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

10 25 50

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Chen S (2020) Mechanical and morphometric study of mitral valve chordae tendineae and related papillary muscle. in Journal of the mechanical behavior of biomedical materials

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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 (2021) Effective behavior of long and short fiber-reinforced viscoelastic composites in Applications in 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

 
Description Cell modelling: Using Gaussian process enhanced semi-automatic approximate Bayesian computation, we have performed parameter inference in a stochastic differential equation system for chemotaxis. Our findings show how local deformations of the cell membrane (so-called pseudopods) drive cell movement, how these deformations depend on the diffusion and reactions of certain chemicals (activators and inhibitors) in the cell membrane, how a variation of the chemical reaction and diffusion parameters induces different cell movement modes, and how these parameters can be estimated, along with sound uncertainty quantification, from cell movement data. Dr Jakub Koery (RA1) has constructed an extensive literature review on the structure of the eukaryotic cell cytoskeleton and models for cross-linked polymer networks. He has formulated a new discrete model for a cross-linked cytoskeletal network formed of both actin and vimentin filaments and shown how this model can be upscaled to a continuum description. He has used these models to examine the deformation of the network in response to the prescribed motion of an embedded rigid bead (to mimic optical tweezers experiments for estimating cell rheology conducted by our collaborators at MIT), elucidating the force-displacement curve. Asymptotic reductions of the continuum model facilitate an analytical approximation for the gradient of the force-displacement curve in terms of the cell and bead properties, providing a new way to use the experiments to estimate cell material parameters. He has further been able to extend his continuum description of the cell cytoskeleton to formulate a new strain energy functional which can be implemented directly into computational descriptions of the cell. Dr Namshad Thekkethil (RA2) has performed finite element simulations using this new strain energy functional, incorporating into a large-scale poroviscoelastic formulation including viscosity of both the cytoskeletal structure and the cytosol. The predictions of this model show good qualitative agreement the experimental results from the MIT lab.
Poroelasticity and porous media flow: We have modelled cardiac perfusion with improved numerical efficiency, we studied the fibre effects on poroelasticity as well as set up several reproducible numerical examples for future benchmark. This computational framework is published in IJNMBE. We also have developed new numerical methods for an immerse interface model for both hyperelastic and poroelastic material, which allows higher resolution and is much faster than the original solver. We revealed the role of microscale solid matrix compressibility (Dehghani et al. 2020) on the mechanical behaviour of poroelastic materials and derived a new model which describes the macroscale mechanics and effective coefficients of both linear elastic (Miller et al. 2021) and hyperleastic poroelastic composites (Millar et al. 2021), as well as the homogenised governing equations for double poroelastic media (Miller et al. 2021). We also investigated the role of inhomogeneous body forces in driving fluid flow in heterogeneous porous media. We derived a new model which can be used to predict the role of magnetic (or electric) fields on ferrofluids (or electrolytes) flowing in porous and their interplay with the heterogeneous porous structure (Penta et al. 2021).

Mechanics of complex systems/composites: We investigated the behaviour of electrosensitive multiscale materials and derived a new set of effective balance equations for composites characterised by a discontinuity in both the electric and the mechanical properties (Stefano, et al. ZAMP, 2020).

Growth and Remodelling: We have developed a new theory that allows the growth tensor to be defined in the current loaded configuration, which is a significant development since existing models of volumetric growth all defined the growth tensor in the reference configuration, which cannot describe the nature of soft tissue growth properly. With this new theory, we can produce residual strain that is consistent with experimental observations. The work is published in BMMB.

Viscoelasticity: Since his appointment six months ago Dr Yangkun Du (RA3) has produced an excellent and thorough survey of the literature on both theoretical and experimental aspects of the elasticity and viscoelasticity of cells and tissues and identified suitable theoretical models for the purposes of comparison with experimental results. This has been used as a basis for formulating the finite deformation indentation of a soft half-space with a rigid indenter in order to obtain a finite deformation generalization of the linearly elastic Hertz indentation result. This work has proved to be very successful, and he has prepared a substantial paper that improves upon the second-order results for indentation of a model cell on a soft half-space, which we are now revising ready for submission. We also developed a new model for hierarchical viscoelastic composites and computed three-scales homogenised properties for wavy layered structures analytically. We also implemented a new semi-analytical scheme (AHMFE, i.e. Asymptotic Homogenisation Method Finite Elements) via which we computed (a) the effective properties of isotropic viscoelastic composites in three dimensions (IJES, 2020), (b) extended the formulation to compute the effective properties for both long and short (i.e. cylindrical inclusions) anisotropic fibres (AES, 2021) We have also recently developed a new theoretical model for three-scales, hierarchical viscoelastic materials and derived the homogenised effective coefficients for non-perfectly periodic laminated composites (MAMS, 2021).

