Category: Standard Studentships

Modelling drug transfer through placental nanopores

Project No. 2154

Primary Supervisor

Dr Bram Sengers – University of Southampton

Co-Supervisor(s)

Professor Rohan Lewis – University of Southampton

Dr Anthony Lewis – University of Portsmouth

Summary

Rationale:

How pharmaceuticals and environmental toxins cross the placenta is not clear and this has a direct impact on drug safety.

There is physiological evidence for a diffusive pathway across the placenta, but no anatomical route has been previously demonstrated.

Recently we performed the first three-dimensional ultrastructural analysis of the human placental barrier. This analysis revealed novel trans-syncytial nanopores directly connecting the maternal and fetal sides of the placental barrier (Fig. 1). Computational modelling of diffusion through these complex trans-syncytial nanopores can estimate their permeability.

Figure 1: 3D image based computational model of solute transport through a placental nanopore, showing the gradient between the high maternal (red) and low fetal concentrations (blue).

Many drugs are charged and the physiological significance of these nanopores will critically depend on the pore density, molecular size and electrochemical gradients.

The aim of this project is to establish the role of nanopores in placental transfer in a quantitative manner, using a fully integrated experimental and computational modelling approach.

Approach:

To clearly distinguish the contribution of nanopores to placental transfer, we will use charged and uncharged solutes of different molecular size, including those that are not membrane permeable and are not transporter substrates.

Imaging – 3D serial-section SEM will be used to determine the density of nanopores and their geometry, including key parameters such as path length and pore diameter.
Computational modelling – Image based 3D computational (Finite Element) models of electrodiffusion in individual nanopores will be used to predict the overall effective transfer at the tissue scale.
Electrophysiology – Measurements of solute influx in placental tissue fragments will be used to determine the effective membrane permeability for the modelling.

Impact:

Trans-syncytial nanopores may provide an essential mechanism to maintain hydrostatic and osmotic pressure homeostasis but may expose the fetus to pharmaceuticals and environmental pollutants.