Developing a digital twin of 3D vascular systems to study haemorrhagic viral diseases

We will develop a digital twin of 3D microvascular organoid culture systems to investigate haemorrhagic diseases. A biological digital twin is a computer simulation designed to mimic all aspects of an experimental system or in vivo tissue. Here we adopt an individual-based approach where each cell is simulated, enabling the twin to capture cell-cell interactions as well as whole tissue dynamics. The advantages of developing a digital twin include that large parameter ranges can be explored quickly and easily far beyond the capacity of experimental investigation and also in regimes that would be inaccessible. Importantly there is increasing recognition that the use of digital twins can reduce the need for animal experimentation with interest spanning biological science and pharmaceutical drug development. We will use the digital twin to look at dysfunctions of the microvasculature (capillary systems) drawing on the experimental results of the co-supervisor Dr Paola Campagnolo. In many common viral diseases additional complications can be generated by microvasculature pathologies. We will focus on the tropical disease Dengue, which although mostly a mild disease can progress to a life-threatening haemorrhagic disease. The precise mechanisms leading to the disruption of the microvascular barrier leading to the observed acute leakage and hypovolemic shock are only partially elucidated. There are two key cell types involved in the structures of capillary system: endothelial cells and pericytes, and Dr Campagnolo has demonstrated for the first time that pericyte dysfunction is a driver in dengue haemorrhage. Specifically, she observed that the circulating protein NS1 affects pericyte function. We will focus on these results and construct a simulation of populations of pericytes and endothelial cells. We will simulate these populations within the 3D spheroids looking at cellular self-organisation and at viability. We will explore NS1 treatment and explain how the observed changes in pericyte behaviour (including changes in adhesion and contractility) would alter tissue functionality. The aim is to give mechanistic explanations of disease progression without the need for experiment. The models will, however, be validated against and parameterised from experimental data. Self-organisation, specifically cell sorting in tissues is additionally an area of broad and current biological interest and this study will resolve the relative importance of contractility control and differences in adhesion strength in this key process.