A Numerical Study Of A Permeable Capsule Under Stokes Flows By The Immersed Interface Method

Ph.DDOCTOR OF PHILOSOPH

Individual based model links thermodynamics, chemical speciation and environmental conditions to microbial growth

Individual based Models (IbM) must transition from research tools to engineering tools. To make the transition we must aspire to develop large, three dimensional and physically and biologically credible models. Biological credibility can be promoted by grounding, as far as possible, the biology in thermodynamics. Thermodynamic principles are known to have predictive power in microbial ecology. However, this in turn requires a model that incorporates pH and chemical speciation. Physical credibility implies plausible mechanics and a connection with the wider environment. Here, we propose a step toward that ideal by presenting an individual based model connecting thermodynamics, pH and chemical speciation and environmental conditions to microbial growth for 5·105 individuals. We have showcased the model in two scenarios: a two functional group nitrification model and a three functional group anaerobic community. In the former, pH and connection to the environment had an important effect on the outcomes simulated. Whilst in the latter pH was less important but the spatial arrangements and community productivity (that is, methane production) were highly dependent on thermodynamic and reactor coupling. We conclude that if IbM are to attain their potential as tools to evaluate the emergent properties of engineered biological systems it will be necessary to combine the chemical, physical, mechanical and biological along the lines we have proposed. We have still fallen short of our ideals because we cannot (yet) calculate specific uptake rates and must develop the capacity for longer runs in larger models. However, we believe such advances are attainable. Ideally in a common, fast and modular platform. For future innovations in IbM will only be of use if they can be coupled with all the previous advances

Three-dimensional numerical analysis of periciliary liquid layer: Ciliary abnormalities in respiratory diseases

Human pulmonary epithelial cells are protected by two layers of fluid—the outer watery periciliary liquid layer (PCL) and the uppermost non-Newtonian mucus layer (ML). Aerosols and inhaled toxic particles are trapped by the ML which must then be removed swiftly to avoid adverse health implications. Epithelial cells are covered with cilia that beat rapidly within the PCL. Such ciliary motion drives the mucus transport. Although cilia can penetrate slightly inside the mucus to assist mucus movement, the motion of the underlying PCL layer within the airway surface liquid (ASL) is significant in mucus and pathogens transport. As such, a detailed parametric study of the influence of different abnormal cilia characteristics, such as low beating frequency, short length, abnormal beating pattern, reduced ciliary density, and epithelium patchiness due to missing cilia on the PCL transport, is carried out numerically. Such abnormalities are found in various chronic respiratory diseases. In addition, the shear stress at the epithelium is assessed due to the importance of shear stress on the epithelial function. Using the immersed boundary (IB) method combined with the finite-difference projection method, we found that the PCL, under standard healthy conditions, has net forward motion but that different diseased conditions decrease the forward motion of the PCL, as is expected based on clinical understanding

Transport and fate of inhaled particles after deposition onto the airway surface liquid: A 3D numerical study

In this paper, a numerical investigation is carried out to provide insights into the fate of inhaled aerosols after their deposition on the lung lining fluid in both healthy and diseased states. Pulmonary drug delivery is a well-known non-invasive route of administration compared to intravenous delivery. Aerosol particles are formulated and used as drug carriers, which are then sent to the airways using aerosol drug delivery devices. This approach is useful for site-specific treatment of lung diseases, treatment of central nervous system (CNS) disorders and a variety of other diseases. Bioavailability of the inhaled therapeutic particles after landing on the airway lining fluid can be significantly altered by the lung muco-ciliary clearance, a process through which hairlike structures known as cilia beat in a harmonised manner and induce the mucus in the proximal direction, leading to an effective clearance of the foreign inhaled particles entrapped by this sticky layer from the airways. Here, we set up a 3D computational model of ciliary arrays interacting with periciliary liquid film (i.e. confined between the epithelium and mucus layer) and a detailed analysis is conducted to better understand the fate of drug nanoparticles that are able to penetrate the mucus. Consistent with clinical findings, we find that the actions of cilia result in a low rate of drug retention and absorption by the pulmonary tissues in healthy lungs. However, under conditions associated with abnormal ciliary beats, the retention time of particles is notably increased at the site of release. Nonetheless, the results associated with some of the ciliary impairments reveal that deposition of drug aerosols on the ciliated cells may still be a significant challenge. These findings have potentially important implications on the modification of therapeutic drug particles to achieve a higher absorption rate.</p

Bayesian emulation and calibration of an individual-based model of microbial communities

Individual-based (IB) modelling has been widely used for studying the emergence of complex interactions of bacterial biofilms and their environment. We describe the emulation and calibration of an expensive dynamic simulator of an IB model of microbial communities. We used a combination of multivariate dynamic linear models (DLM) and a Gaussian process to estimate the model parameters of our dynamic emulators. The emulators incorporate a smoothly varying and nonstationary trend that is modelled as a deterministic function of explanatory variables while the Gaussian process (GP) is allowed to capture the remaining intrinsic local variations. We applied this emulation strategy for parameter calibration of a newly developed model for simulation of microbial communities against the iDynoMiCS model. The percentage of variance explained for the four outputs biomass concentration, the total number of particles, biofilm average height and surface roughness range between 84—92% and 97–99% for univariate and multivariate emulators respectively. The simulation-based sensitivity analysis identified carbon substrate, oxygen concentration and maximum specific growth rate for heterotrophic bacteria as the most critical variables for predictions. The calibration results also indicated a general reduction of uncertainty levels in most of the parameters. The study has helped us identify the tradeoff in using different types of models for microbial simulation. The approach illustrated here provides a tractable and computationally efficient technique for calibrating the parameters of an expensive computer model

