Cortical bone is a natural composite, heterogeneous material with a complex hierarchical microstructure. The description of this microstructure in terms of the mechanical properties of cortical bone may be important in the understanding of periprosthetic stress concentrations. Micropolar elasticity is a higher order continuum theory which may more effectively describe the influence of the microstructure in cortical bone on its mechanical behaviour. Micropolar elasticity predicts a size effect in three-point bending, which has been investigated computationally and experimentally on bovine mid-diaphyseal cortical bone. Computational models of an idealised heterogeneous material, with vascular canal-like structures running along the length of the beam, demonstrated a size effect in the longitudinal and transverse directions which was dependent on the surface condition of the beam. Idealised models with smooth surface layers increased in stiffness as specimens decreased in size, whilst idealised model beams intersected by the internal microstructure demonstrated an equally strong, yet opposite, effect. These FE size effects were further corroborated by analytical studies which demonstrated similar size effects. Experimental three-point bending studies of bovine cortical bone specimens orientated both longitudinally and transversely were consistent with the equivalent numerical models where the internal microstructure intersected the surface. These results suggest the micropolar characteristic length in bending is of the order of the size of the Haversian canal system in secondary osteons and the vascular channels in plexiform cortical bone. The ramifications of this are that the microstructure of cortical bone is of fundamental importance in understanding size effects and stress concentrations in the material. This finding is important in understanding and developing the design and longevity of prosthetic devices and in being able to improve the interaction between an implant and the surrounding cortical bone.

Complex networks are an important tool for the study of biological data. There are two main aims in this data-driven work, which are explored in tandem. We study (1) the nature of schizophrenia and (2) utility in novel additions to traditional network based spectral clustering methods. More specifcally, we explore three facets of schizophrenia. First, we study functional brain data in animal models of relevance to the condition. Second, we examine the impact of antipsychotic medication on gene expression in humans, and third we assess whole blood for potential as a suitable alternative to brain tissue. With regard to spectral clustering, we employ the Singular Value Decomposition and the Generalized Singular Value Decomposition in a way that allows us to incorporate additional information into the clustering problem. This work is of interest in the life sciences due to the complex heterogeneous nature of schizophrenia, which has created desire for analysis of large amounts of data. In addition, development of network based approaches is a timely area of study in general given recent explosions in the amount of data produced across many subject areas. Our interdisciplinary work leads to four main conclusions: (a) network approaches for functional brain animal model studies can produce results that are biologically meaningful in humans, (b) a novel node-weighted version of the Laplacian is a flexible tool that allows multiple sources of network information to be combined, (c) antipsychotic medication, used routinely to treat schizophrenia, has a dominant effect on gene expression as compared to the control state, masking the underlying nature of the disease and (d) human whole blood is useful for the study of gene expression in schizophrenia.

Diabetic foot ulceration is a global health problem that often leads to amputation. While peripheral vascular disease and neuropathy are common risk factors for foot ulcers, excessive mechanical stress would directly cause the breakdown of plantar tissue. Once the skin is broken, many factors may contribute to defective healing and putting one at greater risk for ulceration. Clinical measurement of plantar pressure distribution, therefore, is commonly used to identify feet at risk of ulceration. However, plantar pressures are poor predictors and there is evidence that shear load is at least equally important in ulcer development. Compared to the numerous commercial systems available for plantar pressure distribution measurement, only a few experimental devices exist for shear distribution measurement. These are typically either too large for high spatial resolution measurement or expensive to manufacture, limiting their suitability for routine clinical use. The aim of this study was to develop a low-cost multi-axial load transducer array to measure the distribution of stress beneath the human foot during walking. A preexisting piezoelectric-based load transducer and several novel transducer designs using hydraulic, optoelectronic and magnetic-based technologies were manufactured and their performance relative to 29 criteria evaluated. The magnetic-based design was found to possess the highest performance (accuracy <3%RC, hysteresis <4%RC, non-linearity <2%RC) and physical characteristics (sensing area 10x10mm). Subsequently, an array consisting of 20 discrete magnetic-based transducers was constructed. In a single subject trial, the total shear load measured by the array was <2N of that measured by a Kistler® force platform. Although the array was capable of measuring biaxial shear load distribution, further work is required to expand the current design to measure load distribution beneath the entire plantar surface. Once realised, such a system has the potential to provide valuable biomechanical data that may help clinicians identify diabetic feet at risk of ulceration.

