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Implant surface topography modulates macrophage morphology and subsequent signaling cascades Ghrebi, Salem


Implant surface topography is a major determinant in the success of dental implants. The objective of this thesis was to investigate macrophage responses to implant surface topography in vitro and in vivo. The in vitro studies investigated the effects of surface topography on the RAW 264.7 macrophage cell line’s morphology and signaling over time. Cells plated on surfaces of varying degrees of roughness responded with specific topography-directed time-dependent changes in cell morphology. These changes were accompanied by alterations in F-actin and vinculin organization and localization. Activation of focal adhesion kinase (FAK), proto-oncogenic tyrosine kinase (Src), and extracellular signal-regulated kinases1/2 (ERK 1/2) signaling molecules were also found to be both surface topography and time dependent. Phosphorylation of FAK and ERK1/2 appeared to be integrin-mediated as the Src inhibitor pyrazolopyrimidine (PP1) blocked their activation. Surface topography also affected RAW 264.7 cell number. The in vivo section comprised two parts. First, an immunostaining technique was developed that allowed recognition of the lysosomal marker ED1 on macrophages embedded in L.R-White embedding medium. We then used this technique to identify recruited ED1-positive macrophages at the implant-tissue interface in cryosections and in sections of L.R-White-embedded polished and rough implants placed in rats. We conclude that RAW 264.7 cells are highly sensitive to micron-scale features of surface topography; the features affected cell morphology as well as the organization and localization of F-actin and vinculin. For the first time ever we report that topographies used in clinical implants differentially regulate activation of FAK, Src and ERK1/2 signaling molecules. As these pathways lead to production of inflammatory cytokines, surface topography may be important in deciding host responses to/and eventual outcomes of implantation. The results point to the possibility of designing implants with specific surface features to control host responses and thereby improve clinical outcomes.

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