Platform Grant Strategic Research Areas

1. Mechanics and mechano-signalling at the sub-cellular, cellular and tissue levels. The response of living cells and tissues to mechanical forces is critical to tissue health and homeostasis. Consequently this field of mechanobiology has enormous potential to be exploited in the development of Tissue Engineering strategies for the regeneration of diseased or damaged tissue. Fundamental to the success of these strategies, is the ability to predicate the effect of physiological mechanical loading on the cellular response. Consequently, a key strategic aim is to develop and use methods to quantify biomechanical and biophysical parameters at a variety of hierarchical levels, within tissues and tissue engineered constructs. Furthermore, it is also necessary to identify the mechanosensory behaviour, such as cytoskeletal dynamics protein trafficking etc, and the important mechanoreceptors and signalling pathways which mediate the biological metabolic and genomic responses to mechanical loading.
    
2. Micorenvironmental sensing/manipulation and predictive in silico modelling in 3-D The culture of cells in three-dimensional scaffolds induces the formation of spatial gradients of key nutrients and metabolites, potentially leading to spatial heterogeneity of cell response. The processes underlying this phenomenon are poorly understood and complex, involving tightly regulated interplay between nutrient/transport provision, associated with diffusion/perfusion, and metabolic utilisation or sequestration of soluble bio-regulators by cells. The application of mechanical loading influences these processes, thereby affecting cellular function and neo-tissue elaboration, via direct mechanosensing by cells and also through altered nutrient/metabolite transport. This represents a key strategic research area for the platform grant with the aim of developing novel, non-destructive analytic techniques to interrogate the micro-environmental milieu within 3-D constructs with mechanical perturbation. Mathematical modelling can provide an enhanced understanding of the complex interplay between an array of factors that control neo-tissue growth. Moreover, modelling may be used for control systems in bioreactors. A further key strategic aim is to interrogate the effects of manipulation of the micro-environmental milieu through external manipulation of oxygen levels in combination with mechanical perturbation. This permits the provision of a more physiological mechano/metabolic environmental conditions that will be a powerful tool for tissue engineering, but also for studying patho-physiological processes and by providing more relevant 3-D model systems for drug discovery applications.
    
3. Construct technology and advanced tissue processing The translation of basic science to therapeutic application requires the development of novel, efficient and efficacious construct and process technologies, with integrated conditioning and monitoring, to ensure reliable neo-tissue production prior to implantation. Tissue growth, repair and maintenance is defined and sustained through the appropriate distribution of specific biological and biophysical cues, which form microenvironmental domains within the extracellular milieu. This complex interplay between molecular and biophysical signals and the associated cellular response is necessary for functional tissue development. The platform grant may be used to push forward the development of novel scaffold technologies and bioreactor systems, designed to provide defined biochemical and mechanical cues to seeded cells in distinct spatial and temporal domains, thereby creating a defined bioengineered ‘cell-niche’ that controls cell differentiation and activity. One basic strategy might involve heirarchical functionalisation, at the nano- and meso-scales, of natural and synthetic polymeric biomaterials, selected due to their track record for use as components of bioresorbable implants. Differential properties may be achieved at the mesoscale using a variety of complementary synthetic approaches. Cutting edge technologies such as emulsion templating may be utilised to develop porous surface modified biomimetic supports. Ultimately ‘on-demand’ release systems are envisaged, activated by metabolic mediators associated with cell stress and nutrient deprivation. Thorough characterisation of neo-tissue elaboration in the resultant tissue engineered constructs will be achieved using bioreactor systems designed to provide defined biomechanical perturbation and modification of the extracellular milieu via medium perfusion and/or control of the oxygen environment. Platform Grant Flexibility The platform grant provides exciting flexibility enabling new research avenues to be explored within the broad remit of the proposal outlined above. Consequently individuals interested in applying for a post doctoral research assistant (PDRA) position on this platform grant will be encouraged to explore and develop their own research niche. Thus the PDRA positions within the Cell and Tissue Engineering group should provide an extremely attractive spring board to scientific independence and career progression.