This proposal is to develop new collaborative and sustainable interdisciplinary research teams at the University of Southampton (UoS) involving researchers from a wide spectrum of the Mathematical Sciences, with researchers in Nano-engineering and in Bio-engineering. The University has significant strengths in these rapidly developing engineering areas but, despite its strong commitment and long-standing involvement in interdisciplinary research, has yet to fully develop engagement between these areas and the Mathematical Sciences. The project will develop a dynamic and flexible programme of activities, under the name SYMBIOSIS, which aims to overcome current barriers at the University to develop collaborative teams. There are two broad themes in the programme: Mathematics in Bio-engineering and Mathematics in Nano-engineering. These themes will create focussed interaction between researchers in the disciplines of mathematics and engineering, so that new questions will be asked and new ideas formulated, in both disciplines. The interactions will also enable the transfer of state-of-the/art techniques across the interfaces of these disciplines. The programme will have various mechanisms that provide researchers with ring-fenced time to learn about new scientific areas, to become familiar with different scientific languages, to identify and carry out preliminary investigations of potential projects and to prepare proposals for external funding to develop and sustain research activity. In addition, SYMBIOSIS will take advantage of the tremendous potential at the University of Southampton for future collaborations involving the large pool of recently appointed academic staff members who have only just started on an academic career. The programme will encourage their participation in interdisciplinary research and, more importantly, allow them to gain crucial mentoring and experience in initiating and developing such collaborations. Finally, SYMBIOSIS will give opportunities to break down the geographical, social and hence academic distances between the various different disciplines. SYMBIOSIS will use a physical presence on campus to focus attention and to allow uninterrupted direct discussions, a facilitator to initiate and foster new collaborations, a strong virtual presence and an electronic work environment, all of which will grow a culture of interdisciplinary research and new collaboration. Specific activities will also include: an extensive set of workshops, both real and virtual, which will act as a pipeline to developing new collaborations; fellowships to allow immersion in alternative disciplines within the programme; a Visitor programme and SYMBIOSIS seminars; UoS- funded interdisciplinary PhD studentships for long-term focus. Four broad areas of mathematics have been identified as likely to be stimulated within the themes through new research challenges: Mathematical Modelling and Multiscale Physics; Combinatorics, Geometry and Mathematical Analysis; Understanding Uncertainty - Experiment and Analysis; Optimisation, Computation and Simulation. These areas will, in turn, contribute to the engineering research. Examples of possible research areas include: engineering design of sensors for the environment and for robotics, developing and assessing novel joint replacements in humans, and designing and improving micro-engineered machines (MEMs) through the use of new materials.

When a person undergoes hip replacement surgery, there are many factors that can affect how long it will last, many of which are not immediately apparent to the patient. Within each patient, the properties of bone can vary considerably; this difference in bone quality may be even more apparent between patients, particularly if one patient is more active than another, is heavier, or even if their diets are different. Other factors to consider are the geometries of the bone and implant, the quality of the surrounding tissues, the trauma associated with surgery and how well aligned the implant is, the last two of which are related to the surgical technique. Traditionally, experimental investigations into the performance of hip replacements have been limited to analysing one situation per experiment (e.g. one alignment and one bone). The results of these investigations can really only provide a good qualitative indicator as the biological environment can not be adequately simulated in the laboratory. Add to this, the huge number of experiments that would be required to simulate all possible scenarios (combinations of alignment, geometries, bone quality etc.) and experimental investigations soon become unfeasible. In order to address this shortcoming, computational methods have been developed that are capable of simulating an experimental test in a much shorter time. However, to date, most of these investigations again describe only one situation and many computational models are required to fully describe the effect of variations in only a single parameter. The proposed research program therefore, will deliver new computational tools that can account for variations in parameters such as the properties of bone, the loading conditions and the surgical technique simultaneously and efficiently, in a single analysis. It is anticipated that the immediate benefits of this research will include the development of models capable of determining which current implant designs are more forgiving of variations in misalignment and bone geometry, and are therefore likely to perform well regardless of the patient. In the medium term, these analyses should enable the surgeon to make an informed decision when selecting the most appropriate implant for his/her patient. In the longer term, it is believed that the research will help prosthesis manufacturers to arrive at new designs with improved performance and longevity, to the benefit of the manufacturer, the health provider, and of course, the patient.

The Innovation and Knowledge Centre in Regenerative Therapies and Devices will provide a sustainable platform to address the creation of new technologies in Regenerative Therapies and Devices. It will promote their accelerated adoption, with increased reliability, within a complex global marketplace with increasing cost constraints. Therapies and devices which facilitate the regeneration of body tissues offer the potential to revolutionise healthcare and be a catalyst for economic growth, creating a new business sector within healthcare technology. The IKC RTD will build upon the culture and research landscape of the University and its partners (industry, NHS and intermediaries/users) through the development of new innovation infrastructure and practices which deliver major clinical, health and industry outcomes.In the first year of operation the IKC has:1. Recruited and established a core innovation team to manage and grow the activities of the IKC.2. Established academic supply chain, new centre with 160 researchers.3. Won 50m new research income, funding over 120 research projects.4. Defined a new strategic framework for innovation.5. Established an innovation pipeline with stage gates and criteria for progression.6. Defined and developed the IP portfolio through definition of the unique capabilities.7. Established a pipeline of 63 collaborative innovation projects.8. Engaged with 26 different companies in collaborative innovation projects.9. Established a wider network of 80 plus companies.10. Contributed to nine new products that have reached the market.11. Defined a model for sustainability of IKC RTD.12. Received significant national and global recognition through political visits and extensive media coverage for research and innovation.

