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For several years, microwave engineers have dreamed of using non-ionising electromagnetic waves in medical imaging applications. The rate of evolution of microwave techniques for medical application has been immense and shows no signs of relenting. Since the limitations of X-ray mammography are well reported, alternative techniques using microwaves for breast cancer detection are developed. Some of these techniques have progressed to the point where positive clinical experience has emerged.

Introduction: Paediatric low grade brain tumours present diagnostic and prognostic challenges, providing a need for better non-invasive imaging characterization. The value of \(^1\)H Magnetic Resonance Spectroscopy (MRS) performed on 5 scanners in the diagnosis and prognostication of an extensive bi-centre cohort of low-grade gliomas is investigated. Methods: Single voxel MRS was performed routinely in children with brain tumours at the Birmingham Children’s Hospital and Queen’s Medical Centre. Histopathological features were semi-quantified and in vitro \(^1\)H NMR used to study pilocytic astrocytoma cell lines. Magnetic Resonance Spectroscopic Imaging (MRSI) and texture analysis of MR images were performed. Results: MRS detects differences between subgroups of low grade brain tumours in children and between tumours of the same histology. High myo-inositol and glycerophosphocholine and low phosphocholine are markers of good prognosis. Histological correlates for MRS metabolites have been identified and paediatric pilocytic astrocytoma cell lines (‘typical’, metastatic and recurrence) have been discriminated. The value of MRSI in answering clinical questions has been demonstrated. Texture analysis achieved high accuracy in the diagnosis of paediatric posterior fossa tumours. Conclusion: Advanced MR techniques have a significant role in the study of paediatric brain tumours, and promising results from MRS, MRSI and texture analysis are reported here.

Electrical Impedance Tomography (EIT) is a medical imaging technique that reconstructs internal electrical conductivity distribution of a body from impedance data that is measured on the body surface, and Electrical Impedance Mammography (EIM) is the technique that applies EIT in breast cancer detection. The use of EIM for breast cancer identification is highly desirable because it is a non-invasive and low-cost imaging technology. EIM has the potential in detecting early stage cancer, however there are still challenges that hindering EIM to be provided as a routine health care system. There are three major groups of obstacles. One is the hardware design, which includes the selection of electronic components, electrode-skin contacting methods, etc. Second is theoretical problems such as electrode configurations, image reconstruction and regularization methods. Third is the development of analysis methods and generation of a cancerous tissue database. Research reported in this thesis strives to understand these problems and aims to provide possible solutions to build a clinical EIM system. The studies are carried out in four parts. First the functionalities of the Sussex Mk4 EIM system have been studied. Sensitivity of the system was investigated to find out the strength and weakness of the system. Then work has been made on image reconstruction and regularization methods in order to enhance the system's endurance to noise, also to balance the reconstruction conductivity distribution throughout the reconstructed object. Then a novel cancer diagnosis technique was proposed. It was developed based on the electrical property of human breast tissue and the behaviour or systematic noise, to provide repeatable results for each patient. Finally evaluation has been made on previous EIM systems to find out the major problems. Based on sensitivity analysis, an optimal combined electrode configuration has been proposed to improve sensitivity. The system has been developed and produced meaningful clinical images. The work makes significant contributions to society. This novel cancer diagnosis method has high accuracy for cancer identification. The combined electrode configuration has also provided flexibilities in the designing of current driving and voltage receiving patterns, thus sensitivity of the EIM system can be greatly improved.

There is a growing recognition that there is a requirement for methods of age estimation of the living to be rigorously tested to ensure that they are accurate, reliable and valid for use in forensic and humanitarian age estimation. The necessity for accurate and reliable methods of age estimation are driven both by humanitarian, political and judicial need. Age estimation methods commonly in use today are based on the application of reference standards, known as atlases, which were developed using data collected from children who participated in longitudinal studies in the early to mid-1900s. The standards were originally developed to provide a baseline to which radiographs could be compared in order to assess the child’s stage of skeletal development in relation to their chronological age, a purpose for which they are still utilised in the medical community. These atlases provide a testable link between skeletal age and chronological age which has been recognised by forensic practitioners who have essentially hijacked this medical capability and applied it to their fields. This has resulted in an increased use of these standards as a method of predicting the chronological age from the skeletal age of a child when the former is unknown. This novel use of the atlases on populations who are distinct, ethnically, temporally and geographically, from those whose data was gathered and was used in the design of the standard leaves the forensic outcomes vulnerable to challenge in court. This study aims to examine the reliability and accuracy of these standards in relation to a modern population, providing a sound statistical base for the use of these standards for forensic purposes. Radiographs were collected from the local hospital from children who had been X-rayed for investigation during attendance at the local A&E department. Four body areas were selected for investigation; the hand-wrist, the elbow, the knee and the foot-ankle and tests were undertaken to assess the radiographs using six commonly uses methods of age estimation. Further images of the wrist and elbow were collected from children in New Delhi, India. These images were subject to age estimation utilising the methods described.

Magnetic Resonance Imaging (MRI) is a non-ionising imaging modality which can provide excellent soft-tissue contrast because of a large number of flexible contrast parameters. One major limitation of MRI is its long acquisition time. Parallel MRI provides a framework to reduce the scan time. The aim of this thesis is to investigate and develop new methods to improve the performance of Parallel MRI. A new GUI (Graphical User Interface) based platform is developed using Matlab which provides an interactive environment to apply different Parallel MRI algorithms as well as helps to analyse the results. Regularization based reconstruction in Parallel MRI utilizes some prior information about the image to achieve better reconstruction results. The use of regularization in Parallel MRI is investigated and a new algorithm is proposed which uses wavelet-denoising of the coil sensitivity estimates before applying SENSE (a Parallel MRI algorithm). The results show that the proposed method is computationally efficient and offers a good alternative to regularization for lower acceleration factors (AF) in Parallel MRI. A good choice of the regularization parameter in regularization based Parallel MRI reconstructions plays a pivotal role to have good results. A new algorithm to choose the regularization parameter efficiently has been developed. This method uses the g-Factor (noise amplification parameter in Parallel MRI) as a regularization parameter and provides better reconstruction results than the contemporary methods. The proposed algorithm improves the computational efficiency of regularization based reconstructions in Parallel MRI. The use of Parallel MRI in interventional imaging can greatly reduce the time required for imaging. A novel catheter based phased array coil, composed of two independent coil elements has been developed. This phased array receiver coil can implement Parallel MRI. Some initial imaging experiments using this coil system have been performed and the results show a successful implementation of Parallel MRI on the acquired data.

Background: Cardiomyopathy (CM) frequently leads to heart failure which is associated with a high degree of mortality, morbidity and financial burden on healthcare providers. Confidence in the recognition of risk factors or in early diagnosis allows timely intervention, before heart failure develops. The right ventricle (RV) has historically been overlooked when assessing cardiac function and response to therapy but its importance is increasingly recognised. Cardiovascular magnetic resonance (CMR) is established as the gold standard for assessing the functional consequences of cardiovascular disease, being non-invasive and with high accuracy and reproducibility. It can also provide in-vivo tissue information which may be diagnostic before functional changes are apparent. With this backdrop I tested the hypothesis that CMR can provide early disease markers in patients at risk of heart failure in 3 unrelated conditions associated with heart failure including: Emery-Dreifuss muscular dystrophy (EDMD), anthracycline induced cardiomyopathy and cardiac iron overload in transfusion dependent patients. Methods and Results: Patients with 3 different clinical substrates for the development of CM were studied. In group 1, patients with EDMD were studied by CMR and echo. There was a significant reduction in inferior wall contractility using CMR tagging (-0.062±0.02 versus -0.094±0.03 in the control group, p=0.048) and in echo derived early diastolic myocardial posterior wall velocity gradients (4±1.2 vs. 7.1±2.7 s-1, p=0.02). Bi-ventricular ejection fraction (EF) was normal and no late gadolinium enhancement (LGE) was detected. These findings demonstrated the relative insensitivity of EF in the detection of early disease and the need for careful follow up in these patients. In group 2, anthracycline mediated cardiotoxicity (AMC) was studied. The risk of heart failure rises with cumulative dose but not all individuals are susceptible. In a cohort of patients with early breast cancer an increase in early gadolinium relative enhancement (EGRE) from baseline to day 3 correlated with a reduction in LVEF after a year (R=0.34, p=0.01) suggesting a potential clinical role for EGRE in the prediction of late AMC. In group 3, patients with thalassaemia major (TM) were studied. The coefficient of variance (CV) for a new black blood T2* sequence was found to be significantly lower than the white blood sequence (1.47% vs 4.23%, p<0.001) and this was adopted for clinical use. The RV response to iron chelation therapy was examined in 3 clinical trials. Using deferiprone monotherapy RVEF increased from 69.6±5.2 to 72.2±5.3% (p=0.001) with a reduction in RV end-systolic volume (ESV) from 37.7±11.7 to 34.2±11.3 mL (p=0.009). With deferiprone/deferoxamine combination therapy the RVEF increase from 60.2±7.2 to 63.8±5.9% (p<0.001) and RVESV decreased from 60.8±24.2 to 50.6±17.3 mL (p<0.01). These improvements mirrored the LV response. However, the response to deferasirox monotherapy was different with no change in LVEF, but an increase in RVEF from 66.1±6.1 to 68.8±5.4 (p=0.001) driven by an increase in RV end diastolic volume (EDV) from 69.3±19.8 to 76.1±17.1 (p<0.001) with a reduction in RV mass from 32.8±7.8 to 24.7±5.6 (p<0.001) and LV mass (78.6±16.9 to 66.5±12.9, p<0.001). These results suggest a different pharmacological action to deferiprone and deferoxamine, and indicate a possible role of RV measurements in risk assessment. Conclusions: This thesis has demonstrated that CMR can be used to identify a variety of markers of early CM, namely that: Strain abnormalities in EDMD are not associated with identifiable fibrosis in EDMD, early inflammatory changes post anthracycline exposure can predict late functional changes and that CMR provides sensitive markers of therapeutic efficacy on RV function in iron overloaded patients. These data improve our understanding of the early effects of CM and demonstrate that novel CMR techniques may play a clinically useful role in earlier detection of ventricular abnormality, and assessment of differential treatment responses.