Heart mechanics modelling: Ventricle-valve Interaction we extended the left ventricle model to include the mitral valve model, and then added the left atrium model, linked with the pulmonary circulation. In collaboration with Mark Danton (consultant cardiac surgeon), we obtained interesting new results about these sub-systems of the heart, compared with clinical observations. The work is published in BMMB and presented at various conferences, workshops. We also improved the modelling of the myocardium by adding details of the cellular level. The heart muscle cells (myocytes) in the myocardium and the scaffold (collagen network) have very delicate structures to maximize the pumping function. Existing studies usually consider main features (i.e. average muscle orientations), but miss features like dispersion. In this new work both the passive and active heart muscle models include the myocyte and collagen dispersions, and the work is published in R Soc Open Science (2020) and JEM (2021).
Electrophysiology: Five further studies of the electrophysiology of cardiomyocytes and hiPSC-cardiomyocytes have been published in this period. In (Mortensen et al., 2021) we developed an analytical theory of action potential block due to non-uniform distributions of fibroblast cells in atrial tissue, namely fibroblast barrier distribution and myocyte strait distribution. In (Costa et al., 2021) we tested the hypothesis that the co-culturing of human-induced pluripotent stem cell-derived cardiomyocytes (hiCMs) with a human embryonic kidney (HEK) cell-line expressing the Kir2.1 channel (HEK-IK1) can generate an electrical syncytium with an adult-like cardiac electrophysiology. The electrical and mechanical activity of co-cultures using different HEK-IK1:hiCM ratios was measured and compared with co-cultures using wildtype (HEK-WT:hiCM) or hiCM alone on days 3-8 after plating and a computational model of the co-culture was developed to explain the observed electrophysiological effects. In (Huethorst et al., 2022) we studied the spatiotemporal features of contraction of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) arranged in monolayers interacting mechanically via cell-cell and cell-substrate adhesion and in the presence of Isoprenaline. To clarify the underlying mechanisms, further gene expression and computational studies were performed. We found that HiPSC-CM monolayers exhibited multiphasic contractile profiles on rigid surfaces in contrast to hydrogels, substrate-free cultures or single cells where only simple twitch-like time-courses were observed and concluded that flexible substrates are necessary for normal twitch-like contractility kinetics and interpretation of inotropic interventions. In (Lachaud et al. 2022) we reported and analysed electrophysiological heterogeneity in large populations of rabbit ventricular cardiomyocytes. APD in ~50 isolated cells from subregions of the LV free wall of 17 rabbit hearts were measured using a voltage-sensitive dye and significant (i) regional differences in action potential (AP) waveform, (ii) AP waveform differences in cells isolated from a single region, (iii) variability of the contribution of individual ion currents in cells with similar AP durations (APDs) were found. Highly variable changes in APD occurred after IK(r) or ICa(L) block that included a sub-population of cells (HR) with an exaggerated (hyper) response to IK(r) inhibition. A set of 4471 AP models matching the experimental APD90 distribution was generated from a larger population of models created by random variation of the maximum conductances (Gmax) of 8 key ion channels/exchangers/pumps. This set reproduced the pattern of cell-specific responses to ICa(L) and IK(r) block, including the HR sub-population. The models exhibited a wide range of Gmax values with constrained relationships linking ICa(L) with IK(r), ICl, INCX, and INaK. In (Aziz and Simitev, 2022) we developed a robust method along with open-source numerical code for estimation of the parameter values of a relatively simple but mathematically accurate archetypal model of single-cell cardiac from measurements of the morphology of single-stimulus action potentials derived from detailed ionic current models and from experimental myocyte measurements. An archetypal model that accurately reproduces a variety of wet-lab and synthetic electrophysiology data offers a number of mathematical and computational advantages.

Damage and homogenization: We have been developing a new theoretical multiscale model which couples the mechanical response of a linear elastic composite with the evolution of the damage.

Application to aortic dissection: The medical device manufacturer, Terumo-Aortic, has funded a PhD student, Sathish Kumar, to study the design and deployment of fabric-coated stents to treat aortic dissection, with a focus on reducing the likelihood of stent-induced new entry tear (SINE). The deliverables for Terumo-Aortic will include Abaqus computer programs to simulate and test the biomechanical performance, and interaction with the soft tissue of the arterial wall, of new and existing stents. The research project will make use of the new mathematical and computational models of soft tissue damage being developed by SofTMechMP. To date, representative computational models of arteries have been constructed from images and meshed. Algorithms have been developed to estimate residual stress and the unloaded configuration for these models to permit realistic calculations of stress and strain in the arterial wall based on the HGO constitutive law. Computational models of specific stents and their deployment have been constructed and used to identify contact regions of high stress and strain that are likely sites of damage to the wall. Studies of critical pressures for tear propagation in idealised 3D aortic wall models have been undertaken, and current work is focussed on integrating the dissection models with in situ stents.

