The Postdoctoral Fellowship provides the opportunity for the applicant to undertake research and research training in one of Europe's foremost medical engineering research groups at the University of Leeds. The fellowship seeks to enhance the modelling approaches already developed by the applicant in bone remodelling with the advanced cartilage models being generated in Leeds to provide a key tool to mitigate the rising incidence of avascular necrosis (AVN) in Asia. AVN is a destructive disease, mainly found in the younger population, arising due to the disruption of blood supply to the femur head. It is the most common diagnosis (40%) for patients undergoing total hip replacement (THR) in Asia. Some patients may have the risk of collapse of the femoral head, depending upon the size of the lesion. Studies have observed a reduction in strength and stiffness in the pre-collapse stage of the AVN, which reduces the structural competence of the bone as well as the adjacent articular cartilage that covers the femoral head. Any disruption of the articular cartilage that arises from abnormal loading due to damage in the underlying bone has severe consequences for the overall joint function and ultimately pain and disability. The proposed research will investigate the link between AVN induced bone deterioration and joint function - biotribology - using a dynamic computational model that incorporates the evolution of the AVN from a bone function perspective. In the first instance, this will be an examination of the relationship between the cartilage function and bone properties in early stage AVN there are more conservative treatments. Such interventions are in urgent need of scientific underpinning; an aim that this model could achieve in the medium term. The second project, which will be delivered whilst on placement, will focus on late stage interventions for AVN, that is surface replacement where the design will be considered in terms of bone remodelling.

The International Centre-to-Centre collaboration focuses on a significant area of research activity at the three Universities: Pathological Fractures. Fracture rates are expected to surge as the population ages and therefore constitute an urgent, unmet clinical need. Recent co-creation and engagement activities, by the principal investigator, with clinicians and patients, has noted the need for optimised, patient-specific minimally invasive approaches, fracture prevention and the use of localised delivery of therapeutic agents to reduce infection, disease burden and improve bone quality/fixation. The aim of the Centre-to-Centre is to respond to this clinical need and develop an International Centre of Excellence in Research of Pathological Fractures building on the substantial synergies that exist at the three institutions. These include: University of Leeds (UoL): Advanced assessment of medical devices, substantial investments in research for spinal fractures arising from bone metastases (EPSRC Programme Grant: Oncological Engineering) and peri-prosthetic fractures (Zimmer-Biomet). Uppsala University: Additive Manufacturing for the Life Sciences (VINNOVA funded Competence Centre) and Soft Bone (EIT Health funded) a new generation of low modulus materials designed to fix and prevent fractures in the vertebrae as well as augmentation of the disc. ETH Zurich: Advanced imaging and modelling for pathological fractures (FHT Singapore) and fracture modelling in metastatic disease (EU funded METASTRA). We have further support from 4 industrial partners and UoL. We will bring these attributes together into a more holistic, multidisciplinary collaboration that would significantly enhance the scope for generating novel underpinning engineering science together with appropriate impact through our industrial and healthcare partners. The objectives, building on and enhancing the activities outlined above, are: (1) An integrated, multiscale, Fracture Prediction Modelling Framework to identify bones that are at risk of fracture in given pathologies so as. a. to aid prophylactic interventions to reduce this fracture risk and enable pathology-specific approaches, b. utilise modelling to improve the design of patient-specific/custom made implants. Developed from research at ETHZ and UoL. (2) Develop a Framework for Prophylactically Amenable, Pathology-Specific, Minimally-Invasive interventions to support the load-bearing bone and prevent fracture so to a. significantly inhibit instability, bone pain and, in the vertebra, the potential for spinal cord injury, with the aid of the modelling developed in objective 1 b. develop tools and interventions for hip peri-prosthetic fracture. Developed from the research at Uppsala in the Additive Manufacturing for Life Competence Centre and SoftBone and the UoL. (3) A new generation of innovative coatings specific to treatment requirements including reduction in infection & disease burden, promotion of bone growth and enhanced fixation. a. to take advantage of the material and cement technologies outlined in objectives 1 and 2 to provide better functional outcomes. Based on the research at Uppsala and UoL. The proposal is underpinned by a set of cross-cutting themes which are: (1) Responsible Innovation is central to this activity and includes the appropriate (a) ethical principles ensuring that the research benefits a wider set of stakeholders including patients, (b) patient and clinical co-creation and meaningful interactions so as to enhance the overall design process and (c) appropriate mechanisms that enhance impact including dissemination, continued patient engagement and exploitation. (2) Workforce development, to ensure that both researchers and investigators have the appropriate knowledge for the successful execution of the research and wider career aspirations. (3) Equality, Diversity and Inclusion, of both the researchers and the patients involved.