Muco-ciliary clearance:A review of modelling techniques

The airways of the human respiratory system are covered by a protective layer, which is known as airway surface liquid (ASL). This layer consists of two relatively distinct sub-layers; a mucus layer (ML), and a periciliary liquid layer (PCL). In addition, the airways are lined with a dense mat of hair-like structures, called cilia, which beat back and forth in a co-ordinated manner and mainly propel the mucus layer. Such interaction between the cilia and mucus is called ‘muco-ciliary clearance’ (MCC) which is essential to clear the respiratory airways from the inhaled toxic particles deposited on the mucus. The complex nature of lung clearance mechanisms limit the ability to conduct experiments to investigate micro-scale physiological phenomena. As such, modelling techniques are commonly implemented to investigate the effects of biological parameters on the lung muco-ciliary clearance. In the present work, modelling techniques of cilia-ASL interactions – including continuum cilia modelling and discrete cilia modelling – are reviewed and the numerical procedures and level of complexity related to each technique are explained. This is followed by a detailed analysis of the airway surface liquid modelling approaches. In addition, findings of numerical investigations related to the effects of various parameters such as ciliary beat frequency (CBF), mucus rheology, metachronal waves of cilia, surface tension at the PCL-mucus interface, ciliary length, ciliary density, and airway surface liquid depth on the bronchial and tracheal ASL transport are reviewed. This review also explains how these biological parameters can alter the internal power required to perform ciliary beating. Lastly, the main limitations of current numerical works are discussed and significant research directions are brought forward that may be considered in future models to better understand this complex human biological system and its vital clearance mechanism.</p

Coupled CFD-DEM modelling to predict how EPS affects bacterial biofilm deformation, recovery and detachment under flow conditions

The deformation and detachment of bacterial biofilm are related to the structural and mechanical properties of the biofilm itself. Extracellular polymeric substances (EPS) play an important role on keeping the mechanical stability of biofilms. The understanding of biofilm mechanics and detachment can help to reveal biofilm survival mechanisms under fluid shear and provide insight about what flows might be needed to remove biofilm in a cleaning cycle or for a ship to remove biofilms. However, how the EPS may affect biofilm mechanics and its deformation in flow conditions remains elusive. To address this, a coupled computational fluid dynamic – discrete element method (CFD-DEM) model was developed. The mechanisms of biofilm detachment, such as erosion and sloughing have been revealed by imposing hydrodynamic fluid flow at different velocities and loading rates. The model, which also allows adjustment of the proportion of different functional group of microorganisms in the biofilm, enables the study of the contribution of EPS towards biofilm resistance to fluid shear stress. Furthermore, the stress-strain curves during biofilm deformation have been captured by loading and unloading fluid shear stress to study the viscoelastic properties of the biofilm.Keywords: biofilm deformation, mechanical properties, discrete element method, computational fluid dynamics, shear modulu

NUFEB: A massively parallel simulator for individual-based modelling of microbial communities.

We present NUFEB (Newcastle University Frontiers in Engineering Biology), a flexible, efficient, and open source software for simulating the 3D dynamics of microbial communities. The tool is based on the Individual-based Modelling (IbM) approach, where microbes are represented as discrete units and their behaviour changes over time due to a variety of processes. This approach allows us to study population behaviours that emerge from the interaction between individuals and their environment. NUFEB is built on top of the classical molecular dynamics simulator LAMMPS (Large-scale Atomic/Molecular Massively Parallel Simulator), which we extended with IbM features. A wide range of biological, physical and chemical processes are implemented to explicitly model microbial systems, with particular emphasis on biofilms. NUFEB is fully parallelised and allows for the simulation of large numbers of microbes (107 individuals and beyond). The parallelisation is based on a domain decomposition scheme that divides the domain into multiple sub-domains which are distributed to different processors. NUFEB also offers a collection of post-processing routines for the visualisation and analysis of simulation output. In this article, we give an overview of NUFEB's functionalities and implementation details. We provide examples that illustrate the type of microbial systems NUFEB can be used to model and simulate

A Bayesian approach to modelling the impact of hydrodynamic shear stress on biofilm deformation

We investigate the feasibility of using a surrogate-based method to emulate the deformation and detachment behaviour of a biofilm in response to hydrodynamic shear stress. The influence of shear force, growth rate and viscoelastic parameters on the patterns of growth, structure and resulting shape of microbial biofilms was examined. We develop a statistical modelling approach to this problem, using combination of Bayesian Poisson regression and dynamic linear models for the emulation. We observe that the hydrodynamic shear force affects biofilm deformation in line with some literature. Sensitivity results also showed that the expected number of shear events, shear flow, yield coefficient for heterotrophic bacteria and extracellular polymeric substance (EPS) stiffness per unit EPS mass are the four principal mechanisms governing the bacteria detachment in this study. The sensitivity of the model parameters is temporally dynamic, emphasising the significance of conducting the sensitivity analysis across multiple time points. The surrogate models are shown to perform well, and produced ≈ 480 fold increase in computational efficiency. We conclude that a surrogate-based approach is effective, and resulting biofilm structure is determined primarily by a balance between bacteria growth, viscoelastic parameters and applied shear stress

Biofilm structures showing temporal evolution of effect of shear rate on biofilm deformation and bacteria detachment for different shear rates for the period the flow is applied.

<p>Left-plot: <i>γ</i> = 0.26<i>s</i>⁻¹ and right-plot: <i>γ</i> = 0.37<i>s</i>⁻¹ for 40,000, 80,000, 120,000, 160,000 and 200,000 seconds respectively.</p