Various bioactive wound dressing materials exist on the market that are designed to aid recovery and comfort of patients with chronic wounds. However, one of the persistent issues is the control of bacterial activity in the wound, which can influence infection rates, efficacy of wound healing and odour generation. A key requirement of a wound dressing is to facilitate a moist wound-healing environment and simultaneously control the growth of bacteria using an antibacterial agent. Manuka honey is currently utilised in bioactive wound dressing materials as an antibacterial agent via the direct impregnation or coating of honey onto a suitable material. It provides a unique antibacterial potency, attributable to one of its constituents, methylglyoxal (MGO). Commercially, there have been relatively few examples of electrospun fabric components being integrated into advanced wound care products. However, many studies have explored the potential of electrospun webs as part of a novel wound dressing material, due to their inherent nano and micro-fibrous structure, which provides a high surface area available for active delivery. In this research, synthetic MGO was evaluated for its effectiveness as a novel antibacterial agent, when encapsulated into an electrospun poly(vinyl alcohol) (PVA) hydrogel forming web. In the first phase of this research, the antibacterial activity of both Manuka honey and synthetic MGO when applied as a topical coating to a nonwoven fabric was assessed via two British standard methods using Gram positive and Gram negative bacteria in-vitro. BS EN ISO 20743:2007 was employed as a quantitative method to establish if Manuka honey and synthetic MGO provided an antibacterial effect at equivalent MGO concentrations. It was found that concentrations of 0.0054 mg cm -2 of MGO in the form of Manuka honey and synthetic MGO was sufficient to achieve 100% reduction in bacteria for both Gram positive and Gram negative strains. Further tests were then carried out using BS EN ISO 20645:2004, which assessed the zone of inhibition using a seeded bacteria agar plate. In this case, higher concentrations between 0.0170 mg cm -2 and 0.1 mg cm -2 were required to facilitate a good antibacterial effect. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) was also assessed for MGO in liquid form against the three most prevalent wound pathogens, Staphylococcus. aureus, Pseudomonas. aeruginosa and Enterococcus. faecalis. Concentrations similar to that found in the literature, between and 128 mg L -1 and 1024 mg L were shown to provide either a bacteriostatic or bactericidal effect. Most importantly, the MIC and MBC of MGO against Enterococcus. faecalis was reported for the first time. -1. The encapsulation of synthetic MGO in electrospun PVA fibres was explored using both needle and free surface (needleless) electrospinning technologies, with a successful outcome. It was found that an 11.22 wt % MGO solution with 16% (w/v) PVA was most favourable for producing fibres free from beads when using needle electrospinning. A higher PVA concentration of 20% (w/v) was required to achieve bead free fibres using free surface electrospinning. Two different collector materials were utilised during free surface electrospinning, where an aluminium foil collector was found to produce a smaller mean fibre diameter when compared with a less conductive polypropylene spundbond substrate. Characterisation of the as-spun webs was determined via Fourier transform infrared spectroscopy (FTIR) and proton nuclear magnetic resonance (NMR), where the presence of MGO in the PVA webs was confirmed by the characteristic carbonyl groups associated with MGO’s keto-aldehyde groups. A continuation of the zone of inhibition method highlighted that concentrations of MGO between 1.14 mg cm -2 and 1.50 mg cm -2 were required to have an antibacterial effect in-vitro. Finally the release behaviour of MGO from the electrospun webs was investigated using high performance liquid chromatography (HPLC). Crosslinking of the PVA/MGO webs with glutaraldehyde (GA), in the form of a vapour and a novel plasma technique showed promising results for controlling the release rate of MGO from the fibres. Prior to crosslinking, 93.7% of the MGO was released from the PVA fibres within 30 minutes. After crosslinking the amount of MGO released was considerably reduced over a period of 24 h, with a maximum of 75% released. The novel plasma crosslinking technique was further confirmed using FTIR and it is believed this is the first time this technique has been employed.

