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This work is concerned with the mechanics of periodic structures for biomedical applications. Classical work on the apparent elastic properties of infinite planar and cylindrical lattice structures is generalised to the non-linear elasto-plastic regime. The elastic recoil upon unloading is also assessed. Elastic instability behaviour of constrained perforated films upon stretching is studied. The elasto-plastic response and recoil analysis of two-dimensional honeycomb is presented. The apparent non-linear structural response obtained analytically here is observed to be smooth, even though the material model of the constituent material is elastic-perfectly-plastic. We show that the Poisson's ratio in the non-linear deformation remains the same as that during the elastic phase. A non-trivial scaling transformation for apparent stress and strain, which separates the individual cell wall response from the mechanics of the overall honeycomb sheet, is identified. This leads to a non-linear master deformation prole that fully describes the plastic response of hexagonal honeycomb with different geometries. The effects of material hardening are introduced by using a novel hyperbolic hardening model. This is then generalised for lattices whom struts possess circular cross-section. Such analysis is relevant to lattice materials and scaffolds manufactured using 3D printing techniques, such as fused deposition modelling, that inevitably makes use of cylindrical laments. Analytical expressions for the elasto-plastic response of a sinusoidal structure wrapped over a cylinder, as a model of crown found within cardiovascular stents, is developed. The response of the cylinder under internal pressure is well approximated by that of the opened-up attened configuration under remote stretch. A scaling ansatz that collapses the response for dierent geometries on a family of 'master-curves' is proposed. We show that the stiffness scales as the cube of the ratio between the amplitude and the wavelength of the sinusoid. Such analysis is then successfully applied to the development of two novel biodegradable stents. Thin membranes with positive apparent Poisson's ratio wrinkle when stretched. Here we show that membranes with negative apparent Poisson's ratio are wrinkle-free upon stretching, except at the edges where localised wrinkling occurs. Here we develop a simple analytical kinematic model to characterise the amplitude and wavelength of the instability behaviour. The model is then validated experimentally and computationally.

Graphene has been publicised as the electrode material of the future due to its large surface area and excellent electrical properties. However when considering electrochemical sensors, true monolayer graphene is of limited use owing to its basal nature which results in electrochemical performance akin to basal plane pyrolytic graphite. The future of electrochemical sensing requires electrodes with performance superior to edge plane pyrolytic graphite the ‘gold standard’ of carbon electrodes. Such electrodes must not only be simple and cost effective to produce but also capable of high sensitivity and precision. Here, two new materials are presented which demonstrate excellent electrochemical responses whilst being amenable to disposable point of care sensors, akin to the planar three electrode screen printed predecessors. Laser scribed graphene and laser induced graphene both rely on a simple laser reduction method to fabricate electrodes. Laser scribed graphene, utilises the laser within Lightscribe enabled DVD drives to thermally reduce graphene oxide to a multi-layered graphene material. The expanded surface area and low oxygen content of 6.5 % result in electrochemical performance surpassing that of edge plane pyrolytic graphite. Laser induced graphene employs a CO2 laser to reduce Kapton to a highly porous graphene material. It also retains low levels of oxygen (10 %) making it an interesting prospect for electrochemical sensing. These materials have been extensively characterised physicochemically and electrochemically. Regarding electrochemistry both inner- and outer-sphere redox probes were used in comparative studies with conventional carbon based electrodes. Here the graphene electrodes demonstrated enhanced performance compared to other carbon electrodes. The heterogeneous electron transfer rate of laser scribed graphene was calculated as 0.02373 cm s−1, compared with edge plane pyrolytic graphite at 0.002601 cm s−1 and basal plane pyrolytic graphite at 0.00033 cm s−1. Electrochemical performance of such materials is clearly influenced by small changes in the oxygen content of the material but most importantly by the morphology of the electrode surface. Ability to detect biologically relevant molecules dopamine, ascorbic acid, uric acid and NADH was then investigated. Laser scribed graphene and laser induced graphene demonstrated successful simultaneous detection of dopamine, ascorbic acid and uric acid which was not achieved with edge plane pyrolytic graphite or glassy carbon electrodes. Detection limits of 0.17 μM were achieved for detection of dopamine with laser scribed 3 graphene electrodes comparing well with the literature. In conclusion both laser scribed graphene and laser induced graphene electrodes have demonstrated exceptional electrochemical behaviour with promise for future use in disposable point of care electrochemical sensors.

