Modelling nutrient transfer across the placenta

Abstract

The placenta is a fetal organ that separates the maternal from the fetal circulation and mediates the transfer of nutrients between the mother and the fetus. Placental transfer of nutrients occurs across the placental villi, which are finely branched tree-like structures. Nutrients from the maternal blood in the intervillous space cross the villous barrier and then enter the fetal capillaries. A healthy pregnancy outcome is dependent on adequate placental transfer of gases and nutrients from the maternal to the fetal circulation. Impairments in nutrient transfer lead to altered fetal growth, which also has health implications in later life. While the transport mechanisms that mediate this transfer are known, the ways in which these interact as a system are not well understood.

Mathematical modelling provides a tool to enhance the interpretation of placental transfer experiments. In this thesis, physiologically based compartmental models were employed for the study of nutrient transfer between the mother and the fetus and validated with data from ex vivo placental perfusion and in vivo clinical experiments. With respect to previous models, a more extensive range of modelling applications is presented in this thesis including several different transport mechanisms. Model implementation was carried out for fatty acids, amino acids and cortisol. In particular, fatty acids were studied extensively in vivo and in vitro. In addition, a 3D image based modelling approach of the placental microstructures was carried out. The main novelty compared to previous approaches was that the transport of nutrients in the maternal blood was modelled explicitly and a study of nutrient uptake with respect to different maternal blood flow rates was performed.

The main objectives of this thesis were to increase the biological understanding of placental transfer and to provide a platform for quantification, prediction and evaluation of nutrient transfer across the placenta. This may ultimately form the basis for clinical tools to help physicians to prevent, recognise, intervene and cure problematic pregnancies.

The main results of the thesis were that placental metabolism was found to play a rate-limiting role in fatty acid and amino acid transfer and that the flow environment in the placental microstructure had a significant effect on limiting transfer. Examples of application of the proposed models to experimental data from external collaborators was successful and enhanced their interpretation and value.

Future work needs to focus on the further investigation of placental metabolism, such as the localisation and characterisation of metabolic sub compartments. Moreover, future modelling investigation of the 3D microstructure of the placenta should focus on the inclusion of both maternal and fetal capillary flow and the implememntation of more complex transport mechanisms. The models developed in this thesis could equally be used to study the transfer of other substances, e.g. drugs or toxins, in normal and altered pregnancies. In this respect, the models presented should be integrated as part of the realisation of a “virtual” placenta.

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Identifiers

ORCID for Bram Sengers: orcid.org/0000-0001-5859-6984

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