Precision Medicine Doctoral Training Programme

Reverse-engineering blood flow and transport in complex vascular organs: an in-silico approach to characterising pregnancy pathologies

Precision Medicine Project - Reverse-engineering blood flow and transport in complex vascular organs: an in-silico approach to characterising pregnancy pathologies

Supervisors: Dr Timm Krüger & Dr Miguel O. Bernabeu

Centre/Institute: School of Engineering 

Background

The human placenta performs diverse functions later taken on by several different organs. In particular, it mediates the exchange of vital solutes, including respiratory gases and nutrients, between the mother and the developing fetus. The complex heterogeneous structure of the placenta is adapted to perform these various functions. However, despite its availability for ex-vivo perfusion experiments just after birth and the importance of placental dysfunction in conditions such as fetal growth restriction, the link between placental structure and function in health and disease remains poorly understood [1].

Recent advances in three-dimensional (3D) imaging have revealed aspects of placental structure in intricate detail [1, 2]. Fetal blood flows from the umbilical cord through a complex network of vessels that are confined within multiple villous trees; the trees sit in chambers that are perfused with maternal blood. Much of the solute exchange between maternal and fetal blood takes place across the thin-walled peripheral branches of the trees (terminal villi) which contain the smallest feto-placental capillaries. Quantitative measurements have demonstrated structural differences between healthy and pathological placentas [3], but physical explanations for the observed symptoms of diseases such as pre-eclampsia and diabetes have so far been confined mainly to studies on two-dimensional histological data [2]. Little is known about how the elaborate and irregular 3D organisation of capillaries within terminal villi, the primary functional exchange units of the feto-placental circulation, contributes to solute exchange in health and disease.

The research will employ a state-of-the-art 3D imaging catalogue of placental microstructure to derive theoretical models of solute transport. The output of 3D confocal microscopy and X-ray micro-computed tomography covers a wide range of spatial scales, from 1 μm to 1 cm, which will aid in the design of computational models. The structural datasets will be complemented by the linked anonymised clinical characteristics from the National Pregnancy Biobank (St Mary’s Hospital, Manchester).

Aims

In this study, we will combine image analysis and computer simulations of blood flow as a suspension of deformable particles [4] to examine the dependence of solute transport on the geometrical arrangement of capillaries within terminal villi of the placenta. The properties of these functional exchange units will be quantified and encapsulated in a general theory of feto-placental transport that links the complex 3D structure of fetal microvascular networks to their solute exchange capacity. Particular emphasis will be placed in understanding how these mechanisms are compromised in pathological placentas taking advantage of recorded clinical endpoints. Future studies will investigate how this theory can complement current imaging modalities used for the risk-assessment and diagnosis of pregnancy complications in vivo.

Training Outcomes

The student will receive state-of-the-art training in the core disciplines of image analysis, computational modelling, and physiology while gaining expert knowledge in the context of placental research. This highly interdisciplinary approach is well aligned with the “T-shaped researcher” training requirements identified as key in the DTP in Precision Medicine. The student will develop the essential soft and domain-specific skills necessary to design and implement novel quantitative and computational methods that could solve challenging problems across the entire spectrum of cardiovascular medicine both in academic and industrial settings.

References

[1] Erlich A, et al. (2019) Physical and geometric determinants of transport in fetoplacental microvascular networks. Sci Adv 5:eaav6326.

[2] Jensen OE & Chernyavsky IL (2019) Blood flow and transport in the human placenta. Ann Rev Fluid Mech 51:25.

[3] Junaid TO, et al. (2017) Whole organ vascular casting and micro-CT examination of the human placental vascular tree reveals novel alterations associated with pregnancy disease. Sci Rep 7:4144.

[4] Bernabeu MO, et al. (2019) Abnormal morphology biases haematocrit distribution in tumour vasculature and contributes to heterogeneity in tissue oxygenation. preprint: https://www.biorxiv.org/content/10.1101/640060v1

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  • The deadline for 20/21 applications is Monday 6th April 2020.
  • Applicants must apply to a specific project, ensure you include details of the project you are applying to in Section 4 of your application. We encourage you to contact the primary supervisor prior to making your application.  
  • As you are applying to a specific project, you are not required to submit a Research Proposal as part of your application. 
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