Coy, Rachel Hannah; (2020) Modelling the Impact of Cell Seeding Strategies on Cell Survival and Vascularisation in Engineered Tissue. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Currently, the design of tissue engineered constructs for peripheral nerve repair is informed predominantly by experiments. However, translation to the clinical setting is slow, and engineered tissues have not surpassed the outcomes achieved by nerve grafts. Therapeutic cell survival and vascularisation are important for the assimilation of engineered tissue, and vascularisation provides vital directional cues for regenerating nerves. In this thesis, mathematical modelling informed by experimental data is used to investigate the impact of different therapeutic cell seeding strategies on cell survival and vascularisation in engineered tissue nerve repair constructs. A mathematical model of interactions between cells, oxygen and vascular endothelial growth factor (VEGF), consisting of three partial differential equations, is developed and parameterised against in vitro data. Key cell type-specific parameter values are derived, and the model is then used to simulate cell-solute interactions in a nerve repair construct over the first five days post-implantation in vivo. Simulations using uniform seeding cell densities of 88 and 13 × 10⁶ cells/ml result in the highest mean viable cell densities across the construct after 1 and 5 days respectively. However, simulations using seeding densities in the range of 200 – 300 ×10⁶ cells/ml result in steeper VEGF gradients and higher total VEGF concentrations across the construct, which could be beneficial for vascularisation. Simulations incorporating a porous construct sheath result in higher viable cell density predictions, but also lower total VEGF concentrations, than those run using an impermeable sheath. Subsequently, the cell-solute model is combined with a discrete model of angiogenesis that simulates vascular growth in response to gradients of VEGF. Simulation results suggest that different cell seeding strategies could influence the density, rate and morphology of vascularisation. The predictions generated in this work demonstrate how mathematical modelling as part of a wider multidisciplinary approach can provide direction for future experimental work.

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