Skin wounds are common in accidental injuries, and the intricacies of wound repair are closely linked to endogenous electric fields. Electrical stimulation plays a pivotal role in the restorative processes of skin injuries, encompassing collagen deposition, angiogenesis, inflammation, and re-epithelialization. Employing electrical stimulation therapy replicates and enhances the effects of endogenous wound electric fields by applying an external electric field to the wound site, thereby promoting skin wound healing. In this study, we developed a self-powered repetitive mechanical impacts-electrical stimulation (RMI-ES) system utilizing a BaTiO₃/polydimethylsiloxane (PDMS) piezoelectric composite film. Compared to conventional electrical stimulation devices, the fabricated piezoelectric composite film efficiently harvests energy from the pressure applied by the stimulation device and the tensile force occurring during natural rat activities. The results demonstrated that piezoelectric stimulation generated by the composite membrane expedited the cell cycle, promoting fibroblast proliferation. Additionally, piezoelectric stimulation induced favorable changes in fibroblast gene expression, including increased expression of transforming growth factor-β1 (TGF-β1), connective tissue growth factor (CTGF), collagen 1, collagen 3, vascular endothelial growth factor (VEGF), and alpha-smooth muscle actin (α-SMA), while reducing interleukin-6 (IL-6) expression. Transcriptome analysis revealed that piezoelectric stimulation may induce fibroblast migration, proliferation, and collagen expression by influencing PI3K/AKT serine/threonine kinase (AKT) pathways. Further confirmation through the addition of the PI3K inhibitor LY294002 validated that piezoelectric stimulation can regulate the repair process after skin injury through the pathway. Importantly, in vivo results demonstrated that the electric field at the wound site effectively promoted wound healing, reduced inflammation, and stimulated collagen deposition and neovascularization. This study emphasizes the role of the piezoelectric membrane as an effective, safe, and battery-free electrical stimulator crucial for skin wound healing.

Regeneration and maturation of native-like endothelium is crucial for material-guided small-diameter vascular regeneration. Although parallel-microgroove-patterned (micropatterned) substrates are capable of promoting endothelial regeneration with native-like endothelial cell (EC) alignment, their unbefitting high-stiffness acutely inhibits cell–matrix interaction and endothelial maturation. Given that the sufficient softness of nanofibers allows cells to deform the local matrix architecture to satisfy cell survival and functional requirements, in this study, an effective strategy of decorating micropatterned substrate with soft nanofibers was exploited to enhance cell–matrix interaction for engineering healthy endothelium. Results demonstrated that the micropatterned nanofibrous membranes were successfully obtained with high-resolution parallel microgrooves (groove width: ~ 15 µm; groove depth: ~ 5 µm) and adequate softness (bulk modulus: 2.27 ± 0.18 MPa). This particular substrate markedly accelerated the formation and maturation of confluent native-like endothelium by synchronously increasing cell–cell and cell–matrix interactions. Transcriptome analysis revealed that compared with smooth features, the microgrooved pattern was likely to promote endothelial remodeling via integrin α5-mediated microtubule disassembly and type I interleukin 1 receptor-mediated signaling pathways, whereas the nanofibrous pattern was likely to guide endothelial regeneration via integrin α5β8-guided actin cytoskeleton remodeling. Nevertheless, endowing micropatterned substrate with soft nanofibers was demonstrated to accelerate endothelial maturation via chemokine (C-X-C motif) receptor 4/calcium-mediated actin cytoskeleton assembly. Furthermore, numerical simulation results of hemodynamics indicated the positive impact of the micropatterned nanofibers on maintaining stable hemodynamics. Summarily, our current work supports an affirmation that the micropatterned nanofibrous substrates can significantly promote regeneration and maturation of native-like endothelium, which provides an innovative method for constructing vascular grafts with functional endothelium.