We continue to address the hypothesis that the monocyte/macrophage (MC/MO) is the major cellular component controlling the tissue/material inflammatory and healing responses. Our goal is to demonstrate that biomedical polymers selectively affect the activation and cytokine production of tissue MO, which can be correlated to in vitro and in vivo cellular proliferation and synthesis. A second hypothesis encompasses the induction of adhesion mechanisms in the MC/MO phenotypic response to biomedical polymers, i.e. that (i) MC-to-MO development and foreign body giant cell (FBGC) formation on polymers are initiated and promoted by specific adhesion mechanisms, (ii) material-dependent protein absorption specifies the cellular adhesion molecules engaged, and (iii) the engagement of adhesion mechanisms influences MC/MO/FBGC functions which are relevant to issues of biocompatibility. Our second major goal is to determine the receptors that mediate MC adhesion, MO development and FBGC formation on polymers. Materials to be investigated in our MC/MO/FBGC studies are: 1) Plastek RFGD modified culture dishes, 2) surface modified FEP, 3) HK and other anti-adhesive proteins, 4) anti-adhesive and/or anti-activating polymers, and 5) phospholipid polymers. Specifically, we will 1) evaluate the effect of polymers with varying surface properties on the activation and cytokine (IL-1alpha, IL-1Beta, TNF-alpha, IL-6, TGF-Beta and IL-1ra) production of adherent MC/MO; 2) evaluate the effect of variable surface properties on the ability to adhere and activate MC/MO; 3) identify adhesion receptors using our MC/MO culture system and antibodies to specific adhesion receptors, synthetic RGD-type peptides, electrophoretic/immunoblot analysis of absorbed plasma proteins, and trapping of receptor-ligand complexes by chemical crosslinking; 4) investigate how the engagement of receptors by MC/MO/FBGC influences cell functions. Material-dependent production of reactive oxygen intermediates, cell-associated thrombogenic and thrombolytic activities, and the secretion of cytokines during the morphologic progression will be analyzed. In addition, proliferation and synthesis studies will be carried out on target cells, i.e., endothelial and smooth muscle cells and fibroblasts; 5) explore surface absorbed proteins or modified polymers which are anti-adhesive and/or activating for MC/MO. These studies will provide a quantitative understanding of biomedical polymer biocompatibility from a cell interaction and activation perspective. Results from the studies proposed in this application will provide insight into cell-material, cell-protein and cell-cell interactions as they relate to the biocompatibility of polymers.
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