We will establish a technology platform that changes the way we diagnose and treat patients. It involves detecting and producing nano-sized biological particles that act as communication machinery in nature. These particles are called exosomes and with significant investment in the engineering required to accurately capture and profile them, it will be possible to create a new class of diagnostics that can detect disease earlier than is currently possible, based on the release and detection of specific exosomes. It will also be possible to distinguish between different stages of disease, which will help to tailor the right treatment to an individual patient. The diagnostics platform will also form the basis for manufacturing analytics that will enable cell and gene therapies to be carefully monitoring during manufacture. Cell and gene therapies currently cost in the order of £100,000 to £1,000,000 per dose and is related to the fact that bioprocesses (the manufacturing approaches used to create them) are sub-optimal. A radical advance in manufacturing analytics will help to better monitor and control manufacturing, which will lead to improved product consistency and ultimately drive down cost of manufacturing, which will catalyse the routine adoption of cell and gene therapies in the NHS. Finally, by producing exosomes using industrial bioprocesses it will be possible to create new drugs based on exosomes, exploiting their communication machinery to target therapies to sites of disease. This will involve a combination of engineering exosomes to have increased potency, or loading them with powerful drugs and targeting them directly at the diseased tissue. Ultimately, this will radically advance personalised medicine across diagnostics, analytics and drug delivery. In 30 years' time this technology platform will be widely used in healthcare to diagnose and treat disease with high fidelity using bespoke formulations. In order to advance this vision, phase 1 feasibility studies will address engineering challenges in sensor development to detect exosomes at different orders of sensitivity. It will also address the consistent production of exosomes at pilot scale in order to advance the exosome therapeutic platform.

We will establish a technology platform that changes the way we diagnose and treat patients. It involves detecting and producing nano-sized biological particles that act as communication machinery in nature. These particles are called exosomes and with significant investment in the engineering required to accurately capture and profile them, it will be possible to create a new class of diagnostics that can detect disease earlier than is currently possible, based on the release and detection of specific exosomes. It will also be possible to distinguish between different stages of disease, which will help to tailor the right treatment to an individual patient. The diagnostics platform will also form the basis for manufacturing analytics that will enable cell and gene therapies to be carefully monitoring during manufacture. Cell and gene therapies currently cost in the order of £100,000 to £1,000,000 per dose and is related to the fact that bioprocesses (the manufacturing approaches used to create them) are sub-optimal. A radical advance in manufacturing analytics will help to better monitor and control manufacturing, which will lead to improved product consistency and ultimately drive down cost of manufacturing, which will catalyse the routine adoption of cell and gene therapies in the NHS. Finally, by producing exosomes using industrial bioprocesses it will be possible to create new drugs based on exosomes, exploiting their communication machinery to target therapies to sites of disease. This will involve a combination of engineering exosomes to have increased potency, or loading them with powerful drugs and targeting them directly at the diseased tissue. Ultimately, this will radically advance personalised medicine across diagnostics, analytics and drug delivery. In 30 years' time this technology platform will be widely used in healthcare to diagnose and treat disease with high fidelity using bespoke formulations. In order to advance this vision, phase 1 feasibility studies will address engineering challenges in sensor development to detect exosomes at different orders of sensitivity. It will also address the consistent production of exosomes at pilot scale in order to advance the exosome therapeutic platform.

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.

The development of implantable prosthetics has revolutionised medicine. Where joint injury or destruction would once have once significantly reduced quality of life, to the detriment of a patient's fitness and health, we can now almost fully restore function. The manufacturing methods used for the production of prosthetics are quite crude and often require the casting of metal into a mould before finishing by hand. As a consequence they are usually made to only a few different sizes and the resulting structures must be made to fit by the surgeon. This is acceptable for the majority of patients who require joint replacement, but there are some medical conditions that require very irregularly shaped (customised) structures to enable an adequate repair. For example, bone cancers often require extensive cutting away of the bone and this can leave a very large and irregular defect. Similarly the bone structure of the face and skull is very specific to an individual and when bone must be removed, again due to cancer or following physical damage. To restore physical appearance, it would be best if a clinician were able to generate a plate that could allow them to replace like for like. In this project, we will refine an Additive Layer Manufacturing (ALM) technology called selective laser meeting (SLM) to allow us to produce implants that are individual to a patient. These technologies use lasers to fuse powder and create a three dimensional object in a layer by layer fashion. By taking three dimensional images (MRI and CT) from a patient, operators can design structures that will be able to directly replace tissue with the optimum shaped implant. In this project, we will work with doctors from the Royal Orthopaedic Hospital, Queen Elizabeth Hospital and the Royal Centre for Defence Medicine to develop a process that we hope will eventually allow these clinicians to produce implants in their own hospitals or even on the front-line of a conflict and enable better treatment for their patients. As well as allowing the production of complex-shaped parts, ALM has another significant advantage over casting in that it allows the production of very complex porous structures within a material. This means that we can modify the physical properties of the material by incorporating holes or structured porosity into the structure. These holes can be sealed from the surface of the prosthesis, or can be linked to the surface using a network of even narrower holes. We would like to explore the use of this added manufacturing capability to make prosthetics with a very closely defined internal structure that is completely interconnected. A second, cement like, material can then be injected into the pore structure and will harden in place. This second phase can be used to modify mechanical properties or could be used as a carrier for drugs that may stop infection or help the tissue to heal. It is hoped that this modification could help us eliminate implant-based infections, which is the leading cause of failure following prosthetic implantation.