The focus of the thesis is interfacial crack problems in anisotropic and piezoelectric bimaterials. We seek to solve a variety of problems using weight function techniques and singular integral equations. We begin by studying a dynamic crack along a perfectly bonded interface in an anisotropic bimaterial. Using a weight function de- rived from a mirrored problem it is possible to derive important ma- terial parameters which govern the crack propagation. Following this a static crack is considered. However, in this case the materials are not bonded perfectly, an imperfect interface is present instead. A method is derived where singular integral equations for the imperfect interface problem are derived through use of perfect interface weight functions. The weight functions are then extended to fracture in piezoelectric bimaterials which allows equivalent integral equations to be derived relating the mechanical and electrical elds. In past literature a num- ber of results have been found which can only be used when consider- ing a symmetric load system on the crack faces. All of the problems considered here have asymmetric loading. Firstly, a steady-state formulation is used to derive asymptotic coe cients of the crack displacement and interfacial tractions for a dynamic crack along a perfect interface. The method can be used to nd many asymptotic coe cients but the one of most importance here is the stress intensity factor which therefore enables the calculation of energy release rate at the crack tip. As an example an orthotropic bimaterial with two di erent loading con gurations is used to examine the importance of crack speed and load asymmetry on the properties of the crack propagation. iv We proceed to study imperfect interface conditions for an anisotropic bimaterial. Usually when looking at such a problem it is necessary to derive new weight functions which correspond to the imperfect inter- face. An innovative method which makes use of the Betti formula and existing weight functions for the analogous perfect interface problem is derived. This procedure is used to obtain singular integral equations which relate the crack loading, which is assumed to be known, to the displacement jump over both the crack and interface and tractions along the bonded area between the materials. Examples of the results obtained through solving the integral equations numerically are given. Finally, we extend the weight functions used previously in the the- sis to a piezoelectric setting. The general form of the weight function for any piezoelectric bimaterial is given before two speci c examples are studied in depth. The examples are chosen in such a way to illus- trate the e ect that the poling direction of the bimaterial can have on both the mechanical and electrical elds. For both examples explicit expressions are derived for the weight functions which are then used to derive singular integral equations which can be used to study the e ect of both mechanical loading and electrical charges being applied to the crack faces. To nish we present some examples for both poling directions to illustrate the use of the derived equations.

The aim of this work has been to investigate the formation of films and to couple their properties with the bulk behaviour of the film forming components. The primary goal was to improve the biocompatibility of the films, as films are of great interest to the biomedical industry. The investigated films form spontaneous at an air-water interface and some are robust enough to be removed from the surface. The films are formed by mixed surfactants of the cationic CTAB and the zwitterionic SB3-14 together with the polymer PEI, in a short and long form. The film structures are investigated with varying CTAB:SB3-14 ratio. It was found replacing CTAB with SB3-14 reduced mesostructure in the films, however when PEI was used to form the films in its long form there was sufficient polymer network to kinetically trap mesostructure in the films. To increase biocompatibility, CTAB was replaced with calcium chloride to emulate the cationic charge and present opportunites for complex formation with the polymers. SB3-14 was still present as the surfactant to impart mesostructure with PEI as the polymer. Here it was found that mesostructure could be controlled with calcium chloride concentration due to its hygroscopic nature modulating the amount of water in the films and therefore the resulstant mesophases. Finally, anionic biopolymers were investigated with the spray coated films. Here it was found that they complexed with calcium chloride more fully than PEI and thus the competition between calcium chloride and SB3-14 for water resulted in more hydrated mesophases than when PEI was used as the film forming polymer. The bulk solutions and films were investigated mainly with small angle scattering and reflectivity techniques. It was found that as a progression to previous work in the research group that more biocompatible methods could be used to form structured films.

The mechanical repair of parts of the human body destroyed by trauma or disease has been attempted by surgeons with little success over the centuries. Present day technology has provided the orthopaedic surgeon with materials and techniques which allow him not only to repair but also to completely replace malfunctioning joints and to restore his patient to full pain-free activity. Two sites of implantation, the knee and finger joints, are examined in this study, more specifically an investigation of the wear of a prosthetic polymer bearing and the development of an elastomer to replace damaged Joints of the hand. The wear study was undertaken to try and find a replacement for the stainless steel of the Platt interposing membrane type knee prosthesis which is known to fail in service. A more flexible material capable of withstanding the stresses across the knee joint and able to act as a bearing between femur and tibia was sought. The wear behaviour of U.H.M.W. polyethylene was examined and compared with polypropylene suggested as the replacement material for the steel joint. Wear coefficients for the polyethylene were determined when the polymer was mated with several different counter-faces. The effect of polyethylene structure on its wear behaviour was also examined along with the effect of crystalline orientation and physical properties. The development of a prosthetic elastomer is based on a practical need arising out of experience with the current silicone rubber joint. Joint stiffness is the major requirement and blending, physical property evaluation and biological testing of an E.P.D.M./polybutadiene formulation are reported. In both projects recommendations as to the use of the materials under examination are made.

