters relevant for a secure storage of spent nuclear fuel in a long-term repository, such as e.g. burnup and decay heat, are shown to be determined with adequate accuracy. The techniques developed are expected to be implemented in the planned encapsulation facility in Sweden. Also, a device for tomographic measurements of the spatial distribution of thermal power in nuclear fuel assemblies has been built, tested and evaluated. The device utilizes single photon emission computed tomography (SPECT) in order to reconstruct the gamma-ray source distribution within a fuel assembly. The device is expected to be an important tool for validating reactor core simulators regarding new fuel designs. For safeguards purposes, two experimental methods for verifying the integrity, i.e. the possible loss of fissile material from a nuclear fuel assembly, are presented. Verification of integrity is shown to be possible on an individual fuel rod level.

Two-pion production reactions in proton-proton collisions have been studied using the PROMICE/WASA detector and an internal cluster gas-jet target at the CELSIUS storage ring in Uppsala. Three out of the four isospin-independent reaction channels have been measured at several energies in the intermediate and near threshold energy region. Important parts of the analysis include the identification of neutral pions from the invariant mass of the decay gammas, the identification of positive pions with the delayed pulse technique and the use of Monte Carlo simulations to understand the detector response. The total cross sections for the pp®ppπ+π-, the pp®ppπ0π0 and the pp®pnπ+π0 reactions are presented at beam energies ranging from 650 to 775 MeV. The production mechanism for two-pion production near threshold seems to be dominated by resonance production. The contribution from the non-resonant terms alone can not reproduce the total cross sections. In most models, two-pion production is governed by the δ and the N* resonances in either one or both of the participating nucleons. The N*(1440)®N(πp)T=0S−wave transition has been suggested as the dominating production mechanism for two-pion production in proton-proton collisions. However, the total cross sections presented in this thesis show that other production mechanisms also must give large contributions.

Tumour targeted radiotherapy is an appealing approach for treatment of disseminated tumour cells. A targeting agent that specifically binds to a structure on tumour cells is then used to transport therapeutically relevant radionuclides. The epidermal growth factor receptor, EGFR, is overexpressed on tumour cells in several malignancies, e.g. highly malignant gliomas. In this thesis, three types of radiolabelled EGF-conjugates, aimed for targeting to EGFR-expressing tumour cells, were developed and studied: EGF-dextran labelled with 125I, EGF labelled with 211At, and two EGF-chelates, DTPA-EGF and Bz-DTPA-EGF, labelled with the radioactive metals 111In and 177Lu. The targeting properties of radioiodinated EGF-dextran were first studied in cultured glioma cells. Radioiodine coupled to the dextran part of EGF-dextran was retained in cells appreciably longer than radioiodine coupled to EGF. This can give about 100 times increased radiation dose to tumour cells. Targeting with 211At-EGF was investigated in combination with the tyrosine kinase inhibitor gefitinib (Iressa™, ZD1839). The uptake of 211At-EGF in EGFR-expressing tumour cells increased with increasing gefitinib concentrations. This was the case for both gefitinib-resistant and gefitinib-sensitive cell lines. The effect of the combined treatment on cell survival, however, differed between the cell lines in an unexpected way. In gefitinib resistant cells, combined treatment decreased cell survival approximately 3.5 times relative to 211At-EGF treatment alone. In gefitinib sensitive cells, however, combined treatment increased the cell survival (i.e. a protective effect). The EGF-chelates studied ([111In]DTPA-EGF, [111In]Bz-DTPA-EGF and [177Lu]Bz-DTPA-EGF) all bound specifically with high affinity (Kd≈2 nM) to EGFR on cultured glioma cells. They were internalised after binding, and the cellular retention of radionuclides was high (60% remained after 45 h). A biodistribution study in mice showed that liver and kidneys accumulated a majority of the radioactivity. The EGF-chelates bound EGFR specifically also in vivo. A tumour-to-blood ratio of 25 was achieved in a preliminary study.

One of the main problems in curing cancer resides in the different microenvironment existing in tumours compared to the normal tissues. The mechanisms of failure are different for radiotherapy and chemotherapy, but they all relate to the poor blood supply known to exist in tumours. It is therefore very important to know the tumour microenvironmental conditions in order to devise techniques that will overcome the problems and will therefore improve the result of the treatment. The aims of the thesis were the modelling of tumour oxygenation and the simulation of polarographic oxygen measurements in order to assess and possibly to improve the accuracy of the electrode in measuring tumour oxygenation. It also aimed to evaluate the implications of tumour microenvironment for the radiotherapy outcome. The project used theoretical modelling as the main tool. The processes of oxygen diffusion and consumption were described mathematically for different conditions, the result being very accurate distributions of oxygen in tissues. A first simple model of tissue oxygenation was based on the oxygen diffusion around a single blood vessel. A more complex model built from the basic physical processes and measurable parameters allowed the simulation of realistical tissues with heterogeneous vasculature. This model also allowed the modelling of the two types of hypoxia known to appear in tumours and their influence on the tumour microenvironment. The computer simulation of tissues was also used for assessing the accuracy of the polarographic technique for measuring tumour oxygenation. The results of this study have shown that it is possible to model theoretically the tissue oxygenation starting from the basic physical processes. The particular application of our theoretical simulation to the polarographic oxygen electrode has shown that this experimental method does not give the oxygen values in individual cells. Because the electrode measures the average oxygenation in a relatively large tissue volume, the resulting oxygen distributions are different from the real ones and the extreme high and low values are not detected. It has further been found that the polarographic electrode cannot make distinction between various types of hypoxia existing in tumours, the geometrical distribution of the hypoxic cells influencing mostly the accuracy of the measurement. It was also shown that because of the averaging implied by the measurement process, electrode results should not be used directly to predict the response to radiation. Thus, the differences between the predictions in clinical tumour control obtained from the real or the measured oxygenations are of the order of tens of percents in absolute value. A method to improve the accuracy of the electrode, i.e. to improve the correlation between the results of the measurements and the actual tissue oxygenation, was proposed. In conclusion, theoretical modelling has been shown to be a very powerful tool for predicting the outcome of radiotherapy and it has the advantage of describing the tumour oxygenation in the least invasive manner. Furthermore it allows the investigation of the invasiveness and the accuracy of various experimental methods.

