Wound healing properties of flavonoids: A systematic review highlighting the mechanisms of action

Flavonoids are a class of compounds with a wide variety of biological functions, being an important source of new products with pharmaceutical potential, including treatment of skin wounds. This review aimed to summarize and evaluate the evidence in the literature in respect of the healing properties of flavonoids on skin wounds in animal models. This is a systematic review following the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. This was carried out through a specialized search of four databases: PubMed, Scopus, Web of Science and Embase. The following keyword combinations were used: "flavonoidal" OR "flavonoid" OR "flavonoidic" OR "flavonoids" AND "wound healing" as well as MeSH terms, Emtree terms and free-text words. Fifty-five (55) articles met the established inclusion and exclusion criteria. Flavonoids presented effects in respect of the inflammatory process, angiogenesis, re-epithelialization and oxidative stress. They were shown to be able to act on macrophages, fibroblasts and endothelial cells by mediating the release and expression of TGF-β1, VEGF, Ang, Tie, Smad 2 and 3, and IL-10. Moreover, they were able to reduce the release of inflammatory cytokines, NFκB, ROS and the M1 phenotype. Flavonoids acted by positively regulating MMPs 2, 8, 9 and 13, and the Ras/Raf/MEK/ERK, PI3K/Akt and NO pathways. Flavonoids are useful tools in the development of therapies to treat skin lesions, and our review provides a scientific basis for future basic and translational research.