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

Lead Research Organisation: University of Manchester
Department Name: Mathematics

Abstract

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.

Planned Impact

Modern healthcare requires individualised approaches, evidence-based therapies and decision-making strengthened by modelling. At the same time, there are gaps in the fundamental understanding of soft matter physics and continuum mechanics in complex biological systems. The proposed project aims to address these obstacles and will engage with healthcare practitioners and biotechnology engineers, moving to a long-term goal of personalised obstetrics and novel therapies for currently untreatable pregnancy complications. Our integrative interdisciplinary approach will set a new standard for placental systems biology and reproductive bioengineering in general.

The beneficiaries of this research include mathematics, physics, engineering, physiology and obstetrics academic communities, as well as biomedical industry, clinicians and healthcare professionals, and, ultimately, patients and the general public. The study will transform our understanding of blood flow and transport in complex porous media, such as the intervillous space of the human placenta and its artificial analogues for the support of extremely premature babies, as well as for numerous other biological, geophysical and chemical engineering applications.

The grant will bring together a critical mass of experimental and theoretical expertise to match the rapidly growing imaging capacity for a new generation of placental technologies. This activity will be facilitated by organising two international interdisciplinary workshops on Haemodynamics and Transport in Complex Media, with world-leading experts in obstetrics and clinical technologies. The research impacts will be further strengthened by exchange visits, resource and time commitment by Project Partners from St Mary's Hospital, Manchester and McMaster University, Canada (see Letters of Support). We will regularly review, in consultation with Partners and a healthcare economist, the Technology Readiness Level of the developed software and microfluidics tools, and we anticipate future translation to a pre-clinical stage by seeking follow-up support from appropriate schemes (such as BHF Translational Award).

The created research group will supervise and train a new generation of T-shaped researchers and professionals to become familiar with a broad spectrum of complementary bioengineering approaches (such as placental physiology, image processing and image-based computational modelling, experimental microfluidics and mathematical upscaling techniques) while developing in-depth knowledge in any of these topics. Such individuals have the potential to transform biomedical research and guide the medicine of the future into personalised precision engineering. We will also take career development of PDRA members of the team very seriously via a combination of career planning, multiple networking opportunities and training in Science Policy and Communication.

The project has ambitious aims for public engagement and communication of science. We will engage with GCSE- & A-level students, particularly from under-represented groups, to encourage an interest in STEM subjects and science in general by a combination of school talks, lab visits and public science festivals. The project team will work together with a motion graphics professional to produce a short film explaining the role of interdisciplinarity in modern research and healthcare. We will also develop an interactive user interface for computer simulations of blood flow that will be available to the general public and stakeholders at science fairs and online.

Please see Pathways to Impact for more details.

Publications

10 25 50
 
Title Advancing Placental Research: Unlocking the Mysteries of Blood Flow in Pregnancy 
Description This short film has been the result of a three year-long collaboration between scientists, engineers, clinicians and professional film-makers. 
Type Of Art Film/Video/Animation 
Year Produced 2023 
Impact The production has helped better understand interdisciplinary challenges and opportunities in biomedical research. The film has been used as a communication tool for academic colleagues, healthcare professionals and the general public. 
URL https://youtu.be/DXtKvrAFQsQ
 
Title Archer2 Image Competition 
Description A simulation snapshot by Dr Qi Zhou (The University of Edinburgh, School of Engineering) entitled "Maternal blood flow through the intervillous space of human placenta" was submitted to the national ARCHER2 2022 image competition of high-performance computational models (https://www.archer2.ac.uk/about/gallery/2022-image-comp). 
Type Of Art Artefact (including digital) 
Year Produced 2023 
Impact The image entry has been selected to feature in the ARCHER2 Calendar 2023, which is distributed nationally. 
URL https://www.archer2.ac.uk/about/gallery/2022-image-comp
 
Title The Secret Science of Baby: The Surprising Physics of Creating a Human, from Conception to Birth - and Beyond 
Description The PI (IC) provided academic consultancy for a popular science book "The Secret Science of Baby: The Surprising Physics of Creating a Human, from Conception to Birth - and Beyond" by Michael Banks. 
Type Of Art Creative Writing 
Year Produced 2022 
Impact The book was released by BenBella Books in December 2022 (https://www.penguinrandomhouse.com/books/710898/the-secret-science-of-baby-by-michael-banks/); see also a press release by Physics Today magazine (https://physicsworld.com/a/the-surprising-physics-of-babies-how-were-improving-our-understanding-of-human-reproduction). 
URL https://physicsworld.com/a/the-surprising-physics-of-babies-how-were-improving-our-understanding-of-...
 