BACKGROUND: Ischaemic heart disease is the leading cause of mortality and morbidity in the developed world. Cardiovascular magnetic resonance (CMR) is a non-invasive imaging modality providing in vivo myocardial tissue characterisation and quantification. We aimed to validate CMR in the field of interventional cardiology as a tool for guiding patient selection and management to the assessment of the results of interventions both in the acute and chronic settings. METHODS AND RESULTS: We investigated the impact of primary angioplasty delay on the presence and extent of myocardial salvage, microvascular obstruction and infarct size. We found that “time is muscle”, and that shorter time to reperfusion was associated with smaller infarct size (p=0.05), less microvascular obstruction (p=0.04) and a greater amount of salvaged myocardium (p=0.003). Microvascular obstruction was then used as an endpoint in a prospective randomised trial assessing the impact of a thrombectomy device as adjunctive therapy in primary PCI. The incidence and extent of microvascular damage was significantly reduced in the thrombectomy group compared to standard primary PCI (p=0.0005). CMR can identify 2 degrees of microvascular damage: early or persistent microvascular dysfunction. The latter was the strongest predictor of LV remodelling (p=0.03), it was predicted by infarct size (p=0.002), and infarct healing (shrinkage) occurred to a greater extent (p<0.006). We validated the clinical use of CMR perfusion in a cohort of patients with chronic coronary occlusion whose management is currently controversial. CMR identified myocardial viability and inducible myocardial ischaemia in a significant percentage of patients, guided revascularisation that reduced ischaemic burden (p<0.0001) with improvements in left ventricular function (p<0.0001) and health outcome measures (p<0.0001). Finally, improved CMR perfusion image quality was pursued with a new imaging protocol but this demonstrated increased incidence of artefacts (p<0.001) and lower diagnostic accuracy compared to the standard technique. CONCLUSIONS: Cardiovascular magnetic resonance provides in vivo myocardial tissue characterisation that can potentially not only guide treatment but also assess its effects. The result of this work suggests that CMR could emerge as a clinical valuable technique in numerous interventional clinical settings within acute to chronic myocardial ischaemia, in addition to providing surrogate endpoints for clinical trials.

Epithelial ovarian cancer is the commonest cause of death from gynaecological malignancy. Platinum based chemotherapy remains the cornerstone of first-line therapy for ovarian cancer, however relapse is common and acquired resistance is frequently observed on subsequent lines of platinum based treatment. Because activation of the PI3K/AKT pathway has been shown to play a role in acquired platinum resistance phenotype of ovarian cancer, combination of platinum with AKT pathway inhibitors holds promise for resensitising tumours to platinum. The aims of this thesis were i) to evaluate the effect of pharmacological AKT inhibitors AKT on the resensitisation of clinically-derived platinum resistant ovarian cancer cells to platinum, and ii) establish molecular imaging approaches for monitoring resensitisation to platinum in vivo combined with biochemical profiling of pathway activity. Treatment of platinum sensitive PEO1 ovarian cancer cells with cisplatin induced growth inhibition and apoptosis. The AKT inhibitor, API-2, resensitised paired platinum resistant PEO4 cells to cisplatin. These in vitro studies established 1h pre-treatment time point with API-2 followed by cisplatin as the most appropriate schedule for further studies. Resensitisation to platinum appeared to be a pathway effect rather than a specific effect of API-2. In order to establish the utility of PET imaging for therapy response, a bilateral tumour xenograft model comprising of platinum sensitive PEO1 and the platinum resistant cell line PEO4 was developed. Both [18F]fluorothymidine ([18F]FLT)-PET, which measures proliferation, and [18F]fluorodeoxyglucose ([18F]FDG)-PET, which measures glucose metabolism detected responses to cisplatin alone in PEO1 tumours and the combination of cisplatin and API-2 in both PEO1 and PEO4 tumours. Correlative reduction in phosphorylated PRAS40, a direct downstream marker of AKT activity indicated that in vivo changes in imaging variables of the combination treatment resulted from AKT inhibition. The imaging changes were also linked to histological reductions in Ki67 labelling index. AKT Biochemical profiling of tumours obtained after imaging confirmed that the changes in tumour [18F]FDG and [18F]FLT uptake were due, at least in part, to reductions in the expression of glucose transporter Glut-1 and hexokinase activity, as well as decreases in TK1 expression, respectively. These studies demonstrated that [18F]FDG-and [18F]FLT-PET hold promise for clinical evaluation of platinum resensitisation in patients with platinum resistant ovarian cancer. Given also that combination treatment with cisplatin and API-2 induced apoptosis in PEO4 cells in vitro, further studies were conducted with the aim of establishing [18F]ICMT11 PET, a specific cleaved caspase-3/7 radiotracer, for monitoring re-sensitisation to platinum in PEO4 tumours. [18F]ICMT11 uptake detected by PET increased after combination treatment but not with cisplatin alone. Parallel increases in TUNEL and cleaved caspase-3 staining by immunohistochemistry were observed consistent with the PET outcome. Thus, [18F]ICMT11 PET could also find utility in monitoring early responses to platinum therapy in combination with AKT inhibition. In addition to the 3 imaging agents described above, analysis of baseline levels of integrin αvβ3/5 expression, an index of angiogenesis, as well as myo-inositol uptake were investigated as potential discriminators of platinum resistant phenotype. These preliminary experiments were inconclusive. In summary PET imaging of proliferation, glucose metabolism and apoptosis were shown to be promising techniques for early detection of resensitisation to platinum therapy in platinum resistant ovarian cancer and warrant further investigation.

Cardiovascular diseases (CVDs) are one of the major causes of death in the world. In recent years, significant progress has been made in the care and treatment of patients with such diseases. A crucial factor for this progress has been the development of magnetic resonance (MR) imaging which makes it possible to diagnose and assess the cardiovascular function of the patient. The ability to obtain high-resolution, cine volume images easily and safely has made it the preferred method for diagnosis of CVDs. MRI is also unique in its ability to introduce noninvasive markers directly into the tissue being imaged(MR tagging) during the image acquisition process. With the development of advanced MR imaging acquisition technologies, 3D MR imaging is more and more clinically feasible. This recent development has allowed new potentially 3D image analysis technologies to be deployed. However, quantitative analysis of cardiovascular system from the images remains a challenging topic. The work presented in this thesis describes the development of segmentation and motion analysis techniques for the study of the cardiac anatomy and function in cardiac magnetic resonance (CMR) images. The first main contribution of the thesis is the development of a fully automatic cardiac segmentation technique that integrates and combines a series of state-of-the-art techniques. The proposed segmentation technique is capable of generating an accurate 3D segmentation from multiple image sequences. The proposed segmentation technique is robust even in the presence of pathological changes, large anatomical shape variations and locally varying contrast in the images. Another main contribution of this thesis is the development of motion tracking techniques that can integrate motion information from different sources. For example, the radial motion of the myocardium can be tracked easily in untagged MR imaging since the epi- and endocardial surfaces are clearly visible. On the other hand, tagged MR imaging allows easy tracking of both longitudinal and circumferential motion. We propose a novel technique based on non-rigid image registration for the myocardial motion estimation using both untagged and 3D tagged MR images. The novel aspect of our technique is its simultaneous use of complementary information from both untagged and 3D tagged MR imaging. The similarity measure is spatially weighted to maximise the utility of information from both images. The thesis also proposes a sparse representation for free-form deformations (FFDs) using the principles of compressed sensing. The sparse free-form deformation (SFFD) model can capture fine local details such as motion discontinuities without sacrificing robustness. We demonstrate the capabilities of the proposed framework to accurately estimate smooth as well as discontinuous deformations in 2D and 3D CMR image sequences. Compared to the standard FFD approach, a significant increase in registration accuracy can be observed in datasets with discontinuous motion patterns. Both the segmentation and motion tracking techniques presented in this thesis have been applied to clinical studies. We focus on two important clinical applications that can be addressed by the techniques proposed in this thesis. The first clinical application aims at measuring longitudinal changes in cardiac morphology and function during the cardiac remodelling process. The second clinical application aims at selecting patients that positively respond to cardiac resynchronization therapy (CRT). The final chapter of this thesis summarises the main conclusions that can be drawn from the work presented here and also discusses possible avenues for future research.

