In the diagnosis and treatment of disease, clinicians base their decisions on understanding of the many factors that contribute to medical conditions, together with the particular circumstances of each patient. This is a "modelling" process, in which the patient's data are matched with an existing conceptual framework to guide selection of a treatment strategy based on experience. Now, after a long gestation, the world of in silico medicine is bringing sophisticated mathematics and computer simulation to this fundamental aspect of healthcare, adding to - and perhaps ultimately replacing - less structured approaches to disease representation. The in silico specialisation is now maturing into a separate engineering discipline, and is establishing sophisticated mathematical frameworks, both to describe the structures and interactions of the human body itself, and to solve the complex equations that represent the evolution of any particular biological process. So far the discipline has established excellent applications, but it has been slower to succeed in the more complex area of soft tissue behaviour, particularly across wide ranges of length scales (subcellular to organ). This EPSRC SoftMech initiative proposes to accelerate the development of multiscale soft-tissue modelling by constructing a generic mathematical multiscale framework. This will be a truly innovative step, as it will provide a common language with which all relevant materials, interactions and evolutions can be portrayed, and it will be designed from a standardised viewpoint to integrate with the totality of the work of the in silico community as a whole. In particular, it will integrate with the EPSRC MultiSim multiscale musculoskeletal simulation framework being developed by SoftMech partner Insigneo, and it will be validated in the two highest-mortality clinical areas of cardiac disease and cancer. The mathematics we will develop will have a vocabulary that is both rich and extensible, meaning that we will equip it for the majority of the known representations required but design it with an open architecture allowing others to contribute additional formulations as the need arises. It will already include novel constructions developed during the SoftMech project itself, and we will provide many detailed examples of usage drawn from our twin validation domains. The project will be seriously collaborative as we establish a strong network of interested parties across the UK. The key elements of the planned scientific advances relate to the feedback loop of the structural adaptations that cells make in response to mechanical and chemical stimuli. A major challenge is the current lack of models that operate across multiple length scales, and it is here that we will focus our developmental activities. Over recent years we have developed mathematical descriptions of the relevant mechanical properties of soft tissues (arteries, myocardium, cancer cells), and we have access to new experimental and statistical techniques (such as atomic force microscopy, MRI, DT-MRI and model selection), meaning that the resulting tools will bring much-need facilities and will be applicable across problems, including wound healing and cancer cell proliferation. The many detailed outputs of the work include, most importantly, the new mathematical framework, which will immediately enable all researchers to participate in fresh modelling activities. Beyond this our new methods of representation will simplify and extend the range of targets that can be modelled and, significantly, we will be devoting major effort to developing complex usage examples across cancer and cardiac domains. The tools will be ready for incorporation in commercial products, and our industrial partners plan extensions to their current systems. The practical results of improved modelling will be a better understanding of how our bodies work, leading to new therapies for cancer and cardiac disease.

Growth factors are molecules within our body that participate in many physiological process that are key during development as they control stem cell function. These molecules thus have the potential to drive the regeneration of tissues in a broad range of medical conditions, including in musculoskeletal (bone repair), haematological (bone marrow transplantation) and cardiovascular (infarction, heart attack) diseases. Growth factors are currently produced commercially and are used regularly in clinical applications. However, they are very power cell signalling molecules and dose is critical as balance between effect and safety has to be considered. To date the use of growth factors in regenerative medicine has been only partially successful and even controversial. The growth factors are rapidly broken down and cleared by the body. This makes prolonged delivery (as is required to effect repair) a problem and typically higher than wanted doses are administered to get around this. While their help in regeneration is undoubted, collateral side effects can be catastrophic e.g. tumour formation. We have developed new technology that directly addresses these concerns as it uses materials (that can be topically implanted) to deliver low, but effective, growth factor doses; this programme is about the safe use of growth factors in clinical applications. This will not only reduce risks for patients who currently receive growth factor treatments, but will open up therapies that can include co-transplantation with stem cells to a wider range of patients as doctors would not have to keep these therapies back for cases of most pressing need. This increased use would minimise costs as growth factors are very expensive and reduced dose would save money per treatment. Our approach is unique and this programme grant will allow us to enhance the UK's world leading position through innovative bioengineering. We know that stem cells have huge regenerative potential and that growth factors provide exquisite stem cell control - both are currently untapped. We will engineer new materials to enable growth factor technology, and critically stem cell technologies, where traditional approaches are falling very short of the mark.

The AFib-TrainNet consortium will enable promising young scientists to become excellent research leaders of the future, capable of fighting the challenges that Atrial Fibrillation (AF) presents to the European population. AF is the most common sustained cardiac arrhythmia, occurring in between 1-2% of the general population. More than 6 million Europeans suffer from this arrhythmia and its prevalence is expected to increase by more than two-fold during the next 40 years due to increased life expectancy. Thus, AF is said to assume epidemic proportions. Current options for pharmacological therapy are limited by both low efficacy and side effects, including life‐threatening ventricular arrhythmias and severe extra-cardiac toxicities. A very limited number of novel AF drug therapies have been introduced in the last 20 years. This imbalance reflects a gap in understanding in both how AF develops and how it can be treated, which thereby limits the development of new medicines. Our ambition with the AFib-TrainNet is to fill this gap by producing new knowledge, leading to critical insight into origins and mechanisms of sustenance of atrial fibrillation. We will accomplish this by developing novel experimental and computational models recapitulating human AF, and employing these models on two very promising atrial biological targets. Experimental models will be instrumental in improving the understanding AF’s underlying mechanisms, and will, along with clinical data, inform state-of-the-art computational models of human atrial electrophysiology. These new tools will permit fresh insight into the molecular, cellular and electrical mechanisms involved in the progression of healthy atria into an AF state. Our endeavor will deliver results which can be leveraged by the pharmaceutical industry to target AF drug development, and the work accomplished in AFib-TrainNet will thus constitute a beacon in the search for new AF medicine.