Li, Yutong Amy; (2019) Understanding the role of orthopaedic implant dissolution ions in bone remodelling. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The ions released from materials used in orthopaedic repair can affect bone remodelling. These ions can be released as unintentional by-products of implant wear or can be intentionally released as part of implant design (e.g. bioactive glasses, cements and hydrogel). Furthering the understandings of how these ions (with a focus on Cobalt (Co) and Silicate (Si)) interact in vitro in this study, these ions affect bone remodelling and will allow the development of new materials with improved outcomes following implantation. The effects of these ions on bone remodelling cells, specifically on monocytes, osteoblasts and osteoclasts were performed and potential mechanistic cellular pathways (the hypoxia inducible factor (HIF) pathway and Fenton reaction) were investigated. This included the development of a new in vitro model of bone resorption using a sub-clone of mouse macrophage cell-line (RAW264.7), creating a novel non- primary cell line that demonstrates bone resorbing activity. Co ions, at concentration range below 200μM reported in the bone implant interface of failed implants (25-100μM), were found to increase the sub-unit of Tartrate resistant acid phosphatase 5b (TRAP-5b) expression, this enzyme is osteoclast specific in the osteoclast sub-clone cell lines, hence correlated to increased osteolysis (p<0.001). Co ions also increased osteoblast expression of the osteoclastic differentiation factor RANKL, reactive oxygen species (ROS) generation and macrophage phagocytic activity (p<0.001). These results suggest that Co ions may contribute inflammatory osteolysis and cause aseptic implant failure. Furthermore, inhibition of the HIF pathway using echinomycin (an inhibitor of HIF-1a transcriptional factor binding), reduced these Co ion dependent osteoclastogenic and inflammatory effects, supplying evidence of Co ion stabilization of the HIF-1a pathway. Bioactive glasses release Si which hypothesise to encourage bone formation. There is, however, little understanding of how Si interacts with osteoclasts. A possible cellular mechanism for this inhibition was investigated, whereby Si was found (concentration dependently) to inhibit ROS generation in osteoclasts via the Fenton reaction. The addition of iron (II) ions (10 μM FeCl2) restored osteoclastogenesis (p<0.001), suggesting, for the first time, that Si chelation of iron, may be responsible for enhanced bone formation. These results furthered our understanding on how Co and Si released from materials influence bone remodelling and may enable the development of materials that control bone resorption and bone formation depending on the disease and patient.

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