Lower back pain places an enormous economic burden on society and health authorities as it affects up to 80% of the population and has been attributed to intervertebral disc injury as well as the degenerative adaptations which occur with advancing age. Much of our understanding of disc mechanics comes from mathematical and finite element models; however, there is a lack of empirical data which is required for model validation. Additionally, the influence of mechano-electrochemical phenomena on fundamental mechanical properties such as permeability and Poisson's ratio is still not fully understood. Therefore, this thesis aimed to investigate the influence of such phenomena on disc mechanics whilst providing a comparison between multiphasic FE models and experimental data. Direct permeation experiments found that fluid velocity may be augmented through the nucleus pulposus via ionic osmotic pressure gradients which consist of fixed charge, mobile ion and electrical potential gradient s. A novel method to fully characterise, for the first time, the Poisson's ratio of the disc was developed. Poisson's ratio of the nucleus pulposus was found to be strain dependent and lower than previously thought, whilst solid matrix viscoelasticity may influence disc mechanics at high strain-rates. Confined compression experiments on the degenerate human nucleus pulposus found that the solid matrix bears the majority of load under axial compression due to the depletion of proteoglycans and the consequential reduction in mechano-electrochemical effects in this tissue. Poor agreement with biphasic theory may provide evidence of the degenerate nucleus pulposus exhibiting a heterogeneous structure and a dual permeability phase. Multiphasic models were developed and compared to experimental data. Differences were found between biphasic and triphasic models which resulted in varying agreement with experimental data thus the correct selection of numerical framework was found crucial when investigating disc mechanics. The data presented in this thesis are important for informing our overall understanding of disc mechanics, aiding the development future models as well as providing a benchmark for potential replacement materials to be critiqued against, particularly in terms of permeability and fluid pressurisation which are crucial to the load bearing capacity of the tissue.

Artificial turf is increasingly becoming prevalent in field sports traditionally played on natural grass surfaces. However, current artificial turf test methods are not biomechanically representative. This study investigated the interaction between players and sports surfaces in order to develop a new biomechanically valid testing rig for the mechanical characterisation of artificial turf. A biomechanical analysis of thirteen sports players performing five running and turning movements on three types of artificial turf was conducted. Three-dimensional ground loadings (ground reaction forces (GRFs), free moment) and knee biomechanics (angles, moments) were measured. A subset of eight subjects who completed trials on all three tyes of surfaces were included in statistical analyses. There were no significant differences in ground loadings or knee biomechanics between the turfs. However, ground loadings and knee biomechanics varied significantly between movements, according to movemen t velocity and the degree of turn. Larger vertical GRFs, peak knee flexion, and sagittal knee moments were measured in faster movements. Larger horizontal GRFs, free moment, traction coefficient, peak fontal knee angle, frontal and transverse knee moment were measured in turning movements. Using two weighted pendulums, the Strathclyde Sports Turf Testing Rig (SSTTR) can apply simultaneous vertical, horizontal and rotational loads. Initial testing of the rig was conducted in situ on nine outdoor artificial turfs. Linear and rotational traction, and vertical, shear and torque loading was measured on each surface and compared with the biomechanical results. The SSTTR produced loads typical of a range of sports movement that are performed on artificial turf, indicating that the biomechanical validity of the SSTTR was broadly demonstrated in that it applies realistic biomechanical loads in a timely fashion. In summary, this study has generated new knowledge and further understanding regarding the three-dimensional biomechanical interaction of players and artificial turf. The biomechanically validated SSTTR is unique in terms of its ability to combine three load actions of different magnitudes which are truly representative of the loading that occur in a number of typical sporting movements.

Aging and disease processes are known to compromise tissue strength and consequently increase the risk of harmful movement or detachment of a heart valve prosthesis in vivo when exposed to strong magnetic forces associated with magnetic resonance imaging (MRI). Research however, has failed to fully assess prosthetic valve movement or functional valve impedance in the MR environment. This study seeks to design and evaluate an MR compatible device which aims to detect and measure ex vivo, frequency, direction and magnitude of movements and leaflet function in vitro of nine prosthetic heart valves in the static magnetic field (B0) of a 1.5 Tesla (T) and a 3.0 T MR system. A valve holder incorporating strain gauges connected to a strain gauge recorder and laptop computer were used to detect and record displacement and rotational valve movements and, a hydro-pneumatic system recorded pressure changes across the valve indicative of any MR induced alteration in leaflet performance in vitro. The data confirms the compatibility of the test apparatus in the MR environment and its capacity to detect and record valve movement and changes in functional valve performance in field strengths =3.0 T. Real-time three-dimensional movements were detected in both B0 fields in all valves, differences in entry and return profiles and static and dynamic measurements were recorded. Furthermore, applied magnetic forces leading to prosthesis movement were greater than previously reported. Functional valve impedance was detected in three valves but no commonality between valve types or sub-groups regarding this, type, frequency, magnitude or patterns of valve movements were noted. These data suggests magnetism is induced and retained in valve prostheses during exposure to the MR environment and patients with friable valvular tissue are at significantly increased risk of prosthetic valve movement and/or dehiscence. Furthermore, current uses of static measurements to assess risk are inadequate.

