Dual gene‐activated dermal scaffolds regulate angiogenesis and wound healing by mediating the coexpression of VEGF and angiopoietin‐1

The vascularization of dermal substitutes is a key challenge in efforts to heal deep skin defects. In this study, dual gene‐activated dermal scaffolds (DGADSs‐1) were fabricated by loading nanocomposite particles of polyethylenimine (PEI)/multiple plasmid DNAs (pDNAs) encoding vascular endothelial growth factor and angiopoietin‐1 at a ratio of 1:1. In a similar manner, DGADSs‐2 were loaded with a chimeric plasmid encoding both VEGF and Ang‐1. In vitro studies showed that both types of DGADSs released PEI/pDNA nanoparticles in a sustained manner; they demonstrated effective transfection ability, leading to upregulated expression of VEGF and Ang‐1. Furthermore, both types of DGADSs promoted fibroblast proliferation and blood vessel formation, although DGADSs‐1 showed a more obvious promotion effect. A rat full‐thickness skin defect model showed that split‐thickness skin transplanted using a one‐step method could achieve full survival at the 12th day after surgery in both DGADSs‐1 and DGADSs‐2 groups, and the vascularization time of dermal substitutes was significantly shortened. Compared with the other three groups of scaffolds, the DGADSs‐1 group had significantly greater cell infiltration, collagen deposition, neovascularization, and vascular maturation, all of which promoted wound healing. Thus, compared with single‐gene‐activated dermal scaffolds, DGADSs show greater potential for enhancing angiogenesis. DGADSs with different loading modes also exhibited differences in terms of angiogenesis; the effect of loading two genes (DGADSs‐1) was better than the effect of loading a chimeric gene (DGADSs‐2). In summary, DGADSs, which continuously upregulate VEGF and Ang‐1 expression, offer a new functional tissue‐engineered dermal substitute with the ability to activate vascularization.