Over 60 million patients worldwide suffer from hip osteoarthritis, and increasing numbers of patients are requiring total hip replacement surgery. Although the surgery is highly successful, the ageing active population and rise in obesity are placing extra demands on hip replacements: devices must now withstand higher loads and survive for longer durations in the body. The number of revision surgery procedures to replace worn out or damaged components is rising, and there is a need to develop more robust hip replacement devices that can withstand these increasing demands across all patient groups. One of the major causes of failure of hip replacements is due to wear and fatigue of the device components. These damage processes can increase dramatically if the components are not well aligned relative to each another, or relative to the direction of the loads they experience in the body. There can be many factors which affect the alignment, including the device design and surgical procedure as well as the patient anatomy and biomechanics. In this proposal, we will develop computer models to simulate hip replacement performance under different misalignment conditions. We will incorporate patient and surgical variations into the model so that we can define exactly what levels of alignment are required for specific devices to operate adequately. This will enable us to provide better guidance on the choice of device for individual patients to reduce the likelihood of misalignment. It will also help inform surgeons on the positioning of the components for different patient characteristics. We will work with a major orthopaedic company (DePuy Synthes) to integrate the computer models into their new product development process, so that the next generation of devices can be designed to be more robust to alignment variations, and surgical tools can be developed to help align devices with better precision in the most critical directions. We will also work with regulators and standards agencies to develop new testing requirements that take account of the variations in patients and surgery, so that all new products will have to undergo more robust testing before they are introduced onto the market. In the longer term, the methods we develop will help extend the lifetime and reliability of the next generation of hip replacements and enable these devices to meet the increasing demands of our ageing active population.

Osteoarthritis affects over eight million people in the UK alone, with nearly three quarters of patients reporting some form of constant pain. Treatment for arthritis is estimated to cost the UK healthcare system over £10 billion per year, with significant additional societal costs for lost working hours and welfare payments. Although hip and knee replacement surgeries are considered successful, these treatments are not suitable for all patients and some devices fail early, requiring costly and less successful revision surgery. There are over 15,000 revision surgeries performed in the UK alone each year. Younger and more active patients, as well as rising numbers with obesity, are placing greater demands on these treatments: implants need to last for longer and withstand more extreme loading than ever before. There is evidence that both individual patient biomechanics and surgical choices influence the outcomes of these treatments. Improved outcomes, particularly for more challenging patient groups, can only be achieved by better matching the treatment to the functional requirements of the individual patient. This proposal will bring together complementary research expertise from two of the world's leading research institutes in the field to build the evidence needed to enable treatments for osteoarthritis to be better tailored to individual patient needs. The Institute of Medical and Biological Engineering at the University of Leeds has developed unique capability and expertise to evaluate artificial and natural joints. These include the world's largest academic facility for experimentally testing joint replacements, as well as computational modelling methods to simulate how implants perform in the body. These capabilities enable the mechanical performance of implants to be evaluated under a range of different conditions, for example to study how the implant wears over time or becomes damaged with usage. The Center for Orthopaedic Biomechanics at the University of Denver has developed world-leading capability in measuring patient joint mechanics in vivo, including methods of imaging patient joints as they undertake different activities, and parallel computational methods for deriving biomechanical information. These methods enable the forces and motions on an individual patient's hip or knee joints to be derived and, by collecting data on many patients, examine how these differ from one individual to another. By combining the expertise across both groups, this Centre-to-Centre Research Collaboration will enable relationships to be developed between an individual patient's characteristics (e.g. their anatomy and how they load their joints) and the mechanical performance of the implant. Specifically, in the hip we will combine methodologies developed at the two centres to evaluate how patient and surgical factors affect the risk of early failure in hip replacements due to the device components pushing into each other or the surrounding bone (impingement), or the way the components are aligned. We will also examine how different choices of implant can influence the outcomes. In the knee, we will combine methodologies to identify how patient factors (such as the anatomy of the knee and the way it is loaded during different activities) affect early-stage treatments for knee osteoarthritis. We will also examine the effects of a greater range of activities, such as squatting and stair climbing, on the outcomes of knee replacements. These studies will bring together different methodologies and build new pathways for acquiring and sharing data that can be adopted more widely and applied to other musculoskeletal systems in the future. The work will build the evidence needed to improve hip and knee implant design, inform clinical decision-making, enhance patient quality of life and reduce early complications.

