In vitro and in vivo studies of 3D orthopaedic implants with cell-instructive nanotopographies

The demand for total hip and knee replacements (THR & TKR) has been steadily increasing worldwide. This is due to an ageing population, the rise in obesity and a change to more active lifestyles; together, these factors are leading to more osteoarthritis and degeneration of cartilage and subchondral bone in joints. The two leading causes of this type of orthopaedic implant failure are loosening (due to poor bone contact with the implant) and infection (due to bacterial infiltration and biofilm formation). In the case of THR/TKR, the incidence rate of joint infections is reported to be 1%- 4% in primary surgery and up to 30% in revision surgery. Our previous work showed that certain nanostructured surfaces on titanium (many orthopaedic implants are made from titanium) surfaces could be both bactericidal and bioactive (bone forming). However, most of the work so far was carried out on nanostructured 2D surfaces rather than real implant surfaces.

This project is aimed at conducting in vitro and pre-clinical studies based on 3D porous Ti implants with nanostructured surfaces, hence translating our current understanding in 2D into real 3D implants. We have assembled a multidisciplinary team from universities of Bristol, Glasgow and Cambridge, in partnership with clinical and industrial partners, to progress our research findings from previous EPSRC projects focusing on the basic science of bactericidal topographies on 2D surfaces towards the real world applications. We will bring together expertise in biomaterials, nanotechnology, stem cell biology, microbiology and pre-clinical studies, with a clear vision to apply new smart cell-instructive surfaces to orthopaedic implants. We hope to improve the quality of life of patients who require implants and save the costs of NHS by avoiding the need for revision due to implant loosening and infection.

This project is aimed at conducting in vitro and in vivo studies cell/microbiological studies of 3D porous Ti implants with nanostructured surfaces; translating our current understanding of 2D nanotechnology into 3D. We have assembled a multidisciplinary team from universities of Bristol, Glasgow and Cambridge in partnership with clinical and industrial partners to address important scientific and technological questions that will permit us to progress towards preclinical/clinical trials. For example (1) do MSCs and bacterial cells respond similarly to 3D curved nanostructured Ti surfaces on porous implants as they do on 2D nanostructured surfaces? (2) do the osteogenic-antibacterial effects remain if MSCs and bacteria are cultured together on the surfaces? (3) do the nanotopographies remain cell instructive in the dynamic in vivo microenvironment? (4) can we further functionalise the nanotopographies to enhance the synergy of antibacterial properties and osteogenic potential? To this end, we will investigate two 'non-line-of-sight' nanostructuring techniques to generate nanotopographies on 3D porous Ti implants and assess their robustness under simulated surgical conditions. We will use flow-cell microbiology screening, stem cell/bacteria co-culturing and infected animal models to study their response to bacteria and/or stem cells in order to understand their interactions and optimise the cell-instructive surface nanotopographies to develop 3D smart implants for orthopaedics.

The proposed project will focus on the development of smart 3D Ti implants for use in orthopaedics that are able to prevent bacterial infections while promoting osseointegration. The immediate beneficiaries will be biomedical and biomaterials researchers and then end users i.e. orthopaedic surgeons and companies who implement and make medical implants and devices. The knowledge generated in this project will broadly benefit researchers from a wide range of backgrounds of both fundamental and applied nature, including biomaterials, nanoscience and nanotechnology, microbiology, stem cell biology, biomedical engineering and orthopaedics. Anticipated benefits to orthopaedic surgeons will be improved success rate of implant surgeries using the developed products. Orthopaedic implant companies will benefit from the knowledge generated in this project to guide the rational design and manufacture of future smart implants to combat AMR infection, with long term benefits of profits, turnover and job creation. They will be closely involved in the project from the outset, providing 3D printed implant samples for testing, and advising on possible regulatory pathways during the course of the project. This means they can take our technology being developed and quickly incorporate it into their own products. Ultimately, our research will benefit those individuals requiring orthopaedic implants, including the increasingly elderly population and more active younger generation, by offering longer lasting implants without the need of revision in their lifetime. The research will also benefit the NHS that bears the costs of current ineffective treatment of infection based on antibiotics. Revision is often the only option to totally eliminate implant infection. However, infection alone in total hip replacement (THR) and total knee replacement (TKR) revision can cost £70,000 per patient to treat. Thus an implant solution that eliminates the need for revision surgery has potential to save the NHS up to £300 million per annum.