The development and implementation of nanomaterials for a variety of clinical applications is increasing as their utility in improving healthcare is demonstrated. However, consideration must be given to appropriate pre-clinical testing to fully translate these materials into clinical use. A library of 22 nanomaterials, both commercially available and those developed in-house, were subject to an assay cascade forming the basis of a preclinical in vitro assessment which utilised a broad and widely accessible range of techniques. The library comprised numerous material classes; metallic (gold, silver, iron oxide, titanium dioxide, zinc oxide), non-metal (silica), and polymeric (polystyrene, liposome, emulsion, polydendron), varying in manufacturer stated particle size, charge, and functionalization. Chapter 2 details characterisation of the size and zeta potential of the nanomaterial library in biologically relevant matrices. When combined with information provided by the manufacturers regarding stabilisation and surface functionalization, where available, these measures allowed associations to be made between nanoparticle physicochemical characteristics and the biological effects observed in subsequent chapters. Inherent optical properties of the nanomaterials in biologically relevant matrices and sample sterility were assessed in order to gain indication of any potential incompatibility with subsequent assays. The haemocompatibility of nanomaterials is of primary concern in their application as nanomedicines, especially those administered intravenously. The work presented in Chapter 3 assessed the haemolytic potential of a subset of nanomaterials. All nanomaterial treatments were found to result in a lower level of complement activation compared to untreated cells, and cases of prolongation or reduction in plasma coagulation times via the extrinsic, intrinsic, and common pathways were observed. In Chapter 4 the impact of nanomaterials on pro-inflammatory and antiin ammatory cytokine secretion by primary immune cells demonstrated. Endotoxin was shown to exacerbate the inflammatory responses toward tested nanoparticles. Further to this; the inhibitory effects of polystyrene nanoparticles to caspase-1 activity described in the literature was confirmed. Proliferation in primary human leukocytes was shown to be significantly affected by certain nanomaterials where particular variants of silver and silica nanoparticles had antiproliferative and proliferation effects, respectively. The work presented in Chapter 5 describes the development and utilisation of screening methodologies to investigate the influence of nanomaterials on reactive oxygen species generation, reduced glutathione and autophagy. Trends have been observed within assays e.g. the reduction in levels of autophagy appears to be linked with surface charge of the nanomaterials with the most negative having the greatest effect. Chapter 6 details the application of methods optimised throughout the thesis to perform a preclinical assessment on a novel class of polymeric nanomaterial termed polydendrons. It was found that variants composed of a higher ratio of novel G2' initiator demonstrated less immunogenic potential than those with an equal ratio to PEG. Given the heterogeneity of engineered nanomaterials in terms of composition, coatings, particle characteristics and functionalization, the identification of particle characteristics that influence biological interactions will enable the rational design of future nanomaterials. The work presented in this thesis has found associations between nanoparticle characteristics and biological effects. These included concentration-dependent correlations between zeta potential and reactive oxygen species generation, and nanoparticle size and autophagic impact. Additionally, the need for thorough physicochemical characterisation, to generate as many parameters as possible for determining structure-activity relationships, has been presented. The methodologies used, and developed, throughout this thesis will aid future preclinical characterisation of novel nanomaterials.

