Novel Models for Haemodynamics and Transport in Complex Media: Towards Precision Healthcare for Placental Disorders

Pre-term and stillbirths affect up to 10% of all deliveries, including in developed countries, such as the UK. Among these complications, pre-eclampsia, or the compromised supply of blood between mother and fetus via the placenta, costs over £1.2 billion each year in neonatal and infant care to the NHS and public sector services in the UK alone.

The human placenta is a vital life-support system for the developing fetus. The supply of oxygen and nutrients by the mother's blood has to be well orchestrated within a complex fetal blood vessel network. There are two reasons for our limited progress in the understanding of the interaction of the structure and the function of the placenta: on the one hand, the human placenta has an extraordinarily complex structure; on the other hand, the structure and physiology of the human placenta are unique and therefore animal studies are of limited use. A direct consequence of the lack of understanding are very limited options for clinical management of pregnancy diseases such as pre-eclampsia and fetal growth restriction. Furthermore, placental insufficiency does not only result in stillbirth or premature delivery, but it has also been associated with a higher risk of heart attack, stroke, diabetes or neurological disorders later in adult life.

Recognition of these challenges has resulted in a recent surge of research interest world-wide and in establishing the $41M US Human Placenta Project and the EU Placentology Network for experimental and theoretical testing of chemicals' safety in pregnancy. Moreover, a recent breakthrough in 'artificial placenta' design for life-support of extremely premature infants offers new opportunities for design optimisation by systematic 'reverse engineering' of the normal human placenta. Thus, the UK needs a critical mass of expertise in placental technologies to match the US and EU capacities and to remain an active player in international collaborations in this important area.

Based on our research to date, we hypothesise that blood flow and nutrient transport in the placenta are altered in pre-eclampsia and fetal growth restriction. In this project, we propose an interdisciplinary and innovative approach harnessing our theoretical and experimental expertise to deliver precision medicine for obstetrics and neonatal critical care. We will develop and validate a framework for image-based modelling and simulation of blood flow and nutrient transport in patient-specific placentas. Thanks to existing datasets describing the structure of both healthy and diseased placentas, we will be able to explore which anatomical changes in the placenta are associated with compromised nutrient transport. This will establish a sound theoretical basis for the development of interventions and artificial solutions for the treatment of pre-eclampsia and fetal growth restriction. The long-term translational impacts include (i) model-based patient-specific treatment with drugs avoiding placental dysfunction in high-risk pregnancies and (ii) design optimisation of an 'artificial placenta' for the support of extremely premature babies.

Modern healthcare requires individualised approaches, evidence-based therapies and decision-making strengthened by modelling. At the same time, there are gaps in the fundamental understanding of soft matter physics and continuum mechanics in complex biological systems. The proposed project aims to address these obstacles and will engage with healthcare practitioners and biotechnology engineers, moving to a long-term goal of personalised obstetrics and novel therapies for currently untreatable pregnancy complications. Our integrative interdisciplinary approach will set a new standard for placental systems biology and reproductive bioengineering in general.

The beneficiaries of this research include mathematics, physics, engineering, physiology and obstetrics academic communities, as well as biomedical industry, clinicians and healthcare professionals, and, ultimately, patients and the general public. The study will transform our understanding of blood flow and transport in complex porous media, such as the intervillous space of the human placenta and its artificial analogues for the support of extremely premature babies, as well as for numerous other biological, geophysical and chemical engineering applications.

The grant will bring together a critical mass of experimental and theoretical expertise to match the rapidly growing imaging capacity for a new generation of placental technologies. This activity will be facilitated by organising two international interdisciplinary workshops on Haemodynamics and Transport in Complex Media, with world-leading experts in obstetrics and clinical technologies. The research impacts will be further strengthened by exchange visits, resource and time commitment by Project Partners from St Mary's Hospital, Manchester and McMaster University, Canada (see Letters of Support). We will regularly review, in consultation with Partners and a healthcare economist, the Technology Readiness Level of the developed software and microfluidics tools, and we anticipate future translation to a pre-clinical stage by seeking follow-up support from appropriate schemes (such as BHF Translational Award).

The created research group will supervise and train a new generation of T-shaped researchers and professionals to become familiar with a broad spectrum of complementary bioengineering approaches (such as placental physiology, image processing and image-based computational modelling, experimental microfluidics and mathematical upscaling techniques) while developing in-depth knowledge in any of these topics. Such individuals have the potential to transform biomedical research and guide the medicine of the future into personalised precision engineering. We will also take career development of PDRA members of the team very seriously via a combination of career planning, multiple networking opportunities and training in Science Policy and Communication.

The project has ambitious aims for public engagement and communication of science. We will engage with GCSE- & A-level students, particularly from under-represented groups, to encourage an interest in STEM subjects and science in general by a combination of school talks, lab visits and public science festivals. The project team will work together with a motion graphics professional to produce a short film explaining the role of interdisciplinarity in modern research and healthcare. We will also develop an interactive user interface for computer simulations of blood flow that will be available to the general public and stakeholders at science fairs and online.

Please see Pathways to Impact for more details.