• In vitro and computational modelling of drug delivery across the outer blood–retinal barrier

      Davies, Alys E.; orcid: 0000-0002-3489-0182; Williams, Rachel L.; Lugano, Gaia; Pop, Serban R.; Kearns, Victoria R.; orcid: 0000-0003-1426-6048 (The Royal Society, 2020-02-14)
      The ability to produce rapid, cost-effective and human-relevant data has the potential to accelerate the development of new drug delivery systems. Intraocular drug delivery is an area undergoing rapid expansion, due to the increase in sight-threatening diseases linked to increasing age and lifestyle factors. The outer blood–retinal barrier (OBRB) is important in this area of drug delivery, as it separates the eye from the systemic blood flow. This study reports the development of complementary in vitro and in silico models to study drug transport from silicone oil across the OBRB. Monolayer cultures of a human retinal pigmented epithelium cell line, ARPE-19, were added to chambers and exposed to a controlled flow to simulate drug clearance across the OBRB. Movement of dextran molecules and release of ibuprofen from silicone oil in this model were measured. Corresponding simulations were developed using COMSOL Multiphysics computational fluid dynamics software and validated using independent in vitro datasets. Computational simulations were able to predict dextran movement and ibuprofen release, with all of the features of the experimental release profiles being observed in the simulated data. Simulated values for peak concentrations of permeated dextran and ibuprofen released from silicone oil were within 18% of the in vitro results. This model could be used as a predictive tool for drug transport across this important tissue.
    • In vitro and computational modelling of drug delivery across the outer blood–retinal barrier

      Davies, Alys E.; orcid: 0000-0002-3489-0182; Williams, Rachel L.; Lugano, Gaia; Pop, Serban R.; Kearns, Victoria R.; orcid: 0000-0003-1426-6048 (The Royal Society, 2020-02-14)
      The ability to produce rapid, cost-effective and human-relevant data has the potential to accelerate the development of new drug delivery systems. Intraocular drug delivery is an area undergoing rapid expansion, due to the increase in sight-threatening diseases linked to increasing age and lifestyle factors. The outer blood–retinal barrier (OBRB) is important in this area of drug delivery, as it separates the eye from the systemic blood flow. This study reports the development of complementary in vitro and in silico models to study drug transport from silicone oil across the OBRB. Monolayer cultures of a human retinal pigmented epithelium cell line, ARPE-19, were added to chambers and exposed to a controlled flow to simulate drug clearance across the OBRB. Movement of dextran molecules and release of ibuprofen from silicone oil in this model were measured. Corresponding simulations were developed using COMSOL Multiphysics computational fluid dynamics software and validated using independent in vitro datasets. Computational simulations were able to predict dextran movement and ibuprofen release, with all of the features of the experimental release profiles being observed in the simulated data. Simulated values for peak concentrations of permeated dextran and ibuprofen released from silicone oil were within 18% of the in vitro results. This model could be used as a predictive tool for drug transport across this important tissue.
    • Quantifying the impact of tissue metabolism on solute transport in feto-placental microvascular networks

      Erlich, Alexander; orcid: 0000-0002-2294-1894; Nye, Gareth A.; orcid: 0000-0003-4508-0406; Brownbill, Paul; orcid: 0000-0002-8328-7072; Jensen, Oliver E.; orcid: 0000-0003-0172-6578; Chernyavsky, Igor L.; orcid: 0000-0003-0284-9318 (The Royal Society, 2019-08-16)
      The primary exchange units in the human placenta are terminal villi, in which fetal capillary networks are surrounded by a thin layer of villous tissue, separating fetal from maternal blood. To understand how the complex spatial structure of villi influences their function, we use an image-based theoretical model to study the effect of tissue metabolism on the transport of solutes from maternal blood into the fetal circulation. For solute that is taken up under first-order kinetics, we show that the transition between flow-limited and diffusion-limited transport depends on two new dimensionless parameters defined in terms of key geometric quantities, with strong solute uptake promoting flow-limited transport conditions. We present a simple algebraic approximation for solute uptake rate as a function of flow conditions, metabolic rate and villous geometry. For oxygen, accounting for nonlinear kinetics using physiological parameter values, our model predicts that villous metabolism does not significantly impact oxygen transfer to fetal blood, although the partitioning of fluxes between the villous tissue and the capillary network depends strongly on the flow regime.
    • Quantifying the impact of tissue metabolism on solute transport in feto-placental microvascular networks

      Erlich, Alexander; orcid: 0000-0002-2294-1894; Nye, Gareth A.; orcid: 0000-0003-4508-0406; Brownbill, Paul; orcid: 0000-0002-8328-7072; Jensen, Oliver E.; orcid: 0000-0003-0172-6578; Chernyavsky, Igor L.; orcid: 0000-0003-0284-9318 (The Royal Society, 2019-08-16)
      The primary exchange units in the human placenta are terminal villi, in which fetal capillary networks are surrounded by a thin layer of villous tissue, separating fetal from maternal blood. To understand how the complex spatial structure of villi influences their function, we use an image-based theoretical model to study the effect of tissue metabolism on the transport of solutes from maternal blood into the fetal circulation. For solute that is taken up under first-order kinetics, we show that the transition between flow-limited and diffusion-limited transport depends on two new dimensionless parameters defined in terms of key geometric quantities, with strong solute uptake promoting flow-limited transport conditions. We present a simple algebraic approximation for solute uptake rate as a function of flow conditions, metabolic rate and villous geometry. For oxygen, accounting for nonlinear kinetics using physiological parameter values, our model predicts that villous metabolism does not significantly impact oxygen transfer to fetal blood, although the partitioning of fluxes between the villous tissue and the capillary network depends strongly on the flow regime.