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

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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.