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

Abstract

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.

Growth factors and growth factor gene therapies for treating chronic wounds

“… 152 , 153 One study demonstrated increased angiogenesis in a rat full‐thickness wound model treated with gene‐activated dermal scaffolds loaded with PEI/plasmid DNAs encoding VEGF and angiopoietin‐1, compared to scaffolds loaded with plasmid VEGF alone or with the plasmid VEGF/angiopoietin‐1 chimeric plasmid alone. 130 In another study, Wang et al concluded accelerated wound healing, as evidenced by increased angiogenesis and decreased inflammation, in a splinted excisional burn wound model, when the wound was treated with a hydrogel scaffold loaded with resveratrol and PEI/plasmid DNA encoding VEGF (Figure 5a,b ). 125 Despite these promising features, the high cationic charge density of PEI can result in cytotoxicity that originates from cell membrane disruption through electrostatic interactions.…”

Biomaterials for immunomodulation in wound healing

“…In a rat full-thickness skin defect model, they demonstrated that these DGADSs led to significantly increased fibroblast infiltration, collagen deposition and neovascularization, accompanied by maturation of the vascular network. Hence, DGADSs show promise in facilitating the vascularization of functional tissue-engineered dermal substitutes for applications in wound repair [ 75 ].…”

Advances in skin gene therapy: utilizing innovative dressing scaffolds for wound healing, a comprehensive review

“…According to the findings, the dual gene delivery method accelerates the healing of skin injuries by promoting angiogenesis and dermal tissue regeneration in a rat skin defect model. 40–42…”