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

Lead Research Organisation: University of Manchester
Department Name: Mathematics

Abstract

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.

Technical Summary

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.

Planned Impact

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.

Publications

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Title Behind the Scenes of Placental Research: Helping Babies to Breathe and Grow 
Description This short film has been the result of a two year-long collaboration between researchers, clinicians and professional film-makers. The video explains the role of the human placenta for a healthy baby and shows the work of an interdesciplinary team of scientists and clinicians on their mission to better understand and prevent pregnancy complications. 
Type Of Art Film/Video/Animation 
Year Produced 2018 
Impact The production has helped better understand interdisciplinary challenges of biomedical research both for academic colleagues and general public alike. It has been used during open days and visits by A-level students. The film has been viewed over 500 times on YouTube in less than 6 months. 
URL https://www.youtube.com/watch?v=8sl5WWtaAkU
 
Title Research Image Competition 
Description A PDRA Dr Gareth Nye created and submitted a scientifically-motivated photograph "Shine a light: Measuring placental oxygen" to the research image competition during a major international meeting (IFPA, September 2017; www.ifpa2017.org/image-competition). 
Type Of Art Image 
Year Produced 2017 
Impact Dr Gareth Nye's creative photograph has been selected for public exhibition (see https://www.facebook.com/media/set/?set=a.368405763631509.1073741831.271331530005600) and awarded a runner-up prize by the international scientific IFPA committee. 
URL https://twitter.com/MFH_Research/status/906183825344139266
 
Description Group member's participation in the Parliamentary Select Committee
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
URL https://www.rsb.org.uk/news/14-news/2119-stem-researchers-grill-mps-on-post-brexit-science-at-rsb-s-...
 
Description NICE interventional procedure overview of bronchial thermoplasty for severe asthma
Geographic Reach National 
Policy Influence Type Citation in systematic reviews
URL https://www.nice.org.uk/guidance/ipg635/evidence/overview-final-pdf-6651284509
 
Description Novel Models for Haemodynamics and Transport in Complex Media: Towards Precision Healthcare for Placental Disorders
Amount £1,050,147 (GBP)
Funding ID EP/T008725/1, EP/T008806/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 01/2020 
End 12/2022
 
Title Placentome Atlas 
Description The Placentome Atlas is a curated international catalogue of placental structural and functional datasets. It has been established as an outcome of the first International Placental Biophysics Workshop (Manchester, August 2017). 
Type Of Material Database/Collection of data 
Year Produced 2017 
Provided To Others? Yes  
Impact This is the first international catalogue of human placenta-related data that aims to (i) identify mechanisms of placental structure and function interaction in norm and pathology (ii) provide a platform for collaboration, data and model sharing, standardization and validation The Placentome Atlas has so far compiled the interdisciplinary data generated by 14 research centres from seven countries. The vast majority of the data is either freely available or available upon request. 
URL http://www.placentome.org/
 
Description "Before You Were Born" public engagement activity event day - September 2017 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Held at the Manchester Convention Centre. Research photographic competition, where the public voted on images; 3 minute soap box presentations; a large room filed with interactive display items and games for children and families relating to their time in the womb; stillbirth art gallery; public voting on their experiences.
Year(s) Of Engagement Activity 2017
URL http://www.socialresponsibility.manchester.ac.uk/news/october-2017/before-you-were-born/
 
Description International Placental Biophysics Workshop 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact The first international workshop on Placental Biophysics at the School of Mathematics, University of Manchester brought together mathematicians, bioengineers and physiologists in the emerging field of Placental Biophysics (https://twitter.com/oeskildjensen/status/902915622593601537). The interdisciplinary workshop featured speakers from 8 countries and three continents who discussed topics ranging from fundamental mathematical problems of transport in complex media to the development of state-of-the-art bioengineering, imaging and computational tools to understand placental physiology and its clinical implications in pregnancy pathologies.
Year(s) Of Engagement Activity 2017
URL http://www.maths.manchester.ac.uk/news-and-events/events/placentalbiophysics2017/
 
Description Placental Biophysics YouTube Channel 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Although pregnancy complications cost over £1.2 billion each year in neonatal and infant care to the NHS and public sector services, many health professionals are unaware of the research efforts into the function of the human placenta.

