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Title: Bioengineering: Stratifying the Immune Response to Biomaterials
Authors: Mawdesley, Amy Elizabeth
Issue Date: 2020
Publisher: Newcastle University
Abstract: Early failure of Metal-on-Metal (MoM) joint implants is often due to adverse reaction to metal debris (ARMD). These MoM implants are composed of a cobalt-chromium (CoCr) alloy which generates nanoscale particles and metal ions. Cobalt ions can activate the innate immune receptor, Toll-like receptor 4 (TLR4), increasing secretion of inflammatory cytokines/chemokines. For this study, CoCr particles were generated in a multi-directional pin-on-plate wear simulator and characterised for use in cell treatments. In human THP-1 macrophages, CoCr particles were found to increase secretion of pro-inflammatory chemokines and cytokines including IL-8, CCL2, CCL3, CCL4 and IL-1 The gene expression of IL-8 and CCL3 was also up-regulated in response to CoCr particles. The expression of these markers was found to be largely TLR4-dependent as a small molecule TLR4 antagonist, CLI-095, significantly reduced these observed effects. Further investigation demonstrated that CoCr particles can also increase expression of the adhesion molecules ICAM-1 and VCAM-1 in the human endothelial cell line, HMEC-1. Furthermore, CoCr particle stimulation in HMEC-1 cells led to increased neutrophil migration in a chemotaxis assay. In periprosthetic tissue retrieved from patients undergoing hip and knee revision surgery, there was evidence of immune cell infiltration and the presence of macrophages and T cells. THP-1 macrophages were also treated with aluminium and zirconium oxides which are commonly used in ceramic hip implants. Both treatments resulted in significant TLR4- dependent increases to IL-8, CCL2, CCL3 and CCL4 gene expression and protein secretion. Use of ATP to mimic ‘danger’ signalling following initial priming with ceramics caused significant increases to IL-1 expression. These data demonstrate that CoCr particles and ceramic oxides can induce an immune response by up-regulating the expression of pro-inflammatory chemokines by a mechanism that appears to be largely TLR4-dependent. This study demonstrates a potential role for innate immunological mechanisms in the development of ARMD in patients with failed prosthetic joint implants.
Description: PhD Thesis
Appears in Collections:Translational and Clinical Research Institute

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