The regulation of cell motility on ligand-adsorbed poly(ethylene glycol) (PEG)-based polymeric biomaterials is governed by variables that are not well characterized. In this report, we examined keratinocyte migratory responsiveness to PEG-variant tyrosine-derived polycarbonates adsorbed with equivalent levels of the cell adhesion ligand, fibronectin. The equivalently adsorbed ligand adopted differential distributions, confirmed via atomic force microscopy, and the total number of exposed cell-binding domains (CBD), quantified through immunosorbent fluorometry, varied as a function of PEG concentration. Specifically, the CBD exposure was maximized at 4 mol % PEG and diminished at 8 mol % PEG, suggesting, based on our previous work (Tziampazis et al., Biomaterials 2000;21:511-520), that activation of cell adhesion and motility could be potentially promoted through increased CBD exposure at intermediate levels of PEG. This was confirmed through cell migration studies wherein cell speed values increased from 11 to 22 microm/h as the PEG concentration was increased from 0 to 4 mol %. Unexpectedly, however, high cell motility rates were sustained at 8 mol % PEG despite diminished levels of initial CBD exposure beyond 4 mol % PEG, suggesting that factors other than the initial CBD exposure may additionally have a role in activating cell migration at higher levels of PEG. Through studies of direct ligand mobility, cell-ligand-polymer interactions via atomic force microscopy, and CBD variation and integrin receptor roles in ligand remodeling, we offer evidence that cell motility is enhanced by a new mechanism for the regimen of higher PEG concentration: upon cell attachment and spreading, the ligand exhibits greater "slippage" at the polymer interface, and undergoes cell-engendered remodeling, which further activates cell motility, likely through enhanced exposure of hitherto encrypted sites for cell binding and signaling.