What's MEW in the UK? Engineering basement membranes using state-of-the-art biofabrication technologies

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Tissue engineering commonly uses scaffolds that aim to mimic the structure of biological tissues; however, the scale and geometry of current approaches are dissimilar to those found in nature and these differences hamper the scaffolds' ability to support and control cell behaviour. A recent technological innovation however has led to a demonstrable advancement in producing scaffolds that possess appropriate scale and tailorable geometrical features. This state-of-the-art technology is called melt electro-writing (MEW); a high-resolution version of 3D printing where the material is produced from synthetic polymers, the fibre is laid down in defined orientations and geometries and, most importantly, where this fibre is much closer in size to the native extracellular matrix. MEW was invented by my International Collaborator - Prof. Paul Dalton (University of Oregon), and this project focuses on establishing MEW in the UK to allow superior tissue-mimic structures to be created that will then allow us to better study the structural effects of these scaffolds on cell and tissue behaviour. More specifically, this grant focuses on the growth and assembly of specialised tissues known as basement membranes.Basement membranes are an essential tissue present throughout the body. They provide the interaction point between sheets of cells and the underlying extracellular matrix. Here they act as signalling hubs controlling a wide variety of cellular responses including determining the specific cell types that the cells will become, and protecting these cells from the mechanical forces that move through the extracellular matrix. How basement membranes achieve this is through localised and specific differences in their make-up (i.e. composition) and by differences in the way those proteins are assembled (i.e. structure). Whilst the compositional aspects have been widely studied over many years, the structural aspects have only recently come to the fore.Our overarching hypothesis is that the structure of the extracellular matrix in terms of its topography and geometry, stiffness and pore size will each contribute to how basement membranes assemble on top of that matrix. Those differences in basement membrane assembly will then translate into changes in cell behaviour. In this project we will test this hypothesis by determining how the underlying extracellular matrix influences the way that basement membranes assemble and function. This is a large and fundamental question which is central to many aspects of mammalian biology and with potential therapeutic implications for degenerative and age-related health conditions. Robustly testing this hypothesis has historically been hampered by difficulties in producing accurate experimental models where the specific aspects of the extracellular matrix could be independently modified and their contribution evaluated. However, combining MEW with our existing scaffold fabrication technologies, which represents a step-change advancement in substrate production, means we are now able to precisely tailor the characteristics of the scaffolds and then analyse the cellular and basement membrane responses to these scaffolds.Our project therefore has one distinct aim: to create synthetic structures using scaffold fabrication technologies that mimic the physical properties of extracellular matrix topography, geometry and mechanics, and which go on to influence basement membrane assembly and cell behaviour.