In England and Wales in 2017, 15,091 surgeries were performed due to failed hip and knee replacements. Although loosening of the implant is the main cause of failure, infection still remains a major problem, accounting for 2,865 of these procedures and over £73 million in annual costs for the NHS. This number is expected to rise with an ageing population and the number of joint replacement surgeries increasing annually. Infected joint replacements are more complicated and costly to treat, requiring longer surgical and hospital inpatient times, and are often at a higher risk of repeated failure. This significantly affects patient quality-of-life through increased morbidity and in severe cases it can also result in amputation or death. Few commercial technologies exist to prevent this problem. Often oral or intravenous antibiotics are used; however only low concentrations reach the implant site. Coatings attempt to achieve a prolonged local release of antibiotics; however long-term exposure to antibiotics can cause toxicity issues or even encourage antibiotic resistance. Other technologies such as implant surface treatments or topographies, only slow down bacterial attachment and do not eliminate the problem entirely. There is clearly a need for smarter, more effective technologies to prevent infections in orthopaedics. This project aims to achieve this by developing a novel smart implant coating that only releases an antimicrobial in the presence of bacteria. The concept exploits the fact that Staphylococcus aureus, a bacterium that causes joint replacement infections, releases a pore-shaped protein known as alpha-haemolysin. This protein inserts itself in cell membranes causing leakage and cell death. The implant coating consists of the same molecules as cell membranes however it contains a reservoir of antimicrobial within it. When the bacteria release alpha-haemolysin, this creates pores within the implant coating, releasing the antimicrobial and eradicating the infection locally. Three key objectives have been identified to achieve the aim of this project: Objective 1: Optimise and characterise the coating to maximise triggered antimicrobial release. Objective 2: Scale up the coating process and evaluate the antimicrobial activity and toxicity of the coating. Objective 3: Evaluate the performance of the coating in a more relevant bone infection model. Unlike existing coatings, which attempt to stimulate a response, this coating will react to the environment when bacteria are present. Using this approach, the amount of antimicrobial released will be proportional to the number of bacteria and the amount of alpha-haemolysin produced. This triggered delivery system therefore has the potential to overcome numerous issues with existing technologies. Outside of orthopaedics, this technology would have numerous applications, for example in dental and maxillofacial implants and ophthalmic and cardiovascular medical devices, where infections also pose major problems. This project also has the potential to lead to a completely new area of research, where cell and bacterial characteristics are exploited to develop smarter, more effective implant coatings and targeted drug delivery systems.

Untreatable infections are one of the biggest modern-day dangers to society, which the current SARS-CoV-2 pandemic has highlighted. The development of antibiotics has been one of the major medical successes of the last 100 years. However, the capacity of pathogens to evolve and acquire resistance to new antibiotics makes their effectiveness necessarily precarious. Meanwhile, studies on the spread of drug-resistant pathogens such as MRSA, respiratory syncytial virus, norovirus and CoVID-19 suggest that surfaces are a major point of transmission with CoVID-19 remaining infectious on plastic and stainless steel surfaces for up to 6 days. Surfaces with an antimicrobial function that avoid or minimise the use of antibiotics whilst maintaining good efficacy after prolonged use are critically needed in hospitals, living spaces, and on biomedical implants, to reduce healthcare-acquired and public space-acquired infections, reduce healthcare costs, and promote healthier lives. However standard antimicrobial surfaces are not sufficiently robust to withstand the wear and tear encountered in a biomedical implant environment and in public spaces. Sheffield Hallam University and Imperial College London aim to develop superhard nanostructured surfaces with plasmonically-enhanced photocatalysis which will enable microbial inactivation in both illuminated and dark environments whilst retaining their robustness and effectiveness in the long term and which, as a result, will lead to orthopaedic implants and anti-microbial surfaces that are more functional than those produced with the current technologies. The innovative antimicrobial surfaces will be robust due to the use of superhard nanoscale multilayer coatings with wear rates up to 1000 times better than conventional metal alloys. At the same time the robust antimicrobial surfaces will have a dual functionality - (1) active, they will be able to kill microorganisms by photocatalysing the production of highly reactive singlet oxygen - one of the most effective killers of pathogens. The photocatalysis will be activated by visible light from the environment. The light will interact with a carefully prepared coating material to induce plasmonic resonance on its surface and generate high energy electrons which are needed to boost the photocatalytic reaction. (2) passive, mimicking naturally occurring surfaces such as the cicada wing, the surfaces will contain a number of appropriately dimensioned nanopillars which will stretch and mechanically rupture the walls of microorganisms. This functionality is potent in wet, dry, illuminated or dark environments. We have developed a new plasmonic nanoscale multilayer material which activates photocatalysis under standard (visible) light and have developed technology based on high power impulse magnetron sputtering which can produce these materials at room temperature on polymers. We will study the plasma processes needed to produce the materials and nanopillars, their response to light activation and the effect they have on microbials. This will help us to develop a cost-effective manufacturing technology to enable large scale production by upgrading systems which are already available in industry for coating deposition and nanopatterning with a digitalised system control which is driven by artificial intelligence algorithms. Together with the local NHS hospital trust we will trial the material on metal plates for door furniture and polymer sheets to cover surfaces in hospitals (beds, seating areas). When successful we will have some of the most exciting new developments in robust antimicrobial materials and their manufacturing and take a step closer to a world with fully effective infection control.