The motor-related electroencephalographic (EEG) activity pattern in humans during motor behaviour is of interest to provide insight into normal motor control processes and for development of brain-computer interfaces (BCI), brain stimulation and rehabilitation systems. While the patterns preceding brisk voluntary movements, and especially movement execution, are well described, there are few EEG studies that address the cortical activation patterns seen in isometric exertions, and their planning. Furthermore, the effect of exertion direction on EEG signatures needs investigation. This study explores and reports on the time and time-frequency surface EEG signatures in isometric task experiments in normal subjects (n=8). Multichannel EEG is recorded during motor preparation, planning and execution of directional centre-out arm isometric exertions performed at the wrist in the horizontal plane, in response to instruction-delay visual cues. The directional information of surface EEG and modulation of EEG signatures by cue direction are investigated by statistical measures and linear classifiers. The observations suggest that isometric force exertion is accompanied by transient and sustained forms of event-related potentials (ERP) and event-related (de-)synchronisations (ERD/ERS), comparable to those of a movement task. Furthermore, the ERP and ERD/ERS are observed not only during execution, but also during preparation and planning of the isometric task. Transient synchronisation in 2-7 Hz frequency band and both transient and sustained desynchronisation in a (u) and β frequency bands were observed. Low-γ ERD is observed in all areas, except over the parietal region where ERS is seen. While ERP and ERD/ERS are not consistently modulated by task direction, the direction of exertion can be predicted by single-trial classification. Classification rates reach 69% and 83% in planning and execution stages, respectively. As no physical displaceme happens during the task, it can be hypothesised that the underlying mechanisms of motor-related ERD/ERS and the directional information do not only depend on limb coordinate change or target coordinates. The results contribute to the current understanding of different brain region functions during voluntary motor tasks and can help to clarify the relationships between invasive brain recordings and large-scale recordings such as EEG in this context. Ultimately, this will contribute to further clinical applications, including (BCI-)rehabilitation and electrical/magnetic brain stimulation research.

Joint replacements have been used for over 30 years with considerable success as treatment for bone diseases. As a surgical alternative to metal on metal (MoM) total hip replacement, hip resurfacing was developed using Cobalt-Chromium (CoCr) alloys. However, debris particles are generated by wear at the articulating CoCr surfaces. The nanoparticles and ions produced disseminate throughout the body and interact with different cell types. In order to evaluate the effects of CoCr particles and ions released from MoM implants, U937 cells and primary human lymphocytes were exposed in vitro to artificially produced wear debris derived from an ASRTM MoM hip resurfacing. MoM implants release both Cr and Co ions into patients' circulation, with the latter ion being more mobile, and disseminating more widely in the body. U937 cells were treated with Co ions before being exposed to wear debris to investigate the scenario of patients undergoing revision surgery or receiving a second implant. In addition to this, metal ion levels were measured in clinical whole blood samples of patients with MoM hip implants and the relationship between those levels and the expression of key genes involved in the process of bone remodelling was explored. The findings from this study demonstrated that exposure to high concentrations of CoCr wear debris led to decrease in U937 cell viability after 120h but increased cell proliferation of primary human lymphocytes. Moreover, assessment of apoptosis revealed that metal debris, but not low concentrations of Co ions (0.1μM), induced apoptosis in both U937 cells and primary human lymphocytes. Additionally, results showed that whereas cytokine production by U937 cells is affected by both metal debris and metal ions, it is mainly affected by metal debris in primary human lymphocytes. Changes in human general toxicology-related gene expression in response CoCr wear and Co ions exposure was also evaluated in U937 cells. Real time PCR analysis indicated that CoCr particles were more effective as an inducer of changes in gene expression when cells were pre-treated with Co ions. Together, results seemed to suggest that the toxicity of Co ions in macrophages could be related to nitric oxide metabolic processes and apoptosis and to IL-2 production modulation in lymphocytes. ICP-MS analysis of culture medium from cells exposed to increasing concentration of CoCr wear debris demostrated increasing Co and Cr ion levels representing the corrosion process of the metal debris. Since metal wear debris corrodes under physiological conditions, the ions released may play an important role in the cellular response at the peri-implant tissues. Finally, whole blood Co and Cr ion levels from patients with MoM implants were also analysed by ICP-MS. The ion levels measured were elevated compared to patients without implants, and one patient had levels that were just above the 7μg/l(7ppb)threshold recommended by the Medicines and Health care products Regulatory Agency (MHRA) for Co+Cr in the circulation. A correlation between the ion levels measured and gene expression changes could not be established, due to the low number of patients available for this study. Results from this investigation showed that metal debris tends to be more toxic and has a greater influence on gene expression in the presence of Co ion pre-treatment. This could have great health implications as it potentially means that patients undergoing revision surgery or receiving a second implant may be at higher risk of adverse tissue response and implant failure.

