Self-assembled peptide RADA16 hydrogel supports wound epithelialization by a laminin-332-dependent binding mechanism

Abstract

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 a scaffold that permits keratinocyte adhesion, proliferation and migration, enabling wound closure both in vitro and in vivo. We demonstrate an effect based on RADA16-specific binding to the keratinocyte major adhesion protein laminin-332, which is essential for these cellular processes. Our study describes the RADA16 hydrogel as the first synthetic, hydrating, stable and resorbable hydrogel that fosters re-epithelialization of wounds through an endogenous and spontaneous laminin-332 binding mechanism. STATEMENT OF SIGNIFICANCE: The study reports on the characterization of a self-assembling peptide hydrogel (RADA16), already in clinical use for its hemostatic properties, with a view to its use 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 supports wound resurfacing, based on its endogenous and spontaneous interaction with 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.

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