The 19 channel Neuromagnetometer system in the Clinical Neurophysiology Unit at Aston University is a multi-channel system, unique in the United Kingdom. A bite bar head localisation and MRI co-registration strategy which enabled accurate and reproducible localisation of MEG data into cortical space was developed. This afforded the opportunity to study magnetic fields of the human cortex generated by stimulation of peripheral nerve, by stimulation of visceral sensory receptors and by those evoked through voluntary finger movement. Initially, a study of sensory-motor evoked data was performed in a healthy control population. The techniques developed were then applied to patients who were to undergo neurosurgical intervention for the treatment of epilepsy and I or space occupying lesions. This enabled both validation of the effective accuracy of source localisation using MEG as well as to determine the clinical value of MEG in presurgical assessment of functional localisation in human cortex. The studies in this thesis have demonstrated that MEG can repeatedly and reliably locate sources contained within a single gyrus and thus potentially differentiate between disparate gyral activation. This ability is critical in the clinical application of any functional imaging technique; which is yet to be fully validated by any other 'non-invasive' functional imaging methodology. The technique was also applied to the study of visceral sensory representation in the cortex which yielded important data about the multiple cortical representation of visceral sensory function.

Bio-impedance analysis (BIA) provides a rapid, non-invasive technique for body composition estimation. BIA offers a convenient alternative to standard techniques such as MRI, CT scan or DEXA scan for selected types of body composition analysis. The accuracy of BIA is limited because it is an indirect method of composition analysis. It relies on linear relationships between measured impedance and morphological parameters such as height and weight to derive estimates. To overcome these underlying limitations of BIA, a multi-frequency segmental bio-impedance device was constructed through a series of iterative enhancements and improvements of existing BIA instrumentation. Key features of the design included an easy to construct current-source and compact PCB design. The final device was trialled with 22 human volunteers and measured impedance was compared against body composition estimates obtained by DEXA scan. This enabled the development of newer techniques to make BIA predictions. To add a ‘visual aspect’ to BIA, volunteers were scanned in 3D using an inexpensive scattered light gadget (Xbox Kinect controller) and 3D volumes of their limbs were compared with BIA measurements to further improve BIA predictions. A three-stage digital filtering scheme was also implemented to enable extraction of heart-rate data from recorded bio-electrical signals. Additionally modifications have been introduced to measure change in bio-impedance with motion, this could be adapted to further improve accuracy and veracity for limb composition analysis. The findings in this thesis aim to give new direction to the prediction of body composition using BIA. The design development and refinement applied to BIA in this research programme suggest new opportunities to enhance the accuracy and clinical utility of BIA for the prediction of body composition analysis. In particular, the use of bio-impedance to predict limb volumes which would provide an additional metric for body composition measurement and help distinguish between fat and muscle content.

Respiratory motion of the heart limits the utility of image-guided cardiac interventions, causing misalignments between the pre-procedure information used for guidance and the intra-procedure moving anatomy and instruments. As a result, the guidance can be misleading, compromising the accuracy and success of the intervention. Respiratory motion models have been proposed to estimate and correct for respiratory motion, but to date their clinical uptake has been very limited due to a lack of accuracy and robustness, and the interruptions that they typically introduce into the clinical work flow. The scope of this project was to devise methods to address these limitations and foster the clinical translation of respiratory motion models. A novel Bayesian respiratory motion model was developed in the first part of the project. The Bayesian framework enables the combination of the robustness of a pre-procedure motion model derived from Magnetic Resonance Imaging with the intraprocedure information provided by 3D echography (echo) images. The main novelties of the approach lie in its probabilistic formulation and its ability to adapt to variable breathing patterns. The Bayesian motion model was further evaluated using live 2D echo images, proving to be accurate using both 2D and 3D echo images. Furthermore, a new motion model-driven echo acquisition framework was developed to acquire 2D echo images that automatically compensates for respiratory motion. The second part of the project addressed the limitations associated with the dynamic calibration scan used to derive the motion model, the acquisition of which causes interruptions to the clinical work flow. A personalisation framework for population based motion models that uses anatomical features to predict cardiac respiratory motion was developed. Results show an average value for the 50th and 95th quantiles of the estimation error of 1:6mm and 4:7mm respectively, without the need for a subject-specific dynamic calibration scan. Finally, the above mentioned parts were combined to produce a personalised Bayesian motion model. The technique is accurate and does not significantly complicate the clinical workflow, thus making it suitable for clinical uptake.

