Reducing the failure rate of artificial replacement hips and knees by understanding the mechanism of adverse biological reactions that currently cause

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Key aims of the research: The aim of this research is to understand why artificial hips and knees sometimes fail prematurely in patients. This will be done by combining laboratory, clinical and engineering disciplines to find out what causes the adverse reactions that results in pain and failure of hip and knee implants. When artificial hips and knees operate in the patient's body, they release particles of wear debris. It is understood that these particles contribute to the implant failing, but exactly why that is unknown and our research question is: Why does particulate wear debris cause implants to fail and can we predict this for existing patients in order to make them safe?The overall approach is to use a novel in vitro methodology to simulate inflammatory and osteolytic responses that more closely matches reality in vivo conditions. This is twofold: (1) create aseptic wear particles for study of several types of polymer including the next generation of implant polymers, and (2) develop a truly representative in vitro cell model to study the patient-implant domain to compare different types of debris and investigate the biological responses. These will be followed by (3) developing a simple bedside method to assess the patient risk of implant failure in the future.The research questions we intend to answer are; (a) Can clinically relevant wear debris induce proinflammatory phenotypic changes in a human macrophage model in vitro? (b) Are clinically relevant wear debris capable of eliciting osteolytic responses in an in vitro human osteoblast cell model? (c) Can wear debris be isolated from patient samples and characterised using NanoSight Particle Tracking analysis? (d) Do human tissue samples taken at the point of revision show an increase in inflammatory markers?Novel science and engineering methodology: Clinically relevant wear debris will be generated using a four-station multi-directional pin-on-plate machine housed in a class II microbiology laminar flow cabinet. Debris will be characterised using NanoSight Particle Tracking analysis and scanning electron microscopy (SEM) to determine size and morphology. Endotoxin and mycoplasma testing will be carried out in order to ensure that the wear debris generated is not contaminated and will be suitable for subsequent in vitro experiments. Two human cell lines will be used to investigate the in vitro biological effects of the generated wear debris including inflammation and osteolysis. Functional analyses of immunomodulatory and osteolytic processes will be used in conjunction with the human cell lines in order to characterise the mechanism of ongoing biological processes. Human tissue samples will be acquired at the point of revision surgery and used for immunohistochemistry in order to stain for specific inflammatory markers as well as structural analysis. Patient sample analysis of synovial fluid collected during revision surgery will be used for debris isolation and protein secretion analysis.