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

人胎盘中的血流（失调）调节和转移功能：胎儿生长限制的综合计算机模拟和离体方法

• 批准号: MR/N011538/1
• 负责人: Igor Chernyavsky
• 金额: $ 80.83万
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FN011538%2F1
• 关键词: Blood; flow; dys; regulation; transfer

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.

胎盘或胞衣是妊娠期间负责维持胎儿生命的器官。在一个令人惊讶的大3-10%的怀孕胎盘发育不足，导致婴儿出生时没有达到理想的出生体重。这种情况被称为胎儿生长受限（FGR），目前还没有很好的了解。胎儿生长迟缓具有终身的后果，因为现在已知低出生体重与日后患心脏病、糖尿病或中风的风险较高有关。人类胎盘的特征是独特的密集血管排列，从母体血液中吸取氧气和营养，以确保发育中的婴儿健康成长。不幸的是，人类胎盘非常复杂和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胎盘（例如脐带）的血流，但不可能获得详细的胎盘健康指标，如摄氧效率，这可能有助于早期检测和治疗FGR。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，从多个角度同时攻击FGR条件。通过超声扫描测量脐带和子宫胎盘供应动脉中的血流，然后获取3D胎盘结构的全面信息，我们将能够建立一个理论上的胎盘特定模型，可以作为计算机模拟进行查询。然后我们将能够观察到什么样的结构变化和改变的血流条件的组合会导致正常和FGR胎盘中胎儿氧气供应的最大损失。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。我们将通过部署一个理论机器（以前开发和测试）来解决这个挑战，该机器从一系列近距离检查中提取最重要的氧气传输特征，然后使用这些信息来运行简化的器官规模的计算机模型。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经历的条件下，我们将直接测量器官中的氧气分布，并记录胎盘对改变的流动条件的反应。这些数据将被用于对开发的计算'虚拟胎盘'进行微调和验证，并将其转变为一种预测工具，将氧气传输与胎盘精细结构和临床可测量的胎盘血液供应两者联系起来，这是数学家的共同努力来自曼彻斯特大学和南安普顿大学的生理学家和临床医生可能会导致计算机的长期发展，基于超声波扫描的胎盘氧适应性辅助诊断。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）或缓解（作为治疗目标）FGR和其他相关胎盘疾病来影响胎盘血流和氧气输送的潜力的工具。

项目成果

A novel oxygen sampling method in perfused ex vivo human placentas to understand the pathogenesis of fetal growth restriction

一种新型的体外灌注人胎盘氧气采样方法，以了解胎儿生长受限的发病机制

• DOI: 10.1016/j.placenta.2017.07.325
• 发表时间: 2017
• 期刊: Placenta
• 影响因子: 3.8
• 作者: Nye G

Human placental oxygenation in late gestation: experimental and theoretical approaches.

• DOI: 10.1113/jp275633
• 发表时间: 2018-12
• 期刊: The Journal of physiology
• 作者: Nye GA;Ingram E;Johnstone ED;Jensen OE;Schneider H;Lewis RM;Chernyavsky IL;Brownbill P
• 通讯作者: Brownbill P

In vitro, in silico and in vivo study challenges the impact of bronchial thermoplasty on acute airway smooth muscle mass loss.

• DOI: 10.1183/13993003.01680-2017
• 发表时间: 2018-05
• 期刊: The European respiratory journal
• 作者: Chernyavsky IL;Russell RJ;Saunders RM;Morris GE;Berair R;Singapuri A;Chachi L;Mansur AH;Howarth PH;Dennison P;Chaudhuri R;Bicknell S;Rose FRAJ;Siddiqui S;Brook BS;Brightling CE
• 通讯作者: Brightling CE

Image-Based Modeling of Blood Flow and Oxygen Transfer in Feto-Placental Capillaries.

• DOI: 10.1371/journal.pone.0165369
• 发表时间: 2016
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Pearce P;Brownbill P;Janáček J;Jirkovská M;Kubínová L;Chernyavsky IL;Jensen OE
• 通讯作者: Jensen OE

Placenta Imaging Workshop 2018 report: Multiscale and multimodal approaches.

• DOI: 10.1016/j.placenta.2018.10.010
• 发表时间: 2019-04
• 期刊: Placenta
• 影响因子: 3.8
• 作者: Slator P;Aughwane R;Cade G;Taylor D;David AL;Lewis R;Jauniaux E;Desjardins A;Salomon LJ;Millischer AE;Tsatsaris V;Rutherford M;Johnstone ED;Melbourne A;participants of the workshop
• 通讯作者: participants of the workshop