Keratinocyte Growth Factor-Based Strategies for Wound Re-Epithelialization

Wound re-epithelialization is a dynamic process that comprises the formation of new epithelium through an active signaling network between several growth factors (GFs) and various cell types. The main players are keratinocytes (KCs) that migrate from the wound edges over the wound bed to restore the epidermal barrier. One of the most important molecules involved in the re-epithelialization process is keratinocyte growth factor (KGF), a central player on promoting both migration and proliferation of KCs. Stromal cells, such as dermal fibroblasts, are the main producers of this factor, acting on KCs through paracrine signaling. Multiple therapeutic strategies to deliver KGF have been proposed to boost wound healing by targeting re-epithelialization. Different approaches have been explored to attain that purpose, such as topical application of this factor, controlled release of KGF from different biomaterials (hydrogels, nanoparticles, and membranes), and also gene delivery techniques. Among these strategies, KGF release via biomaterials- and genetic-based strategies shows great effectiveness in maintaining sustained KGF levels at the wound site, which is reflected in an efficient wound closure. Under this scope, this review aims not only to elucidate the potential of KGF in wound re-epithelialization but also to describe the underlying mechanism of action and further explore the therapeutic approaches using this GF. Impact statement Upon skin injury, wound re-epithelialization is one of the major milestones of the healing process. This is especially difficult to achieve on hard-to-heal wounds that are often open for long periods, as the dysregulation of the growth factors involved in this response contributes to an impaired proliferation and migration of keratinocytes. Keratinocyte growth factor (KGF) plays a central role in this problematic, as it is a potent factor that in the normal healing scenario promotes direct proliferation and migration of epidermal cells, consequently impacting re-epithelialization. Under this context, in the first part of this review, the process of wound healing and the mechanism of action of KGF are described. In the second part, various KGF delivery approaches aiming at skin re-epithelialization are reported and actively discussed. In this sense, it is herein highlighted the role of KGF in wound re-epithelialization and provided a critical overview of potential therapeutic strategies exploited so far.