Flow and transport in tissue engineering scaffolds: A network modelling approach

This paper was presented at the 2nd Micro and Nano Flows Conference (MNF2009), which was held at Brunel University, West London, UK. The conference was organised by Brunel University and supported by the Institution of Mechanical Engineers, IPEM, the Italian Union of Thermofluid dynamics, the Process Intensification Network, HEXAG - the Heat Exchange Action Group and the Institute of Mathematics and its Applications.Tissue engineers aim to grow functional tissues in the laboratory. One approach is to seed cells on a porous biomaterial scaffold, which is then cultured in a flow perfusion bioreactor. Such bioreactors enhance the transport of nutrients and growth factors to the cells by convection, and provide mechanical loads to mechanosensitive tissues. In this paper, we adopt a network modelling approach to provide insight into the nature of the flow, nutrient transport and cell distribution through the porous scaffold. The approach resolves flow and nutrient transport at the pore scale, and thus enables the local cellular environment to be determined. We demonstrate how this method can be used to study the impact of scaffold geometry (e.g. porosity, connectivity) on the cellular environment, and hence provide insight into the optimum culture conditions required to obtain functional tissues.This study is funded by the EPSRC

Multiphase modelling of the effect of fluid shear stress on cell yield and distribution in a hollow fibre membrane bioreactor

We present a simplified two-dimensional model of fluid flow, nutrient transport and cell distribution in a hollow fibre membrane bioreactor, with the aim of exploring how fluid flow can be used to control the distribution and yield of a cell population which is sensitive to both fluid shear stress and nutrient concentration. The cells are seeded in a scaffold in a layer on top of the hollow fibre, only partially occupying the extracapillary space. Above this layer is a region of free-flowing fluid which we refer to as the upper fluid layer. The flow in the lumen and upper fluid layer is described by the Stokes equations, whilst the flow in the porous fibre membrane is assumed to follow Darcy’s law. Porous mixture theory is used to model the dynamics of and interactions between the cells, scaffold and fluid in the cell–scaffold construct. The concentration of a limiting nutrient (e.g. oxygen) is governed by an advection–reaction–diffusion equation in each region. Through exploitation of the small aspect ratio of each region and asymptotic analysis, we derive a coupled system of partial differential equations for the cell volume fraction and nutrient concentration. We use this model to investigate the effect of mechanotransduction on the distribution and yield of the cell population, by considering cases in which cell proliferation is either enhanced or limited by fluid shear stress and by varying experimentally controllable parameters such as flow rate and cell–scaffold construct thickness

A continuum model for the elongation and orientation of Von Willebrand factor with applications in arterial flow

The blood protein Von Willebrand factor (VWF) is critical in facilitating arterial thrombosis. At pathologically high shear rates, the protein unfolds and binds to the arterial wall, enabling the rapid deposition of platelets from the blood. We present a novel continuum model for VWF dynamics in fow based on a modifed viscoelastic fuid model that incorporates a single constitutive relation to describe the propensity of VWF to unfold as a function of the scalar shear rate. Using experimental data of VWF unfolding in pure shear fow, we fx the parameters for VWF’s unfolding propensity and the maximum VWF length, so that the protein is half unfolded at a shear rate of approximately 5000 s−1 . We then use the theoretical model to predict VWF’s behaviour in two complex fows where experimental data are challenging to obtain: pure elongational fow and stenotic arterial fow. In pure elongational fow, our model predicts that VWF is 50% unfolded at approximately 2000 s−1 , matching the established hypothesis that VWF unfolds at lower shear rates in elongational fow than in shear fow. We demonstrate the sensitivity of this elongational fow prediction to the value of maximum VWF length used in the model, which varies signifcantly across experimental studies, predicting that VWF can unfold between 2000 and 3200 s−1 depending on the selected value. Finally, we examine VWF dynamics in a range of idealised arterial stenoses, predicting the relative extension of VWF in elongational fow structures in the centre of the artery compared to high shear regions near the arterial walls

Mathematical modelling of nanoparticle delivery to vascular tumours

This paper was presented at the 2nd Micro and Nano Flows Conference (MNF2009), which was held at Brunel University, West London, UK. The conference was organised by Brunel University and supported by the Institution of Mechanical Engineers, IPEM, the Italian Union of Thermofluid dynamics, the Process Intensification Network, HEXAG - the Heat Exchange Action Group and the Institute of Mathematics and its Applications.The goal of any cancer therapy is to achieve efficient, tissue-specific targeting of drugs to cancer cells. However, most anticancer agents act on healthy and malignant tissue alike, potentially resulting in side effects to healthy tissue. This has motivated the development of treatment strategies that are cancer-cell specific; one approach uses biomimetic polymer vesicles (BPV) to deliver chemotherapeutic drugs into cells before releasing them. BPVs are synthetic membrane enclosed, nanometre-sized structures, and provide ideal drug delivery vectors because specific targeting to cancer cells can be achieved by coating with tumourspecific molecules. We present several mathematical models covering a wide range of length-scales pertinent to BPV-mediated delivery protocols and focus on capturing the in vivo environment by evaluating the impact of the underlying vascular structure upon the governing transport mechanisms. Firstly, we present models of specific binding of BPVs to cancer cells. Subsequently we examine the implications of these model outputs in the contexts of both discrete capillary architectures and higher level homogenized-models that track blood and BPV transport at the tissue scale (both intra- and extra-tumorally). Numerical solutions are discussed, and recommendations are presented on that optimal integration of the models to generate quantitative predictions associated with BPV treatment efficacy