Biomedical signals are records from human and animal bodies. These records are considered as nonlinear time series, which hold important information about the physiological activities of organisms, and embrace many subjects of interest. However, biomedical signals are often corrupted by artifacts and noise, which require separation or signal extraction before any statistical evaluation. Another challenge in analysing biomedical signals is that their data is often non-stationary, particularly when there is an abnormal event observed within the signal, such as epileptic seizure, and can also present chaotic behaviour. The literature suggests that distinguishing chaos from noise continues to remain a highly contentious issue in the modern age, as it has been historically. This is because chaos and noise share common properties, which in turn make them indistinguishable. We seek to provide a viable solution to this problem by presenting a novel approach for the separability between signal and noise components and the differentiation of noise from chaos. Several methods have been used for the analysis of and discrimination between different categories of biomedical signals, but many of these are based on restrictive assumptions of the normality, stationarity and linearity of the observed data. Therefore, an improved technique which is robust in its analysis of non-stationary time series is of paramount importance in accurate diagnosis of human diseases. The SSA (Singular Spectrum Analysis) technique does not depend on these assumptions, which could be very helpful for analysing and modelling biomedical data. Therefore, the main aim of the thesis is to provide a novel approach for developing the SSA technique, and then apply it to the analysis of biomedical signals. SSA is a reliable technique for separating an arbitrary signal from a noisy time series (signal+noise). It is based upon two main selections: window length, L; and the number of eigenvalues, r. These values play an important role in the reconstruction and forecasting stages. However, the main issue in extracting signals using the SSA procedure lies in identifying the optimal values of L and r required for signal reconstruction. The aim of this thesis is to develop theoretical and methodological aspects of the SSA technique, to present a novel approach to distinguishing between deterministic and stochastic processes, and to present an algorithm for identifying the eigenvalues corresponding to the noise component, and thereby choosing the optimal value of r relating to the desired signal for separability between signal and noise. The algorithm used is considered as an enhanced version of the SSA method, which decomposes a noisy signal into the sum of a signal and noise. Although the main focus of this thesis is on the selection of the optimal value of r, we also provide some results and recommendations to the choice of L for separability. Several criteria are introduced which characterise this separability. The proposed approach is based on the distribution of the eigenvalues of a scaled Hankel matrix, and on dynamical systems, embedding theorem, matrix algebra and statistical theory. The research demonstrates that the proposed approach can be considered as an alternative and promising technique for choosing the optimal values of r and L in SSA, especially for biomedical signals and genetic time series. For the theoretical development of the approach, we present new theoretical results on the eigenvalues of a scaled Hankel matrix, provide some properties of the eigenvalues, and show the effect of the window length and the rank of the Hankel matrix on the eigenvalues. The new theoretical results are examined using simulated and real time series. Furthermore, the effect of window length on the distribution of the largest and smallest eigenvalues of the scaled Hankel matrix is also considered for the white noise process. The results indicate that the distribution of the largest eigenvalue for the white noise process has a positive skewed distribution for different series lengths and different values of window length, whereas the distribution of the smallest eigenvalue has a different pattern with L; the distribution changes from left to right when L increases. These results, together with other results obtained by the different criteria introduced and used in this research, are very promising for the identification of the signal subspace. For the practical aspect and empirical results, various biomedical signals and genetics time series are used. First, to achieve the objectives of the thesis, a comprehensive study has been made on the distribution, pattern; and behaviour of scaled Furthermore, the normal distribution with different parameters is considered and the effect of scale and shape parameters are evaluated. The correlation between eigenvalues is also assessed, using parametric and non-parametric association criteria. In addition, the distribution of eigenvalues for synthetic time series generated from some well known low dimensional chaotic systems are analysed in-depth. The results yield several important properties with broad application, enabling the distinction between chaos and noise in time series analysis. At this stage, the main result of the simulation study is that the findings related to the series generated from normal distribution with mean zero (white noise process) are totally different from those obtained for other series considered in this research, which makes a novel contribution to the area of signal processing and noise reduction. Second, the proposed approach and its criteria are applied to a number of simulated and real data with different levels of noise and structures. Our results are compared with those obtained by common and well known criteria in order to evaluate, enhance and confirm the accuracy of the approach and its criteria. The results indicate that the proposed approach has the potential to split the eigenvalues into two groups; the first corresponding to the signal and the second to the noise component. In addition, based on the results, the optimal value of L that one needs for the reconstruction of a noise free signal from a noisy series should be the median of the series length. The results confirm that the performance of the proposed approach can improve the quality of the reconstruction step for signal extraction. Finally, the thesis seeks to explore the applicability of the proposed approach for discriminating between normal and epileptic seizure electroencephalography (EEG) signals, and filtering the signal segments to make them free from noise. Various criteria based on the largest eigenvalue are also presented and used as features to distinguish between normal and epileptic EEG segments. These features can be considered as useful information to classify brain signals. In addition, the approach is applied to the removal of nonspecific noise from Drosophila segmentation genes. Our findings indicate that when extracting signal from different genes, for optimised signal and noise separation, a different number of eigenvalues need to be chosen for each gene.