Applications to stent for occluded coronary arteries: We obtained analytical and numerical studies of shape memory polymers stent and found that radial strength of stent is a function of the radius of the stent and periodic numbers of the unit cell in the circumferential direction. We identified influences of vessel curvature and plaque composition on drug transport in the arterial wall following drug-eluting stent implantation. We identified how stent expansion alters drug transport properties of the arterial wall. Arising from this work are a number of publications:
https://app.researchfish.com/portfolio/0/publications/61f7e5987823c7.27886320/view?name=61f7e5987823c7.27886320&filter=41547001_884800256b74f5_AW
Investigators from UoG and POLIMI reported on a novel 3D model of drug-coated balloon treatment of calcified superficial arteries, uncovering the influence on drug kinetics of the geometrical and compositional features of the vessel, balloon design characteristics and procedural aspects.
https://app.researchfish.com/portfolio/0/publications/6203af7216e8d0.50619209/view?name=6203af7216e8d0.50619209&filter=41547001_884800256b74f5_AW
In collaboration with clinical and experimental collaborators, we re-explored our current understanding of how antiproliferative drugs coated on stents and balloons reduce proliferation of vascular smooth muscle cells (SMCs). Our findings call into question the accuracy of existing mathematical models of cell proliferation subject to drug exposure and current thinking regarding the drugs' mechanism of action, potentially having important implications on the interpretation of current computational models and their future use to optimise and control drug release from stents and drug-coated balloons. We developed a series of multiphysics models to explore the influence of fluid flow on drug release from drug-filled implants, used in cardiovascular ad orthopaedic applications, elucidating the influence of fluid flow and material properties on the drug release profile. We developed a series of multiphysics models to explore the influence of fluid flow on drug release from drug-filled implants, used in cardiovascular ad orthopaedic applications, elucidating the influence of fluid flow and material properties on the drug release profile (King et al. Phar. Res, 2022).

Applications to the eye: In collaboration with clinicians, we used a computational model to study routine cataract operations and identified key parameters in affecting tissue damage during these operations and pointed out how to minimise these damages. Dr Jakub Koery (RA1) has also developed a new mechanical model for the human cornea, describing the tissue as a discrete array of cross-linked collagen lamellae, in collaboration with Prof Anna Pandolfi (POLIMI). This model has been upscaled to form a novel new continuum description of the cornea and will be used to investigate (and optimise) corneal cross-linking therapies for keratoconus.

Parameter inference and sensitivity study: Personalized computational cardiac models are considered to be a unique and powerful tool in modern cardiology, integrating the knowledge of physiology, pathology and fundamental laws of mechanics in one framework. They have the potential to improve risk prediction in cardiac patients and assist in the development of new treatments. However, in order to use these models for clinical decision support, it is important that both the impact of model parameter perturbations on the predicted clinical quantities of interest as well as the uncertainty of parameter estimation are properly quantified, where the first task is a priori in nature (meaning independent of any specific clinical data), while the second task is carried out a posteriori (meaning after specific clinical data have been obtained). We have addressed these challenges for a widely used constitutive law of passive myocardium (the Holzapfel-Ogden model), using global sensitivity analysis (SA) to address the first challenge, and inverse uncertainty quantification (UQ) for the second challenge. Our study reveals insights into the relation between SA and UQ, elucidates the dependence of parameter sensitivity and estimation uncertainty on external factors, like left ventricular cavity pressure, and sheds new light on cardio-mechanic model formulation, with particular focus on the Holzapfel-Ogden myocardial model (Lazarus et al., 2022). A challenging problem of in vivo parameter estimation in cardiac mechanics is the substantial computational complexity; this is a result of the fact that we have to repeatedly carry out forward simulations from the mathematical model as part of an iterative optimisation scheme. We have addressed this difficulty by building a black-box emulator, which replaces the original mathematical model by a statistical surrogate model. We have compared (Dalton et al., 2020a) and improved on (Dalton et al., 2020b) state-of-the-art methods. To further expand this work, we have worked on "opening the black box" by applying message passing algorithms from machine learning to the left ventricular mesh as a computationally faster alternative to numerically solving the finite element equations (Dalton et al., 2021).
Exploitation Route Journal publications, open-source software, conference presentations, new collaborations, research visits, talks to clinicians.
Sectors Education,Healthcare