Traditional methods of treatment for conditions such as arthritis of the knee involve physiotherapy and medication. However, when the condition becomes excessively painful for the patient, surgical intervention is undertaken. Movement of the natural knee joint involves the base of the femur bone articulating against the top of the tibia bone. The surfaces of these bones are covered by articular cartilage which allows smooth, pain free movement at the joint. The base of the femur and the top of the tibia have two surfaces or 'condyles'; in severe cases, the cartilage is worn away from both condyles, and they have to be replaced by a total knee arthroplasty (TKA). In some cases only one of the condyles is affected by arthritis, and yet both condyles are replaced in a TKA procedure. Unicondylar Knee Arthroplasty (UKA), which resurfaces only the affected side, is an alternative to TKA which is becoming an increasingly popular because of its improved functional outcome, favourable long term clinical results and the benefits of minimally invasive surgical techniques. In particular, UKA offers a more effective solution than TKA for more active patients with single compartment knee disease, because the mechanics of the knee are better preserved, and more functional anatomy is maintained. UKA also has advantage of rapid rehabilitation, short hospital stay, quicker operation and quicker recovery. Evidence suggests that revision of a UKA to a TKA results in performance similar to a primary TKA and has been reported to be an easier procedure than the typical revision TKA. However, despite this, UKA is still under-exploited as an alternative to TKA. This is partly related to perception issues, and partly to historically higher failure rates due to improper technique. Therefore, it is desirable to improve the understanding of how surgical technique impacts UKA performance and failure risks, to inform clinical decision-making for UKA with best-practice surgical technique. Most attempts to assess the performance of a joint replacement computationally have involved a 'deterministic' approach, that is, a single implant is modelled in a single bone and a single load is applied. This represents only one possible situation, when potentially many thousands could exist. Recently, there has been a move to replace deterministic approaches with statistical approaches, which attempt to take into account all sources of variability in the system. For example, the performance of an implant in a series of bones under varying loads can be analysed. In this project, statistical approaches will be applied to analyse the performance of UKA. The research will utilise a 'statistical knee joint' based on a large library of bone CT scans. This statistical knee joint represents a wide population of patients into which the unicondylar implant will be implanted. Variations in surgical technique will be accounted for by altering the nature of the surgical cuts and positions of the surrounding soft tissue structures. In this way, a knowledge of how the surgical technique can affect implant performance, in how quickly it wears and how likely it is to loosen, can be ascertained. This knowledge will be used to develop a tool that can be used to guide surgeons on what aspects of their surgical technique need careful consideration when planning their surgery in order to achieve improved patient outcomes. Industry can also benefit from the tool as part of the implant design process. The performance of new and existing implants can be robustly evaluated rapidly at the design stage, and the number of physical tests required can be reduced dramatically. In addition, designs that are predicted to perform poorly can be eliminated at an early stage, leading to substantial cost and time benefits for the design process. The commensurate benefit of this tool will be more robust implants with a longer lifespan, benefiting both the patient and the healthcare provider.

The Innovation and Knowledge Centre in Regenerative Therapies and Devices will provide a sustainable regional and international platform to address the creation of new technologies in Regenerative Therapies and Devices and their accelerated adoption within a complex global market place with increasing cost constraints. Therapies and devices which facilitate the regeneration of body tissues offer the potential to revolutionise healthcare and be a catalyst for economic growth, creating a new business sector within healthcare technology (Foresight Healthcare 2020). This centre is focused on emerging novel technologies in biological scaffolds, nano-biomaterials and self assembling peptides. These hybrid technologies utilise novel physical and biological functionality to enhance and accelerate the regeneration of tissues by harnessing the potential of endogenous stem cells in vivo. These novel technologies will also provide a vehicle for the delivery of exogenous stem cells to patients in the future and can be used to generate neo-tissues in vitro. The delivery of these emerging technologies to patients will be accelerated by improved diagnostics and imaging for enhanced patient targeting and by new complex simulation methodologies (patient in the lab) for improved short term predictions of the long term clinical outcomes. The life expectancy and average age of the population continues to increase as a result of advances in biomedicine and healthcare and this is generating additional social and economic burden. The Regenerative Technologies and Devices IKC will address the needs and quality of life of the ageing population, and address their expectations of an active lifestyle for fifty more years after fifty . It will specifically, but not exclusively, focus on areas of clinical need in musculoskeletal disease, dentistry, cardiovascular disease and cancer, which have been strategically prioritised by the University and the Leeds Hospitals Trust. The centre will build upon and develop substantial clinical, academic and industry partnerships. Additional new collaborative funding of over 58 million has already been confirmed to match the IKC award, and the centre has plans which have identified research and innovation funding in this area of over 100 million during the initial five year period of its activities.This rapidly growing multidisciplinary area will require innovative scientists and engineers who can cross disciplinary boundaries, work in broader systems based projects and work flexibly and collaboratively with industry and clinicians at different stages of the innovation pipeline. The centre and its partners will develop new and different approaches to innovation at an early stage of the innovation cycle, to substantially accelerate innovation, shorten the time period to clinical trials and market, and mitigate technology risks associated with this emergent sector. Collaborators in the Leeds University Business School will develop and evaluate open innovation methodologies. The University of Leeds is ideally placed to take advantage of this EPSRC call for four important reasons. First it has considerable competency in technology and science, as well as capabilities in managing collaborative innovation and entrepreneurship. Second it has the capability to both manage facilitate and create accelerated innovation in emerging healthcare technologies. Third the University already has excellent facilities and a track record (WRHIP) for innovation and is working with Yorkshire Forward to establish an Innovation Hub in Healthcare Technologies. Fourth the strategic partnership with the Clinical Trials Research Unit and the Unit of Health Economics will enable transition into NHS practice.