Myocardial perfusion SPECT imaging is a sensitive and specific indicator of coronary artery disease (Fleischman et al. 1998). The clinical value of coronary scintigraphy is now established with a utilisation rate of eight procedures per 1000 population per year in the USA and two per 1000 in the EU (Pennell et al. 1998). While myocardial perfusion SPECT images are routinely interpreted by expert observers the classification is inevitably subject to inter-observer and intra-observer variability. An optimised and validated quantitative index of the presence or absence of coronary artery disease (CAD) could improve reproducibility, accuracy and diagnostic confidence. There are segmental techniques to automatically detect CAD from myocardial perfusion SPECT studies such as the CEqual quantitative analysis software (Van Train et al. 1994). However, they have not been shown to be significantly better than expert observers (Berman et al. 1998). The overall aim of this thesis was to develop, optimise and evaluate quantitative techniques for the detection of CAD in myocardial perfusion SPECT studies. This task was divided into three areas; quantification of transient ischaemic dilation (TID); quantitative detection and localisation of CAD; count normalisation of patient studies. Transient ischaemic dilation (TED) is the transient dilation of the left ventricle on immediate post stress images compared to resting technetium-99m imaging. Stolzenberg (1980) first noted TID as a specific marker for severe CAD. There are few published studies of fully quantitative evaluations of TID. The first aim of this thesis was to compare the performance of methods for quantifying TDD in myocardial perfusion SPECT. The second aim of this thesis was to investigate the use of image registration in myocardial perfusion SPECT for quantitative detection and localisation of CAD. This thesis describes two studies comparing six count normalisation techniques. These techniques were; normalise to the maximum value; to the mean voxel value; to the mean of the top 10% or 20% of counts; minimise the sum of squares between studies or the sum of absolute differences. Ten normal myocardial perfusion SPECT studies each with 300 different simulated perfusion defects were count normalised to the original studies. The fractional count normalisation error was consistently lower when the sum of absolute differences was minimised. However, a more clinically applicable measure of count normalisation performance is the effect on quantitative CAD detection. The Z-score method of automatic detection of CAD was repeated using each count normalisation technique. There was no statistically significant difference between the methods although the power of the ROC analysis was poor due to low patient numbers. The balance of evidence suggested that count normalisation by minimisation of the of absolute differences produced the best performance.

Functional electrical stimulation (FES) is the controlled use of electrical pulses to produce contraction of muscles in such a way as to support functional movement. FES is now widely used to aid walking in stroke patients and research into using FES to support other tasks is growing. However, in the more complex applications, it is very challenging to achieve satisfactory levels of FES control. The overall aim of the author’s PhD thesis is to develop improved techniques for real-time Finite State Machine (FSM) control of upper limb FES, using multiple accelerometers for tracking upper limb movement and triggering state transitions. Specific achievements include: 1) Development of new methods for using accelerometers to capture body segment angle during performance of an upper limb task and use of that data to trigger state transitions (angle triggering); 2) Development of new methods to improve the robustness of angle triggering; 3) Development of a flexible finite state-machine controller for control of upper limb FES in real time; 4) In collaboration with a clinical PhD student, implementation of a graphical user interface (GUI) that allows clinical users (e.g. physiotherapists) to set up FSM controllers for FES-assisted upper limb functional tasks. Three alternative methods that use 3-axis accelerometer data to track body segment angle with respect to gravity have been reported. The first uncalibrated method calculates the change in angle during a rotation using the gravity vectors before and after the rotation. The second uncalibrated method calculates the angle between the accelerometer x-axis and the gravity vector. The third calibrated method uses a calibration rotation to define the measurement plane and the positive rotation direction. This method then calculates the component of rotation that is in the same plane as the calibration rotation. All three methods use an algorithm that switches between using sine and cosine, depending on the measured angle, which overcomes the poor sensitivity problem seen in previous methods. xviii A number of methods can be included in the transition triggering algorithm to improve robustness and hence the usability of the system. The aim of such methods is to reduce the number of incorrect transition timings caused by signal noise, jerky arm movements and other negative effects, which lead to poor control of FES during reaching tasks. Those methods are: 1) Using the change in angle since entering a state rather than absolute angle; 2) Ignoring readings where the acceleration vector is significant in comparison to the gravity vector (i.e. the magnitude of the measured vector is significantly different from 9.81); and 3) Requiring a given number of consecutive or non-consecutive valid readings before triggering a transition. These have been implemented with the second uncalibrated angle tracking method and incorporated into a flexible FSM controller. The flexible FSM controller and the associated setup software are also presented in this thesis, for control of electrical stimulation to support upper limb functional task practice. In order to achieve varied functional task practice across a range of patients, the user should be able to set up a variety of different state machines, corresponding to different functional tasks, tailored to the individual patient. The goal of the work is to design a FSM controller and produce an interface that clinicians (even potentially patients) can use to design and set up their own task and patient-specific FSMs. The software has been implemented in the Matlab-Simulink environment, using the Hasomed RehaStim stimulator and Xsens MTx inertial sensors. The full system has been tested with stroke patients practicing a range of tasks in the laboratory environment, demonstrating the potential for further exploitation of the work.

