Acute and chronic wounds, caused by trauma, tumors, diabetic foot ulcers, etc., are usually difficult to heal, while applying exogenous electrical stimulation to enhance the endogenous electric field in the wound has been proven to significantly accelerate wound healing. However, traditional electrical stimulation devices require an additional external power supply, making them poor in portability and comfort. In this work, a self-powered piezoelectric poly(vinyl alcohol) (PVA)/polyvinylidene fluoride (PVDF) composite hydrogel is constructed by establishing a distinctive preparation process of freezing/thawing-solvent replacement-annealing-swelling. The hydrogen bonding in the hydrogel is remarkably enhanced by the annealing-swelling process, which is stronger between PVA/PVDF molecules than that between PVA molecules, promoting transformation of the α-phase into the electroactive β-phase PVDF and facilitating formation of a much more crystalline structure with high cross-linking density. Hence, an obvious piezoelectric response with high piezoelectric coefficient and electrical signal output with superior stability and sensitivity and excellent mechanical strength and stretchability was achieved for hydrogels. PVA/PVDF composite hydrogels with good cytocompatibility significantly promote proliferation, migration, and secretion of extracellular matrix proteins and growth factors of fibroblasts, possibly through activating the AKT and ERK1/2 signaling pathways. In a wound model of diabetic rats, piezoelectric hydrogels could not only rapidly attract wound exudate and maintain the wet environment of the wound bed but also convert the mechanical energy generated by rats' physical activities into electrical energy, so as to provide local piezoelectric stimulation to the wound bed evenly and symmetrically in real time. Such an effect significantly promotes re-epithelialization and collagen deposition and increases angiogenesis and secretion of growth factors in wound tissue. Besides, it regulates the macrophage phenotype from the M1 subtype (pro-inflammatory subtype) to the M2 subtype (anti-inflammatory subtype) and reduces the expression levels of inflammatory factors, thus accelerating wound healing. The development of such a novel piezoelectric hydrogel provides new therapeutic strategies for chronic wound healing.
Keywords: cell behavior; chronic wound healing; cytocompatibility; electroactive β-phase; piezoelectric response; self-powered hydrogel.