Table 3.

Common nucleic acids used in wound healing studies by VVDM and nVVDM

Nucleic acids	Delivery mode	Wound model	Results	References
VEGF	Recombinant adenovirus vector	Excisional wounds of streptozotocin-induced diabetic mice.	Significantly accelerate wound closure; promote angiogenesis.	[73]
	rAAV vectors	Full-thickness excisional skin wound in diabetic mice.	Accelerated stimulation of angiogenesis, reepithelization, synthesis and maturation of extracellular matrix.	[74,75]
	pXC1 containing adenovirus type 5 sequences and a Rous sarcoma virus promoter	Full-thickness excisional wounds (1. 4 cm in diameter) in 8-week-old db/db mice.	Accelerate wound closure by stimulating angiogenesis, epithelialization and collagen deposition.	[76]
	Adenovirus vector Electroporation Cationic polymers, (N,N,N-TMC) Copolymer-protected gene vectors	Full-thickness excisional skin wounds (3–5 mm diameter) in 10-week-old db/db mice. Rat skin flap model. Full-thickness excisional skin wounds (3 cm diameter) in a porcine model. Full-thickness excisional skin wounds (12 mm diameter) in 6–8-week-old db/db mice.	Enhanced angiogenesis and lymphangiogenesis; significantly accelerated wound healing. Significantly increased the expression of VEGF. Significant increase in the number of newly-formed and mature vessels and the fastest dermal regeneration; increased the tensile strength of the repaired tissue. The transient release of VEGF up to 3 weeks; promoted the formation of blood vessels.	[77] [95] [98] [99]
FGF4-VEGF PDGF-BB HGF Ang1	AAV vector Adenovirus vector Adenovirus vector rAAV vectors	Full-thickness excisional skin wounds (4 mm diameter) in 14-week-old db/db mice. Full-thickness excisional skin wounds (8 mm diameter) in db/db mice. Skin flap transplantation model in Sprague–Dawley rats. Incisional skin wound in 14-week-old db/db mice.	Significantly increased granulation tissue formation, vascularity and dermal matrix deposition. Enhance wound healing, improve neovascularization and recruit EPCs to the epithelial wound. Improve the survival rate of flap; both the number of CD31-positive vessels and the expression of VEGF were significantly increased. Improved the healing process, stimulate reepithelization and collagen maturation, increase breaking strength and significantly augment the number of new vessels.	[77] [79] [80][81]
eNOS HIF-1α TGF-β1 IGF-I—KGF	Adenoviral vector in a fibrin scaffold Electroporation Pegylated poly-l-lysine (PLL-g-PEG) polymer Electroporation Liposome gene transfer	Full-thickness excisional skin wounds (6 mm diameter) on the ear of New Zealand white rabbits. Full-thickness excisional skin wounds (5 mm diameter) in db/db mice. Full-thickness excisional skin wounds (10 mm diameter) in Sprague–Dawley rats Full-thickness excisional skin wounds (7 × 7 mm) in db/db mice Full-thickness scald burn on back of Sprague–Dawley rats	Enhanced eNOS expression, inflammatory response, and increased the rate of re-epithelialization. Up-regulated the expressions of VEGF, PGF, PDGF and angiopoietin and promoted the epithelization of the wound surface and angiogenesis. Transiently induced gene expression of angiogenesis-related genes Acta2, Pecam1 and VEGF; enhance the number endothelial cells and smooth muscle cells Promoted epithelial regeneration, granulation tissue formation, angiogenesis. Increase the concentration of VEGF, thereby increasing the formation of new blood vessels; improved epidermal regeneration	[85] [93] [101] [94] [105]

VEGF vascular endothelial growth factor receptor, rAAV recombinant adeno-associated virus, HIF-1 hypoxia-inducible factor-1, HGF hepatocyte growth factor, nVVDM non-viral vector delivery system, TMC trimethyl chitosan chloride, FGF fibroblast growth factor, Ang1 angiopoietin-1, eNOS endothelial nitric oxide synthase, TGF transforming growth factor, IGF insulin-like growth factor, KGF keratinocyte growth factor