Osteoarthritis (OA) is a degenerative joint disease, typified by a loss of quality of cartilage and changes in bone at the interface of a joint, resulting in pain, stiffness and reduced mobility. BAMOS project particularly addresses the challenges in OA treatment by providing novel cost effective osteochondral scaffold technology for early intervention of OA to delay or avoid the joint replacement operations. This project has the potential to relieve pain in patients with OA improving their quality of life by keeping people active. It fits with the scope of EU Societal Changellenges to encourage the provision of improved clinical care for patients in the field of healthcare, especially for elderly patients. In the course of developing this new treatment for mid- to late stage OA, BAMOS aims to establish and embed a new collaboration between six internationally leading research organisations (four universities, one healthcare provider and one manufacturer with expertise in additive manufacturing). The partners propose an integrated programme of research activities and the development of a collaborative graduate training scheme. The dissemination of research will result in at least 15 high profile joint research publications, and the consortium will organise two international scientific conferences (one in the EU, one in China) and 3 workshops. BAMOS will develop new materials and manufacturing technologies for the fabrication of custom-tailored osteochondral scaffolds. Novel biopolymeric composites, processed by additive manufacturing, will be characterized and tested as well as coatings on titanium scaffolds. Also, thermal welding technique will be used to join the cartilage component with the bone component to form an osteochondral unit. The new technologies will undergo full pre-clinical evaluation in order that the scaffolds are able to enter clinical trial after the project.

Low back pain is the leading cause of disability worldwide and is estimated to cost the NHS £500 million annually. A link has been found between degeneration of the intervertebral discs and low back pain, suggesting degeneration may be a contributing factor. Identifying patients where this is the case is not straight forward, particularly as it is possible to have degenerate discs without experiencing any pain at all. Initially, patients with low back pain are treated conservatively, but for those who require surgery, fusion of the vertebrae is the most common procedure, although increasingly total or partial disc replacement technologies are considered to preserve motion at the joint. Outcomes from these procedures are relatively poor, with revision surgeries required in as many as 20% of patients who undergo a lumbar fusion within 10 years. Improving patient selection is important for good clinical outcomes using these treatments, however the tools currently available (usually Magnetic Resonance Imaging (MRI) or X-ray) provide little information of how the disc is functioning before a clinical decision is made. The ability to assess quantitatively the deformations within discs would provide a unique tool to allow treatments to be targeted towards appropriate patients and therefore improve outcomes. Recent advances have been made in measuring disc deformations in human cadaveric specimens by combining a technique called Digital Volume Correlation (DVC) and MR images captured with a high-resolution research scanner (9.4T). The technique works by obtaining two sets of images of the same specimen, one unloaded, and one loaded. Three dimensional patterns within the images are then tracked between the two sets of images such that deformations and strains can be calculated. Results from this study show huge potential but a real breakthrough will come when the tool can be used clinically, this is not currently possible because the bore of research MRI scanners is less than 10cm in diameter. This study will utilise DVC in clinical MRI scanners (that is, scanners used in every hospital to image patients) to create a non-invasive clinical method of measuring intervertebral disc deformations. This novel diagnostic tool will allow better stratification in treatment. It will also provide fresh insight into the intricate mechanics of healthy and degenerate discs, information that will guide future surgical treatments and medical device designs.

Context - Spinal cord injury causes devastating changes to many of the normal functions of the body. Paralysis of the limbs is obvious, but the accompanying loss of pelvic floor function is sometimes more debilitating. For example, the social stigma of double incontinence, the medical dangers of pressure sores and the inconvenience of spasm are serious conditions requiring long-term treatment. Ideally, neural repair and the development of a so-called cure would be the best solution, but even though this branch of science is exciting and expanding rapidly, the prospect for success is likely to be many years away. So, for the foreseeable future, other approaches to functional restoration must be pursued, particularly for the tens of thousands of patients with a chronic injury in the UK for whom a future cure may not even be an option. The most successful device for functional restoration in spinal cord injury has been the well-known Brindley implant that stimulates the motor nerves to empty the bladder. About 3000 people have been implanted with such stimulators during the last 25 years. The main disadvantage of this implant, clinically and commercially, is that some sensory nerves have to be cut to prevent incontinence, and people perceive this as an obstacle to benefiting from the cure .Rather than cutting sensory nerves, it is possible to stimulate them to prevent urinary incontinence. This is commonly known as neuromodulation. Neuromodulation also improves bowel capacity and suppresses spasm. In addition to these benefits, stimulating the motor nerves, not only gives efficient bladder and bowel emptying but also erections, and, by stimulating the gluteal muscles, reduces the likelihood of pressure sores over the buttocks. We believe that all this can be achieved with a 4-channel stimulator.The main questions for this study are: (i) can we empty the bladder and provide the other functions by stimulating the motor nerves within the spinal canal? (ii) can we use feedback from bladder sensory nerves to initiate neuromodulation when the bladder contracts? Aims - The aim of this project is to develop and make a novel multi-functional implant. This will be tested in eight volunteers with spinal cord injury so that the functions mentioned above can be assessed in the laboratory and evaluated in everyday life. The engineering and clinical testing of this device will be a necessary step towards designing a commercial system. Application & Benefits - The principal beneficiaries of this project are people with a spinal cord injury. They can be expected to achieve a level of functional restoration that will significantly improve quality of life, decrease medical complications and give greater opportunity for re-integration into society. The multi-functional implant, described here, would achieve many significant advances for the patient. Most importantly, in addition to restoring many functions, it would also preserve the sensory nerves, reflex erections and ejaculation. As a result of preserving the nerves, more people will benefit from treatment by implant. Use of the implant means that patients will have less dependence on a cocktail of pharmaceutical treatments. Best of all, this multi-functional implant would not preclude the possibility of applying a future cure.