Description The research project was aimed at understanding the dynamics of blood flow on a cellular scale within biological tissues, particularly focusing on the human placenta. Through a series of experiments and simulations, the project team has identified several key findings.

Firstly, we have successfully created tunable soft microcapsules that mimic the behaviour of red blood cells in terms of flow dynamics and deformability. These microcapsules can be manipulated and studied in a controlled manner, and flowing a large number of such capsules in complex geometries has provided new insights into blood flow at both the cell and tissue scale.

Secondly, we have investigated how solutes, such as oxygen, move past isolated sinks in a domain where flow dominates diffusion. The study has revealed that corrections to existing approximations can be complex and non-local, impacting solute distribution patterns significantly. We have also developed a method to estimate these corrections and validated the predictions through computer simulations.

Lastly, informed by advanced three-dimensional scans of the placenta at the national synchrotron facility and with the help of supercomputers, the research team has simulated blood flow in porous media representing the human placental tissue. The simulations indicate that the structural disorder can strongly influence the flow distribution and the dynamics of red blood cells. Understanding these effects could shed light on how tissue structure impacts blood flow and oxygen delivery, crucial for developing precision healthcare strategies for placental disorders and beyond.
Exploitation Route All of the project's objectives have been fully met.

1. Using the synchrotron X-ray tomography, we have characterised the three-dimensional structure of human placental tissue at the unprecedented range of scales (spanning from microns to centimetres; see Tun et al., J R Soc Interface, 2021). Informed by the placental microstructure, we have simulated cell-resolved three-dimensional blood flow in microporous domains of up to 0.3 mm in length, demonstrating both short-range and long-range interactions (Zhou et al., Interface Focus, 2022).

2. We have developed a novel biomimetic microfluidics framework for manufacturing ultra-soft tunable microcapsules that capture key mechanical features of the red blood cells, including a reduced cell volume-to-surface ratio (Chen et al., Soft Matter, 2023). We have further characterised the flow of the suspensions of such microcapsules in complex geometries at a large scale, linking the global flow rheology with local micro-haemodynamics (unpublished; manuscript in preparation).

3. We have developed a framework to characterise the impact of complex microstructure on the flow and transport of certain solutes, such as oxygen. Our analysis has revealed that traditional upscaling approaches fail to capture the non-local effects of structural disorder, resulting in statistically biased estimates, and we offered an alternative approach to correct for these factors (Price et al., Proc R Soc A, 2022). We have further extended this approach, using a reduced-order discrete network that is capable of quantifying the impact of red blood cells on tissue-scale flow distribution.

The theoretical and experimental tools and datasets resulting from this project have applications in reproductive medicine and neonatal healthcare, as well as in multiple other sectors. We have taken specific steps to maximise the potential impacts by fostering new collaborations and securing follow-up funding. Please see more details in the Narrative Impact.
Sectors Aerospace