URL http://www.softmech.org
 
Description SofTMechMP is a new International Centre to Centre Collaboration between the SofTMech Centre for Multiscale Soft Tissue Mechanics (www.softmech.org) and two world-leading research centres, Massachusetts Institute of Technology (MIT) in the USA and Politecnico di Milano (POLIMI) in Italy, funded by the EPSRC. Its exciting programme of research addresses important new mathematical challenges driven by clinical needs, such as tissue damage and healing, by developing multiscale soft tissue models that are reproducible and testable against experiments. Long term impacts are envisioned in areas such as tissue dissection, stent-related tissue damage, and wound healing development. Heart disease has a strong negative impact on society. In the United Kingdom alone, there are ~1.5 million people living with the burden of a heart attack. In developing countries, too, heart disease is becoming an increasing problem. Unfortunately, the exact mechanisms by which heart failure occurs are poorly understood. On a more optimistic note, a revolution is underway in healthcare and medicine - numerical simulations are increasingly being used to help diagnose and treat heart disease and devise patient-specific therapies. The Centre started on 1st January 2020 and economic and social impacts are not expected till later in the award. However, SofTMechMP has an impressive range of project partners that it engages with to advance research and ultimately deliver real-world impact. These include Biomer Technology Ltd; Boston Scientific; Dassault Systemes; GlaxoSmithKline plc (GSK); Humanitas University; InSilicoTrials Technologies; Kirkstall Ltd; Massachusetts Institute of Technology; NHS; Polytechnic University of Milan; Scottish Health Innovations Ltd; Siemens; Terumo Aortic; Translumina GmbH; Vascular Flow Technologies.
First Year Of Impact 2021
Sector Education,Healthcare
 
Description IEC\NSFC\191622 - International Exchanges 2019 Cost Share (NSFC) Royal Society-Newton Mobility Grant
Amount £12,000 (GBP)
Funding ID IEC\NSFC\191622 - International Exchanges 2019 Cost Share (NSFC) 
Organisation The Royal Society 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2020 
End 03/2022
 
Description Leverhulme Research Fellowship (Professor Nick Hill)
Amount £55,000 (GBP)
Organisation The Leverhulme Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2021 
End 04/2022
 
Description SofTMech with MIT and POLIMI (SofTMechMP)
Amount £1,599,530 (GBP)
Funding ID EP/S030875/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 05/2019 
End 06/2023
 
Description The SofTMech Statistical Emulation and Translation Hub
Amount £1,225,134 (GBP)
Funding ID EP/T017899/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 03/2021 
End 02/2025
 
Description The SofTMech Statistical Emulation and Translation Hub
Amount £1,225,134 (GBP)
Funding ID EP/T017899/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 03/2021 
End 02/2025
 
Title Action potential propagation and block in a model of atrial tissue with myocyte-fibroblast coupling 
Description n/a 
Type Of Material Database/Collection of data 
Year Produced 2020 
Provided To Others? Yes  
Impact n/a 
URL http://researchdata.gla.ac.uk/id/eprint/1104
 
Title Cardiac Modelling with dispersed myofibre and collagen structures 
Description It is the accompanying dataset and model the paper "modelling of fibre dispersion and its effects on cardiac mechanics from diastole to systole", accepted in the Journal of Engineering Mathematics. It implements two different fibre dispersion models within two ventricular finite element models: a bi-ventricular rabbit heart and a human left ventricular model. 
Type Of Material Computer model/algorithm 
Year Produced 2021 
Provided To Others? Yes  
Impact This study highlights the importance of fibre dispersion in cardiac mechanics, and for the first time to investigate how to incorporate a complex fibre dispersion distribution into a cardiac mechanics model. This work has been presented in the Living Heart Project Seminar, and we are working with the Virtual Human Team from Dassault System to implement it in the Living Heart Project. 
URL https://github.com/HaoGao/DispersedFibresMyocardiumModelling
 
Title Code for Estimation of Parameters for an Archetypal Model of Cardiomyocyte Membrane Potentials 
Description This is a suite of MATLAB/Octave functions for numerical solution of and for estimation of the parameter values of the cardiomyocyte membrane potential model of Biktashev et al. (Bull Math Biol, 70(2), 2008,doi:10.1007/s11538-007-9267-0) - "the archetypal model". In particular, the code can be used determine parameter values for the archetypal model such that its solutions approximate the action potential traces and the action potential duration restitution curves of (a) other electrophysiologically detailed mathematical models of the transmembrane ionic currents of single cardiac myocytes - "target models", as well as (b) traces and curves measured experimentally - "target data". Data and functions for several detailed ionic models from the CellML physiological model repository (cellml.org) are included as examples of usage. 
Type Of Material Database/Collection of data 
Year Produced 2021 
Provided To Others? Yes  
Impact N/A 
URL https://zenodo.org/record/4568662
 