Satellite cells (SC) are muscle-specific stem cells involved in muscle growth and repair in adults. The niche of SC consists of basement membrane (basal lamina), muscle fibre and supporting cells. A major component of basement membranes (BM) is laminin, a heterotrimer protein composed of α, β and γ chains. During the transition from embryonic to foetal and to adult, the muscle basement membrane is extensively remodelled. Indeed, the embryonic basement membrane that is associated with the myotome contains Laminin-111 and -511. During foetal stages, Laminin-111 and -511 are progressively replaced by Laminin-211, which is the main Laminin constituent of the adult basement membrane surrounding muscle fibres. As similarities exist between the myogenic programme carried out by satellite cells and that executed by embryonic muscle progenitor cells, I hypothesized that the composition of the basal lamina in adult muscles may be dynamic at the site of satellite cells to support their activation and progression through myogenesis. In this study, immunofluorescence and quantitative PCR data on ex-vivo culture system of mouse extensor digitorum longus (EDL) muscle fibres revealed the expression of Laminin a1 at the site of activated satellite cells, in contrast to previous reports showing that the adult skeletal muscle basal lamina has a uniform Laminin composition (Laminin- 211). Laminin a1 association with activated satellite cells was also observed in vivo in two distinct models of muscle regeneration, the Dystrophin-deficient mdx mouse and in cardiotoxin-injured tibialis anterior (TA) muscles. Laminin a1, secreted by satellite cells, is also expressed at the surface of macrophages in vivo. Finally, I provide evidence that Integrin α6β1, the preferred receptor for Laminin a1, is expressed at the surface of activated satellite cells ex-vivo. Altogether these results reveal that a remodelling of the basal lamina occurs during skeletal muscle regeneration with the concomitant secretion and deposition of Laminin α1 in the basal lamina overlying activated satellite cells. Laminin a1 may signal through its specific receptor Integrin α6β1 to promote satellite cell progression through myogenesis. Finally, the presence of Laminin a1 may also act as a mediator between activated satellite cells and macrophages, promoting the recruitment of macrophages to the vicinity of satellite cells to support muscle regeneration. Thus, this study provides an insight into a mechanism allowing for the remodelling of the satellite cell niche during muscle regeneration.

In spite of recent progress in the field of adipose tissue engineering, the optimal adipose tissue scaffold still remains illusive and the tailoring of the structure and properties of tissue scaffolds according to adipose tissue were less explored or even neglected. Thus, synthetic poly(glycerol sebacate) (PGS)-based scaffolds and hydrogels which mimic the properties of adipose tissue were developed in this PhD project for potential application in adipose tissue engineering.

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About half of the human body mass is comprised of skeletal muscles, a component of the musculoskeletal system involved in maintaining body posture, gait and locomotion. Additionally, skeletal muscles have essential function in glucose metabolism and thermoregulation. Thus, maintenance of skeletal muscle homeostasis is critical for the health of organisms. Satellite cells are muscle-specific stem cells responsible for postnatal growth, regeneration upon injury, and maintenance of skeletal muscle homeostasis. Satellite cell's activity is regulated by a sophisticated network of signalling pathways, which act in a combinatorial manner to regulate satellite cell expansion and differentiation, and to preserve a pool of stem cells during the life course of skeletal muscles. Many of these signalling pathways are known to operate during embryonic myogenesis and are re-activated in adult myogenesis. One such signalling pathway, Sonic hedgehog (Shh) signalling, controls several aspects of myogenesis in the embryo and previous studies have indicated that it plays a role in adult myogenesis. However, it remains unclear whether Shh signalling acts upon satellite cells or non-myogenic resident cells. This study builds on previous work in the lab showing that Shh signalling is cell-autonomously required in satellite cells for efficient muscle regeneration. Through a combination of ex vivo and in vivo genetic approaches, I demonstrated that up-regulation of Shh signalling increased the proliferation of satellite cells by accelerating their entry into cell cycle and progression through the cycle program. Up-regulation of Shh signalling in satellite cells altered also the balance between self-renewal and differentiation, by promoting asymmetric cell division at the expense of symmetric cell division. Given the involvement of Shh signalling in tumour development in other systems and in skeletal muscle tumours i.e. Rhabdomyosarcoma (RMS), the present study may provide novel insights into the role of Shh signalling in the pathogenesis of RMS through the deregulation of satellite cell homeostasis.