Defence and Marine

Education

Energy

Environment

Healthcare

Manufacturing

including Industrial Biotechology

Pharmaceuticals and Medical Biotechnology

Other

 
Description This research project has demonstrated significant impacts across various sectors. Utilising novel biomimetic manufacturing technology and national facilities like the Diamond Light Source and ARCHER2 Supercomputing facility, this project has paved the way for significant advancements in understanding the blood flow in the complex microstructure of the human placenta and its role in pregnancy complications. By conducting high-resolution X-ray microscopy on human placental tissues and associated image-based theoretical modelling and advanced experiments, the research team has produced new models and datasets, leading to multiple publications, keynote academic and public talks that have benefited the broader scientific community as well as non-academic sectors. Moreover, the creation and sharing of research datasets, such as X-ray tomography data, and simulation codes have facilitated collaborations nationally and globally, enhancing knowledge exchange. For example, these datasets and tools enabled the team members to join a major global $50M clinical challenge supported by Wellcome Leap to reduce stillbirths worldwide by a combination of novel measurements and predictive modelling. On the other hand, the developed novel microfluidic approaches that mimic the mechanics of red blood cells have shown strong potential for direct knowledge transfer, including in optimising the 3D bioprinting technology (in collaboration with the EU and UK space agencies). Likewise, the precision-engineering approach to placental physiology has contributed to a new collaboration with AstraZeneca to develop and characterise a placenta-on-a-chip using a microfluidics framework. The creative outputs of the project, including an image feature for the ARCHER2 portal, a popular mathematical magazine article and the academic consultancy for a popular science book on the physics of pregnancy, have extended the reach of the research to a wider audience, bridging the gap between academia and the public. The production of a short film titled "Advancing Placental Research" further highlights the interdisciplinary collaboration and serves as a valuable communication tool for disseminating research findings to academic peers, healthcare professionals and the general public. This impact has been further strengthened by contributing to two UK-wide case studies that highlighted the economic and societal role of fluid dynamics in reproductive health. In summary, this research project has not only made significant contributions to the academic community but also holds promise for improving outcomes of placental disorders and for developing the next generation of precision healthcare technologies.
First Year Of Impact 2022
Sector Aerospace, Defence and Marine,Healthcare,Pharmaceuticals and Medical Biotechnology,Other
Impact Types Societal

Economic

Policy & public services

 
Description "In Utero" Program
Amount $1,990,109 (USD)
Funding ID Project title: "Multi-modal studies to understand pregnancy and prevent stillbirth" 
Organisation Wellcome LEAP 
Sector Charity/Non Profit
Country United States
Start 09/2022 
End 03/2024
 
Description Mathematical models of MS medications in the placenta
Amount £249,599 (GBP)
Funding ID https://www.mssociety.org.uk/research/explore-our-research/research-we-fund/search-our-research-projects/which-dmts-cross 
Organisation Multiple Sclerosis Society 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2023 
End 03/2027
 
Description Robust Extrusion Bioprinting of Mesoscopic Tissue Constructs: Optimising Flow and Transport Regimes
Amount £255,120 (GBP)
Funding ID ST/Y00356X/1 
Organisation UK Space Agency 
Sector Public
Country United Kingdom
Start 06/2023 
End 12/2024
 
Title Micro X-ray tomography of mesoscopic placental tissue 
Description This dataset has been generated as part of the study "A massively multi-scale approach to characterising tissue architecture by synchrotron micro-CT applied to the human placenta" by Tun W, et al. (2021) J R Soc Interface 18:20210140 (doi:10.1098/rsif.2021.0140); see also an associated dataset https://doi.org/10.6019/EMPIAR-10563/. 
Type Of Material Database/Collection of data 
Year Produced 2021 
Provided To Others? Yes  
Impact This unique dataset has been shared with and used by colleagues nationally and internationally, stimulating new collaborations. 
URL https://doi.org/10.6019/EMPIAR-10562
 
Title Simulation Files from Red blood cell dynamics in extravascular biological tissues modelled as canonical disordered porous media 
Description The dynamics of blood flow in the smallest vessels and passages of the human body, where the cellular character of blood becomes prominent, plays a dominant role in the transport and exchange of solutes. Recent studies have revealed that the micro-haemodynamics of a vascular network is underpinned by its interconnected structure, and certain structural alterations such as capillary dilation and blockage can substantially change blood flow patterns. However, for extravascular media with disordered microstructure (e.g. the porous intervillous space in the placenta), it remains unclear how the medium's structure affects the haemodynamics. Here, we simulate cellular blood flow in simple models of canonical porous media representative of extravascular biological tissue, with corroborative microfluidic experiments performed for validation purposes. For the media considered here, we observe three main effects: first, the relative apparent viscosity of blood increases with the structural disorder of the medium; second, the presence of red blood cells (RBCs) dynamically alters the flow distribution in the medium; third, symmetry breaking introduced by moderate structural disorder can promote more homogeneous distribution of RBCs. Our findings contribute to a better understanding of the cell-scale haemodynamics that mediates the relationship linking the function of certain biological tissues to their microstructure. 
Type Of Material Database/Collection of data 
Year Produced 2022 
Provided To Others? Yes  
Impact This in silico modelling framework provides a new tool for investigating micro-haemodynamics in the human placenta and other complex microvascular tissues. 
URL https://rs.figshare.com/articles/dataset/Simulation_Files_from_Red_blood_cell_dynamics_in_extravascu...
 
