Dihydromyricetin-Incorporated Multilayer Nanofibers Accelerate Chronic Wound Healing by Remodeling the Harsh Wound Microenvironment

The harsh microenvironment in wound (HMW) remains a major obstacle to chronic wound healing. Although a series of bioactive materials have been developed, few of them are multi-functional and able to accelerate wound healing via precisely remodeling the HMW. Herein, a series of dihydromyricetin (DHM)-incorporated multilayer nanofibers (termed DQHP-n, n = 0, 2, 6 and 10) are fabricated using a layer-by-layer (LBL) self-assembly technique. The average diameters of DQHP-n significantly increase from 0.30 ± 0.16 μm to 0.84 ± 0.28 μm (P < 0.05) along with the n value increased from 0 to 10, the tensile strength of that is also significantly improved from 1.12 ± 0.15 MPa to 2.16 ± 0.30 MPa (P < 0.05), and the water contact angle of that significantly decreases from 129.1 ± 1.5° to 76.6 ± 3.9° (P < 0.05). The DQHP-n are found to be biocompatible, in which DQHP-6 promoted cell migration through activation of the epithelial–mesenchymal transformation (EMT) pathway and reconstruction of the HMW by stopping bleeding, killing bacteria, eliminating inflammation, and scavenging reactive oxygen species (ROS). The in vivo evaluation is carried out via an E. coli-infected rat skin regeneration model. The DQHP-6 group demonstrates the best effect, as it healed up to 98.5 ± 1.0% of the wound area at day 15. DQHP-6 differentially regulates the mRNA expressions of several cytokines (FGF2, PDGF, IL-1α, IL-6, IL10, and TGF-β), which ends to reductions of total inflammatory cells (CD45+ cells) and M1 macrophages (CD80+ and CD86+ cells), proliferation of host cell (Ki67+ cells), and enhancement of collagen synthesis. In conclusion, DQHP-6 exhibits multifunctional properties for HMW, and can serve as a promising wound dressing for clinical transformation.Graphical abstract