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Nanoparticle-containing antimicrobial coatings, validation in laboratory tissue model of orthopaedic prosthesis


Project Description

Hypothesis:
An antimicrobial sol-gel coating containing nanoparticles can be developed for prosthetic devices, and shown to be effective in a novel 3D tissue culture model of orthopaedic infections.

Aim

To develop an optimised prosthetic coating to provide (1) a burst release of antibiotics to prevent infection from surgery and (2) a depot of antibiotic-containing nanoparticles from which antimicrobial release will be activated if infection occurs in future. This will be achieved via cycles of coating/nanoparticle formulation improvement and multidisciplinary testing.

Methodology

Sol-Gel formulation and Characterisation
Coatings will be adapted to incorporate antimicrobials and nanoparticle combinations. Elution will be assessed by LC-MS and ICP-MS. Antimicrobial activity will be assessed against planktonic bacteria and biofilms.

Biofilm Modelling
We will develop polymicrobial biofilm models to determine effects of antimicrobials on bacterial transcriptomes, to characterise how harmful microorganisms can colonise orthopaedic materials. Prof Rob Townsend, Consultant Clinical Microbiologist (Northern General Hospital Sheffield) will advise on relevant species to include. Dr Melissa Lacey, who has expertise in bacterial signalling and biofilm formation, will advise on transcriptomic analysis.

Ex vivo tissue model for biocompatibility testing and modelling of later-occurring infections:
Bovine tail vertebrae will be utilised to develop an ex vivo culture system within a biomechanically loaded environment using an Electroforce 5210 system. Bone fixation to the coatings will be assessed using μCT, histology and immunohistochemical analysis. Efficacy of the coatings to combat infection that may occur much later than surgery (e.g. haematogenous infections) will be tested by perfusion of bacteria through the loaded culture system. Fluorescently tagged nanoparticles will be utilised to monitor penetration of the particles into the deep tissue surrounding implants.

In vitro pull out testing:
Following culture under dynamic loading for 3 weeks (to enable bone fixation and attachment) tensile testing will be performed to determine the strength of implant fixation into the bone.

Innovations

We will develop bifunctional coatings for prosthetic implants to (1) prevent infection during surgery and (2) trigger controlled release of antibiotic to combat future infections. The ex vivo biomechanical loading model of bone infection will enable testing of implant coatings and other future bone therapies, reducing animal testing in line with 3Rs. We will also develop a biofilm model to determine the changes in gene expression in response to antimicrobial challenge. Collectively, the results will provide valuable insights into improved antimicrobial therapies and increased quality of life, particularly for older patients.

Applications

Applicants must apply using the online form on the University Alliance website at https://unialliance.ac.uk/dta/cofund/how-to-apply/. Full details of the programme, eligibility details and a list of available research projects can be seen at https://unialliance.ac.uk/dta/cofund/

The final deadline for application is 12 April 2019.

Funding Notes

DTA3/COFUND participants will be employed for 36 months with a minimum salary of (approximately) £20,989 per annum. Tuition fees will waived for DTA3/COFUND participants who will also be able to access an annual DTA elective bursary to enable attendance at DTA training events and interact with colleagues across the Doctoral Training Alliance(s).
This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 801604.

References

1. National Joint Registry for England, Wales, Northern Ireland and the Isle of Man. 15th Annual Report 2018, http://www.njrreports.org.uk/Portals/0/PDFdownloads/NJR%2015th%20Annual%20Report%202018.pdf.
2. Piuzzi, N. S., Ng, M., Song, S., Bigach, S., Khlopas, A., Salas-Vega, S., & Mont, M. A. (2019). Consolidation and maturation of the orthopaedic medical device market between 1999 and 2015. European Journal of Orthopaedic Surgery & Traumatology, 1-8.
3. Kurtz, S. M., Lau, E., Watson, H., Schmier, J. K., & Parvizi, J. (2012). Economic burden of periprosthetic joint infection in the United States. The Journal of arthroplasty, 27(8), 61-65.
4. Vanhegan, I. S., Malik, A. K., Jayakumar, P., Ul Islam, S., & Haddad, F. S. (2012). A financial analysis of revision hip arthroplasty: the economic burden in relation to the national tariff. The Journal of bone and joint surgery. British volume, 94(5), 619-623.

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