The cross-sensitivity of microcantilever sensors presents a major obstacle in the development of a commercially viable microcantilever biosensor for point of care testing. This thesis concerns electrothermally actuated bi-material microcantilevers with piezoresistive read out, developed for use as a blood coagulometer. Thermal properties of the sensor environment including the heat capacity and thermal conductivity affect the ‘thermal profile’ onto which the higher frequency mechanical signal is superimposed. In addition, polymer microcantilevers are known to have cross-sensitivity to relative humidity due to moisture absorption in the beam. However it is not known whether any of these cross sensitivities have a significant impact on performance of the sensor during pulsed mode operation or following immersion into liquid. When analysing patient blood samples, any change in signal that is not caused by the change in blood viscosity during clotting could lead to a false result and consequently an incorrect dose of anticoagulants may be taken by the patient. In order to address these issues three aspects of the operation of polymer bi-material strip cantilevers has been researched and investigated: relative humidity; viscosity/density, and thermal conductivity of a liquid environment. The relative humidity was not found to affect the resonant frequency of a microcantilever operated in air, or to affect the ability of the cantilever to measure clot times. However, a decrease in deflection with increasing relative humidity of the SmartStrip microcantilever beams is observed at 1.1 ± 0.4 μm per 1% RH, and is constant with temperature over the range 10 – 37 °C, which is an issue that should be considered in quality control. In this study, the SmartStrip was shown to have viscosity sensitivity of 2 cP within the range 0.7 – 15.2 cP, and it was also shown that the influence of inertial effects is negligible in comparison to the viscosity. To investigate cross-sensitivity to the thermal properties of the environment, the first demonstration of a cantilever designed specifically to observe the thermal background is presented. Characterisation experiments showed that the piezoresistive component of the signal was minimised to -0.8% ± 0.2% of the total signal by repositioning the read out tracks onto the neutral axis of the beam. Characterisations of the signal in a range of silicone oils with different thermal conductivities gave a resolution to thermal conductivity of 0.3 Wm-1K-1 and resulted in a suggestion for design improvements in the sensor: the time taken for the thermal background signal to reach a maximum can be increased by increasing the distance between the heater and sensor, thus lessening the impact of the thermal crosstalk within the cantilever beam. A preliminary investigation into thermal properties of clotting blood plasma showed that the sensor can distinguish the change between fresh and clotted plasma.

Brain-computer interfaces (BCI) are devices that allow for the brain to communicate information to a computer. In situations where a victim of brain trauma or disease has suffered damage causing paralysis or impaired movement, BCIs may be the answer in providing assistance to neurological function. Development of BCIs continues to increase, but literature suggests the next step is the hybrid brain computer interface (hBCI). The simplified concept behind the hBCI is by having two BCIs, in which both signals can be detected simultaneously, creates the situation that if one BCI is to fail to show user intent the other may succeed. Using a non-invasive method such as surface electroencephalogram (sEEG), able to detect signals from brain activity, this pilot study will look into the development of a hBCI combining the modalities of event-related de-synchronisation (ERS) and steady-state visual evoked potentials (SSVEP). The aim of this project is to show the hBCI proposed works, to find where improvements can be made and to identify the synergies of SSVEP and ERD modalities. A duel task experiment was performed on 4 healthy subject, ages 22-35, in which they must look at a flickering LED and move their wrist in the direction corresponding to that LED. Four LEDs are setup about a point, providing intuitive directions for wrist movement, and only one will flicker at any time. Results show that the SSVEP and ERD hBCI can work, but there may be limitations. The main limitation suggested by the results have also been found in other literature and is known as 'dual-task interference'. The cause of dual-task interference hasn't been well documented and only suggested or speculated so far. Future experiments should validate the cause of this dual-task interference in hBCIs.

