SofTMech with MIT and POLIMI (SofTMechMP)

Lead Research Organisation: University of Glasgow
Department Name: School of Mathematics & Statistics

Abstract

Soft tissue related diseases (heart, cancer, eyes) are among the leading causes of death worldwide. Despite extensive
biomedical research, a major challenge is a lack of mathematical models that predict soft tissue mechanics across
subcellular to whole organ scales during disease progression. Given the tremendous scope, the unmet clinical needs, our
limited manpower, and the existence of complementary expertise, we seek to forge NEW collaborations with two world-leading
research centres: MIT and POLIMI, to embark on two challenging themes that will significantly stretch the initial
SofTMech remit: A) Test-based microscale modelling and upscaling, and B) Beyond static hyperelastic material to include
viscoelasticity, nonlinear poroelasticity, tissue damage and healing. Our research will lead to a better understanding of how
our bodies work, and this knowledge will be applied to help medical researchers and clinicians in developing new therapies
to minimise the damage caused by disease progression and implants, and to develop more effective treatments.
The added value will be a major leap forward in the UK research. It will enable us to model soft tissue damage and healing
in many clinical applications, to study the interaction between tissue and implants, and to ensure model reproducibility
through in vitro validations. The two underlying themes will provide the key feedback between tissue and cells and the
response of cells to dynamic local environments. For example, advanced continuum mechanics approaches will shed new
light on the influence of cell adhesion, angiogenesis and stromal cell-tumour interactions in cancer growth and spread, and
on wound healing implant insertion that can be tested with in vitro and in vivo systems. Our theoretical framework will
provide insight for the design of new experiments.
Our proposal is unique, timely and cost-effectively because advances in micro- and nanotechnology from MIT and POLIMI
now enable measurements of sub-cellular, single cell, and cell-ECM dynamics, so that new theories of soft tissue
mechanics at the nano- and micro-scales can be tested using in vitro prototypes purposely built for SofTMech. Bridging
the gaps between models at different scales is beyond the ability of any single centre. SofTMech-MP will cluster the critical
mass to develop novel multiscale models that can be experimentally tested by biological experts within the three world-leading
Centres. SofTMech-MP will endeavour to unlock the chain of events leading from mechanical factors at subcellular
nanoscales to cell and tissue level biological responses in healthy and pathological states by building a new mathematics
capacity.
Our novel multiscale modelling will lead to new mathematics including new numerical methods, that will be informed
and validated by the design and implementation of experiments at the MIT and POLIMI centres. This will be of enormous
benefit in attacking problems involving large deformation poroelasticity, nonlinear viscoelasticity, tissue dissection, stent-related
tissue damage, and wound healing development. We will construct and analyse data-based models of cellular and
sub-cellular mechanics and other responses to dynamic local anisotropic environments, test hypotheses in mechanistic
models, and scale these up to tissue-level models (evolutionary equations) for growth and remodelling that will take into
account the dynamic, inhomogeneous, and anisotropic movement of the tissue. Our models will be simulated in the
various projects by making use of the scientific computing methodologies, including the new computer-intensive methods
for learning the parameters of the differential equations directly from noisy measurements of the system, and new methods
for assessing alternative structures of the differential equations, corresponding to alternative hypotheses about the
underlying biological mechanisms.

Planned Impact

Academic beneficiaries:

Multi-scale soft tissue modelling, based on biological processes and specifically designed
experiments, attacks the grand challenge of integrating cellular and sub-cellular mechanics with tissue and organ scale
mechanics that lies at the core of biomechanics research. Thus, the project will contribute to both basic and applied
sciences, as well as the translational (healthcare) domain. Our novel statistical inference methods will provide powerful
tools that will also be of benefit to cognate disciplines, like pathway medicine and systems biology.

The project will train 2 RAs and 11 PhD students, and benefit 50+ PhD students supervised by the applicants. It will aid early career researchers in the team to develop their international leadership, and expand cutting-edge soft tissue mechanics research in the UK. The
computational framework will be licensed for commercial software development to provide easy access for nonmathematicians.

Beneficiaries in EPSRC Healthcare Technologies:

The research will generate new models for studying many different soft
tissue diseases, and form the backbone of generic soft tissue modelling applicable to many additional health challenges. It
will contribute to "Novel treatment and therapeutic technologies" by providing the means to simulate tissue growth, cancer
invasion and cell migration, and inform the design of new experimental methods for cell and tissue growth, and drug
delivery, for heart and cancer applications and beyond. Our models will help to identify new biomarkers in MRI,
contributing to "Enhanced prediction and diagnosis in real time and at the point of care". As the tools can be used for the
development of experimental methods and translation of experimental results into clinical practice, it is also linked to
"Design, Manufacture and Integration of Healthcare Technologies".

Socio-Economic impact:

SofTMech-MP will enhance the quality of life and health in the UK, and beyond, and enhance the
UK's global competitiveness by addressing the most important healthcare problems. Heart disease is the leading killer in
the world, responsible for ~30% of all deaths each year. Cancer is the second deadliest disease, and the World Health
Organization projects that without immediate action, the global number of deaths from cancer will increase by nearly 80%
by 2030. Retinal degenerative diseases will affect 196 million people worldwide in 2020, predicted to rise to 288 million by 2040. Our
research will generate a range of reproducible models for studying these diseases that will facilitate translational medical
research to enhance diagnosis, treatment, and prevention. By developing test- and data-based modelling, we will examine
how cellular changes affect stress and strain distributions within organs, what drives functional responses within cells, and
which parameters are strongly associated with adverse remodelling leading to heart failure, wound healing after implants,
retinal detachment, or cancer metastasis. This fundamental research will significantly advance our understanding of
disease pathogenesis, diagnosis and responses to therapy, and hence move clinical research forward.
SofTMech-MP will raise awareness of our research to new and existing groups by networking activities, increase
knowledge transfers by involving new clinical/industrial partners through networking and Dialogues, and influence the
effectiveness of public services and policy by engagement with the Turing Gateway to Mathematics. Ultimately, our research will improve
the quality of life of all and lead to health economic benefits for the NHS and wider society.

Publications

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Escuer J (2020) How does stent expansion alter drug transport properties of the arterial wall? in Journal of the mechanical behavior of biomedical materials

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Di Stefano S (2020) Effective balance equations for electrostrictive composites in Zeitschrift für angewandte Mathematik und Physik

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Cruz-González O (2020) On the effective behavior of viscoelastic composites in three dimensions in International Journal of Engineering Science

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Cruz-González O (2020) A hierarchical asymptotic homogenization approach for viscoelastic composites in Mechanics of Advanced Materials and Structures

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Miller L (2020) Effective balance equations for poroelastic composites in Continuum Mechanics and Thermodynamics