title: Mathematical modelling of cell layer growth in a hollow fibre bioreactor.
abstract: Generating autologous tissue grafts of a clinically useful volume requires efficient and controlled expansion of cell populations harvested from patients. Hollow fibre bioreactors show promise as cell expansion devices, owing to their potential for scale-up. However, further research is required to establish how to specify appropriate hollow fibre bioreactor operating conditions for expanding different cell types. In this study we develop a simple model for the growth of a cell layer seeded on the outer surface of a single fibre in a perfused hollow fibre bioreactor. Nutrient-rich culture medium is pumped through the fibre lumen and leaves the bioreactor via the lumen outlet or passes through the porous fibre walls and cell layer, and out via ports on the outer wall of the extra-capillary space. Stokes and Darcy equations for fluid flow in the fibre lumen, fibre wall, cell layer and extra-capillary space are coupled to reaction-advection-diffusion equations for oxygen and lactate transport through the bioreactor, and to a simple growth law for the evolution of the free boundary of the cell layer. Cells at the free boundary are assumed to proliferate at a rate that increases with the local oxygen concentration, and to die and detach from the layer if the local fluid shear stress or lactate concentration exceed critical thresholds. We use the model to predict operating conditions that maximise the cell layer growth for different cell types. In particular, we predict the optimal flow rate of culture medium into the fibre lumen and fluid pressure imposed at the lumen outlet for cell types with different oxygen demands and fluid shear stress tolerances, and compare the growth of the cell layer when the exit ports on the outside of the bioreactor are open with that when they are closed. Model simulations reveal that increasing the inlet flow rate and outlet fluid pressure increases oxygen delivery to the cell layer and, therefore, the growth rate of cells that are tolerant to high shear stresses, but may be detrimental for shear-sensitive cells. The cell layer growth rate is predicted to increase, and be less sensitive to the lactate tolerance of the cells, when the exit ports are opened, as the radial flow through the bioreactor is enhanced and the lactate produced by the cells cleared more rapidly from the cell layer.
authors.affiliation: Mathematical Institute, University of Oxford, Andrew Wiles Building, Radcliffe Observatory Quarter, Woodstock Road, Oxford OX2 6GG, UK; Department of Computer Science, University of Oxford, Wolfson Building, Parks Road, Oxford OX1 3QD, UK. Electronic address: l.chapman.1@warwick.ac.uk.
authors.forename: Lloyd A C
authors.initials: LAC
authors.lastname: Chapman
authors.affiliation: Department of Computer Science, University of Oxford, Wolfson Building, Parks Road, Oxford OX1 3QD, UK. Electronic address: jonathan.whiteley@cs.ox.ac.uk.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Whiteley
authors.affiliation: Mathematical Institute, University of Oxford, Andrew Wiles Building, Radcliffe Observatory Quarter, Woodstock Road, Oxford OX2 6GG, UK; Department of Computer Science, University of Oxford, Wolfson Building, Parks Road, Oxford OX1 3QD, UK. Electronic address: helen.byrne@maths.ox.ac.uk.
authors.forename: Helen M
authors.initials: HM
authors.lastname: Byrne
authors.affiliation: Mathematical Institute, University of Oxford, Andrew Wiles Building, Radcliffe Observatory Quarter, Woodstock Road, Oxford OX2 6GG, UK. Electronic address: waters@maths.ox.ac.uk.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Waters
authors.affiliation: Department of Mechanical Engineering, University College London, Torrington Place, London WC1E 7JE, UK. Electronic address: rebecca.shipley@ucl.ac.uk.
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Shipley
mesh_terms: D000818:Animals; D019149:Bioreactors; D002417:Cattle; D018929:Cell Culture Techniques; D002460:Cell Line; D006801:Humans; D008954:Models, Biological; D051381:Rats
keywords: Bioreactor; Cell population growth; Fluid shear stress; Oxygen and lactate transport; Tissue engineering