Work was undertaken in this thesis to assess the use of somatostatin image quantification with SPET and SPET-CT to aid the characterisation of disease within the body. Two radionuclide somatostatin analogues were used for this assessment, the first was NeoSPECT and the second, OctreoScan. The primary aim of work in this thesis was to assess the role of NeoSPECT imaging in the characterisation of disease within the lungs, that is, to differentiate benign from malignant disease. Two forms of image quantification were used in the NeoSPECT assessment, a tumour to background ratio (T:B) and a value of tumour percentage uptake (% uptake). Values of T:B and % uptake were calculated from SPET images acquired 2 hours post injection. T:B results from the benign group (n = 8) demonstrated a median T:B of 2.21, whilst the malignant group (n = 28) demonstrated a median T:B of 2.01. The differences between the groups were tested statistically via a Mann-Whitney test, which showed there to be no statistical difference between the groups (p=0.90, 95.4% CI of (-0.5598, 0.5498)). To undertake the calculation of % uptake a non-patient acquisition (a standard acquisition) was also required, unfortunately not all of the patient cohort used for the T:B assessment had this additional acquisition. As a result of this numbers were low for the % uptake assessment in patients with a benign histology (n = 2), therefore statistical analysis could not be performed. However, review of the range of values for each histology within the malignant group proved useful as no differences were demonstrated between the ranges of values which could help to differentiate between the histologies. Quantification of dual time point imaging was also assessed to determine if there were any variations in values calculated that could also help differentiate the different histologies. For this assessment patients were images at 2 and 4 hours post injection. Results from the Wilcoxon Signed Rank test of the T:B assessment found there to be no statistically significant difference between values of T:B calculated at 2 and 4 hours that was characteristic of tumour type (p=1.0 and p=0.14). The difference in % uptake between 2 and 4 hours was also assessed via a Wilcoxon Signed Rank test, this test also concluded there to be no significant difference value of % uptake between the two acquisitions of the malignant group (p = 0.73). An attempt was also made to quantify ‘other’ uptake within the mediastinum, however, a lack of anatomical information made correlation with histology impossible and as a result no firm conclusions relating image quantification to histology could be drawn from this work. Work from this thesis concluded no quantitative difference between tissue histology could be demonstrated using NeoSPECT, either from single or dual time point imaging. As a result of the NeoSPECT work a number of factors which limited the accuracy and reproducibility of SPET image quantification were identified. Towards the end of the NeoSPECT work hybrid imaging (SPET-CT) became available within the department at Glasgow Royal Infirmary. It was believed that hybrid imaging could resolve some of the limitations and subsequently improve the accuracy of SPET image quantification. However, NeoSPECT was removed from the market for a short period of time and therefore a similar somatostatin analogue, OctreoScan, was used to investigate if the accuracy of somatostatin image quantification could be improved as a result of SPET-CT and its associated reconstruction algorithms including a CT based attenuation correction. Firstly, a qualitative assessment of image quality using the new hybrid reconstructions techniques was undertaken via an observer study. Images were reconstructed with the existing reconstruction techniques, as used for the NeoSPECT work, and with the new hybrid imaging techniques. Four experienced observers blinded to reconstruction technique were asked to score images in terms of their overall image quality. A Friedman test was performed on the scores for each observer, three of the four observers demonstrated a statistically significant difference in their scores between the existing and new hybrid technique (p = 0.00, p = 0.003, p= 0.00), with the new hybrid technique being assigned the highest scores in terms of image quality. Images were also assessed semi-quantitatively via profile analysis which also demonstrated a clear differentiation between the existing and new hybrid techniques with increased image quality being demonstrated in the hybrid data set. The quantitative accuracy of hybrid imaging was also assessed using phantom data. For 111In the difference of the value of absolute activity calculated and that measured varied by 35% but this improved to 21 % when scatter and CT-attenuation based corrections were applied. For 99mTc a much more notable difference between the existing techniques used in chapter 2 and those available from the use of hybrid imaging was demonstrated, the difference in the value of absolute activity calculated and that measured improved from 67% to 0.04%, respectively. Work in this thesis clearly demonstrated an improvement in image quality and accuracy in SPET quantification as a result of hybrid imaging techniques.

Osteoporosis is a disease characterised by reduced bone mass and altered microarchitecture leading to an increased risk of fracture. The consequences of osteoporosis include reduced quality of life and pain, associated with fractures. Its financial burden on health services are significant. Characterisation of osteoporosis using imaging techniques is therefore important. Peripheral Quantitative Computed Tomography (pQCT) is a cross-sectional imaging method which is used to scan bones in the appendicular skeleton. pQCT imaging may be particularly useful in clinical groups where changes in bone mineral density (BMD) and structure are known to occur in the limbs. Two such groups are patients following spinal cord injury (SCI) or anterior cruciate ligament (ACL) injury. Aims. This project aimed to develop analysis techniques to characterise bone in pQCT images. Their purpose was to describe localised changes within pQCT images of the bone, as opposed to the standard global measurements. Methods. Fully automated segmentation and registration software was developed and tested followed by two independent processing algorithms. The first generates spatial maps to characterise local changes in BMD. This is achieved using both quadrant analysis software and a voxel-based approach, the latter comparing pairs of images and generating a voxel-by-voxel ΔBMD map of changes in BMD. The second processing algorithm uses morphological granulometries to investigate the bone microarchitecture. Results. Evaluation of these image analysis methods was carried out using two clinical studies. The first investigates acute longitudinal changes in the distal tibia (DT) and distal femur (DF) post-motor-complete-SCI using pQCT. Images from 15 subjects (13M, 2F) with a mean age of 36y±19y, were acquired at 4-monthly intervals during the first year post-injury. The second comprises of ACL injury subjects, with imaging of the injured and contralateral proximal tibia (PT) and distal femur before (n=19, 18M 1F, 30y±9y of age) and after (n=8, 8M 0F, 31y±9y of age) surgical ACL reconstruction. The software developed to automatically segment bone from surrounding structures was successful: 98% success rate for epiphyseal tibial regions, 67% success rate for the distal femur. Registration of images was then performed and the spatial analysis methods to automatically produce quadrants of trabecular bone were applied, displaying individual results graphically. The voxel based analysis method was developed, tested and applied to produce ΔBMD maps, utilising statistical inference and corrections for multiple comparisons using a false-discovery rate technique. These maps characterised localised changes in BMD between pairs of both longitudinal and contralateral images. Software was also developed to apply morphological granulometries to pQCT images, calculating global and local pattern spectrum moments. On application of the analysis methods to the longitudinal SCI images, the BMD and microarchitecture findings were observed to be disparate amongst subjects, with large variations in bone characteristics both globally and regionally. The quadrant and voxel based analysis methods provided information on longitudinal regional changes in each subject, indicating individual patterns of change. Structural analysis of bone microarchitecture using granulometries was demonstrated to have potential as a useful adjunct to BMD in identifying SCI subjects more susceptible to rapid bone loss. The analysis methods were also successfully applied to the ACL injury subjects. Following segmentation and registration, the total and trabecular BMD in the injured knee was observed to be significantly lower than that of the contralateral control knee pre-operatively for both the PT and DF (p<0.05). Post-operatively the total and trabecular BMD in the injured DF remained significantly low (p<0.05), however the PT demonstrated significantly lower BMD in the injured leg for the trabecular bone only (p<0.05). Reduced BMD in the PT post-operatively in humans is a novel observation, and indicates a benefit afforded by segmenting trabecular from cortical bone. Regional analysis using quadrants indicated some anatomical variation in bone loss within the injured limb, although it is acknowledged that these are preliminary findings which would require to be confirmed in larger studies. The voxel ΔBMD maps generally indicated global losses across the bones of the ACL injured leg both pre-operatively and post-operatively. No consistent patterns were obtained in the ΔBMD maps for these subjects, suggesting individual patterns of response to ACL injury. The structural information provided by granulometric analysis was limited for the ACL study. Conclusions. Automated software has been developed to characterise bone in pQCT images of the appendicular skeleton. It has been successfully applied to two clinical studies, facilitating localised changes in bone density to be demonstrated and descriptions of microarchitecture to be provided. The SCI subjects appear to have individualistic responses to injury, with a wide range of changes in bone density and microarchitecture observed. ACL injury patients all lost bone mass, but patterns of change were variable. The analysis methods developed to permit characterisation of bones in individual subjects, are proposed to be of value in both clinical and research domains exploring bone mass and microarchitecture, with the ultimate goals being the prediction of fracture risk and tailoring therapy for the individual.

The software package Brainvisa (www.brainvisa.tnfo) offers a wide range of possibilities for cortical analysis using its automatic sulci recognition feature. Automated sulci identification is an attractive feature as the manual labelling of the cortical sulci is often challenging even for the experienced neuro-radiologists. This can also be of interest in fMRI studies of individual subjects where activated regions of the cortex can simply be identified using sulcal labels without the need for normalization to an atlas. As it will be explained later in this thesis, normalization to atlas can especially be problematic for pathologic brains. In addition, Brainvisa allows for sulcal morphometry from structural MR images by estimating a wide range of sulcal properties such as size, coordinates, direction, and pattern. Morphometry of abnormal brains has gained huge interest and has been widely used in finding the biomarkers of several neurological diseases or psychiatric disorders. However mainly because of its complexity, only a limited use of sulcal morphometry has been reported so far. With a wide range of possibilities for sulcal morphometry offered by Brainvisa, it is possible to thoroughly investigate the sulcal changes due to the abnormality. However, as any other automated method, Brainvisa can be susceptible to limitations associated with image quality. Factors such as noise, spatial resolution, and so on, can have an impact on the detection of the cortical folds and estimation of their attributes. Hence the robustness of Brainvisa needs to be assessed. This can be done by estimating the reliability and reproducibility of results as well as exploring the changes in results caused by other factors. This thesis is an attempt to investigate the possible benefits of sulci identification and sulcal morphometry for functional and structural MRI studies as well as the limitations of Brainvisa. In addition, the possibility of improvement of activation localization with functional MRI studies is further investigated. This investigation was motivated by a review of other cortical-based analysis methods, namely the cortical surface-based methods, which are discussed in the literature review chapter of this thesis. The application of these approaches in functional MRI data analysis and their potential benefits is used in this investigation.