Flow in an Elastic Tube Subject to Prescribed Forcing: A Model of Umbilical Venous Flow

We investigate the fluid flow through a finite length, axisymmetric tube when the elastic wall is subject to either a prescribed external pressure or a prescribed motion. The prescribed wall forcing is assumed to consist of a forward travelling wave together with a reflected travelling wave. The dimensionless diameter variation of the tube is taken to be small and perturbation techniques are used to solve the weakly non-linear problem. Particular attention is given to the steady streaming flow that is induced through the non-linear convective acceleration terms. The results are applied to the flow of blood in the umbilical vein (UV), which has important physiological implications.Peer Reviewe

No overall impact on rate of weight gain with integrase inhibitor-containing regimens in antiretroviral-naïve adults

OBJECTIVES: Integrase strand transfer inhibitors (INSTIs) are commonplace in modern antiretroviral therapy (ART). Increased weight gain with their use is increasingly scrutinized. We evaluated weight changes in treatment-naïve adults with HIV-1 attending a UK centre who started regimens including raltegravir or dolutegravir. METHODS: A retrospective cohort study of adults prescribed an INSTI between January 2015 and March 2020 were categorized as having started an ART regimen containing raltegravir, dolutegravir, a protease inhibitor or a nonnucleoside reverse transcriptase inhibitor. Individuals with one or more weight measurement ≤ 5 years both pre- and post-ART initiation, who started a three-drug regimen with ≥ 6 months duration and achieved virological suppression (< 50 copies/mL) within 6 months were included. A random effects model with linear slope pre- and post-ART was used, adjusting for age, gender, ethnicity, ART regimen, backbone and year of initiation. RESULTS: The cohort included 390 adults; 88.7% were male, 66.4% were of white ethnicity, their median age was 40 years, there was a median of six weight measurements, 2.2 years from diagnosis to ART initiation, 2.9 years from ART to the last weight measurement, and weight and body mass index at initiation were 75 kg and 24.1 kg/m2 respectively. Of these, 254 (65%) started an INSTI. The average pre-ART rate of weight gain was 0.44 kg/year [95% confidence interval (CI): 0.19-0.70], increasing to 0.88 kg/year (0.63-1.10, p = 0.04) after ART initiation. Our adjusted model found no evidence of an association between ART regimen and rate of weight gain. CONCLUSIONS: Weight increased in the cohort both pre- and post-ART. We found no evidence of a higher rate of weight gain following ART initiation with an INSTI compared with other regimens

Traces of volcanic ash from the Mediterranean, Iceland and North America in a Holocene record from South Wales, UK

A tephra record is presented for a sediment core from Llyn Llech Owain, south Wales, spanning the early‐ to mid‐Holocene. Seven cryptotephra deposits are discovered with three thought to correlate with known eruptions and the remaining four considered to represent previously undocumented events. One deposit is suggested to correlate with the ~6.9 cal ka bp Lairg A tephra from Iceland, whereas more distant sources are proposed as the origin for two of the tephra deposits. A peak of colourless shards in early‐Holocene sediments is thought to tentatively correlate with the ~9.6 cal ka bp Fondi di Baia tephra (Campi Flegrei) and a second cryptotephra is tentatively correlated with the ~3.6 cal ka bp Aniakchak (CFE) II tephra (Alaska). The Fondi di Baia tephra has never been recorded beyond proximal sites and its discovery in south Wales significantly extends the geographical distribution of ash from this eruption. The remaining four cryptotephra deposits are yet to be correlated with known eruptions, demonstrating that our current understanding of widespread tephra deposits is incomplete. This new tephra record highlights the potential for sites at more southerly and westerly locations in northwest Europe to act as repositories for ash from several volcanic regions

Multiple communication mechanisms between sensor kinases are crucial for virulence in Pseudomonas aeruginosa

This is the author accepted manuscript. The final version is available as an open access article from the publisher via the DOI in this recordBacteria and many non-metazoan Eukaryotes respond to stresses and threats using two-component systems (TCSs) comprising sensor kinases (SKs) and response regulators (RRs). Multikinase networks, where multiple SKs work together, detect and integrate different signals to control important lifestyle decisions such as sporulation and virulence. Here, we study interactions between two SKs from Pseudomonas aeruginosa, GacS and RetS, which control the switch between acute and chronic virulence. We demonstrate three mechanisms by which RetS attenuates GacS signalling: RetS takes phosphoryl groups from GacS-P; RetS has transmitter phosphatase activity against the receiver domain of GacS-P; and RetS inhibits GacS autophosphorylation. These mechanisms play important roles in vivo and during infection, and exemplify an unprecedented degree of signal processing by SKs that may be exploited in other multikinase networks.This work was supported by the Medical Research Council (MRC) (grant number MR/ M020045/1), the Leverhulme Trust (grant number RPG-2014-228), the RoseTrees Trust (grant number M328) and a NERC PhD studentship (grant number 1076449)

Quality of private and public ambulatory health care in low and middle income countries: systematic review of comparative studies

Paul Garner and colleagues conducted a systematic review of 80 studies to compare the quality of private versus public ambulatory health care in low- and middle-income countries