Flexor tendon repair continues to provide surgeons with a challenge. Injuries occurring in zone II are a particular challenge due to the complex arrangement of the anatomy in this area. Poor results postoperatively are costly and lead to even more complex second operations, resulting in long time periods where patients are unable to use their hands fully. The repair techniques are numerous, as are the materials available for such repairs, and the training for surgeons in this field is largely based on practice on simulation models and the apprenticeship method. The literature review in this dissertation highlights the numerous repair variables, the type of repair, suture size and material, number of strands of suture crossing the repair site, as well as testing models. The use of a non-absorbable suture like braided polyester (Ticron) and a monofilament of polypropylene (Prolene) are commonly used in clinical practice, and these are both investigated for effect on tensile properties of the repair, as is the learning curve of one of the investigators. One aim of this research was to develop a realistic, low cost bench-top model for tensile testing of tendon repairs, to enable the primary of the study; an investigation of a new core suture and a new peripheral repair method. A porcine model is investigated for anatomical similarity with human flexor tendons, and a mechanical testing protocol established, that allows investigation of tendon repairs for tensile tests as well as internal work of friction. A comparison of the well-known and tested Pennington Modification of the Modified Kessler (MK) technique is performed with a new repair type that incorporates a ventral locking loop to the standard Modified Kessler (LMK). In addition the work introduces a PolyCaprolactone (PCL) sheet to the repair, as a new peripheral repair method. Early findings showed higher values for the Ticron repairs and a clear learning curve with regards to mechanical properties of the repairs. The importance of conditioning of the tendons was also investigated in the preliminary studies and a clear effect on the work of flexion was found for each cycle tested. No difference was seen in the tensile properties between the repairs, but for the two strand core suture repairs the LMK had lower work of flexion values. This was investigated further by measuring the cross sectional diameters of the two repair types to see if the change in repair technique had influenced the size of the repair. No difference was found. The four strand core suture repairs showed a higher force to gap formation of the LMK repair compared to the MK. The addition of the PCL sheet resulted in lower force to gap formation values. With regards to the work of flexion the PCL resulted in an almost doubling of the values seen with MK or LMK repairs, however no statistical difference was seen with regards to work of flexion between the MK and LMK. This work has shown that the porcine model is similar to human and provides a good model for tendon repair. A mechanical testing procedure for tensile testing as well as work of flexion has been established that allows for testing of tendon repairs. The model would also allow for trainees to practice and get qualitative feedback on their repairs. No clear biomechanical advantage was seen with the addition of the ventral locking loop when compared to the MK, however the MK configuration used had an increased locking loop diameter than those presented in the literature which means that the LMK may provide a biomechanical advantage. Further studies are warranted to investigate how the LMK compares to MK with smaller locking loop areas, and other commonly used repair techniques. The addition of the PCL sheet to the repair, caused a large increase in the work of flexion of the repairs, and the PCL sheets showed large deformation after low loads during tensile testing which means that they would not have any clinical application for zone 2 tendon repairs. The possibility of using the PCL sheet as a tissue engineering scaffold/matrix for tendon repairs out with the hand could be investigated in further studies, however it is likely that modifications need to be done to the PCL before it proves useful in clinical practice.

The homogeneous assay format has been identified as having the potential to make an effective impact in the field of 'point-of-care or near patient testing. Homogeneous assays have the advantage that, by eliminating the need for multiple preparation steps, they can be rapid and easy to use in comparison with most solid-phase assay formats. However homogeneous assays tend to be generally less sensitive than their heterogeneous counterparts, giving results that are qualitative or at best semi-quantitative. This work presents a 'model' fluorescence-based homogeneous immunoassay for the detection of gonadotropin-releasing hormone, type-1, (GnRH-I) described by fluorescence spectroscopy and in particular time-resolved fluorescence techniques. In the model assay a new synthetic labelled 9-amino acid peptide, [des-pGlup1s]-LH-RH-Acp-FITC, is introduced to compete with GnRH-I for the two binding sites on the antibody 7B10.1D10. The core results demonstrate a photophysical characterisation of the binding of [des-pGlup1s]-LH-RH-Acp-FITC and 7B10.1D10 in homogeneous solution based on time-resolved fluorescence techniques. Specifically, values extracted from the plateau region of the time-resolved anisotropy decay curves are used to estimate the amount of free and bound [des-pGlup1s]-LH-RH-Acp-FITC and comment on the presence of interference processes in the assay. Furthermore, disruption to a system of [des-pGlup1s]-LH-RH-Acp-FITC bound to 7B10.1D10 by the addition of GnRH-I is described.