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

胎盘，或称胎体，是在怀孕期间负责维持胎儿生命的器官。令人惊讶的是，3-10%的孕妇胎盘发育不足，导致出生的婴儿未能达到理想的出生体重。这种情况被称为胎儿生长限制（FGR），目前仍未得到很好的理解。FGR有终生的影响，因为低出生体重现在被认为与以后患心脏病、糖尿病或中风的高风险有关。人类胎盘的特点是一种独特的密集排列的血管，从母体血液中吸取氧气和营养，以确保发育中的婴儿的健康成长。不幸的是，人类胎盘非常复杂的结构使得检查其在怀孕期间的功能非常具有挑战性。虽然我们可以通过超声扫描评估进出胎盘（例如脐带）的血流量，但不可能获得详细的胎盘健康指标，如摄氧量效率，这可能有助于FGR的早期发现和治疗。此外，胎盘本身是一个高度动态和快速生长的器官，使其成为传统生物医学研究的一个困难的移动目标。这项研究旨在将现代数学和计算工具的力量与最先进的生物成像技术结合起来，同时从多个角度研究FGR条件。通过超声扫描测量脐带和子宫胎盘供应动脉的血流量，然后获得胎盘结构的三维全面信息，我们将能够建立一个理论的胎盘特异性模型，可以作为计算机模拟进行询问。然后，我们将能够观察到在正常胎盘和FGR胎盘中，结构变化和流动条件改变的哪些组合导致了胎儿最严重的氧气供应损失。人类胎盘的复杂性使得即使是这种胎盘特异性模型的分析也难以实现，尽管目前有丰富的计算能力。我们将通过部署一种理论机制（以前开发和测试过）来解决这一挑战，该机制从一系列近距离检查中提取最基本的氧转移特征，然后使用这些信息运行简化的器官尺度计算机模型。最后，我们的目标是使用一种强大的实验技术，称为离体胎盘灌注，这类似于胎盘分娩后的“人工通气”。通过将人类胎盘保持在尽可能接近其在子宫中的状态，我们将直接测量器官中的氧气分布，并记录胎盘对改变的血流条件的反应。这些数据将用于微调和验证开发的计算“虚拟胎盘”，并将其转化为一种预测工具，将氧气转移与胎盘精细结构和临床可测量的胎盘血液供应联系起来。来自曼彻斯特大学和南安普顿大学的数学家、生理学家和临床医生的共同努力，可能会导致基于超声扫描的胎盘氧适性计算机辅助诊断的长期发展。此外，一旦完全开发和验证，该框架可以被制药行业用作评估药物通过诱导（作为毒副作用）或减轻（作为治疗目标）FGR和其他相关胎盘疾病影响胎盘血流和氧气输送的潜力的工具。

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.