This proposal is tightly focussed on addressing major unmet clinical needs in the repair and rehabilitation of non-union fractures, in particular for long-bone and cranio-facial trauma. A non-union is a broken bone that fails to heal. These result from both civilian and military injuries including the consequences of cancer and lead to pain, suffering and loss of dignity. Our aim is to create a co-ordinated self-sustaining network linking the Trauma HTC and other major UK clinical research centres, both civilian and military, in order to pull solutions from the science and technology research community and assist their translation to the clinic. The network will link with centres of expertise and research excellence in healthcare technologies supported by EPSRC and others, and to industry and other key stakeholders including patients. This network will ensure, by a programme of activities with both proven and novel components, that these disparate communities are empowered to explore together those areas where new scientific and technological opportunities have the promise to resolve important clinical problems.

Most prosthetics used to replace joint function in the body have a very low chance of infection (<2%). When prosthetics must be inserted following trauma or where individualised implants must be made for patients, the chances of infection are significantly increased and can be as high as 50%. Treatment requires removal of the prosthetic and the implantation of another material that releases high-levels of antibiotics to the site of infection and causes a major risk to the health of the patients. The excessive use of antibiotics is one of the factors that has provoked a rise in the frequency of bacteria that are resistant to antibiotics. Consequently, there is a significant need to develop processes and designs for implants that have enhanced resistance to bacterial contamination. In this project, we will use a combination of 3D printing and silver coating to refine current methods of processing and produce surfaces that are resistant to bacterial infection. We will work with clinicians and industrial partners to develop technologies that can be used with lots of different kinds prosthetics, however, our first target is to reduce infections following the implantation of a metallic plate in the skull. Many different clinical conditions require that a surgeon makes a hole in the skull of a patient to allow for treatment. This allows the surgeon to relieve pressure, caused by swelling following head injury, or to work on the underlying brain tissue. Although most orthopaedic implants come in a range of sizes that can be made to fit patients, metallic implants that are used in the skull (and the defect), do not fit without further structural refinement. At the moment, these implants are made in hospitals by bending a titanium (or other metal sheet) over a 3D printed model of the defect and then polishing and dipping the surface in acid before sterilisation at more than 100oC. Although this kills the majority of contaminating bacteria, the incidence of infection following the implantation of these plates is much higher than with other metallic implants made outside the clinic (12-50% compared with 2%). If an infection occurs, the plate must be removed from the patient's skull, the site cleaned, and then another plate can be fixed in place. This process is dangerous for the patients since it increases risk due to anaesthesia, further infection and requires that the individual spends a period of time without a plate in place, meaning that the brain remains relatively unprotected. We aim to use technology that has been developed in a previous EPSRC project (NIDMET) to reduce the incidence of infection following the fitting of a cranial plate. We will refine an existing additive layer manufacturing process so that we are able to produce something quickly, accurately, to a high quality and surface modified with silver such that it is resistant to microbial contamination and therefore unlikely to cause infection. If we are able to reduce the incidence of infection even down to that associated with orthopaedic implants, we will improve the life of a considerable number of patients reducing costs, in terms of days of hospitalisation and cost of treatment. We will use additive layer manufacturing methodologies to address another major problem that is associated with cranial plates: artefacts that are created by the plate material in a type of MRI scanner that mean that the implant or implant site cannot be evaluated using this important imaging method. We will address incompatibility of the material with gradient field MR imaging using a process that is called topological optimisation. This is an operation that is undertaken by a computer to modify the structure of something so that it is possible to minimise the amount of material that is required for a particular structure. Minimising material, particularly around the edge of the implant, will reduce the imaging problems associated with cranial implants.

