Adhesive Hydrogel Patch-mediated Combination Drug Therapy Induces Regenerative Wound Healing Through Reconstruction of Regenerative Microenvironment.

Regenerative wound healing involves the complete regeneration and scarless healing of wounded skin as observed in fetal skin. Multiple features of regenerative wound healing have been well studied; however, the practical application of pro-regenerative materials to recapitulate the regenerative wound healing in adult skins has not yet been achieved. In this study, we identified that our novel pro-regenerative material, pyrogallol-functionalized hyaluronic acid (HA-PG) patches in combination with protein transduction domain-fused Dishevelled (Dvl)-binding motif (PTD-DBM), a peptide inhibiting the CXXC-type zinc finger protein 5 (CXXC5)-Dvl interaction, promoted regenerative wound healing in mice. The HA-PG patches loaded with this competitor peptide and valproic acid (VPA), a glycogen synthase kinase 3β inhibitor, significantly inhibited scar formation during wound healing. The HA-PG patches with PTD-DBM and/or VPA inhibited the expression of differentiated cell markers such as α-smooth muscle actin while inducing the expression of stem cell markers such as CD105 and Nestin. Moreover, Collagen III, an important factor for regenerative healing, was critically induced by the HA-PG patches with PTD-DBM and/or VPA, as also seen in VPA-treated Cxxc5-/- mouse fibroblasts. Overall, these findings suggest that our novel regeneration-promoting material can be utilized as a potential therapeutic agent to promote both wound healing and scar attenuation. This article is protected by copyright. All rights reserved.