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

早产和死产占所有分娩的10%，包括在英国等发达国家。在这些并发症中，先兆子痫，或通过胎盘母亲和胎儿之间的血液供应受损，仅在英国，NHS和公共部门服务每年就花费超过12亿英镑用于新生儿和婴儿护理。人类胎盘是胎儿发育的重要生命支持系统。由母亲的血液提供的氧气和营养物质必须在一个复杂的胎儿血管网络中得到很好的协调。我们对胎盘结构与功能相互作用的认识进展有限，原因有二：一方面，人类胎盘结构异常复杂；另一方面，人类胎盘的结构和生理是独特的，因此动物研究的用途有限。缺乏了解的直接后果是非常有限的选择，临床管理妊娠疾病，如先兆子痫和胎儿生长受限。此外，胎盘功能不全不仅会导致死产或早产，而且还与成年后患心脏病、中风、糖尿病或神经系统疾病的风险增加有关。对这些挑战的认识导致了最近世界范围内研究兴趣的激增，并建立了4100万美元的美国人类胎盘项目和欧盟胎盘学网络，用于对化学品在怀孕期间的安全性进行实验和理论测试。此外，最近在“人工胎盘”设计方面的突破，为极端早产儿的生命支持提供了新的机会，通过对正常人类胎盘进行系统的“逆向工程”来优化设计。因此，英国需要大量胎盘技术方面的专业知识，以匹配美国和欧盟的能力，并在这一重要领域的国际合作中保持积极的角色。根据我们迄今为止的研究，我们假设胎盘中的血流和营养运输在子痫前期和胎儿生长受限中发生了改变。在这个项目中，我们提出了一种跨学科和创新的方法，利用我们的理论和实验专业知识，为产科和新生儿重症监护提供精准医学。我们将开发和验证一个基于图像的模型和模拟患者特定胎盘的血流和营养运输的框架。由于现有的数据集描述了健康和患病胎盘的结构，我们将能够探索胎盘中哪些解剖变化与营养转运受损有关。这将为开发治疗先兆子痫和胎儿生长受限的干预措施和人工解决方案奠定良好的理论基础。长期的转化影响包括(i)基于模型的患者特异性治疗，使用药物避免高危妊娠中的胎盘功能障碍，（ii）设计优化“人工胎盘”以支持极度早产儿。

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.