This work was motivated initially by the desire to develop fully bioresorbable bone plates for fracture fixation applications, in order to meet a clinical need. The purpose of the development is to avoid medical complications related to rigid, non-resorbable metallic bone plates. Phosphate based glass fibre reinforced poly-lactic acid (PGF/PLA) composites containing fully biodegradable and biocompatible constituents can be an effective alternative to metallic bone plates. Appropriate design and manufacture of the PGF IPLA composite bone plates is crucial to ensure that the required mechanical and degradation properties are achieved for the support of bone healing. Rather than considering simply the material propelties of the PGF/PLA composites, it is necessary to take into account all the factors relating to surgical use: constrained plate dimensions, bone topography and contact area, fixation method, sterilisation method, local environment and overall nature of the loading case. Each of these factors will have a profound effect on the design of the composite. In this PhD, studies have been undertaken to develop and produce a PGF/PLA composite bone plate that can fulfil the requirements of a specific application. The composite plates were prepared by using an optimal combination of unidirectional and random fibre reinforcement, before being trimmed and drilled into a desired final geometry. To validate the composite design, mechanical and degradation properties, in vitro mechanical and biomechanical testing were combined with preclinical in vivo testing using an intact rabbit tibia bone model.

The main aim of this project was to assess auxetic (negative Poisson's ratio) materials for potential in biomedical devices. Specifically, a detailed comparative indentation study has been undertaken on auxetic and conventional foams for hip protector devices; radially-gradient one-piece foams having auxetic character have been produced for the first time and shown to have potential in artificial intervertebral disc (IVD) implant devices; and auxetic honeycomb geometries have been assessed for the stem component in hip implant devices. For the hip protector application, combined compression and heat treatment of conventional polyurethane open-cell foam was used to produce monolithic auxetic foams. The foams were characterised structurally using optical microscopy, and mechanically using mechanical testing combined with videoextensometry. Static indentation using six different indenter shapes on each of the six faces of the foam specimens has been undertaken. The key conclusion here is that the enhanced indentation resistance for the converted foam is not a consequence of increased density accompanied by the usual significant increase in foam stiffness. The enhanced indentation resistance is consistent with the auxetic effect associated with the increased density, providing a localised densification mechanism under indentation (i.e. material flows under the indenter). At higher indentation displacement the Poisson’s ratios for both the unconverted and converted foams tend towards zero. In this case, the increase in foam stiffness for the converted foams at higher strain may also contribute to the indentation enhancement at high indentation displacement. New radially-gradient foams mimicking the core-sheath structure of the natural IVD have been produced through the development of a novel thermo-mechanical manufacturing route. Foam microstructural characterisation has been undertaken using optical and scanning electron microscopy, and also micro-CT scans performed by collaborators at the University of Manchester. Detailed x-y strain mapping using combined mechanical testing and videoextensometry enabled the local and global Young's modulus and Poisson's ratio responses of these new materials to be determined. In one example, global auxetic response is achieved in a foam having a positive Poisson's ratio core and auxetic sheath. It is suggested this may be a more realistic representation of the properties of natural IVD tissue. Analytical and Finite Element (FE) models have been developed to design honeycomb geometries for the stems in new total hip replacement implants. FE models of the devices implanted within bone have been developed and the auxetic stems shown to lead to reduced stress shielding effect.

The focus of this thesis was to develop new highly porous (>90% porosity) Bioglass®-based glass-ceramic scaffolds (fabricated by the foam replica method) in order to enhance the scaffold cellular response and biological performance and to improve the scaffold suitability for future clinical applications by adding new functions. In the first part of the project, techniques were developed to introduce or engineer nanoscale topography on the surfaces of 3D scaffolds, these included: i) carbon nanotube (CNT) coating (by electrophoretic deposition), ii) polymer demixing and iii) water treatment. In the second part of the project, aiming at further improving the functionality of scaffolds, a system with drug delivery capability was developed. To this aim, multi-functional poly(3-hydroxybutryate) microsphere (PMS) coated Bioglass®-based composite scaffolds were fabricated and characterised. Tetracycline-encapsulated PMSs (< 2 μm in diameter) were made using a solid-in-oil-in-water emulsion solvent extraction/evaporation technique. The scaffolds were coated with PMSs by slurry-dipping, producing a uniform PMS coating throughout the 3D structure. By studying tetracycline release kinetics, it was found that the drug release from the coated scaffolds was slow and controlled.