Title Energetics of a collapsible channel flow with a nonlinear fluid-beam model 
Description Data for figures in 'Energetics of a collapsible channel flow with a nonlinear fluid-beam model' 
Type Of Material Database/Collection of data 
Year Produced 2021 
Provided To Others? Yes  
URL http://researchdata.gla.ac.uk/id/eprint/1112
 
Title Fibre Dispersion Myocardial Mechanics 
Description It contains the computational models for the following two papers 1. Guan, D., Mei, Y., Xu, L., Cai, L., Luo, X., & Gao, H. (2022). Effects of dispersed fibres in myocardial mechanics, Part I: passive response. Mathematical Biosciences and Engineering, 19(4), 3972-3993. 2. Guan, D., Wang, Y., Xu, L., Cai, L., Luo, X., & Gao, H. (2022). Effects of dispersed fibres in myocardial mechanics, Part II: active response. Mathematical Biosciences and Engineering, 19(4), 4101-4119. Published Year: 2022 
Type Of Material Computer model/algorithm 
Year Produced 2022 
Provided To Others? Yes  
Impact This work has attracted interest from the Virtual Human Team from Dassault System. It will further improve the cardiac modelling by including detailed fibre dispersion, in particular in fibrosis modelling. 
URL https://github.com/HaoGao/FibreDispersionMyocardialMechanics
 
Title GlasgowHeart: A Magnetic Resonance Imaging-derived 'virtual twin' cardiac mechanics platform 
Description A personalized biomechanical cardiac modelling framework, aimed at the mechanistic understanding of individual patients' cardiac remodelling in the longer-term and risk-stratification. Our long-term aim is to be able to revolutionise clinical practice through accurate risk-stratification and virtual testing. Four modules are currently available in GlasgowHeart: 1) image processing, 2) biomechanics modelling, 3) personalization, inference and machine learning of left ventricular (LV) mechanics and 4) statistical emulation as shown in Figure 1. Modules 1, 2 and 3 have been developed in MATLAB by the co-authors, and module 4 is programmed in Python using Tensor Flow, Scikit-learn, XGBoost to use advanced machine-learning methods. For computational modelling in module 2, we further use LibMesh, IBAMR, Fenics for solving nonlinear systems, Visit and Paraview for 3D visualization. Module 2 can also work with other commercial packages for biomechanics simulations (ABAQUS, FEAP). 
Type Of Material Computer model/algorithm 
Year Produced 2021 
Provided To Others? Yes  
Impact This framework has been developed over the last ten years and contributed to various projects and funding applications. Recently it was presented in SCMR 2021 conference in the open-source software demo session. 
URL https://github.com/HaoGao/GlasgowHeart
 
Title Global stability analysis of flexible channel flow with a hyperelastic wall 
Description Data for figures in 'Global stability analysis of flexible channel flow with a hyperelastic wall' 
Type Of Material Database/Collection of data 
Year Produced 2021 
Provided To Others? Yes  
URL http://researchdata.gla.ac.uk/id/eprint/1113
 
Title Multiple Steady and Oscillatory Solutions in a Collapsible Channel Flow 
Description  
Type Of Material Database/Collection of data 
Year Produced 2021 
Provided To Others? Yes  
URL http://researchdata.gla.ac.uk/id/eprint/1165
 
Title Sensitivity Analysis and Inverse Uncertainty Quantification for the Left Ventricular Passive Mechanic 
Description It contains the codes and data for the paper 'Sensitivity Analysis and Inverse Uncertainty Quantification for the Left Ventricular Passive Mechanics'. This work performs structural identifiability and practical identifiability analysis for a widely used constitutive law of passive myocardium (the Holzapfel-Ogden model), using global sensitivity analysis to assess structural identifiability, and inverse-uncertainty quantification to assess practical identifiability. 
Type Of Material Computer model/algorithm 
Year Produced 2022 
Provided To Others? Yes  
Impact It elucidates the dependence of parameter identifiability on external factors for the first time in a nonlinear cardiomechanic model, with a particular focus on the H-O myocardial model. 
URL https://github.com/HaoGao/ho-uncertainty-quantification
 
Description New academic collabration 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Collaboration with Dr. Jack Lee on heart perfusion modelling enables us to make use of their detailed coronary circulation model and expertise.
Collaborator Contribution Expertise and data
Impact Collaboration is still ongoing. No output yet.
Start Year 2021
 
