Sweeney, Paul William; (2018) Realistic numerical image-based modelling of biological tissue substrates. Doctoral thesis (Ph.D), UCL (University College London).

Abstract

The development of preclinical tools to study fluid transport within biological tissue is critical to understanding not only the progression of disease, but the role of the microenvironment in healthy tissue. The limited availability of experimental data across all length scales provides scope for the development of mathematical models to simulate fluid transport throughout the microvasculature and surrounding tissue. Here, the novel REANIMATE (REAlistic Numerical Image-based Modelling of biologicAl Tissue substratEs) platform is developed which, guided by both ex vivo and in vivo imaging data, simulates fluid and solute transport in silico, based on real-world tissue substrates. In this thesis, the intravascular flow model of Fry et al. (2012) and and oxygen transport model of Secomb et al. (2004) are applied to an in vivo cortical microvascular network containing the locations of fluorescently-labelled vascular smooth muscle cells. The simulated results provide insights into the mechanisms underpinning local regulation of cerebral blood flow which would be inaccessible in a conventional experimental setting. Secondly, a transvascular model is developed to simulate the effective transport of fluid through the vasculature and into the interstitium. parameterised against in vivo perfusion data, the model is applied to two ex vivo colorectal tumour datasets to investigate the role of vascular heterogeneity in elevated interstitial fluid pressure within tumours. Next, this platform is used to simulate the steady-state fluid dynamics in a further two murine xenograft models of human colorectal carcinoma, allowing for the prediction of heterogeneous delivery of specific therapeutic agents to be compared with that observed in vivo. Finally, developing upon work by Shipley and Chapman (2010), a discrete-continuum model is developed which allows for the approximation of fluid transport through tissue in the absence of experimental data on tissue-specific vascular micro-structures, thereby providing additional information unavailable in the traditional experimental setting.

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