Biomimetic and Estrogenic Plant-Based Nanofibrous Wound Dressings

Abstract

Naturally healed wounds do not perfectly regenerate cutaneous connective tissue, which often leads to extensive scarring or unhealed wounds. However, engineering regenerative wound dressings, which is a $10 billion market globally, remains a challenge for primary healthcare. Estrogen, a primary female sex hormone, accelerates wound healing via estrogen receptor (ER)-β but also triggers various breast cancers via ER-α, indicating that the use of estrogen is problematic. A better alternative to estrogen is an estrogenic material that can selectively activate the ER-β signaling pathway for enhanced wound healing without a high risk of triggering ER-α-positive cancers. Soy protein possesses phytoestrogens that have a structure and function similar to estrogen. Interestingly, soy phytoestrogens preferentially induce the ER-β signaling pathway. Moreover, soy phytoestrogens carry bioactive peptides that are similar to extracellular matrix (ECM) proteins in healthy skin. Despite these biological advantages, engineering soy-based scaffolds remains a challenge due to the low molecular weight of soy protein and the lack of studies thoroughly characterizing and optimizing processes for biomedical applications. We therefore propose to engineer estrogenic and ECM-mimetic soy-based nanofibrous scaffolds to accelerate wound healing. The engineered soy nanofibers successfully recapitulated the fiber morphology and diameter, pore diameter, and stiffness of native skin and transported bioactive contents (proteins and phytoestrogens). Moreover, the soy-based nanofibers showed high water retention, which could provide a moist environment to promote healing. As a result, soy increased in vitro fibroblast proliferation and migration on nanofibers compared to those without soy protein. The soy-based scaffolds significantly accelerated tissue restoration in both mouse and human skins. More importantly, these scaffolds promoted re-epithelialization, ECM remodeling, and hair follicle formation via the ER-β pathways. This study confirmed that soy-based dressings enhance wound closure and tissue regeneration via the ER-β pathways by providing a biomimetic and estrogenic microenvironment and by improving the physicochemical properties of scaffolds. We envision that our scaffolds will be the next generation of one-step, cost-effective regenerative scaffolds for primary care of severe cutaneous wounds.