A Polyvinyl Alcohol/Acrylamide Hydrogel with Enhanced Mechanical Properties Promotes Full-Thickness Skin Defect Healing by Regulating Immunomodulation and Angiogenesis Through Paracrine Secretion

Abstract

Hydrogel-based tissue-engineered skin has attracted increased attention due to its potential to restore the structural integrity and functionality of skin. However, the mechanical properties of hydrogel scaffolds and natural skin are substantially different. Here, we developed a polyvinyl alcohol (PVA)/acrylamide based interpenetrating network (IPN) hydrogel that was surface modified with polydopamine (PDA) and termed Dopa-gel. The Dopa-gel exhibited mechanical properties similar to native skin tissue and a superior ability to modulate paracrine functions. Furthermore, a tough scaffold with tensile resistance was fabricated using this hydrogel by three-dimensional printing. The results showed that the interpenetration of PVA, alginate, and polyacrylamide networks notably enhanced the mechanical properties of the hydrogel. Surface modification with PDA endowed the hydrogels with increased secretion of immunomodulatory and proangiogenic factors. In an in vivo model, Dopa-gel treatment accelerated wound closure, increased vascularization, and promoted a shift in macrophages from a proinflammatory M1 phenotype to a prohealing and anti-inflammatory M2 phenotype within the wound area. Mechanistically, the focal adhesion kinase (FAK)/extracellular signal-related kinase (ERK) signaling pathway may mediate the promotion of skin defect healing by increasing paracrine secretion via the Dopa-gel. Additionally, proangiogenic factors can be induced through Rho-associated kinase-2 (ROCK-2)/vascular endothelial growth factor (VEGF)-mediated paracrine secretion under tensile stress conditions. Taken together, these findings suggest that the multifunctional Dopa-gel, which has good mechanical properties similar to those of native skin tissue and enhanced immunomodulatory and angiogenic properties, is a promising scaffold for skin tissue regeneration.