Aseptic loosening, as a consequence of an extended inflammatory reaction induced by wear particles, remains the most common complication of total joint replacement (TJR), representing a major problem for the long-term success and survival of prostheses. Despite it is high incidence, in the last decade any therapeutic approach has been found to treat or avoid aseptic loosening, leaving revision as the only effective treatment for this condition. The local delivery of anti-inflammatory drugs to modulate wear-induced inflammation has been regarded as a potential therapeutic approach to avoid aseptic loosening. In this work, an anti-inflammatory drug-eluting implant model system was developed and characterised. The model system was obtained by attaching DEX to functionalised-TiO2 particles, through different synthetic routes: i) by covalently binding DEX to carboxyl-functionalised particles (amino or mercapto routes) or ii) by coating amino-functionalised particles using Layerby- Layer (LbL) technique. The chemical and physical properties of DEXloaded functionalised TiO2 particles have been determined and the release profiles investigated. Depending on the synthetic route, the DEX release period can vary from hours (amino, mercapto routes) to 3 weeks (LbL route). The model system was then tested for its cytotoxic and anti-inflammatory properties in a rapid and reproducible in vitro mouse macrophage-like cellular model, by utilizing murine RAW 264.7 cells. In this model lipopolysaccharide (LPS) was utilized to activate the Raw macrophages, resulting in the secretion of pro-inflammatory cytokines, including nitric oxide (NO) and tumour necrosis factor alpha (TNF-α), the suppression of which was utilized to investigate the anti-inflammatory effect of DEX released from functionalised-TiO2 particles. In vitro studies showed that DEX decreased LPS-induced NO and TNF-α production at non-cytotoxic concentrations, where DEX released from LbL particles showed the most effective suppression of inflammation for at least 2 weeks. Collectively, these findings show that the model system developed can be a potential therapeutic approach to avoid wear-debris induced aseptic loosening of TJR.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:753583 |
| Date | January 2018 |
| Creators | Rodrigues, Melissa |
| Publisher | Cardiff University |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://orca.cf.ac.uk/114163/ |
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