We will train cohorts of graduates from different scientific backgrounds together in a unique interdisciplinary programme that combines physical sciences, computer sciences and biomedicine and breaks down the boundaries between these disciplines. They will apply this interdisciplinary training to develop underpinning new physical science research to address three key UK healthcare challenges: - Rebuilding the ageing and diseased body - Understanding cardiovascular disease - Improving trauma and emergency medicine The research programme will be underpinned by a multi-disciplinary taught programme and enhanced by transferable and project management skills training, as well as Knowledge Transfer and Public Engagement of Science activities. The CDT builds on our four years experience of CDT training of physical scientists at the biomedical interface and harnesses the existing and dynamic research community of excellent physical scientists, distinguished for their ability to and commitment to research at the life science interface, together with a team of leading biomedical scientists and clinicians, with whom there are already established collaborations. This new CDT represents an evolution in our activities and new biomedical foci, while retaining the expertise, ethos and track record of promoting a change in culture at the Physical Science / Biomedicine interface, and of nurturing the next generation of researchers to develop the skills and experience required to explore new physical sciences for biology and healthcare, without the perceived cultural and language barriers. The CDT addresses an identified need from our industrial partners for PhD scientists trained at the interface with biology and medicine, and able to communicate and research across these disciplines, such that they are flexible and innovative workers who can move between projects and indeed disciplines as company priorities evolve and change. This need is reflected in the involvement in and commitment to our bid from our industrial partners. They will co-fund students, offer placements and site-visits, deliver lectures as part of the training and monitor and advise on the training programme. The programme will also benefit from public sector involvement including the Diamond Light Source, local hospitals and Thinktank Science Museum.

The lifETIME CDT will focus on the development of non-animal technologies (NATs) for use in drug development, toxicology and regenerative medicine. The industrial life sciences sector accounts for 22% of all business R&D spend and generates £64B turnover within the UK with growth expected at 10% pa over the next decade. Analysis from multiple sources [1,2] have highlighted the limitations imposed on the sector by skills shortages, particularly in the engineering and physical sciences area. Our success in attracting pay-in partners to invest in training of the skills to deliver next-generation drug development, toxicology and regenerative medicine (advanced therapeutic medicine product, ATMP) solutions in the form of NATs demonstrates UK need in this growth area. The CDT is timely as it is not just the science that needs to be developed, but the whole NAT ecosystem - science, manufacture, regulation, policy and communication. Thus, the CDT model of producing a connected community of skilled field leaders is required to facilitate UK economic growth in the sector. Our stakeholder partners and industry club have agreed to help us deliver the training needed to achieve our goals. Their willingness, again, demonstrates the need for our graduates in the sector. This CDT's training will address all aspects of priority area 7 - 'Engineering for the Bioeconomy'. Specifically, we will: (1) Deliver training that is developed in collaboration with and is relevant to industry. - We align to the needs of the sector by working with our industrial partners from the biomaterials, cell manufacture, contract research organisation and Pharma sectors. (2) Facilitate multidisciplinary engineering and physical sciences training to enable students to exploit the emerging opportunities. - We build in multidisciplinarity through our supervisor pool who have backgrounds ranging from bioengineering, cell engineering, on-chip technology, physics, electronic engineering, -omic technologies, life sciences, clinical sciences, regenerative medicine and manufacturing; the cohort community will share this multidisciplinarity. Each student will have a physical science, a biomedical science and a stakeholder supervisor, again reinforcing multidisciplinarity. (3) Address key challenges associated with medicines manufacturing. - We will address medicines manufacturing challenges through stakeholder involvement from Pharma and CROs active in drug screening including Astra Zeneca, Charles River Laboratories, Cyprotex, LGC, Nissan Chemical, Reprocell, Sygnature Discovery and Tianjin. (4) Embed creative approaches to product scale-up and process development. - We will embed these approaches through close working with partners including the Centre for Process Innovation, the Cell and Gene Therapy Catapult and industrial partners delivering NATs to the marketplace e.g. Cytochroma, InSphero and OxSyBio. (5) Ensure students develop an understanding of responsible research and innovation (RRI), data issues, health economics, regulatory issues, and user-engagement strategies. - To ensure students develop an understanding of RRI, data issues, economics, regulatory issues and user-engagement strategies we have developed our professional skills training with the Entrepreneur Business School to deliver economics and entrepreneurship, use of TERRAIN for RRI, links to NC3Rs, SNBTS and MHRA to help with regulation training and involvement of the stakeholder partners as a whole to help with user-engagement. The statistics produced by Pharma, UKRI and industry, along with our stakeholder willingness to engage with the CDT provides ample proof of need in the sector for highly skilled graduates. Our training has been tailored to deliver these graduates and build an inclusive, cohesive community with well-developed science, professional and RRI skills. [1] https://goo.gl/qNMTTD [2] https://goo.gl/J9u9eQ