Title Code for Estimation of Parameters for an Archetypal Model of Cardiomyocyte Membrane Potentials 
Description This is a suite of MATLAB/Octave functions for numerical solution of and for estimation of the parameter values of the cardiomyocyte membrane potential model of Biktashev et al. (Bull Math Biol, 70(2), 2008,doi:10.1007/s11538-007-9267-0) - "the archetypal model". In particular, the code can be used determine parameter values for the archetypal model such that its solutions approximate the action potential traces and the action potential duration restitution curves of (a) other electrophysiologically detailed mathematical models of the transmembrane ionic currents of single cardiac myocytes - "target models", as well as (b) traces and curves measured experimentally - "target data". Data and functions for several detailed ionic models from the CellML physiological model repository (cellml.org) are included as examples of usage. 
Type Of Technology Software 
Year Produced 2021 
Open Source License? Yes  
Impact NA 
URL https://zenodo.org/record/4568662
 
Title GlasgowHeart 
Description GlasgowHeart platform for personalized modelling of the human heart. It is organized into 4 modules, and each can be run separately. Currently, MatLab is the main programming language and using scripts for run, this will require certain knowledge of Matlab. In the future, we will develop a GUI package for easy use. The four modules are image processing, biomechanics modelling, personalization, and parameter inference of left ventricular (LV) mechanics and statistical emulation. 
Type Of Technology Software 
Year Produced 2021 
Open Source License? Yes  
Impact The package is actively being used by the researchers from the SofTMech Centre and supports a few cardiac research projects. 
 
Description BAMC minisymposium on Soft Tissue Growth and Remodelling 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact I organized a BAMC mini-symposium on Soft Tissue Growth and Remodelling with colleagues, which has attracted more than 50 audience
Year(s) Of Engagement Activity 2022
 
Description Computationally efficient parameter estimation and uncertainty quantification in complex physiological systems 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited keynote lecture given at the 2nd International Conference on Statistics:
Theory and Applications (ICSTA'20),
held as a virtual conference via Zoom, 19-21 August 2020.
Year(s) Of Engagement Activity 2021
URL https://2020.icsta.net/program/
 
Description Interview for BBC Scotland News, 12th November 2020: Colin Berry 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Colin Berry discussing the effects of long COVID on BBC News on the 12th November, 2020. The purpose was to make the general public aware that some people who become infected with COVID suffer long lasting effects.
Year(s) Of Engagement Activity 2020
URL https://twitter.com/UofGMVLS/status/1326844312525606914
 
Description Joint CDT conference (Team member Prof. Matthew Dalby, Director of Glasgow lifETIME CDT) - a meeting between CDTs based in Glasgow, Birmingham, Leeds, Manchester, Liverpool, Aston, Sheffield, Keele, Nottingham and Loughborough 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact The following EPSRC Centres for Doctoral Training across the UK regenerative medicine field and the UK society for biomaterials came together online on 24th and 25th June 2020:
EPSRC-SFI Joint CDT in Engineered Tissues for Discovery, Industry and Medicine (LifETIME)
EPSRC/MRC CDT in Regenerative Medicine
EPSRC/MRC CDT in Regenerative Medicine
EPSRC Advanced Biomedical Materials CDT (ABM)
EPSRC CDT in Tissue Engineering and Regenerative Medicine (TERM)
Doctoral Network for Technologies in Healthy Ageing (Ageing)

The CDTs showcased their research to professionals and other PhD students within the field via Zoom.
The conference will began with keynote speaker Prof Liam Grover, Director of the Healthcare Technologies Institute (HTI) at the University of Birmingham.
The conference then broke out into six themes across two days. During each session there were presentations from later year CDT students within the field and poster and flash talks from early year students. Time was also allowed to view posters on the UKSB website in advance of the poster discussion session.
Year(s) Of Engagement Activity 2020
URL https://lifetime-cdt.org/agenda-of-cdt-events/
 
Description LifETIME Centre for Doctoral Training stakeholder day (Team Member Prof. Matthew Dalby, Director of the LifETIME CDT) - a meeting between industry, academics, charities and funders to enhance student training. Jan 2021. 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Industry/Business
Results and Impact LifeTIME Centre for Doctoral Training (LifeTIME CDT) stakeholder day. Professor Matthew Dalby is the Director of the lifETIME CDT; the meeting was held to discuss ideas on enhancing student training. The partners were from industry, academia, charities and funders.
The stakeholder day will bring together LifETIME students, academics, industry partners, iClub members and steering group.
The purpose of the stakeholder day was to capture our stakeholder views from which the management will use to refine the CDTs impact strategy. In the morning a facilitator captured CDT subjects, highlighted and raised by stakeholders. These subjects then formed the basis for the discussion points in the afternoon.
The afternoon consisted of six co-current discussions over three different sessions. Each session 30 minutes long and stakeholders had the chance to attend the discussion most important and relevant to them. The discussion sessions used open space principles and responses and suggestions will be collected.
There was als an opportunity for all attendees to network.
Year(s) Of Engagement Activity 2021
URL https://lifetime-cdt.org/agenda-of-cdt-events/
 