The main aim of this work was to develop accurate and efficient methods for the verification of Intensity Modulated Radiotherapy (IMRT). IMRT is an advanced form of radiotherapy demanding extensive verification procedures to ensure treatments are delivered accurately. This requires comprehensive sampling of the complex dose distributions impacting on the tumour volume and radiationsensitive ‘organs at risk’. This work has focused on the use of electronic portal imaging devices (EPIDs) for verification purposes. Modern EPIDs are composed of a scintillator and an amorphous silicon detector panel with an array of photodiodes and thin film transistors. They are primarily used to verify the patient position during treatment by capturing transmission images, but they also have the potential to be used as efficient dose verification tools of high spatial resolution. Two complementary dose verification methods have been developed. One approach involves the calculation of portal dose using Monte Carlo (MC) methods. A MC model of the linear accelerator, in combination with the EPID, enables the dose to the detector to be predicted accurately and compared directly with acquired images. An alternative approach has also been developed. This utilises a clinical treatment planning system (TPS) to calculate the dose at the detector level, and convert this to predicted EPID intensity by application of a series of derived correction factors. Additionally, there have been numerous publications in the literature detailing problems in dosimetry caused by non-uniform backscatter to the imager from the model of detector support arm used in this work. Two novel methods to correct for this issue have been developed, a MC modelling solution and a matrix-based correction. These developed methods for IMRT dose verification have been applied both prior to and during treatment. When applied to pre-treatment verification, the MC solution is accurate to the 2%, 2 mm level (an average of 96% of points passing gamma criteria of 2%, 2 mm) and the TPS based method is accurate to the 3%, 3 mm level (an average of 98% of points passing gamma criteria of 3%, 3 mm). Both verification methods achieve acceptable verification results during treatment at the 5%, 5 mm level (average gamma pass rates of 97% and 96% being achieved for the MC and TPS based solutions respectively). Furthermore, in initial clinical studies, both techniques have identified dose delivery errors due to changes in patient position or patient anatomy.

Electrical Impedance Tomography (EIT) is a non-invasive detection technique which is able to distinguish between cancerous and non-cancerous cells. This thesis addresses some of the issues associated with EIT system design. Initially a study was completed to source an improved voltage-to-current convertor for the current Leicester system. Two circuits were designed and simulated using PSpice software and compared for their responses and to ascertain the capacity for improvement through component advancement. Simulated results indicated that the Improved Howland circuit was superior for the specific needs of the Leicester group. Secondly, following a review of current techniques for improving the high frequency response of EIT systems, a theory for using a time response method as a solution was developed. The new method was directly compared to the existing frequency technique by analysing electronic phantom and organic samples with both systems. Finally an investigation was completed in the area of micro EIT which aimed to detect cancerous islets within mouse pancreata with aims to distinguish normal and cancerous cells, and, ultimately, to detect cancerous single cell “escapers”. Three methods were described. The initial technique tested in-vitro pancreata and results from this suggested that the approach was a viable method for indentifying the affected tissue; therefore additional methods were designed to test individual extracted islets. In summary, the thesis provides an improved alternative V-to-I convertor for the Leicester group’s system, which has been adopted in experiments. The time response method investigation showed that it may provide a viable method that could, with further development and analytical refinement, improve the effectiveness of cell modelling in several interesting ways. Further investigation is suggested. The positive results provided by the whole pancreas testing are a convincing reason for further work to be conducted in this area, in particular work to enhance the diagnostic analysis of pancreata.

The aims of this mixed methods research study were twofold: (1) To explore the impact(s) of a cardiac rehabilitation progrmme (CRP) on the quality of life (QOL) of older cardiac patients who experienced either a myocardial infarction (MI) and/or a coronary artery bypass graft (CABG) and/or a percutaneous coronary intervention (PCI), otherwise known as a coronary angioplasty; and (2), To construct a QOL conceptual model based on the quantitative and qualitative aspects of the patient‟s bio-psycho-social-spiritual aspects of QOL on a CRP. The research sought to answer four research questions devised around the physiological, psychological, and sociological domains of QOL. A mixed methods design was used, under the rubric of a critical realist theoretical approach. The physical domains of QOL focused on the cardiac patients specific physiological measurements using a pre-test-post-test design in order to develop a deeper understanding, of the structures, mechanisms, contexts and outcomes of the CRP. Qualitative components focused on the subjective domains of QOL taken from the eclectic perspectives of cardiac health care professionals and cardiac patients using semi-structured interviews to develop an in-depth understanding of the bio-psycho-social-spiritual and health impacts of the programme. Thirty-five cardiac patients (n = 35) formed a non-random purposive sample for the quantitative component of the study. Using the same type of sampling method for the qualitative component, ten cardiac health care professionals (n = 10) and seven cardiac patients (n = 7) were interviewed to determine the various impact(s) that the programme had on the patients different domains of QOL. The results, derived from dual perspectives, indicated that the CRP had strong positive impacts on the patient‟s QOL across the bio-psycho-social-spiritual domains of QOL. The newly created QOL conceptual model, entitled „The Ripple Impact Model (TRIM)‟of QOL for Older Patients with Coronary Heart Disease (CHD)‟ reflects the dynamic nature of an older cardiac patient‟s QOL on a CRP in view of how they define the concept globally from both medical and non-medical perspectives.

The purpose of the study was to explore the proposition that lean is an effective methodology for service improvement within a healthcare setting by evaluating the changes brought about by the application of lean tools to an orthopaedic radiology pathway in a large DGH. Delivery of this service was poor with long waiting times and poor levels of satisfaction amongst patients and staff. This service was evaluated using lean tools in order to identify areas for improvement, and changes were made in the form of a self contained Radiology suite within the Orthopaedic Out Patient department. Changes were also made to the booking templates and the pathway through the department. Staffing levels remained the same, with rosters being changed to include cover for the new department. A mixed model approach was used, with qualitative and quantitative data being collected from staff and patients both before and after the changes took place. The qualitative data consisted of questionnaires completed by staff and patients. The quantitative data was predominantly related to waiting times and was gathered from the Radiology Information System, with some quantitative data being taken from the questionnaires. A comparative analysis of the two services was conducted in order to determine if the changes were consistent with the lean philosophies of 'elimination of waste' and 'respect for people'. The results revealed that the time spent by the patient in clinic and radiology had reduced by up to 69.59% and 66.27% respectively, with a reduction in patients having to wait longer than 30 minutes for their x-ray of 94.93%. The location of the department influenced this reduction as the distance travelled by the patient reduced by up to 60.53%. A further factor was the separation of Orthopaedic patients from Emergency Department patients, leaving the radiographers with only one patient pathway to focus on and a reduction of 60% of radiographers feeling that they had conflicting demands on their time. This increased the levels of patient and staff satisfaction. Furthermore, there was a reduction of 54% in the median waiting time for Emergency Department patients attending radiology. The author proposes that these findings support the proposition that lean is an effective methodology for service improvement within a healthcare setting.

Early breast cancer in women is best identified through high quality mammographic screening. This is achieved by well trained health professionals and appropriate imaging. Traditionally this has used X-ray film but is rapidly changing to utilise digital imaging with the resultant mammograms visually examined on high resolution clinical workstations. These digital images can also be viewed on a range of display devices, such as standard computer monitors or PDAs. In this thesis the potential of using such non-clinical workstation display devices for training purposes in breast screening has been investigated. The research introduces and reviews breast screening both in the UK and internationally where it concentrates upon China which is beginning screening. Various imaging technologies used to examine the breast are described, concentrating upon the move from using X-ray film to digital mammograms. Training in screening in the UK is detailed and it is argued that there is a need to extend this. Initially, a national survey of all UK mammography screeners within the National Health Breast Screening Programme (NHSBSP) was undertaken. This highlighted the current main difficulties of mammographic (film) interpretation training being tied to the device for inspecting these images. The screeners perceived the need for future digital imaging training that could be outside the breast screening centre; namely 3W training (Whatever training required, Whenever and Wherever). This is largely because the clinical workstations would logistically not be available for training purposes due to the daily screening demand. Whilst these workstations must be used for screening and diagnostic purposes to allow visualisation of very small detail in the images, it is argued here that training to identify such features can be undertaken on other devices where there is not the time constraints that exist during breast screening. A series of small pilot studies were then undertaken, trialling experienced radiologists with potential displays (PDAs and laptops) for mammographic image examination. These studies demonstrated that even on a PDA small mammographic features could be identified, albeit with difficulty, even with a very limited HCI manipulation tool. For training purposes the laptop, studied here with no HCI tool, was supported. Such promising results of display acceptability led to an investigation of mammographic inspection on displays of various sizes and resolutions. This study employed radiography students, potentially eventual screeners, who were eye tracked as they examined images on various sized displays. This showed that it could be possible to use a small PDA to deliver training. A detailed study then investigated whether aspects of an expert radiologist s visual inspection behaviour could be used to develop various training approaches. Four approaches were developed and examined using naïve observers who were eye tracked as they were trained and tested. The approaches were found to be all feasible to implement but of variable usefulness for delivering mammographic interpretation training; this was confirmed by opinions from a focus group of screeners. On the basis of the previous studies, over a period of eight months, a large scale study involving 15 film readers from major breast screening centres was conducted where they examined series of digital mammograms on a clinical workstation, monitor and an iPhone. Overall results on individuals performance, image manipulation behaviour and visual search data indicated that a standard monitor could be employed successfully as an alternative for the digital workstation to deliver on-demand mammographic interpretation training using the full mammographic case images. The small iPhone, elicited poor performance, and was therefore judged not suitable for delivering training with the software employed here. However, future software developments may well overcome its shortcomings. The potential to implement training in China was examined by studying the current skill level of some practicing radiologists and an examination of how they responded to the developed training approaches. Results suggest that such an approach would be also applicable in other countries with different levels of screening skills. On-going further work is also discussed: the improvement of performance evaluation in mammography; new visual research on other breast imaging modalities and using visual search with computer aided detection to assist mammographic interpretation training.

