Exploiting bacterial virulence to trigger antimicrobial release from orthopaedic implants

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.

Few commercial technologies exist to prevent infections in cementless joint replacements. The technologies being developed attempt to prevent infections through the use of systemic antibiotics, prolonged release or by deterring initial bacterial attachment. This project proposes a novel approach whereby antimicrobial release will be triggered by bacteria and their characteristics. This will overcome issues with short-term effectiveness, toxicity and the risk of antimicrobial resistance.

In England and Wales in 2017, 2,865 revision procedures for infected joint replacements were performed. These surgeries are complex, require longer surgical and hospital inpatient times and often result in poorer outcomes. This affects patients through increased pain, morbidity and in severe cases long-term disability or even death. By developing a technology that prevents joint replacement infections, patients will return to an active state more rapidly, eliminating health deterioration associated with multiple surgeries and prolonged inpatient time.

This project will also have economic benefit as the cost of treating infected joint replacements in the UK is estimated to be over £73 million per year. A reduction in the number of infected implants would result in more hospital beds being available and surgeon and medical practitioner time being allocated to other areas of need. The effect of such a technology is amplified when considering the ageing population and the growing number of joint replacement surgeries globally.

The development of novel implant technologies will benefit the UK economy through reduced loss of working days, the creation and growth of companies and jobs and by enhancing business revenue and innovative capacity. The project is expected to generate new intellectual property, which will be licensed to orthopaedic companies or implemented through spin out companies. Licensing will result in increased revenue and market share as the technology offers numerous advantages over existing products. Alternatively, creating a spin out company would help grow the UK economy and medical technology sector. Such an approach would also attract external investment (from investors and global businesses) and open additional avenues of research funding (Innovate UK). Ultimately either approach will result in the creation of skilled jobs and expertise in implant coatings (research/manufacturing), strengthening the UK's position as a leader in this field.

To increase the likelihood of achieving the outlined impact, a work package has been dedicated to the pre-clinical and clinical development pathways and project management of the project. The work package includes engagement at an early stage with an advisory panel, consisting of a regulatory adviser, orthopaedic consultant, technology transfer officer, joint replacement patient and orthopaedic company. Sub-contracted work to the regulatory adviser will identify the medical device classification, standard tests required and pre-clinical and clinical development pathways. In-house technology transfer officers will establish an appropriate route to commercialisation and protection of intellectual property. The research team will meet with the advisory panel on a 6-monthly basis to update and help steer the research to fast-track the route to translation and impact.

Finally the project will increase public awareness of joint replacement infections and how novel technologies will prevent them. This will be achieved through patient and public involvement, engagement events (patient days, school visits), promotional content (leaflets, 3D printed models), press releases and through involvement with networks such as the Biomechanics and Bioengineering Research Centre Versus Arthritis, the Cardiff Institute of Tissue Engineering and Repair and the OAtech+ Network.