Muscles help us move, enable us to interact with objects and the environment, and regulate critical internal functions. Unfortunately, they are susceptible to damage due to disease, ageing and trauma and are a central factor in diverse serious healthcare conditions including sarcopenia (age-related loss of muscle mass and function, where decline in muscle mass between 40 and 80 years ranges from 30% to 50%), stroke, muscular dystrophy, multiple sclerosis, soft-tissue cancers, venous ulceration, diabetes, degenerative myopathy and incontinence (between 3 and 6 million people in the UK, and 24% of older people, suffer from urinary incontinence). The emPower Transformative Healthcare Technologies 2050 programme will overcome the limitations of current wearable assistive technologies and regenerative medicine by deploying engineered robotic artificial muscular assistance inside the body, exactly where it is needed, to: 1. restore strength and control in mobility and manipulation in older people who have lost muscle strength and precision; and 2. restore controllable muscular capabilities for sufferers of trauma, stroke, incontinence and degenerative diseases. This will have significant knock-on effects on whole-body and mind health through increased confidence, independence and quality of life, massively reducing the healthcare burden and facilitating the return of sufferers to productive and fulfilling lives. The emPOWER artificial muscles will be engineered to bridge the gap between the nanoscale of fundamental energy transduction phenomena and the centimetre scale of bulk muscle action, and will be implantable using minimally invasive (including robot-assisted) surgery and advanced imaging to replace or supplement ailing muscles, providing short-term rehabilitation, long-term assistance or complete functional restoration as needed. To achieve our vision, we have brought together leading experts in soft robotics, regenerative medicine, bio-interfacing, smart structures, synthetic biology, polymer chemistry, self-assembly, bio-printing and tissue analysis, and clinical partners in neuro-rehabilitation, cardiovascular disease, head and neck surgery, urology, geriatrics and musculoskeletal medicine. Together, and with key industrial and social care partners, we will deliver the foundational technologies and first-stage proof-of-concept of the emPOWER artificial muscles within the five years of this transformative project, leading to major healthcare, economic and social impact to 2050 and beyond.

Biomedical Materials have advanced dramatically over the last 50 years. Historically, they were considered as materials that formed the basis of a simple device, e.g. a hip joint or a wound dressing with a predominant tissue interface. However, biomedical materials have grown to now include the development of smart and responsive materials. Accordingly, such materials provide feedback regarding their changing physiological environment and are able to respond and adapt accordingly, for a range of healthcare applications. Two major areas underpinning this rapid development are advances in biomedical materials manufacture and their characterisation. Medical products arising from novel biomedical materials and the strategies to develop them are of great importance to the UK and Ireland. It is widely recognised that we have a rapidly growing and ageing population, with demand for more effective but also cost effective healthcare interventions, as identified in recent government White Paper and Foresight reports. This links directly to evidence of the world biomaterials market, estimated to be USD 70 billion (2016) and expected to grow to USD 149 billion by 2021 at a CAGR of 16%. To meet this demand an increase of 63% in biomedical materials engineering careers over the next decade is predicted. There is therefore a national need for a CDT to train an interdisciplinary cohort of students and provide them with a comprehensive set of skills so that they can compete in this rapidly growing field. In addition to the training of a highly skilled workforce, clinically and industrially led research will be performed that focuses on developing and translating smart and responsive biomaterials with a particular focus on higher throughput, greater reproducibility of manufacture and characterisation. We therefore propose a CDT in Advanced Biomedical Materials to address the need across The Universities of Manchester, Sheffield and The Centre for Research in Medical Devices (CÚRAM), Republic of Ireland (ROI). Our combined strength and track record in biomaterials innovation, translation and industrial engagement aligns the UK and ROI need with resource, skills, industrial collaboration and cohort training. This is underpinned strategically by the Biomedical Materials axis of the UK's £235 million investment of the Henry Royce Institute, led by Manchester and partner Sheffield. To identify key thematic areas of need the applicants led national Royce scoping workshops with 200 stakeholders through 2016 and 2017. Representation was from clinicians, industry and academia and a national landscape strategy was defined. From this we have defined priority research areas in bioelectronics, fibre technology, additive manufacturing and improved pre- clinical characterisation. In addition the need for improved manufacturing scale up and reproducibility was highlighted. Therefore, this CDT will have a focus on these specific areas, and training will provide a strongly linked multidisciplinary cohort of biomedical materials engineers to address these needs. All projects will have clinical, regulatory and industry engagement which will allow easy translation through our well established clinical trials units and positions the research well to interface with opportunities arising from 'Devolution Manchester', as Greater Manchester now controls long-term health and social care spending, ready for the full devolution of a budget of around £6 billion in 2016/17 which will continue through the CDT lifespan.