The proposed studies in this application focus on the development of a mechanistic understanding of the complexity of host/material interactions that comprise the foreign body response to biomaterials. Our working hypothesis is that lymphokine-mediated macrophage activation and foreign body gift cell (FBGC) formation on biomaterials are the result of complex extracellular and intracellular interactions that can be controlled by biomaterial surface chemistry.
The specific aims of the proposed project are: 1) to modulate and control lymphokine-mediated macrophage activation and FBGC formation through the application of molecularly-engineered surfaces designed to target critical cellular mechanisms and interactions, 2) to demonstrate that the spatial distribution and phenotype of adherent monocytes, macrophages and lymphokine-induced FBGC can be controlled by micropatterned surfaces that exert geometric constraints on these cell types, 3) to determine the effects of material surface properties on the production of specific lymphocyte-derived cytokines that promote macrophage development, activation and fusion to form FBGC or Langhans giant cells (LGC), 4) to elucidate the molecular mechanism(s) of lymphokine-induced FBGC and LGC formation and the cytoskeletal/adhesive structural organizations that underlie morphological differences between these giant cells, and 5) to determine through phenotypic characterization the potential functional significance of giant cells at sites of inflammation and foreign body reaction. Our experimental approach will utilize molecularly-engineered, micropatterned and temperature responsive surfaces to address these related and interactive specific aims. Correlative and quantitative biochemical and immunochemical techniques will be applied to our in vitro systems of FBGC and LGC formation utilizing human monocytes and lymphokines and our murine in vivo cage implant system. Fluorescence confocal scanning laser microscopy (FCSLM) will be exploited to identify extracellular and intracellular molecules and receptors that are critically important in the surface chemistry-dependent events of monocyte/macrophage adhesion and macrophage fusion to form FBGC. Material surface-dependent variations in these cell surface, intracellular, cytoskeletal and adhesive structural molecules will be evaluated. In vivo experiments will focus on identification of material-dependent lymphokine gene expression and secretion profiles and on Th1 versus Th2 lymphokine participation in FBGC formation. Results from our combined studies will lead to a greater appreciation of these complex cell/material interactions and novel design criteria for new biomaterials and tissue-engineered surfaces.
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