Year: 2012
Type: dissertation
Abstract: The main long-term complication of the otherwise very successful total hip replacement surgery is osteolysis and resulting implant loosening that necessitate technically demanding revision operations. This aseptic loosening is primary caused by biomaterial wear particles released from the implant bearing surfaces because of abrasion. These wear particles are in the peri-implant interface tissues phagocytosed by macrophages which are induced to produce inflammatory mediators that cause the local micro-environment to support osteoclast formation and function ultimately leading to implant loosening. The exact mechanisms of this wear-particle-induced macrophage activation have remained elusive. The first aim of the current thesis was to evaluate by immunohistochemistry and qRT-PCR the extent to which Toll-like receptors (TLRs) 1-9 occur and how they localize in the aseptic interface tissues. We found that macrophages of aseptic interface tissue expressed TLR1-9 and, in comparison to control synovial tissue, actively produced all of these except TLR3 and TLR7. It is possible that some of these pattern-recognition receptors are involved in wear-particle recognition and in subsequent macrophage activation. Second, we evaluated the direct effect of titanium particles on TLR levels in a mouse model of wear-particle-induced inflammation and in a macrophage culture system. In the mouse model, particles led to down-regulation rather than to up-regulation of peri-implant TLR levels and, in the macrophage culture, particles had no effect on TLR mRNA levels. The up-regulation of TLRs in aseptic interface tissue is thus likely mediated by factors other than the direct effect of wear particles on macrophages. Third, in hopes of identifying cell populations potentially useful as histopathological diagnostic markers of subclinical implant-related infection, we evaluated cell populations present in typical implant infection and aseptic interface tissue using cell line-specific antibodies and immunohistochemistry. Comparison of inflammatory cell populations between these conditions revealed that, in addition to neutrophils, B lymphocytes and plasma cells might be useful marker cells in the diagnosis of low-grade implant-related infection, but these results must be validated in larger series. Fourth, we hypothesized that macrophages response to wear particles is dependent not only on particle characteristics but also on the state of macrophage polarization as determined by the cytokine milieu of the local microenvironment. We differentiated M1 and M2 macrophages from human monocytes and compared their responses to titanium particles using a genome-wide microarray analysis and multiplex cytokine assay. In comparison to non-activated M0 macrophages, the inflammatory responses to wear particles was greatly enhanced in M1 macrophages and effectively suppressed in M2 macrophages. These results suggest that the local, and possibly systemic, cytokine milieu is one factor determining the extent to which macrophages are activated by wear particles. Limiting the action of M1-polarizing factors in the interface tissue and promoting M2 macrophage polarization might thus be a means to limit osteolysis and implant loosening resulting from inevitably forming wear particles.
Source: Työväentutkimus Vuosikirja
Author: Jukka Pajarinen
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2284359182