Description IOP Workshop on Microrheology and Transport in Complex Biological Media 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact This international workshop brought together established world-leading experts and early-career researchers in the field of "Microrheology and Transport in Complex Biological Media". The event was selected and co-sponsored by the Institute of Physics (IOP), with support of the national UK Fluids Network. The workshop was initiated and organised by the PI and Co-Is of the grant project team.
Year(s) Of Engagement Activity 2022
URL https://iop.eventsair.com/cbm2022
 
Description Meet-the-Mathematician Event (Mar 2022) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact An online public lecture "The Mathematics of Life" (March 2022) was delivered for an audience of A-level students, their teachers and Mathematics undergraduates, as a part of "Meet the Mathematician" outreach event series. The event was organised and hosted by the Department of Mathematics of the University of Manchester.
Year(s) Of Engagement Activity 2022
URL https://gtr.ukri.org/projects?ref=EP%2FG019576%2F1
 
Description North West Festival of Women in Mathematics (Jun, Dec 2021) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact Dr Eleanor Doman, a PDRA researcher, contributed a series of public talks on "Similarities and Scalings in Nature: An Introduction to Mathematical Biology" as a part of North West Festival of Women in Mathematics. The series invites practising researchers to engage with female students who might be considering studying Mathematics or a STEM subject at A Level or University. The series of two online (June 2021) and one in-person (December 2021) events was attended by 70 Key Stage 4 & 5 (year 10 to 13) students and their teachers.
Year(s) Of Engagement Activity 2021
URL https://amsp.org.uk/events/details/8410
 
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 in 2017: "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). This have been followed by explanatory videos done in collaboration with media professionals: "Behind the Scenes of Placental Research: Helping Babies to Breathe and Grow" (2018; https://youtu.be/8sl5WWtaAkU) and "Advancing Placental Research: Unlocking the Mysteries of Blood Flow in Pregnancy" (2023; https://youtu.be/DXtKvrAFQsQ)

The videos have been actively used to broadcast the scope of interdisciplinary research, including mathematical modelling and experimental techniques, to the general public as well as forming part of the training materials for health professionals and patient engagement panel at St Mary's hospital (Manchester University NHS Foundation 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 2100 times (as of February 2024).
Year(s) Of Engagement Activity 2017,2018,2019,2020,2021,2022,2023,2024
URL https://www.youtube.com/channel/UCsAEu5Z9K2-a4VAEKNpvIxA
 
Description Publication in a poplular-science magazine: Chalkdust (May 2023) 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Eleanor Doman and Qi Zhou published a project-related article entitled "Mathematics and Pregnancy" in "Chalkdust: a magazine for the mathematically curious" (issue 17; 22 May 2023).
Year(s) Of Engagement Activity 2023
URL https://chalkdustmagazine.com/features/mathematics-and-pregnancy/
 
Description UK Fluids Network - Impact Case Study on Reproductive Health (Sept 2021) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact The PI and research team contributed an invited case study on reproductive health modelling for the UKRI-funded UK Fluids Network report on the economic impact and significance of fluid dynamics in the UK (https://fluids.ac.uk/files/Our_Fluid_Nation.1631136312.pdf). The report and live YouTube broadcast (https://www.youtube.com/watch?v=FbPAuOmXqkg) engaged a broad audience from the UKRI; Department for Business, Energy and Industrial Strategy; Met Office; Royal Academy of Engineering; and other academic institutions, industry and public sectors (https://www.eventbrite.co.uk/e/uk-fluid-dynamics-report-launch-tickets-167594384315). The case study provided support for establishing a strategic new "EPSRC National Fellowship in Fluid Dynamics" in 2022 (https://gow.epsrc.ukri.org/NGBOViewGrant.aspx?GrantRef=EP/W034255/1).
Year(s) Of Engagement Activity 2021
URL https://fluids.ac.uk/files/Our_Fluid_Nation.1631136312.pdf