The development of digital detectors for X-ray imaging in medical diagnostics receives an increasing amount of attention. The detector under development at the Department of Radiation Sciences at Uppsala University is a hybrid pixel detector, which consists of a semiconductor sensor mounted onto a readout chip. The readout chip is capable of performing photon counting and has an externally adjustable threshold. A simulation tool for the detector and a model applying the linear-systems transfer theory to X-ray hybrid pixel detectors have been developed. Also a characterization of the readout chip has been done. In order to estimate the potential of the detector for diagnostic radiology, we investigate the image quality using the spatial frequency dependent detective quantum efficiency (DQE). By means of the detector simulations, the influence of threshold setting, noise sources, level of exposure and charge sharing on the DQE have been studied. By means of the linear-systems theory, a single analytical expression is provided to obtain the DQE of a hybrid pixel detector. The method developed in this thesis will make it possible to optimize a detector design according to a particular medical application. It will also permit modifications and new features to be included without having to construct a full detector system.

Medical X-ray imaging is an important tool in diagnostic radiology. The ionising-radiation dose to the patient is justified by the clinical benefit of the examination. Nonetheless, detectors that operate at even lower doses and provide more information to the radiologist are desired. A hybrid pixel detector has the potential to provide a leap in detector technology as it incorporates a more advanced signal-processing capability than currently used detectors. The DIXI digital detector is a hybrid pixel detector developed for X-ray imaging. It consists of a readout chip and a semiconductor sensor. The division in two parts makes it possible to optimise each part individually. The detector is divided into square pixels with a size of 270 x 270 μm2. DIXI has the ability to count single photons and every readout pixel has two embedded counters to allow the acquisition of two images close in time. A discriminator enables the selection of photons with energies above a preset threshold level. The readout chip Angie has been developed and its performance has been evaluated in terms of noise, threshold variation and capability to perform energy weighted counting. Silicon sensors have been fabricated, and a control system for DIXI has been designed and built. An electroless process for deposition of Ni/Au bumps on the chip and sensor has been optimised as a preparation for the assembly of a complete detector, which is being assembled by flip-chip bonding using anisotropic conductive film. A simulation library for the DIXI detector has been set up and results on the image quality are reported for different exposures and working conditions. A theoretical model for hybrid pixel detectors based on the cascaded linear system theory has been developed. The model can be used to investigate and optimise the detector for different detector configurations and operating conditions.

Scanned proton beams offer the possibility to take full advantage of the dose deposition properties of proton beams, i.e. the limited range and sharp peak at the end of the range, the Bragg peak. By actively scanning the proton beam, laterally by scanning magnets and longitudinally by shifting the energy, the position of the Bragg peak can be controlled in all three dimensions, thereby enabling high dose delivery to the target volume only. A typical scanned proton beam line consists of a pair of scanning magnets to perform the lateral beam scanning and possibly a range shifter and a multi-leaf collimator (MLC). Part of this thesis deals with the development of control, supervision and verification methods for the scanned proton beam line at the The Svedberg laboratory in Uppsala, Sweden. Radiotherapy is preceded by treatment planning, where one of the main objectives is predicting the dose to the patient. The dose is calculated by a dose calculation engine and the accuracy of the results is of course dependent on the accuracy and sophistication of the transport and interaction models of the dose engine itself. But, for the dose distribution calculation to have any bearing on the reality, it needs to be started with relevant input in accordance with the beam that is emitted from the treatment machine. This input is provided by the beam model. As such, the beam model is the link between the reality (the treatment machine) and the treatment planning system. The beam model contains methods to characterise the treatment machine and provides the dose calculation with the reconstructed beam phase space, in some convenient representation. In order for a beam model to be applicable in a treatment planning system, its methods have to be general. In this thesis, a beam model for a scanned proton beam is developed. The beam model contains models and descriptions of the beam modifying elements of a scanned proton beam line. Based on a well-defined set of generally applicable characterisation measurements, ten beam model parameters are extracted, describing the basic properties of the beam, i.e. the energy spectrum, the radial and the angular distributions and the nominal direction. Optional beam modifying elements such as a range shifter and an MLC are modelled by dedicated Monte Carlo calculation algorithms. The algorithm that describes the MLC contains a parameterisation of collimator scatter, in which the rather complex phase space of collimator scattered protons has been parameterised by a set of analytical functions. Dose calculations based on the phase space reconstructed by the beam model are in good agreement with experimental data. This holds both for the dose distribution of the elementary pencil beam, reflecting the modelling of the basic properties of the scanned beam, as well as for complete calculations of collimated scanned fields.