Heart failure remains a significant cause of morbidity and mortality despite the introduction of new medication. Over the last 10 years attention has focused on improving the mechanical action of the heart using biventricular pacemakers to retime hearts that are thought to be dyssynchronous. Cardiac resynchronisation therapy (CRT) has now been shown to improve morbidity and mortality in a selected population although up to 30% of patients fail to respond. Attention is now focused on improving outcomes in the 'non responders', optimising patient selection and potentially extending the number of patients who might benefit from CRT. Echocardiography may improve patient selection but results have been variable. This thesis attempts to assess the reproducibility of echocardiographic measures of dyssynchrony to see if current tools are fit for purpose. The dual chamber pacemaker population are potentially a group that may benefit from CRT. This thesis will assess the prevalence of dyssynchrony in the normal and dual chamber paced population both at rest and during increased heart rate to ascertain if dyssynchrony is a significant underlying problem. CRT attempts to retime the heart using up to 3 pacemaker leads. It is possible to alter timing of individual lead depolarisation so as to optimise the heart. This thesis compares three tools used for optimisation; echocardiography, thoracic impedance and beat to beat blood pressure (BP), focussing on their reproducibility during optimisation. The thesis examines whether optimisation in the BIV population changes from rest to stress as this may explain the failure of response to CRT in some patients. The thesis concludes that current echocardiographic measures of dyssynchrony, including tissue Doppler imaging, are poorly reproducible and they should not be used for CRT selection. Thoracic impedance appears to be a reliable tool that could be used for CRT optimisation and its simplicity may allow optimisation to be extended to a larger group of individuals. Echocardiography using continuous wave Doppler remains a useful tool for optimisation but pulsed wave Doppler should not be used. Optimisation appears to change significantly from rest to exercise within individuals and further work is needed to discover if this can improve patient outcomes.

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The effect of photodynamic therapy (PDT) on neural cells is important when tumours are adjacent to or within the nervous system. The primary purpose of this study was to investigate PDT treatments using the photosensitiser meta-(tetrahydroxyphenyl) chlorin (m-THPC) on cells of the peripheral nervous system. There is evidence that, during clinical PDT-treatment of tumour sites near important nerve structures, peripheral neural cells respond differently to m-THPC-mediated PDT than do tumour cells. In this study, the response to PDT-treatment of rat dorsal root ganglia (DRG) neurones co-cultured with satellite cells were compared with separately cultured human breast adenocarcinoma cell line (MCF-7) in innovative in vitro culture systems. Epi-fluorescence microscopy confirmed that m-THPC was incorporated into all cell types, excluding photosensitiser uptake as a reason for differences in the response to m-THPC-mediated PDT in vitro. Sensitivity of cells exposed to mTHPC- mediated PDT (0-10 ~g/ml m-THPC with 1 J/cm2 white light) was determined in a 1 mm thin bespoke 3-dimensional (3D) collagen hydrogel culture system. Cell death was quantified using propidium iodide (PI) exclusion and DRG neurones were identified in co-culture using immunocytochemistry for ~III-tubulin. MCF-7 cells, DRG satellite cells and astrocytes (of the central nervous system) were significantly more sensitive to m-THPC-mediated PDT treatments than were DRG neurones. Importantly, the dose of interest, 4 f.lg/ml m-THPC-mediated PDT, caused no significant DRG neurone death in comparison with untreated controls, but was sufficient to elicit substantial cell death in the other cell types The cell death protocol was validated using a second photosensitiser, hypericin (0-3~g/ml with 1 J/cm2 white light), which caused substantial DRG neurone death equivalent to other cell types studiedFollowing m-THPC-mediated PDT treatments, ORG neurones displayed a loss of their neurites. An assessment of the ability of these cells to regenerate neurites after m-THPC-mediated PDT treatments was performed and neurite extension was found to be equivalent to that in untreated controls, demonstrating that the treated ORG neurones were viable and retained their neurite projecting function. Inhibiting specific cell antioxidant pathways gave an insight into the mechanism by which neurones survived m-THPC-mediated PDT. The results suggested that ORG neurones were protected from the phototoxic effects of m-THPC-mediated PDT by superoxide dismutase-1 (500-1) and the glutathione synthase antioxidant pathways. DRG neurones used in this study survived m-THPC-mediated PDT under conditions sufficient to kill tumour cells and other nervous system cells. Identifying and understanding this phenomenon could provide the basis for developing PDT treatments that reduce nerve damage during cancer therapy. The question of whether m-THPC-mediated PDT has different effects on ORG neurone survival and/or function depending on which part of the cell is illuminated is of particular interest. Preliminary experiments are described in which 20 and 3D tissue engineered nerve cultures were developed and assessed for use in evaluating focally applied m-THPC-mediated PDT treatment to different parts of DRG neurones. These peripheral nerve culture systems have controllable cellular environments that make them attractive experimental tools for further investigations into the effect of PDT on peripheral nerves

The aim of the work reported in this thesis was to investigate the possibility of measuring human retinal oxygen saturation using hyperspectral imaging. A direct non-invasive quantitative mapping of retinal oxygen saturation is enabled by hyperspectral imaging whereby the absorption spectra of oxygenated and deoxygenated haemoglobin are recorded and analysed. Implementation of spectral retinal imaging thus requires ophthalmic instrumentation capable of efficiently recording the requisite spectral data cube. For this purpose, a spectral retinal imager was developed for the first time by integrating a liquid crystal tuneable filter into the illumination system of a conventional fundus camera to enable the recording of narrow-band spectral images in time sequence from 400nm to 700nm. Postprocessing algorithms were developed to enable accurate exploitation of spectral retinal images and overcome the confounding problems associated with this technique due to the erratic eye motion and illumination variation. Several algorithms were developed to provide semi-quantitative and quantitative oxygen saturation measurements. Accurate quantitative measurements necessitated an optical model of light propagation into the retina that takes into account the absorption and scattering of light by red blood cells. To validate the oxygen saturation measurements and algorithms, a model eye was constructed and measurements were compared with gold-standard measurements obtained by a Co-Oximeter. The accuracy of the oxygen saturation measurements was (3.31%± 2.19) for oxygenated blood samples. Clinical trials from healthy and diseased subjects were analysed and oxygen saturation measurements were compared to establish a merit of certain retinal diseases. Oxygen saturation measurements were in agreement with clinician expectations in both veins (48%±9) and arteries (96%±5). We also present in this thesis the development of novel clinical instrument based on IRIS to perform retinal oximetry.

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.

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