This thesis describes the role of mathematical modelling in the evaluation of an innovative automated system of wearable and environmental sensors to monitor the activity patterns of patients with Bipolar Disorder (BD). BD is a chronic and recurrent mental disorder associated with severe episodes of mania and depression, interspersed with periods of remission. Early detection of transitions between the normal, manic and depressed stages is crucial for effective self-management and treatment. Personalised Ambient Monitoring (PAM) is an EPSRC-funded multidisciplinary project involving biomedical engineers, computer scientists and operational researchers. The broad aim of PAM is to build and test a network of sensors (chosen by the patient) to collect and analyse daily activity data in order to identify an ‘activity signature’ for that individual in various health states. The hypothesis is that small but potentially significant changes in this activity pattern can then be automatically detected and the patient alerted, enabling him/her to take appropriate action. The research presented in this thesis involves the development and use of a Monte Carlo simulation model to evaluate the potential of PAM without the need for a costly and time-consuming clinical trial. A unique and novel disease state transition model for bipolar disorder is developed, using data from the clinical literature. This model is then used stochastically to test many different scenarios, for example the removal or technical failure of a sensor, or the limited availability of various types of data, for various simulated patient types and a wide range of assumptions and conditions. The feasibility of obtaining sufficient information to derive clinically useful information from a limited set of sensors is analysed statistically. The minimum best set of sensors suitable to detect both aspects of the disorder is identified, and the performance of the PAM system evaluated for a range of personalised choices of sensors

Radiotherapy represents an important phase of treatment for a large number of cancer patients. It is essential that resources used to deliver this treatment are used efficiently. This thesis approaches the problem of scheduling treatments in a radiotherapy centre. Data about the daily intake of patients are collected and analysed. Several approaches are presented to create a schedule every day. The first presented are constructive approaches, developed due to their simplicity and low computational requirements. The approaches vary the preferred treatment start, machine utilisation reservation levels, and the frequency and number of days in advance with which schedules are created. An Integer Linear Programming (ILP) model is also presented for the problem and used in combination with approaches similar to the ones above. A generalisation of the constructive utilisation threshold approach is developed in order to vary the threshold level for each day according to how far it is from the current day. In addition, the model is evaluated for different sizes of the problem by increasing the rate of patient arrivals per day and the number of machines available. Different machine allocation policies are also evaluated. An exact method is introduced for finding a set of solutions representing the whole Pareto frontier for integer programming problems. It is combined with two robust approaches: the first considers known patients before they are ready to be scheduled, while the second considers sets of predicted patients who might arrive in the near future. A rescheduling approach is also suggested and implemented. A comparison is made amongst the best results from each group of approaches to identify the advantages and disadvantages of each. The robust approaches are found to be the best alternative of the set.

This thesis describes the design, construction and testing of a dome coil. The dome coil is hemispherical in shape and is intended to be used within a set of hemispherical gradient coils in a seven tesla magnetic resonance imaging magnet. The dome coil has eight independent elements and is designed to be used for parallel transmission and reception. It is shown that the dome coil produces less specific absorption rate than a conventional birdcage coil and is suitable for head imaging. A study of travelling wave magnetic resonance imaging is also presented. In this study two different methods of generating a travelling wave (using a patch antenna and an end-fire helix antenna) are compared, and the power requirements and specific absorption rate of the travelling wave approach are considered. It is concluded that travelling wave magnetic resonance imaging is best performed using a local receive coil and with the travelling wave antenna placed at least 50 cm from the subject. All theory relevant to the design, construction, testing and use of these coils and antennas is also presented.

The microstructure of the lung is complex, containing many branching airways and alveolar sacs for optimal gas exchange. Lung diseases such as cystic fibrosis (CF), asthma, and emphysema lead to a destruction of this microstructure. As such, there is a growing interest in the early identification and assessment of lung disease using non invasive imaging techniques. Pulmonary function tests such as spirometry and plethysmography are currently used for this purpose but can only provide quantitative lung function measurements rather than direct measurements of lung physiology and disease. Computed tomography (CT) has also been used but due to risk of cell damage and mutation from the ionising radiation, long term monitoring of the lungs is severely constrained. Recently, new methods based on magnetic resonance imaging (MRI) have been developed to provide diagnostic imaging of the lung. Conventional MRI is not very well suited for lung imaging due to the very low proton density of the pulmonary airspaces. This problem can be overcome by making the patient inspire noble gases such as 3He whose polarisations have been vastly increased through optical pumping. Therefore 3He MRI permits a non-invasive determination of lung function. The high diffusion coefficient of 3He can be exploited to probe the microstructure of the lung. By measuring how fast 3He diffuses within the lung, the size of the lung microstructure can be assessed. Normally, the airspace walls impede the diffusion of the gas but for diseased lungs where microstructure has been destroyed, diffusion is less restricted and a higher apparent diffusion coefficient (ADC) is observed. The research conducted for this thesis focused on the measurement of ADC using three different MRI pulse sequences with each sequence being designed to assess the peripheral airspaces over different length scales. These sequences were then implemented on three different subject study groups.

Laser Doppler blood flow imaging is well established as a tool for clinical research. The technique has considerable potential as an aid to diagnosis and as a treatment aid in a number of situations. However, to make widespread clinical use of a blood flow imager feasible a number of refinements are required to make the device easy to use, accurate and safe. Existing LDBF systems consist of 2D imaging systems, and single point scanning systems. 2D imaging systems can offer fast image acquisition time, and hence high frame rate. However, these require high laser power to illuminate the entire target area with sufficient power. Single point scanning systems allow lower laser power to be used, but building up an image of flow in skin requires mechanical scanning of the laser, which results in a high image acquisition time, making the system awkward to use. A new approach developed here involves scanning a line along a target, and imaging the line with a 1D sensor array. This means that only one axis of mechanical scanning is required, reducing the scanning speed, and the laser power is vastly reduced from that required for a 2D system. This approach lends itself well to the use of integrated CMOS detectors, as the smaller pixel number means that a linear sensor array can be implemented on an IC which has integrated processing while keeping overall IC size, and hence cost, lower than equivalent 2D imaging systems. A number of front-end and processing circuits are investigated in terms of their suitability for this application. This is done by simulating a range of possible designs, including several logarithmic pixels, active pixel sensors and opamp-based linear front-ends. Where possible previously fabricated ICs using similar sensors were tested in a laser Doppler flowmetry system to verify simulation results. A first prototype IC (known as BVIPS1) implements a 64x1 array of buffered logarithmic pixels, chosen for their combination of sufficient gain and bandwidth and compact size. The IC makes use of the space available to include two front-end circuits per pixel, allowing other circuits to be prototyped. This allows a linear front-end based on opamps to be tested. It is found that both designs can detect changes in blood flow despite significant discrepancies between simulated and measured IC performance. However, the signal-noise ratio for flux readings is high, and the logarithmic pixel array suffers from high fixed pattern noise, and noise and distortion that makes vein location impossible. A second prototype IC (BVIPS2) consists of dual 64x1 arrays, and integrated processing. The sensor arrays are a logarithmic array, which addresses the problems of the first IC and uses alternative, individually selectable front-ends for each pixel to reduce fixed-pattern noise, and an array of opamp-based linear detectors. Simulation and initial testing is performed to show that this design operates as intended, and partially overcomes the problems found on the previous IC - the IC shows reduced fixed pattern noise and better spatial detection of blood flow changes, although there is still significant noise.

Contemporary management of patients with heart failure (HF) includes treatment with cardiac resynchronisation therapy (CRT). The benefit of CRT results from several mechanisms, predominantly correction of dyssynchrony. The development of a novel method of measuring left ventricular global dyssynchrony using cardiovascular magnetic resonance (CMR), termed CMR-tissue synchronisation index (CMR-TSI) is described. A study of 225 patients with HF who underwent CMR-TSI found that HF appears synonymous with dyssynchrony. The importance of myocardial scar is illustrated in a study of 95 patients which revealed a significantly higher mortality in patients undergoing CRT who had postero-lateral (PL) scar on CMR. A study into the effects of a combination of CMR-TSI and scar imaging found that presence of either CMR-TSI >110ms or PL scar resulted in a worse outcome, whilst the presence of both was associated with the highest mortality. A final study in 148 patients allowed the development of a risk score to predict mortality from CRT on the basis of 16 candidate variables. PL scar, dyssynchrony and creatine discriminated between survivors and non-survivors and were used to derive the score. The score is discussed in the context of data derived from echocardiography and clinical studies.

Dynamic Nuclear Polarisation (DNP) is a method used to increase the signal available for nuclear magnetic resonance (NMR) experiments. DNP is one of many hyperpolarisation methods and one implementation, so called ex-situ DNP, sees the sample polarised with a stable radical doping agent at low temperature and with microwave irradiation in a magnetic field before transfer to a second higher field NMR magnet to acquire a liquid state NMR spectrum. The primary goal of this project has been to gain an understanding of the underlying reasons for unpredictable ex-situ DNP polarisation failures and to develop methods to overcome these limitations. In the course of the work an additional polarisation mechanism arising from hindered methyl rotors was discovered. This thesis describes the preparation of DNP samples and the way in which DNP-NMR experiments are performed have been optimised. The concept of a co-polarisation agent has been introduced and methods employing a Nuclear Overhauser Effect have been implemented. Additionally the identification and characterisation of a quantum tunnelling effect that is a variant of the commonly known Haupt effect. Finally these methods have been combined in a number of situations to give results that would have otherwise been unobtainable.

