Poly(l-lactic acid) Scaffold Releasing an α(4)β(1) Integrin Agonist Promotes Nonfibrotic Skin Wound Healing in Diabetic Mice

[Image: see text] Skin wound healing is a highly complex process that continues to represent a major medical problem, due to chronic nonhealing wounds in several classes of patients and to possible fibrotic complications, which compromise the function of the dermis. Integrins are transmembrane receptors that play key roles in this process and that offer a recognized druggable target. Our group recently synthesized GM18, a specific agonist for α4β1, an integrin that plays a role in skin immunity and in the migration of neutrophils, also regulating the differentiated state of fibroblasts. GM18 can be combined with poly(l-lactic acid) (PLLA) nanofibers to provide a controlled release of this agonist, resulting in a medication particularly suitable for skin wounds. In this study, we first optimized a GM18-PLLA nanofiber combination with a 7-day sustained release for use as skin wound medication. When tested in an experimental pressure ulcer in diabetic mice, a model for chronic nonhealing wounds, both soluble and GM18-PLLA formulations accelerated wound healing, as well as regulated extracellular matrix synthesis toward a nonfibrotic molecular signature. In vitro experiments using the adhesion test showed fibroblasts to be a principal GM18 cellular target, which we then used as an in vitro model to explore possible mechanisms of GM18 action. Our results suggest that the observed antifibrotic behavior of GM18 may exert a dual action on fibroblasts at the α4β1 binding site and that GM18 may prevent profibrotic EDA-fibronectin-α4β1 binding and activate outside-in signaling of the ERK1/2 pathways, a critical component of the wound healing process.