Polyelectrolyte nanofilms, formed by the layer-by-layer (LbL) assembly of oppositely charged polymers, are promising biomaterials due to their highly tunable film properties (i.e. viscosity, elasticity, thickness, degree of hydration). While film properties may be controlled through solution variables (pH and ionic strength) and choice of polymers, the controlled formation of chemical cross-links between functional groups on the polymers offers perhaps the greatest degree of property manipulation. We investigate here the influence on polymer film mechanical and cell-contacting properties brought about by chemical cross-linking employing EDC-NHS chemistry, where carboxylate groups on polyanion species within the film are activated and spontaneously form cross-links with amine groups on polycation species. We also investigate the possibility to confine cross-linking to the outer region of the film by adding a few layers of activated polymer to the top of a film. This type of mechanically inhomogeneous film is motivated by a desire to simultaneously achieve rigidity and bioactivity. We characterize film mechanical properties in situ using quartz crystal microgravimetry with dissipation (QCM-D), and investigate cell-contacting properties using human hepatocellular carcinoma (HepG2) cells.