Gelatin-based semi-interpenetrating networks (sIPNs) containing soluble and covalently-linked bioactive factors have been shown to aid in wound healing; however, the biological responses elicited by the introduction of sIPN biomaterials remain unclear. In the current study, modulation of the re-epithelialization phase of wound healing by sIPNs grafted with PEGylated fibronectin-derived peptides and utilized as platforms for the delivery of exogenous keratinocyte growth factor (KGF) was evaluated. Following wounding, keratinocyte migration, proliferation and protein secretion is largely controlled by diffusible factors, such as KGF, released by the underlying fibroblasts. The impact of sIPNs and exogenous KGF upon the latter keratinocyte-fibroblast paracrine relationship and keratinocyte behavior was explored by monitoring keratinocyte adhesion and cytokine (IL-1alpha, IL-1beta, IL-6, KGF, GM-CSF and TGF-alpha) release. Results were generally similar for keratinocyte monoculture and keratinocyte-fibroblast co-culture systems. Although keratinocyte adhesion increased over time for positive control surfaces, adhesion to the sIPNs remained low throughout the course of the study. Release of IL-1alpha and GM-CSF was increased by exogenous KGF. The effects were more noticeable on the positive control surfaces relative to the sIPN surfaces. Regulation of the release of TGF-alpha was surface dependent, while IL-6 release was dependent upon surface type, the inclusion of exogenous KGF and the presence of fibroblasts. The findings indicate that during re-epithelialization, sIPNs containing soluble bioactive factors aid in wound healing primarily by serving as conduits for KGF, which induces the release of other key cytokines involved in tissue repair.