Description LifeTIME Centre for Doctoral Training student day (Team Member Prof. Matthew Dalby, Director of the lifETIME CDT) - a meeting between industry, academics, charities and funders to develop student networking abilities and allow them to show their work to different sectors. Sept 2020. 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Industry/Business
Results and Impact the first LifETIME Student Day took place on Thursday 10th September 2020 via Zoom.
The student day will brought together lifETIME academics, partners, iClub, steering board and students. During the event the 2019 cohortl showcased their research projects and th industrial partners will presented a 5-minute pitch about their company and technologies. This was followed by talks from the funders.
Year(s) Of Engagement Activity 2020
URL https://lifetime-cdt.org/agenda-of-cdt-events/
 
Description Plenary talk at the International Forum on coompuational heart modelling 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Up to 100 people attended this event, organized by the North-West Polytechnic University
Year(s) Of Engagement Activity 2021
URL http://xygg.nwpu.edu.cn
 
Description Presentation of GlasgowHeart Platform in SCMR 2021 meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact This is the first time to present the Glasgow heart modelling framework to clinicians in one of the largest meetings in the cardiac magnetic resonance imaging community, SCMR 2021. The audiences consist of clinicians, imaging experts, industry partners, etc. The presentation was given in the first software demo session of the SCMR meeting, which brings the mechanic model one step closer to clinicians. The meeting committee believes that biomechanical biomarkers shall be included in the diagnosis guideline, and encourage more open-source software within the society of cardiac magnetic resonance.
Year(s) Of Engagement Activity 2021
URL https://scmr2021.process.y-congress.com/scientificProcess/Schedule/?setLng=en
 
Description Research visits and seminars at the University of Auckland, Auckland Bioengineering Institute, and Department of Maths, University of Canterbury, Christchurch 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Both students and researchers, including other international visitors, attended the talks during the visits, which sparkled questions and discussion afterwards, and laid the foundation for future collaborations.
Year(s) Of Engagement Activity 2020
 
Description SofTMech Soft Tissue workshop 2021 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact The 5th Soft Tissue workshop took place from 1st-3rd June 2021. The workshop focused on the most recent advances in the field of soft tissue mechanics, with a clear vision of the landscape of multiscale soft tissue modelling and both fundamental and translational research.
Year(s) Of Engagement Activity 2021
 
Description SofTMech Training Day 8th January 2021 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact On Friday 8th January 2021 an on-line training day organised by the SofTMech Training Committee led by Professor Dirk Husmeier and Dr Peter Stewart was held. The workshop was mainly aimed at PhD students and postdocs, but also welcomed staff members who were interested in closer future collaborations. 51 people registered for the workshop with 48 attending. Postgraduate and Staff from the University of Glasgow, University of Plymouth, Terumo Aortic, Politecnio Milano (POLIMI) (Italy), MIT (US), EPFL and North Carolina State University attended. The aims of the day were :
To give the mathematical modellers a brief overview of state-of-the-art statistical inference in complex systems.
To give statisticians an opportunity to learn about the basic mathematical modelling principles relevant to our projects.
To allow participants to talk together in small groups of 4/5, repeated a few times via Zoom breakout rooms (Speed dating); meeting people from other institutions with the view to future collaboration.
The day also included a presentation by David Hand on "Dark Data"
This recent training day allowed the University of Glasgow staff and postgraduate students to meet staff and students from their partner Institutions in POLIMI, MIT and working on similar areas and this has the potential to lead to future collaborative projects.
Year(s) Of Engagement Activity 2021
URL http://www.softmech.org/events/headline_763982_en.html
 
Description SofTMech Training Workshop Scientific Computation 2022 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact Training day for PhD students on Scientific Computation, held on 28th January 2022. The event attracted more than 40 participants from Maths-in-Healthcare centres from around the UK. Sparked questions and discussion afterwards.
Year(s) Of Engagement Activity 2022
 
Description Special Interest Group on the Fluid Mechanics of the Eye 
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 Since the COVID lockdown, Peter Stewart has organised virtual study groups on the fluid mechanics of the eye. The first event took place on 30th November 2020 and there have been 6 subsequent meetings across 2021 and 2022. These events have gathered clinicians and modellers (including some PhD students) to derive mathematical models pertinent to the eye. In particular, we have modelled:
(1) uveoscleral flow as a drug delivery platform to the macula
(2) formation of macular holes in aging eyes.
Several publications are in preparation.
We are hosting a follow up conference in Bath in June 2022, funded by the Macular Society.
Year(s) Of Engagement Activity 2020,2021,2022
URL https://eyefluidssig.wordpress.com/history/
 