Blood flow rheology is a complex phenomenon, and the study of blood flow in the human body system under normal and pathological conditions are considered to be of great importance in biomedical engineering. Consequently, it is important to identify the key parameters that influence the flow behaviour of blood. The characterisation of blood flow will also enable us to understand the flow parameters associated with physiological conditions such as atherosclerosis. Thrombosis plays a crucial role in stopping bleeding when a blood vessel is injured. Developing tools that can successfully study the influences of hemodynamics on thrombus formation in arteries and vessels are considered to be essential. This thesis describes the steps taken to develop computational tools that focus on using the meshless particle-based Lagrangian numerical technique, which is named the smoothed particle hydrodynamic (SPH) method, to study the flow behaviour of blood and to explore flow condition that induces the formation of thrombus in blood vessels. A weakly-compressible SPH method is used here to simulate blood flow inside vessels. The basic governing equations solved in the SPH are the mass and momentum conservation equations. Due its simplicity and effectiveness, the SPH method is employed here to simulate the process of thrombogenesis under the influence of various blood flow parameters. In the present SPH simulation, blood is modelled by particles that have the characteristics of plasma and platelets. To simulate a 3-dimensional coagulation of platelets which form a thrombus, the adhesion and aggregation process of platelets are modelled by an effective inter-particle force model. With these models, platelet motion in the flowing blood and platelet adhesion and aggregation are effectively coupled with viscous blood flow. In this study, the adhesion and aggregation of blood particles are performed inside vessels with various geometries and with different flow velocity scenarios. The capabilities of this strategy were evaluated by comparing the simulation results with existing numerical and experimental results. All of these cases realistically model the formation of thrombus including thrombus collapse and partial separation. This thesis is considered to be the first work that is dedicated to the SPH simulation of thrombus formation inside blood vessels with various geometries and under different flow conditions.

Articular cartilage is an anisotropic tissue composed of compositional and functional layers. One clinical approach to the regeneration of articular cartilage defects incorporates a porous polymer scaffold to support and direct cartilage formation in full‐thickness defects. These scaffolds are regularly isotropic in structure, unlike the tissue they aim to regenerate. A number of scaffold production techniques were combined to produce porous anisotropic scaffolds with zonally‐biomimetic microarchitecture and mechanical properties. The final scaffold design featured a combination of an electrospun fibrous superficial zone, isotropic foam intermediate zone and directionally frozen deep zone. The zonal scaffold microenvironments influenced cellular distribution, gene expression, and extracellular matrix deposition in vitro without requiring chemical modification or culture under dynamic loading. The scaffold development work culminated in a porcine in vivo study, currently on‐going. Initial data from the 3‐month preliminary surgical trial suggests full cellular infiltration of acellular scaffolds, no immunological response, and improved articular surface morphologies relative to empty defect controls. Variations on the polymer poly(ϵ‐caprolactone) (PCL) were investigated for use in osteochondral tissue engineering applications. The incorporation of alternate monomers was found to modify the biological and mechanical properties of the resulting materials and scaffolds. The work contained within this thesis has expanded the field of anisotropic scaffold design, with implications for articular cartilage engineering. The combination of electrospun fibres and anisotropic foams for scaffold engineering was the first in the field when published. The design of the third‐generation scaffold is new to the field, as is the order‐of‐magnitude increase in stiffness in a porous polymer scaffold while maintaining interconnectivity and polymer composition. The observation of differentially aligned ECM within a single multi‐layer scaffold without zonally distinct materials or surface functionalisation is also believed to be the first in the field.

