Biomimetic oligopeptides were employed to elucidate the molecular mechanisms of fibronectin-integrin interaction in regulating macrophage function. Oligopeptides were designed based on of the functional structure of fibronectin and grafted onto a polymer network containing polyethyleneglycols. Macrophage adhesion was independent of the peptide identity that contained sequence RGD, PHSRN, PRRARV, or combinations thereof in an integrin-dependent fashion in vitro. However, integrin-dependent foreign body giant cell (FBGC) formation in vitro was highly dependent on both RGD and PHSRN in a single peptide formulation and with a specific orientation. In vivo results showed that peptide identity played a minimal role in modulating the host inflammatory response and adherent macrophage density. RGD-containing peptides mediated a rapid FBGC formation by 4 days of implantation by significantly increasing both the number of macrophages that participate in the cell fusion process and the rate of cell fusion. Both RGD and PHSRN domains were important in mediating FBGC formation at later implantation periods. In vitro intracellular signaling studies revealed that the requirement of protein tyrosine kinase and serine/threonine kinase activation and cross-talk compensation for macrophage adhesion dynamically varied with surfaces and culture time. Protein kinase C-dependent adhesion was related to RGD and PHSRN sequences, and to the sequence orientation thereof in a form of GGGRGDGGGGGGPHSRNG. Furthermore, we observed a multiple effect of the mitogen-activated protein kinase/extracellular-signal-regulated kinase signaling factor in mediating macrophage adhesion, which depended on the method of ligand immobilization. These findings represent a mechanistic correlation between the role of substrates and protein functional architectures in ligand-receptor recognition and post-ligation signaling events that control cellular behavior in vitro and in vivo.