Description Statistical inference in cardiac mechanics 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Talk given to the Royal Statistical Society local Glasgow group on 12th March 2020, which sparked questions and discussions afterwards, both over coffee and via follow-up emails.
Year(s) Of Engagement Activity 2020
URL https://sites.google.com/site/rssglasgow/events
 
Description Statistical inference in cardiovascular modelling 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Three of Dirk Husmeier's PhD students and postdocs gave talks at an event organised by the Royal Statistical Society Glasgow local group on 9 February 2021, with the following titles:
Mihaela Paun
The importance of allowing for model mismatch in cardiovascular modelling
Alan Lazarus
Improving cardio-mechanic parameter estimation by including prior knowledge derived from ex-vivo data
Agnieszka Borowska
Bayesian optimisation for improving accuracy and efficiency of cardio-mechanic parameter estimation
The event was delivered via ZOOM, and lead to a stimulating discussion between speakers and participants (also via Zoom).
Year(s) Of Engagement Activity 2021
URL https://rss.org.uk/training-events/events/statistical-inference-in-cardiovascular-modelling/#eventov...
 
Description Talk at 9th International Biofluid Mechanics And Vascular Mechanobiology Symposium 
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 Maintain the tradition of excellence and the spirit of the International Bio-fluid Mechanics and Vascular Mechano-Biology Symposia that have evolved to be a unique opportunity for reviewing recent major milestones and achievements in all areas of biofluid mechanics, experimental and computational, from molecule and cell to organ levels and corresponding mechano-biological processes, therapeutics, and cardiovascular devices.

The event gathered scientists, clinicians, and practitioners from around the world to explore and assess the latest frontiers of Bio-Fluid Mechanics and Vascular Mechano-Biology, and set important directions for further research and development, and education. The symposium provided an opportunity for investigators to interact with peers, young and seniors, for development of new collaborations, as well as enhancement of existing ones.
Year(s) Of Engagement Activity 2020
URL https://9thbiofluids.com/
 
Description The lifETIME (Engineered Tissues for Discovery, Industry and Medicine) CDT; Director: Matthew Dalby: Stakeholder Day 21.01.21 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Industry/Business
Results and Impact The stakeholder day brought together LifETIME students, academics, industry partners, iClub members and the steering group.
The purpose of the stakeholder day was to capture our stakeholder views from which the management will use to refine the CDTs impact strategy. In the morning a facilitator captured CDT subjects, highlighted and raised by stakeholders. These subjects then formed the basis for the discussion points in the afternoon.
The afternoon consisted of six co-current discussions over three different sessions. Each session waa 30 minutes long and stakeholders attended the discussion most important and relevant to them.
Year(s) Of Engagement Activity 2021
URL https://lifetime-cdt.org/agenda-of-cdt-events/previous-events/
 
Description The lifETIME (Engineered Tissues for Discovery, Industry and Medicine) CDT; Director: Matthew Dalby: Student Day 7.11.21 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact The student day brought together lifETIME academics, partners, iClub, steering board and students. During this event to showcase their research the 2019 students presented posters and the 2020 students presented quickfire presentations. Industrial partners and academics also presented short talks. The questions and discussions helped shape future research.
Year(s) Of Engagement Activity 2021
URL https://lifetime-cdt.org/agenda-of-cdt-events/previous-events/
 
Description The lifETIME (Engineered Tissues for Discovery, Industry and Medicine) CDT; Director: Matthew Dalby: Twitter Conference 10th & 11th June 2021 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact The LifETIME Twitter Conference was an online event held entirely over Twitter using the hashtag #futureleadersinregenmed to bring together the LifETIME CDT cohort and the wider scientific community to share research, engage in scientific discussions and network. The 2019 LifETIME students each presented 3 tweets during the two day event. The discussion could be joined by searching for the hashtag #futureleadersinregenmed allowing people to see all posts that are related to the conference.
Year(s) Of Engagement Activity 2021
URL https://lifetime-cdt.org/agenda-of-cdt-events/previous-events/
 
Description Twitter Account 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact SofTMech Twitter Account which covers a number of SofTMech and SofTMech related grants. Main purpose to give information on research activities, events including social, advertise job opportunities to a wide audience, and announce graduations, prizes and achievements of the group. In addition to use the Re-tweet feature of Twitter to advertise information from partner groups or followers. The account has 201 followers and follows 171 other Twitter accounts. Impacts arising from the Account are quick dissemination of material.
Year(s) Of Engagement Activity 2020,2021,2022
URL https://twitter.com/home