As a result of the collaboration with the Maternal and Fetal Health Research Centre at Manchester St Mary's Hospital, we established a Placental Biophysics behind-the-scenes YouTube channel and produced two short educational films: "Introduction to the Maternal and Fetal Health Research Centre" Part I: Information for Midwives (https://youtu.be/IeXjdVvToHg) and Part II: Information for Patients (https://youtu.be/603PCstdY2M).

The videos have been actively used to broadcast the scope of interdisciplinary research, including mathematical modelling, to the general public at a major international congress (www.ifpa2017.org/public-engagement) in September 2017, as well as a part of training materials for health professionals and patient engagement panel at the Central Manchester Hospital Trust. The initiative helped publicise and create awareness for an important area of research that directly impacts the health and lives of many people. An immediate impact was increased assistance of midwives with handling the placentas donated for research.

The educational and explanatory films created for the Placental Research channel have been viewed over 1300 times since September 2017.
Year(s) Of Engagement Activity 2017,2018,2019,2020
URL https://www.youtube.com/channel/UCsAEu5Z9K2-a4VAEKNpvIxA
 
Description School Work Placement (Greenhead College, 2016-2019) 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact [June 2016] A visit of four A-level biology students from Greenhead College, Huddersfield to the School of Mathematics at the University of Manchester (involving a brief tour to Alan Turing building and Henry Moseley X-ray imaging facility, and a talk on the role of mathematical modelling in medicine and biology). This was a part of an extended placement at St. Mary's Maternal and Fetal Health Research Centre managed by the award's Co-I Dr Paul Brownbill and others.

Below is an excerpt from a report of one of the students: "We also paid a visit to mathematicians, who, surprisingly, were also working on the placenta. It was quite amazing how they had used well known equations such as Ohm's law to model blood flow in the capillaries... This partnership was an unexpected part of the experience, as programming on the computer was such a stark difference to the cutting up a placenta I had seen earlier in the week. Being able to learn about the joint work helped create a bigger picture of work in that it is as much about who you work with as what you do."

[June 2017] Co-hosted (jointly with a Co-I Dr Paul Brownbill) a week-long summer work placement for A-level biology students from Greenhead College, Huddersfield, at the St. Mary's Maternal and Fetal Health Research Centre (MFHRC). The students also had opportunity to video-shadow the MFHRC staff and helped to collect unique footage, showcasing the wide spectrum of experimental work, that was used in an YouTube outreach clip about the placental research at St. Mary's hospital (www.youtube.com/watch?v=603PCstdY2M). It was also very encouraging to see female students' reinforcing their enthusiasm in a STEM research career as a result of the placement.

[June & July 2018] Further talks, presentations and lab tours for A-level students (co-hosted by Dr Paul Brownbill and Ms Chinedu Agwu); a total of 5 students.

Below are some excerpts from the students' reports.

"This really explained to me the importance of trans-discipline cooperation in complex research projects, in this instance, between Mathematics, Physical and Biological science."

"We had the opportunity to take part in a project which involved filming scientists carrying out their experiments on the placenta... I think the concept behind this idea was clever and it gave me another perception on how scientists can use a different type of technology to help them improve their access to research material."

"I was given the great opportunity to film some of the research... for the use of informing the public about the importance of research, and to inspire people to come into research."

"Overall, I found this placement so extremely valuable, and I had the best time at the University... The placement has been so helpful to clarify how much I would love to go in to scientific research."

"I found it really interesting to see how these [Mathematics and Medicine] two departments worked together to produce a final outcome. As biology and maths are both interests of mine, it gave me an insight how I could go into a career where I use both my knowledge of biological processes and mathematical methods."
Year(s) Of Engagement Activity 2016,2017,2018,2019
URL http://www.greenhead.ac.uk
 
Description The University of Manchester's Community Festival 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Over 100 people from Greater Manchester region attended the University of Manchester's Community Festival in June 2018. The Maternal and Fetal Health Research Centre was represented by a stand full of hands-on activities, including live experiments, interactive demonstrations and quizzes aimed at general public (see, e.g. https://tinyurl.com/UoMcommunityfestival18placenta). The research group's contribution has received positive feedback from Festival organisers: "It was lovely to see so many happy faces and people enjoying the day - both the public as well as staff and students."
Year(s) Of Engagement Activity 2018
URL https://www.facebook.com/events/719808404895252/