Substrate-adsorbed collagen and cell secreted fibronectin concertedly induce cell migration on poly(lactide–glycolide) substrates

Limited epithelial cell migration on synthetic polymeric biomaterials, such as polyesters, presents a serious challenge to their use as scaffolds for artificial skin analogs. The mechanisms by which a physiologic matrix interface on such polymers may regulate and promote cell migration under ‘activated conditions’ were the focus of this study. We have quantified the migration behavior of epidermal growth factor (EGF) stimulated epidermal keratinocytes on 50 : 50 poly- , (lactide–glycolide) (PLGA) substrates, following exogenous and cell-derived substrate conditioning based on the model matrix proteins, collagen and fibronectin. We report that ‘non-conditioned’ PLGA substrates elicited poor levels of keratinocyte migration. However, keratinocyte migration was significantly enhanced upon the adsorption of type I collagen, and was only weakly enhanced with fibronectin adsorption. Molecular analysis of the mechanism of enhanced migration on collagen-PLGA substrates showed that keratinocyte migration was sensitive to cell-derived fibronectin conditioning, but not to cell-secreted collagen conditioning. Fibronectin control of cell migration on collagen-PLGA was found to be both stoichiometric and biologically specific, mediated via adhesion involving keratinocyte αv integrin receptors. Based on our results, we propose a unique paradigm for induction of cell migration on a non-physiologic synthetic polymer using concerted interactions between primary, polymer-instructed matrix remodeling and secondary, cell-derived matrix remodeling.