Approximately 2 million people are living with cancer in the UK and this number is set to rise considerably over the next decade to 3.2M. A significant complication of late stage (stage 4) cancer is metastases or secondary tumours which are caused by tumour cells spreading to different locations in the body. Metastases are particularly associated with breast cancer, which is the most common cancer in females and the leading cause of cancer deaths in this group. Figures vary but some studies put a figure of about 50-60 % of patients will have bone metastases in late stage cancer. The tumours weaken the bone and lead to a variety of problems for the patients at a time when quality of life is a paramount consideration, especially as the prognosis is usually terminal. Significant issues include severe pain and spinal fracture which made lead to spinal cord injury. These complications often require major surgery which encroaches, significantly, on the patients' quality of life, when life expectancy is a matter of months and may, in certain cases, provide a mechanism of further spread of the cancer. Currently, there are no implants for supporting the bones before fracture as we cannot identify which vertebrae are likely to fail. OncoEng will deliver a paradigm shift in the current treatment technologies and stratification of care based on the application of core enabling engineering technologies. A more patient-friendly approach is realised in OncoEng in which we predict which vertebrae with tumours are likely to fail in the future enabling informed decision on care. Advanced computational modelling and imaging will be used to look at the growth of the tumour so that predictions of the strength of the vertebrae can be calculated a different points in time. These strengths can then be compared to spinal loads and an assessment of fracture risk undertaken. Those vertebrae at his risk would then receive special implant to support the weakened bone and prevent fracture. This implant would only require key-hole surgery and would not impinge on the patient's quality of life through a lengthy recuperation period or additional pain. The research proposed responds to the Cancer Strategy in the NHS Long Term Plan and the EU's Beating Cancer Plan. Three Universities in the UK, University of Leeds, Imperial College and University College London, have come together to deliver this research so as to make a big change in the way these patients are treated. In addition we have formed an international network of academic, industrial and clinical collaborators from Europe, USA and Australia (OncoEng+ Network) with a focus on novel modelling, imaging, advanced materials and innovative medical devices to overcome the challenges of predicting fracture and producing a new implant. Impacts from the research include (1) new diagnostic tools for predicting bone failure using imaging and advanced computational modelling, which can be used in this and other disease such as osteoporosis, (2) a new patient-specific implant that can be inserted using minimally invasive surgery reducing the trauma to the patient and having a shorter recovery period (days rather than weeks or months); the implant would be inserted before the vertebrae is susceptible to fracture, (3) new manufacturing techniques for the delivery of the minimally invasive implant, which have wide ranging applications outside medicine including the aerospace and automotive sector, and (4) new test methodologies for spinal implants to ensure that these devices are tested under a range of activities including adverse conditions such as high patient loading. Importantly, the programme grant will train and up-skill a new generation engineers and scientists in a novel area of application-based research, that of devices for skeletal cancers and software for fracture prediction, and aims to bring together activities in the UK and internationally to form a holistic integrated activity.

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.

Over 80 million patients worldwide suffer from hip osteoarthritis, and increasing numbers of patients are requiring total hip replacement surgery. This is considered to be a successful intervention, however, an ageing population with increasing orthopaedic treatment needs, greater levels of obesity and patient expectations, and reducing healthcare budgets and surgical training are conspiring to challenge this success. There is also increasing demand for surgical treatments in younger patients that will delay the need for hip replacement surgery, these interventions reshape bone and repair soft tissue. One of the major causes of failure in the natural hip and in hip replacements is impingement, where there is a mechanical abutment between bone on the femoral side and hip socket or hip replacement components. In the natural hip, surgery reshaping the bone can reduce this impingement and soft tissue damage can be repaired; however, the effects of the amount of bone that is removed is not well understood nor is the best way to repair soft tissue. The number of hip replacements needing to be removed from patients and replaced with a new one in revision surgery is increasing; damage to the cup rim because of impingement is often implicated. It is known that this is more likely if the components are not well aligned relative to each another, or relative to the load direction experienced in the body. In this proposal, I seek to ensure long term outcomes of early intervention and hip replacement surgery are always optimum by negating concerns about impingement. To do this, I will develop an experimental anatomical hip simulator. The simulator will apply loads and motions to the hip similar to those observed clinically, and include high fidelity phantoms that mimic the natural hip, into which hip replacement components can also be implanted. This anatomical simulator will be used to assess how variables such as those associated with the patient (e.g. their bony geometry), the extent of early intervention surgery (e.g. the amount of bone removed) or the design of the prosthesis and how the hip is aligned in the body will affect the likelihood of impingement. This improved understanding of factors affecting the likelihood and severity of impingement will enable better guidance on how the surgery should be performed to optimise outcomes to be provided. I will work with orthopaedic surgeons to integrate this improved understanding into their clinical practice and with an orthopaedic company to integrate the findings into new product development processes; so that future interventions and devices can be designed to provide better outcomes for all patients.