The objective of this thesis was to develop a new methodology for the improvement of the interface properties of gold electrodes for neural implants. The goal was to increase the surface area without a change in geometrical footprint of the electrode with nano-fabrication tools. A process has been created that uses Nanosphere Lithography for masking layer deposition and anisotropic etching to fabricate nanostructures on the surface of the electrodes. Optimisation of the process parameters led to a control of structure shape, which allowed to produce a variety of shapes. The effect of the nano-structures on the interface was investigated by impedance spectroscopy and complementary electrochemical measurements. It showed that the interface impedance could be decreased significantly by up to a magnitude of scale with the surface modifications. In addition a porous columnar form of sputtered gold was found that also showed decreased interface impedance compared to standard gold films. A set of neural implants was designed and fabricated to test the effect of surface modification in vitro in neurological tissue. The surface modification process was successfully implemented in the device fabrication. The in-vitro assessment showed signs of improved interface performance compared to unmodified devices.

The measurement of radiation dose in radiotherapy is vital in ensuring the accuracy of treatments. As more advanced techniques using protons and ions emerge, they pose challenges to ensure the same level of accuracy of dosimetry is achieved as for conventional X-ray radiotherapy. A relatively new method of particle acceleration using ultra-high intensity lasers and thin metallic targets has sparked a large effort to investigate the possible application of this technology in radiotherapy, which in turn requires accurate methods of dosimetry to be carried out and is the main motivation for this work. Accurate dosimetry was initially performed here using an air ionisation chamber, various models of GafChromic film and a PMMA phantom in 15 and 29 MeV protons and 38 MeV \(\alpha\)-particles from the Birmingham cyclotron. In developing an accurate protocol for absorbed dose-to-water at these relatively low proton energies, new data was generated on the proton energy response of GafChromic films. This enabled accurate dosimetry of a prototype laser-particle source, and provided improvements to a method of spectroscopic measurement in the resultant mixed field of multi-energy protons, electrons and X-rays. Monte Carlo simulations using MCNPX but mainly FLUKA were performed throughout to support and verify experimental measurements.

This thesis compares theoretical models of ultrasound contrast agents to the acoustic response from single Microbubbles(MBs). The acoustic response was compared using a range of driving parameters. A rigid shelled contrast agent and a lipid shelled contrast agent were used in the comparison. While attempts to model the behaviour of some contrast agents at low mechanical index (MI) have been successful at higher MI the behaviour of MBs is still not well understood. Understanding and predicting the response ofMBs to medical ultrasound can lead to improvements in the clinical use of MBs through improved contrast agent design or improved signal processing. Numerical models were developed to compare to three specific cases; 1) Rigid shelled contrast agents 2) Lipid shelled contrast agents 3) Responses from lipid shelled contrast agents that are hit by subsequent driving pulses. Three models were used to compare to the responses from single rigid shelled contrast agents. Two of these models have been used before and the third was developed based on the optical observations of the responses of these rigid shelled agents at these MI. Two shelled models were used to compare to the response of single lipid shelled MBs. Using statistical methods the parameters defining the shell properties were found. The parameters that gave best agreement with the lipid shelled data was then used with a model to account for the molecular diffusion of gas from a MB and a new model to account for the optically observed shedding of the shell from a MB to compare to the multiple response from single MBs. While the theoretical prediction of an acoustic response of a suspension of MBs or the radial oscillation of single MBs has been compared before to experimental data, the successful comparison of the acoustic response of single MBs to the theoretical prediction is the first of it’s kind known to the author. The new theoretical model of the rigid shelled MB that was developed in this thesis gave better agreement with the experimental data than the other previously used models. The shell parameters of the lipid shelled MB were determined for the lowest driving amplitude and were in agreement with those measured previously from optical observations. Finally, the model for the shedding of the shell was shown to give quantitative agreement with the multiple acoustic responses from single MBs. When shedding of the shell was included the choice of constitutive equation for the shell was shown to strongly affect subsequent responses from the MB.

Image guidance has rapidly become central to current radiotherapy practice. A uniform framework is developed for evaluating image quality across all imaging modalities by modelling the ‘universal phantom’: breaking any phantom down into its constituent fundamental test objects and applying appropriate analysis techniques to these through the construction of an automated analysis tree. This is implemented practically through the new software package ‘IQWorks’ and is applicable to both radiotherapy and diagnostic imaging. For electronic portal imaging (EPI), excellent agreement was observed with two commercial solutions: the QC-3V phantom and PIPS Pro software (Standard Imaging) and EPID QC phantom and epidSoft software (PTW). However, PIPS Pro’s noise correction strategy appears unnecessary for all but the highest frequency modulation transfer function (MTF) point and its contrast to noise ratio (CNR) calculation is not as described. Serious flaws identified in epid- Soft included erroneous file handling leading to incorrect MTF and signal to noise ratio (SNR) results, and a sensitivity to phantom alignment resulting in overestimation of MTF points by up to 150% for alignment errors of only ±1 pixel. The ‘QEPI1’ is introduced as a new EPI performance phantom. Being a simple lead square with a central square hole it is inexpensive and straightforward to manufacture yet enables calculation of a wide range of performance metrics at multiple locations across the field of view. Measured MTF curves agree with those of traditional bar pattern phantoms to within the limits of experimental uncertainty. An intercomparison of the Varian aS1000 and aS500-II detectors demonstrated an improvement in MTF for the aS1000 of 50–100% over the clinically relevant range 0.4–1 cycles/mm, yet with a corresponding reduction in CNR by a factor of p 2. Both detectors therefore offer advantages for different clinical applications. Characterisation of cone-beam CT (CBCT) facilities on two Varian On-Board Imaging (OBI) units revealed that only two out of six clinical modes had been calibrated by default, leading to errors of the order of 400 HU for some modes and materials – well outside the ±40 HU tolerance. Following calibration, all curves agreed sufficiently for dose calculation accuracy within 2%. CNR and MTF experiments demonstrated that a boost in MTF f50 of 20–30% is achievable by using a 5122 rather than a 3842 matrix, but with a reduction in CNR of the order of 30%. The MTF f50 of the single-pulse half-resolution radiographic mode of the Varian PaxScan 4030CB detector was measured in the plane of the detector as 1.0±0.1 cycles/mm using both a traditional tungsten edge and the new QEPI1 phantom. For digitally reconstructed radiographs (DRRs), a reduction in CT slice thickness resulted in an expected improvement in MTF in the patient scanning direction but a deterioration in the orthogonal direction, with the optimum slice thickness being 1–2 mm. Two general purposes display devices were calibrated against the DICOM Greyscale Standard Display Function (GSDF) to within the ±20% limit for Class 2 review devices. By providing an approach to image quality evaluation that is uniform across all radiotherapy imaging modalities this work enables consistent end-to-end optimisation of this fundamental part of the radiotherapy process, thereby supporting enhanced use of image-guidance at all relevant stages of radiotherapy and better supporting the clinical decisions based on it.

The use of bioimpedance techniques for malignancy identification is considered novel, with challenges existing that need to be overcome. In this thesis, such bioimpedance approaches have been developed for identifying malignancies through a systematic study, ranging from the investigation of the technical challenges affecting an imaging based breast cancer detection system, to the study of electrical properties of tissue and cells. Hence, this work provides proof-of-concept for cancer diagnosis based on the electrical signatures that differentiate malignancies from normal tissue, utilising bioimpedance analysis techniques. Further, this work will contribute to the understanding of correlations between electrical properties and biological functions, which will help to explore bioimpedance techniques for wider medical and bioscience applications. Furthermore, this research will also be conducive to investigations of novel devices for cancer diagnosis in clinic. The Ph. D work was carried out in two threads. In the first thread, technical challenges of using Electrical Impedance Mammography (EIM), an imaging modality developed based on bioimpedance technique for breast cancer diagnosis, were studied on 1) effectively reducing measurement errors from electrode contact interfaces, and 2) validating systems by using novel simulation phantoms. In the second thread, bioimpedance spectroscopy (BIS) of tissues and cells was investigated to 1) reveal their electrical properties, 2) identify malignant changes, and 3) establish correlations of electrical properties with biological function changes. By carrying studies in these two threads, bioimpedance was fully investigated for its applications on cancer detection and diagnosis. This work has made significant contributions to the field of study. It comprises the first systematic study on bioimpedance for cancer identification at the tissue and cellular levels. This work has also been pioneering in linking the electrical properties of malignant tissues and cells to the relevant biological changes brought on by the aforementioned malignancies.

