SELF-ASSEMBLED PEPTIDE RADA16 HYDROGEL PROMOTES EPITHELIALIZATION OF WOUNDS BY A LAMININ-332-DEPENDENT SCAVENGING MECHANISM.

Re-epithelialization describes the resurfacing of a skin wound with new epidermis as the first step in restoring its integrity and barrier function. In wounds, re-epithelialization progresses from the surrounding wound edges towards the center, forming a continuum in the regeneration of a differentiated epidermis by adhesion to extracellular matrix proteins. Failure of re-epithelialization is a hallmark of chronic wounds and keeps them in a vicious cycle of infection and uncontrolled inflammation that impairs healing. With the increasing number of all forms of chronic wounds, there is an urgent need to develop appropriate therapeutics. To address the lack of a therapeutic solution specifically targeting this burden, we focused on the self-assembling peptide hydrogel RADA16, whose biocompatibility and therapeutic validation for use in humans as a hemostatic agent make it an attractive candidate. Due to its ability to adopt different stiffness and stability properties depending on the peptide concentration, we investigated its most promising formulation to support epidermal regeneration. Our study shows that RADA16 is able to promote keratinocyte adhesion, proliferation and migration, enabling wound closure both in vitro and in vivo. We demonstrate the original mechanism of action based on RADA16-specific recruitment of the keratinocyte major adhesion protein laminin-332, which is essential for these cellular processes. We also show that RADA biomimetically mimics the tripeptide cell adhesion sequence RGD for both laminin recruitment and dermal fibroblast adhesion. Our study describes the repositioning of the RADA16 hydrogel as the first synthetic, hydrating, stable and resorbable hydrogel that promotes rapid re-epithelialization of wounds through an endogenous and spontaneous laminin-332 functionalization mechanism. STATEMENT OF SIGNIFICANCE: The study reports on the complete characterization of a self-assembling peptide hydrogel (RADA16), already in clinical use for its hemostatic properties, with a view to its repositioning for the reepithelialization of skin wounds. The focus on this indication is important as there is currently no hydrogel with healing-promoting properties in clinical practice. The work is significant as it provides an in-depth investigation of the mechanism by which RADA16 promotes wound resurfacing, based on its endogenous and spontaneous functionalization by the extracellular matrix protein laminin-332, the major adhesion protein produced by epidermal cells. The combination of basic research for therapeutic development with consideration of a global public health problem are assets that characterize this study.