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.

In the past decade, over 2.5 million people in the UK had a metal device implanted to replace a skeletal joint in their body. With our chances of living to 100 years old predicted to double in the next 50 years, these bone implants will need to last substantially longer. Alarmingly, current data demonstrates that failure rates rapidly increase each subsequent year after implantation. The metals we currently make bone implants from were not specifically developed for use within the body. Instead, these materials were originally designed for aerospace applications. In addition to being much stiffer than bone, these metal alloys may also contain toxic elements that cause adverse biological reactions. The aim of this fellowship is to design a new generation of bioinspired alloys that promote advantageous cellular responses while exhibiting mechanical properties that are aligned with the body. In order to design the ideal biomedical alloy, there are a number of properties that need to be balanced, for example biocompatibility (i.e. non-toxic), mechanical performance, and wear resistance. Optimising lots of parameters simultaneously via current trial-and-error approaches may take years or even decades. To significantly speed up this process, a computational modelling approach, called Alloys-By-Design (ABD), will be used to discover a range of titanium compositions that match the mechanical properties of bone. For the first time, by searching for alloys with specific microstructures, ABD will be employed to identify compositions with promising biological functionality, such as infection prevention. Since ABD is a theory-based approach, it will be important to validate the model predictions. This will be done by using a unique laser-based system to melt together all the alloying elements. To maintain rapid progress towards using these new metals clinically, a novel high throughput test will be developed as a screening tool to identify compositions that provoke promising mammalian and bacterial cell responses. From these results, non-toxic and antimicrobial compositions will be selected. High resolution microscopy will subsequently be used to understand the relationships between alloying elements, microstructure and biological behaviour. Before bone implants made of these new alloys may be implanted into patients, it will be critical to deepen our understanding of how the body may respond. Importantly, the behaviour of various cell types involved in bone regeneration will be considered, including bone forming osteoblasts and stem cells found in bone marrow. The rate at which these cells grow and their ability to form new bone on the surface of the novel alloys will be benchmarked against currently used metals. Since it is known that ions may leach from alloys within the body and cause damage to surrounding tissue, this will also be carefully studied. The patient and economic benefits gained from personalised devices that anatomically fit perfectly is rapidly growing in bone implants. As such, the possibility to 3D print bespoke implants made from the most promising bioinspired alloy will be explored. For the first time, the ability to locally tailor alloy composition in-situ using a metal laser-based 3D printer will be investigated. By systematically changing the laser processing parameters and characterising the resultant composition, a universal protocol to optimise in-situ alloy formation will be developed. This will open up an entirely new dimension of bone implant customisation, making it possible to tailor mechanical performance or biological functionality in selected areas of a single implant. Underpinning this fellowship is an experienced clinical and industrial advisory board that will support translation of these novel bioinspired alloys. This will ensure that the research may be transformed into approved medical devices that improve patient lives, reduce healthcare costs, and grow the UK economy.

Viral infections pose one of the biggest global threats to human populations and agriculture. Successful prevention, monitoring and treatment of viral infections requires the availability of fast and reliable diagnostic methods which can not only sensitively, but rapidly detect a viral infection of interest and differentiate between viral infections. This is particularly important in the winter months where rapid diagnosis of viral infections emerging from SARS-Cov-2 relative to influenza strains is essential in order to assist medical practitioners to suggest the most appropriate interventions and treatment. At present, methods do not exist which can rapidly detect viral infections in a low-cost, point-of-care device. We propose to develop a biosensing technology which can not only detect viral components, but also has the potential for the platform to be reusable and regeneratable. Central to these developments is the use of fluorous technology as a tool to immobilise elements which detect viral components. Much akin to Teflon, fluorous technology has the dual advantage as a method which can immobilise molecular components which have a complementary fluorous tag, and reduces non-specific binding to non-fluorous biomolecules, thus improving the sensitivity of the approach. Furthermore, the fluorous-directed immobilisation event is inherently reversible by a simple washing step with organic solvent. In this proposal, we will demonstrate the modularity of the strategy to detect viral RNA (by RT-PCR) or protein (by direct detection of intact viral particles). This will provide a powerful new tool for the biosciences which has the potential to be used for any application which requires rapid detection of pathogenic infections.