Blood flow (dys)regulation and transfer function in the human placenta: an integrated in silico and ex vivo approach to fetal growth restriction

The placenta, or afterbirth, is the organ responsible for maintenance of fetal life during pregnancy. In a surprisingly large 3-10% of pregnancies placental development is inadequate, resulting in the birth of babies that have failed to reach their ideal birthweight. This condition is called fetal growth restriction (FGR) and is still not well understood. The FGR has lifelong consequences as low birthweight is now known to be linked to higher risks of heart disease, diabetes or stroke later in life.

The human placenta is characterised by a unique arrangement of densely packed blood vessels drawing oxygen and nutrients from the maternal blood to ensure the healthy growth of a developing baby. Unfortunately, the very intricate and complex structure of the human placenta makes examining its function in pregnancy very challenging. While we can assess blood flow to and from the placenta (e.g. in an umbilical cord) with ultrasound scans, it is not possible to obtain detailed placental fitness indicators, such as the oxygen uptake efficiency, that could assist in early detection and treatment of FGR. Furthermore, the placenta itself is a highly dynamic and rapidly growing organ, making it a difficult moving target for conventional biomedical research.

This study is set to bring together the power of modern mathematical and computational tools and the state-of-the-art biological imaging to attack the FGR condition simultaneously from several angles. By measuring blood flow in the umbilical cord and the placenta-supplying arteries of the womb with ultrasound scans, and then acquiring a comprehensive information on the placental structure in 3D, we will be able to build a theoretical placenta-specific model that can be interrogated as a computer simulation. We shall then be able to observe what combination of structural changes and altered flow conditions results in the most dramatic loss of oxygen supply to the fetus in normal and FGR placentas.

The complexity of the human placenta makes analysis of even this placental specific model difficult to achieve, despite currently abundant computing power. We will address this challenge by deploying a theoretical machinery (developed and tested previously) that extracts the most essential oxygen transfer features from a series of close-up inspections, and then uses this information to run a simplified organ-scale computer model.

Finally, we aim to use a powerful experimental technique called ex vivo placental perfusion, which is akin to 'artificial ventilation' of the placenta after its delivery. By keeping the human placenta in a condition as close as possible to what it experiences in the womb, we will directly measure the distribution of oxygen in the organ and will also record placental response to altered flow conditions. These data will be used to fine-tune and validate the developed computational 'virtual placenta' and transform it into a predictive tool that connects oxygen transfer to both placental fine structure and clinically-measurable placental blood supply.

The joint efforts of mathematicians, physiologists and clinicians from the Universities of Manchester and Southampton could lead to longer-term development of computer-assisted diagnostics of placental oxygen fitness based on ultrasound scans. Furthermore, once fully developed and validated, the framework could be used by pharmaceutical industry as a tool to assess the potential of drugs to affect placental blood flow and oxygen delivery by either inducing (as toxic side-effects) or alleviating (as treatment targets) FGR and other related placental disorders.

Fetal growth restriction (FGR), the inability of a fetus to achieve complete genetic growth potential, is a serious pregnancy condition that carries a high risk of stillbirth or cardiovascular, metabolic and neurological disorders later in life. FGR is associated with inadequate placental function and altered villous structure, but their interrelation is poorly understood, particularly in the case of flow-limited oxygen transfer. Furthermore, existing clinical tools (such as ultrasound and MRI) cannot resolve fine details of placental circulation and thus fail to assist in the early detection of FGR. Here we aim to dissect the relative contributions of disrupted villous microstructure and dysregulated, via altered flow resistance, placental circulation to the net oxygen delivery in healthy and FGR placentas. We will undertake a systems approach to build an integrative computational framework informed and validated by multiple experimental streams.

We will use in-vivo sonography of umbilical and uterine flow followed by a combination of 3D microscopy for materno- and micro-CT for feto-placental structural characterisation ex-vivo. The formidable complexity of the placenta does not permit direct computation at the organ-scale. We will address this challenge with upscaling technique based on our prior work. Image-based meshing and computational fluid dynamics at the micro-scale will help to estimate key physiological parameters that will then be fed into an upscaled simulation of net oxygen transfer, which will be gauged against ex-vivo placental perfusion with oxygen and inert solute antipyrine, and their modulation in the presence of vasoactive agonists.

The study will be the first to offer a mechanistic placenta-specific model of circulation and oxygen delivery that bridges the gap between structural and functional placental health, and will form a base for further development of computer-aided diagnostics and identifying the best intervention targets in FGR.

The beneficiaries of this research include the physiology, obstetrics, bioengineering and mathematics academic communities, as well as clinicians and healthcare professionals, and ultimately patients and the general public.

The study will broadcast the power of integrative theoretical modelling and multi-modal imaging approach to fetal growth restriction (FGR) by disseminating the results to medical community via high-impact clinical journals and by direct engagement at international conferences and meetings. The Maternal and Fetal Health Research Centre at St Mary's Hospital in Manchester hosts the UK's first placenta clinic that provides an ideal environment for translating basic biomedical research into new technologies and diagnostic tools which could arise from the proposed computational framework.

The grant will bring together a critical mass of expertise in theoretical systems approach to placental research that matches rapidly growing experimental capacity. This activity will be facilitated by organising an international cross-disciplinary workshop on modelling placental blood flow and transfer function in silico and ex vivo, with participation of the world-leading experts in obstetrics and clinical placentology, as well as in medical bioengineering. We will also engage in discussions with pharmaceutical industry to explore the potential of the undertaken approach to accelerate adoption of alternative animal-free technologies in drug design and safety testing that could help protect the mother and the fetus from developing the FGR.

The created research group will supervise and train a new generation of researchers and professionals (master's and medical honours students as well as recruited post-doctoral research associates) to become equally comfortable with advanced biomedical imaging and mathematical modelling. Such individuals have the potential to transform biomedical research and guide the medicine of the future into personalised precision engineering. Our approach will be reinforced by using multiple imaging modalities in each of the studied placentas, making subsequent theoretical modelling more individual placenta-specific.

The project has high aims for public outreach and communication of science. The project team will encourage GCSE- and A-level students to take interest in STEM subjects and science in general by a combination of school talks and lab visits (spanning the many Manchester centres involved: the Physiology Lab, the micro-CT Imaging Unit and the Computational Lab). We also plan to actively engage with local communities via public science festivals. Finally, the research group will work together with a motion graphics professional to produce a short film explaining the role of modern research in understanding the fetal growth restriction disorder. The video will be enriched by placental imaging and computer-generated simulations produced during the lifetime of the project.