Ultrasound, applied in combination with microbubbles, has potential as a means to enhance the uptake of therapeutic agents, which could include drugs and nucleic acids, into biological cells. This process is commonly referred to as 'sonoporation', and the enhanced uptake can be caused through the incident ultrasonic pressure fi eld causing radial oscillations (cavitation) in the microbubbles, amongst other possibilities. However, the mechanisms responsible for any resultant increase in cell membrane permeability are not yet fully understood. This project focussed on achieving a more fundamental understanding of these salient processes by building on a platform of previous work within the group. One strand of the project involved a complete characterisation of the performance of a rotating mirror high speed camera (Cordin 550-62) that was previously used by our group [and others] to investigate microbubble cavitation phenomena and interactions with proximal cell membranes. Speci cally, I present herein an investigation into the image formation process with this type of camera, the essence of which stymied previous data interpretations. I demonstrate that an inherent asynchrony in the exposure of pixels within individual image frames leads to a temporal anomaly. This was achieved using low cost, flashing LED lights and resulted in the extraction of an algorithm to correct for the temporal anomaly. In a slightly diff erent context, the delivery of suitable ultrasonic fields is necessary to achieve a uniform treatment across a therapeutic target. This thesis also reports on a study on the design of ultrasonic lenses to alter the focal region of a focussed ultrasound transducer with the aim of producing focal regions that can enable sonoporation of tumours of varying sizes. We show that the use of lenses can be an inexpensive alternative to more complex systems such as phased array transducers. Design modelling and experimental testing of lens prototypes are presented along with preliminary results with tissue mimicking polyacrylamide gel phantoms. The target environment in which the process of sonoporation will be clinically useful (i.e. in the physiological circulation) can be simpli ed as a microfluidic system. One strategy for bubble mediated therapy involves the use of a pro-drug approach, that is, when two otherwise benign ingredients are loaded onto separate microbubble populations, but can become mixed at the anatomical target site by the action of focussed ultrasound whereupon a potent drug is produced. The required mixing can be achieved by the violent coalescence of nearby cavitating bubbles, their reaction product then being released and di ffused into the interiour of nearby cells through sonoporation. A study related to this field is presented here where laser induced thermocapillary flows are shown to cause mixing of the content of a drop in a microfluidic channel in a bid to understand the mixing process at a level that may assist future microbubble engineering strategy. To summarise then, the work presented in this thesis has consolidated earlier unpublished data sets achieved by the group, providing new and exacting experimental evidence and an accurate algorithm that will facilitate post-processing of that earlier data (Chapters 2-3). Moreover, group aspirations to translate earlier in-vitro work on sonoporation towards next phase medical-phantom exposures have been boosted through the provision of a new direction involving acoustic lensing, the experimental data from which was used to completely validate existing models for our own design scenarios (Chapter 4). Finally, previous unpublished observations on microbubble coalescence undertaken by the group suggested a means to implement pro-drug delivery with direct in-situ mixing. Such suggestions were explored within microfluidic contexts using lasers to control and visualise the mixing processes that might arise in such situations (Chapter 5). All of these new insights have served to consolidate the group's previous and as yet unpublished data, opening the way for dissemination with confidence in the integrity of that data, and have also extended group capability and expertise in the areas of MHz-rate high speed framing cameras, the fabrication of acoustic lenses, and with microfluidic mixing.

Alzheimer’s disease (AD) is the most common cause of dementia. Mild cognitive impairment (MCI) is a transitional state between normal ageing and dementia. Positron emission tomography (PET) can detect the metabolic and neuro-chemical changes that occur in MCI and dementia. The aim of this thesis was to assess the use of PET as an in vivo biomarker for early disease detection, prognosis, and proof of treatment efficacy in AD and MCI. In study I, the prevalence of increased beta-amyloid deposition (assessed by 11C-PIB PET) and microglial activation (assessed by 11C-PK11195 PET) was studied in amnestic MCI (aMCI) subjects. 50% had raised amyloid deposition and 38% evidence of microglial activation. Subjects with increased PIB retention had significantly higher cortical PK11195 binding. In study II, rates at which aMCI subjects with and without increased amyloid load converted to AD were compared over one to three years of follow-up. 55% of aMCI subjects had significantly increased PIB retention at baseline and 82% of these converted to AD compared to 7% of aMCI cases with normal PIB uptake. Faster AD converters had higher PIB retention than slower converters. In study III, changes in regional cerebral Aβ deposition (assessed with 11C-PIB PET) and regional cerebral glucose metabolism (rCMRGlc) (assessed with 18F-FDG PET) were followed over three years in MCI and AD subjects. The MCI subjects demonstrated small but significant increases in 11C-PIB retention and parallel decreases in rCMRGlc. 11C-PIB retention in AD subjects remained unchanged, despite decreases in rCMRGlc and a decline in their MMSE. In study IV, the effects of passive immunisation with infusions of the anti-Aβ monoclonal antibody bapineuzumab on amyloid plaque load was assessed in AD subjects. After 78 weeks, subjects receiving bapineuzumab had reduced cortical 11C-PIB retention compared with their baseline and with placebo treated subjects. Through its detection of fibrillar Aβ, PET can detect the presence of Alzheimer pathology and provides a prognostic indicator of future progression of MCI to AD. However, PIB PET is not a marker of AD progression as the amyloid load remains relatively stable. 18F-FDG PET, a marker of synaptic activity, more closely mirrors cognitive decline as neurodegeneration progresses. Finally, PET allows the changes in glial activation in MCI to be monitored and provides a rationale for therapeutic trials of anti-inflammatory agents.

The health of rich, developed nations has seen drastic improvement in the last two centuries. For it to continue improving at a similar rate new or improved diagnostic and treatment technologies are required, especially for those diseases such as cancer which are forecast to constitute the majority of disease burden in the future. Optical techniques such as microscopy have long played their part in the diagnostic process. However there are several new biophotonic modalities that aim to exploit various interactions between light and tissue to provide enhanced diagnostic information. Many of these show promise in a laboratory setting but few have progressed to a clinical setting. We have designed and constructed a flexible, multi-modal, multi-spectral laparoscopic imaging system that could be used to demonstrate several different techniques in a clinical setting. The core of this system is a dynamic hyperspectral illumination system based around a supercontinuum laser and Digital Micromirror Device that can provide specified excitation light in the visible and near infra-red ranges. This is a powerful tool for spectroscopic techniques as it is not limited to interrogating a fixed range of wavelengths and can switch between excitation bands instantaneously. The excitation spectra can be customised to match particular fluorophores or absorption features, introducing new possibilities for spectral imaging. A standard 10 mm diameter rigid endoscope was incorporated into the system to reduce cost and demonstrate compatibility with existing equipment. The polarization properties of two commercial endoscopes were characterised and found to be unsuited to current polarization imaging techniques as birefringent materials used in their construction introduce complex, spatially dependent transformations of the polarization state. Preliminary exemplar data from phantoms and ex vivo tissue was collected and the feasibility and accuracy of different analysis techniques demonstrated including multiple class classification algorithms. Finally, a novel visualisation method was implemented in order to display the complex hyperspectral data sets in a meaningful and intuitive way to the user.

There is a need for a noninvasive imaging technique for use in longitudinal studies of sub-clinical coronary artery disease. Magnetic resonance (MR) can be used to selectively and non-invasively image the coronary wall without the use of ionising radiation. However, high-resolution 3D studies are often time consuming and unreliable, as data acquisition is generally gated to a small window of diaphragm positions around end-expiration which results in inherently poor and variable respiratory efficiency. This thesis describes the development and application of a novel technique (beat-to-beat respiratory motion correction (B2B-RMC)) for correcting respiratory motion in 3D spiral MR coronary imaging. This technique uses motion of the epicardial fat surrounding the artery as a surrogate for the motion of the artery itself and enables retrospective motion correction with respiratory efficiency close to 100%. This thesis first describes an assessment of the performance of B2B-RMC using a purpose built respiratory motion phantom with realistic coronary artery test objects. Subsequently, MR coronary angiography studies in healthy volunteers show that the respiratory efficiency of B2B-RMC far exceeds that of conventional navigator gating, yet the respiratory motion correction is equally effective. The performance and reproducibility of 3D spiral imaging with B2B-RMC for assessment of the coronary artery vessel wall is subsequently compared to that of commonly used 2D navigator gated techniques. The results demonstrate the high performance, reproducibility and reliability of 3D spiral imaging with B2B-RMC when data acquisition is gated to alternate cardiac cycles. Using this technique, a further in-vivo study demonstrates thickening of the coronary vessel wall with age in healthy subjects and these results are shown to be consistent with outward remodelling of the vessel wall. Finally, the performance of B2B-RMC in a variety of coronary vessel wall applications, including in a small cohort of patients with confirmed coronary artery disease, is presented.

Owing to its ability to capture a systemic and temporal metabolic description of an organism’s response to a treatment, metabonomics is a well-established and valuable approach in elucidating the effects and mechanisms of a given perturbation. However, to optimise information recovery from the complex datasets generated, chemometric methods are essential. The work presented in this thesis focuses on the development of novel methods, and the use of existing methods in new applications to ease data interpretation and enhance information recovery from 1H Nuclear Magnetic Resonance (NMR) metabonomic datasets using correlation based methods. Although the methods here are largely applied to toxicological data, they could be equally valuable in the analysis of any metabonomic dataset, and indeed potentially to other ‘omics’ data presenting similar analytical challenges. The first two methodological approaches relate to novel extensions of Statistical Total Correlation Spectroscopy (STOCSY), a valuable tool in elucidation of both inter- and intra-metabolite spectral intensity correlations in NMR metabonomic datasets. In the first, STOCSY is utilised in STOCSY-editing, a method for the selective identification and downscaling of the peaks from unwanted metabolites such as those arising from xenobiotics. Structurally correlated peaks from drug metabolites are first identified using STOCSY, and the returned correlation information utilised to scale the spectra across these regions, producing a modified set of spectra in which drug metabolite contributions are reduced, endogenous peaks reconstructed and thus, analysis by pattern recognition methods without drug metabolite interferences facilitated. In the second, the STOCSY approach is extended in Iterative-STOCSY, where metabolic associations are followed over several rounds of STOCSY through calculation of correlation coefficients initially from a driver spectral peak of interest, and subsequently from all peaks identified as correlating above a set threshold to peaks picked in the previous round. The condensation of putatively structurally related peaks into single nodes, and representation of the otherwise complex network in a fully interactive plot of node-to-node connections and corresponding spectral data, allows the ready exploration of both inter- and intrametabolite relationships and a more directed approach to the identification of biomarkers of the studied perturbation. Finally various clustering methods are investigated with the aim of providing improved structural (intra-metabolite) versus non-structural (inter-metabolite) assignment. Thus, this thesis presents a framework for the enhanced identification, recovery and characterisation of inter- and intrametabolite relationships and how these are affected by metabonomic perturbation.