Organisms must detect changes in the environment, integrate information from multiple sources, and make informed decisions about how to use resources to respond and adapt. At the cellular level, information is sensed and processed by signalling networks that coordinate sensory information with physiological responses such as regulation of gene expression. Complex phenotypes such as cellular differentiation and disease states derive from decision making processes and depend on whether information is processed correctly. In order to address this complexity, it is necessary to consolidate the molecular mechanisms that process information into an integrative framework. While substantial research has been conducted on each of cellular signalling and gene regulation, a quantitative framework to understand the information flow is still missing. Perception, as defined for humans, comprises fundamental concepts of information processing: identification, organization, representation and interpretation. Here we argue that we can represent the flow of information in cellular systems by developing a framework of cellular perception. In general terms, information has to be sensed and internalized by signalling networks before it can be encoded into internal variables that cells can use to represent the environment. We thus investigate the molecular mechanisms by which cells sense and encode information in the single-cell microbe Saccharomyces cerevisiae as an example organism. In S. cerevisiae, as in all eukaryotes, a main mechanism to regulate gene expression is the dynamic nuclear translocation of transcription factors. We develop a framework of cellular perception in the context of dynamic nuclear translocation by characterizing the sensing and encoding of information necessary to accurately map environmental conditions to specific cellular responses. By investigating the sensing mechanisms of the hyperosmolar glycerol (HOG) MAPK network, we showed how this network improves sensing of dynamic signals by having two specialized input pathways. For the encoding mechanisms, we showed that the dynamic roles of nuclear translocation of transcription factors can function as highly informative intracellular variables. As these internal variables can encode both the magnitude and identity of the stress signal, they can be used by the cell to accurately represent the environment and determine the specific physiological responses. This thesis provided a solid ground for quantitative research in the field of cellular signalling and gene regulation. Moreover, the methods and experimental approaches applied here are broadly applicable in other organisms.

The use of exogenous materials to replace or repair dysfunctional tissues and organs has seen dramatic improvements since the time of the ‘physician-hero’. The past three decades have heralded the advancement of various materials and technologies for medical implant devices to repair, replace or regenerate irreversibly damaged tissues. Improvement in health outcomes, evident in life expectancy increase, has brought in its wake the increased need to replace or repair tissues, particularly weight-bearing bone tissues. Titanium (Ti), a non-magnetic, corrosion resistant, osseo-integrating metal, with a higher strength-to-weight ratio than the traditional stainless steel, has emerged as the material of choice for replacing bone and other support tissues. However, the quest for improved performance (osseointegration) and reduction in implant related infection resulting in the need for resection surgeries, has necessitated the need to improve the titanium-tissue interface mediated osseointegration process, and confer antimicrobial properties to the implant material surface. In this work, a simple cost effective physical and chemical modification strategies have been developed, to alter the surface chemistry, increase the surface water wettability and confer a nano topographic characteristic to the Ti surface. These surface parameters have been demonstrated to enhance the osseointegration process. The chemical treatments resulted in oxides containing the following ions: Calcium (Ca), for improvement of osteogenic cell adhesion to Ti surface, Silver (Ag), and Zinc (Zn) for conferring antimicrobial properties to the novel surface, and their composites (CaAg, CaZn and CaZnAg), Scanning electron microscope (SEM) profiles of the modified surface suggest that, ions are chemically bound and not physically deposited onto the Ti surface. Further evidence of this is provided by the release profile of these elements from the modified surface over a 28-day period. We have also demonstrated that, the physically modified Ti surface is better at incorporating our elements of interest than the commercially pure titanium (cpTi) surface. xi The results from a Staphylococcus aureus biofilm formation assay, and U2OS bone cell adhesion and proliferation studies, suggest that, the physical modifications enhanced both the antimicrobial performance and the osteoblast-like cell adhesion and proliferation. The suggestion also is that, the incorporated Ca further enhances the adhesion and proliferation of bone-like cells, whereas Zn and markedly Ag improve the modified Ti surface’s antimicrobial properties. However, Ag alone has been shown to have a toxic effect on the bone cells; a promising combination treatment involving Ca, Zn and Ag appears to have beneficial response in all tests.

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