Mathematical modelling and optimisation of organ-on-a-chip in vitro systems

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An essential feature of adequate prediction of drug toxicity in preclinical pharmaceutical development is the use of cellular in vitro models that recapitulate the physiology of human tissues as closely as possible. 3D cellular systems that include physiologically realistic fluid flow are important in providing appropriate shear stresses required for mechanobiological responses and correct function of cells. They can also provide the transport and recirculation of drugs, nutrients and waste compounds, as well as signalling molecules such as cytokines and chemokines, which drive cell-cell communication that is critical for physiological functioning of cells in-vitro. The distribution of such solutes is relevant to understanding cellular function and can be used to enhance pharmacokinetic and cell-cell interaction and signalling models in toxicology studies. A specific focus is organ-on-a-chip models of liver cells, since hepatotoxicity is a major cause of clinical failure in drug development. These can be extended to include multiple cell types or multi organ systems (e.g. immune cells, gut cells) to incorporate further interactions relevant to the drug's mechanism of action. Mathematical modelling of such systems not only helps to understand and improve the physiological relevance of in vitro models, but will also enable the optimisation of relevant experimental settings, and most importantly, enable quantitative predictions regarding toxicity in the drug development process.Aims and ObjectivesConstruct mechanistic mathematical models for fluid flow and solute transport for a range of organ-on-a-chip systems, coupled to relevant models of cellular function (e.g. metabolism, immune mediated effector-target toxicity, cytokine release cell-cell communication).Obtain quantitative predictions of fluid flow, shear stresses, and concentration distributions, and compare with results obtained experimentally.Determine optimal design and operating conditions of the in vitro system (flow rates, scaffold properties, system geometry) in order to match the in vivo environment experienced by cells as closely as possible and/or optimise the performance of the systems as a tool for toxicity assessments. Inform and optimise experimental design and pharmacokinetic modelling through understanding of fluid flow.Understand impact of fluid dynamical load on cellular function.Obtain a general mathematical framework that can be applied and adapted to a variety of microfluidic systems, where advanced understanding of fluid mechanics can provide fundamental insights through the interaction between complex fluid flows and cell function, informing the drug discovery process.Novelty of Research MethodologyResearch methodology will include mechanistic mathematical modelling, analysis and in silico computation, in combination with experimental studies performed at Roche. The mathematical model will incorporate a combination of ideas from fluid dynamic modelling (Navier-Stokes, Darcy/Brinkman equations, multiphase flows, reaction-advection-diffusion equations) which apply to different components of the system.The model will be investigated through a combination of numerical techniques (e.g. finite-difference, finite element and spectral methods, use of commercial software) and analytical approaches on reduced models obtained by exploiting different time/length scales (e.g. linear and nonlinear stability theory, regular and singular perturbation theory, multiple-scales analysis, limiting cases in parameter space).Data will be obtained from experimental studies and imaging performed at Roche.