One of the main challenges in molecular imaging with targeted contrast agents is the detection and discrimination of attached agents from the rest of the signals originating from freely flowing agents and tissue. The aim of this thesis was to develop methods for the detection of targeted microbubbles. One approach consisted of investigating the use of nonlinear Doppler for this purpose. Nonlinear Doppler enables the differentiation of moving from non-moving and linear from nonlinear scattering. Targeted microbubbles are static and nonlinear scatterers and they should be detected using this technique. A novel nonlinear Doppler technique: Pulse subtraction Doppler, was developed and compared to pulse inversion Doppler. It is shown that both techniques lead to similar Doppler spectra and depending on the medical applications and the equipment limitations, both techniques have benefits. This served as a starting point for the derivation of a generalised nonlinear Doppler technique, based on combined linear pulse pair sequences and tested in a simulation study. The response from a single microbubble was simulated for different pulse combinations and the pulse sequences were compared with regards to criteria specific to imaging requirements. It was shown that depending on initially set criteria, such as transmitted energy, mechanical index or scanner characteristics, certain pulse combinations offer alternatives to the current imaging modalities and allow to take into account specific constrains due to the targeted application/equipment. Furthermore, the proposed approach is directly applicable in a strict non linear imaging approach, without Doppler processing. An in vitro phantom was designed in order to assess pulse subtraction Doppler for the detection and discrimination of static nonlinear microbubbles in the presence of free flowing ones. It was shown that pulse subtraction Doppler enables such discrimination and the practicability for in vivo situations is discussed. The pulse subtraction Doppler sequences were also tested on a phantom containing magnetic bubbles. It was shown that the magnetic bubbles can be immobilised through a magnetic field to a specific region of interest under flow conditions. The bubbles also showed to be acoustically detectable and to scatter linearly at diagnostic driving pressures. Preliminary work regarding experimental biotinylated microbubbles and their attachment to streptavidin coated surfaces is also presented. Due to their proximity to a wall, researchers have found that targeted microbubbles exhibit different acoustic signatures compared to free ones and this knowledge can improve their detection techniques. The behaviour of microbubbles against a membrane of varying stiffness was also studied through high speed camera observations. It was found both experimentally and by comparison to theoretical modelling that within the stiffness range of human blood vessels the change in acoustical behaviour of microbubbles is negligible. This thesis has taken two complementary research approaches which have shown to constitute advancements for the detection and discrimination of targeted microbubbles.

Photodynamic therapy (PDT) utilises light, oxygen and organic macrocycles, called photosensitisers, to produce reactive oxygen species that can kill malignant cells. Conventional PDT is associated with side effects that have stifled its advance and widespread use. These include low tumour selectivity, slow blood clearance and poor formulation. We proposed that an antibody fragment could be used to carry the photosensitiser to the target cells, significantly overcoming these limitations. Pyropheophorbide-a (PPa) was synthetically modified to enhance its water solubility obtaining two compounds, PS1 and PS4 each more water soluble than PPa. The use of Sonogashira coupling and short polyethylene glycol chains gave PS1, whereas the use of Suzuki coupling and a single positive charge gave PS4. The singlet oxygen quantum yields of these were improved compared to PPa with that of PS4 being 1.5 times higher than PPa. The in vitro characterisation of PPa, PS1 and PS4 using cytotoxicity assays did not correlate with their photophysical characterisation. PS4 was significantly less potent than PPa and PS1 on SKOV3 and KB human cancer cell lines. Confocal microscopy aided further characterisation using stains for intracellular organelles. PS1 was found to localise primarily in the ER and Golgi apparatus, similarly to PPa, while PS4 was found to localise mainly in the lysosomes. PS1 was conjugated to C6.5(-k), an anti-HER2 single chain variable fragment (scFv) using lysine coupling, to obtain a photoimmunoconjugate that was characterised in vitro and subsequently in vivo. In vitro characterisation showed increased potency and specificity but non-specific cell death attributed to the non-covalently bound photosensitiser was observed. However, in vivo therapy studies showed that the C6.5(-k)-PS1 photoimmunoconjugate could be used to cure SKOV3 subcutaneous tumours in nude mice, validating the use of targeted PDT as a successful targeted therapy with the potential to lower the effective drug dose and minimise side effects.

Optical imaging is an emerging field of clinical diagnostics that can address the growing medical need for early cancer detection and diagnosis. Various human cancers are amenable to better prognosis and patient survival if found and treated during early disease onset. Besides providing wide-field, macroscopic diagnostic information similar to existing clinical imaging techniques, optical imaging modalities have the added advantage of microscopic, high resolution cellular-level imaging from in vivo tissues in real time. This comprehensive imaging approach to cancer detection and the possibility of performing an ‘optical biopsy’ without tissue removal has led to growing interest in the field with numerous techniques under investigation. Three optical techniques are discussed in this thesis, namely multispectral fluorescence imaging (MFI), hyperspectral reflectance imaging (HRI) and fluorescence confocal endomicroscopy (FCE). MFI and HRI are novel endoscopic imaging-based extensions of single point detection techniques, such as laser induced fluorescence spectroscopy and diffuse reflectance spectroscopy. This results in the acquisition of spectral data in an intuitive imaging format that allows for quantitative evaluation of tissue disease states. We demonstrate MFI and HRI on fluorophores, tissue phantoms and ex vivo tissues and present the results as an RGB colour image for more intuitive assessment. This follows dimensionality reduction of the acquired spectral data with a fixed-reference isomap diagnostic algorithm to extract only the most meaningful data parameters. FCE is a probe-based point imaging technique offering confocal detection in vivo with almost histology-grade images. We perform FCE imaging on chemotherapy-treated in vitro human ovarian cancer cells, ex vivo human cancer tissues and photosensitiser-treated in vivo murine tumours to show the enhanced detection capabilities of the technique. Finally, the three modalities are applied in combination to demonstrate an optical viewfinder approach as a possible minimally-invasive imaging method for early cancer detection and diagnosis.

In this work, different techniques for the automated extraction of biomarkers for Alzheimer's disease (AD) from brain magnetic resonance imaging (MRI) are proposed. The described work forms part of PredictAD (www.predictad.eu), a joined European research project aiming at the identification of a unified biomarker for AD combining different clinical and imaging measurements. Two different approaches are followed in this thesis towards the extraction of MRI-based biomarkers: (I) the extraction of traditional morphological biomarkers based on neuronatomical structures and (II) the extraction of data-driven biomarkers applying machine-learning techniques. A novel method for a unified and automated estimation of structural volumes and volume changes is proposed. Furthermore, a new technique that allows the low-dimensional representation of a high-dimensional image population for data analysis and visualization is described. All presented methods are evaluated on images from the Alzheimer's Disease Neuroimaging Initiative (ADNI), providing a large and diverse clinical database. A rigorous evaluation of the power of all identified biomarkers to discriminate between clinical subject groups is presented. In addition, the agreement of automatically derived volumes with reference labels as well as the power of the proposed method to measure changes in a subject's atrophy rate are assessed. The proposed methods compare favorably to state-of-the art techniques in neuroimaging in terms of accuracy, robustness and run-time.

This thesis focuses on the requirement for new methodologies to incorporate 11C into biologically active compounds for Positron Emission Tomography (PET). The use of PET has expanded over recent years as a valuable imaging technique for the study of drug delivery as well as the study of neurological diseases and oncology. The short half-life of 11C (20.4 min) limits its use to approximately 1 hour therefore rapid chemistry is required to radiolabel tracer molecules before use in vivo. Chapter 1 includes an overview of the literature in the areas of PET radiochemistry, transition metal-catalysed carbonylation, N-heterocyclic carbenes, hemilabile ligands, titanium and zirconium imido complexes and nickel-/palladium-catalysed carboxylations. Chapters 2 and 3 detail the investigations of a palladium-catalysed carbonylation reaction for the formation of amides commonly found in biologically active compounds. N-benzylbenzamide was synthesised in a model reaction which tested a range of diphosphine ligands and N-heterocyclic carbenes. The best performing systems were taken forward to be tested with [11C]CO in the radiochemistry laboratories at the GSK Clinical Imaging Centre at Hammersmith Hospital with excellent radiochemical purities of [11C]N-benzylbenzamide (99 %) and good radiochemical yields (55 %). Hemilabile phosphorus-thioether (P-S) and phosphorus-ether (P-O) bidentate ligands were also investigated in the synthesis of N-benzylbenzamide and compared to diphosphine ligands in this reaction and new palladium catalysts were prepared with novel P-S ligands. [11C]CO2 was examined as a potentially useful source of [11C] for radiolabelling as research into transition metal-mediated processes to activate CO2 for environmental reasons has grown in recent years. Chapter 4 investigates some recent literature detailing nickel- and palladium-catalysed carboxylation of organozinc halides in the synthesis of carboxylic acids. Titanium and zirconium imido complexes were synthesised with the intention of forming [11C]isocyanate precursors - this work is described in Chapter 5. A range of work has been carried out and potential future studies in all these areas are specified at the end of the thesis.