Peripheral nerve injury is debilitating, causing loss of sensation and muscle control, chronic pain and permanent disability. In addition to the serious impact on patients and their families, nerve injuries impact society economically through reduced productivity (nerve injuries predominantly affect young people) as well as the cost of healthcare and rehabilitation. Transected peripheral nerves have the potential to regenerate following surgical repair, but there are serious limitations for injury sites >3cm, because regeneration requires a supportive microenvironment. The current best option is a nerve autograft harvested from another part of the patient's body, but donor site morbidity, limited availability and poor outcome mean there is a clear clinical need to develop effective alternatives. Advances in tissue engineering together with stem cell technologies provide promising routes for engineering living artificial nerve replacement tissues, but progress is limited due in part to a lack of consensus on how to arrange materials and cells in space to maximize nerve regeneration. This is compounded by a reliance on experimental testing, which precludes elaborate investigations due to time and cost limitations. NerveDesign will address this log-jam, by combining mathematical modelling with state-of-the-art in vitro and in vivo experimentation for the first time, to bring about a paradigm shift in the approach used for neural repair. NerveDesign will focus on the chemical and physical stimuli that promote growth of blood vessels and regenerating nerves through a damaged nerve site. Mathematical models will be developed that incorporate the key mechanisms at play - these mechanisms will be quantified through carefully designed experiments that test them in the laboratory. Computer simulations with then be used to test different potential peripheral nerve repair construct designs, and the leading contenders will be fabricated and then tested. This multidisciplinary approach to nerve repair is entirely novel, and delineates an ambitious approach with significant potential for human health impact. To facilitate the uptake of the approach by clinicians, NerveDesign will create and test a user-friendly software tool that enables end users to set construct design parameters according to individual repair requirements. All computational models will be formulated in Systems Biology Mark-Up Language, and published on our websites (alongside an example experimental dataset) to encourage their uptake in a range of nerve tissue engineering applications. Finally, NerveDesign will work with its clinical and commercial Project Partners to directly engage patient groups, and pave the way for translation and commercialisation of the new repair constructs designs.

Fibrodysplasia ossificans progressiva (FOP) is a rare, disabling and life-shortening congenital syndrome for which no effective therapies exist. Repurposing of AZD0530 (saracatinib, AstraZeneca) would be an ideal solution for de-risking early clinical studies. Using existing assets and investments, this may allow more affordable pricing once an indication is approved. Ectopic bone is formed in soft tissues due to activating mutations in the bone morphogenetic protein receptor kinase ALK2/ACVR1, leading to progressive contractures and early death. Preclinical studies showed AZD0530, previously unexplored in FOP, to be a potent (5nM) inhibitor of ALK2 kinase and ALK2-R206H-mediated neofunction after activin stimulation. In mice, AZD0530 blocked ectopic bone formation preserving limb movement. Hypothesis: AZD0530 will reduce ectopic bone formation and progressive disability in people with FOP. AIM: to provide proof of concept that AZD0530 is an effective drug in the treatment of patients with FOP. Methods: Based on the rarity of the disease and expected drug efficacy (50% reduction in new bone), a phase 2A proof of concept study including a 6 month randomized placebo controlled study and 12 month open label extension study using historical data, is proposed including 16 adults with active FOP disease. The study will be performed in three European FOP expert Centers (Amsterdam The Netherlands – Lead, London UK, and Garmen Partenkirchen Germany). The study will be performed in collaboration with the expert preclinical teams at the Universities of Oxford and Harvard. FOP expert and patient engagement as well as safety will be ensured by establishing advisory, DSM and stakeholder boards. Early involvement of the regulatory agencies are planned. Expectations: we will develop a roadmap for further studies and regulation of this new treatment option in FOP based on the results.