Prevention of distal flap necrosis in a rat random skin flap model by gene electrotransfer delivering VEGF₁₆₅plasmid

Abstract

Background Therapeutic delivery of angiogenic growth factors is a promising approach for treating ischemia observed in skin flaps and chronic wounds.Several studies have demonstrated that vascular endothelial growth factor(VEGF) helps mitigate skin flap necrosis by facilitating angiogenesis. The present study aimed to demonstrate an electrically-mediated nonviral gene delivery approach using a non-invasive multi-electrode array (MEA) for effective treatment of ischemic skin flaps.Methods We used a standard random dorsal skin flap model in rats. The study aimed to determine the optimal treatment sites on the skin flap, optimal plasmid dose and timing of the treatment for preventing distal flap necrosis.Results We determined that two treatment sites on the ischemic flap with a plasmid dose of 50-100 μg per treatment site proved adequate to prevent 95% flap necrosis, and that this was significantly better than the no treatment or injection only group. A 2-day window was critical to deliver the VEGF to achieve flap survival and prevent necrosis. Histological examination demonstrated minimal electro transfer associated tissue damage.Conclusions Our results demonstrate that MEA can be used as a non-invasive physical gene delivery method for plasmid VEGF, resulting in a significant reduction of necrosis in ischemic wounds. We propose that this method could be translated into a potential therapeutic approach to deliver growth factors to prevent ischemia in cases of chronic wounds, burns and skin flap necrosis.

Aging effects on pedicled fasciocutaneous flap survival in rats

“…Given the high levels of activated Caspase‐3, cleaved PARP‐1 and elevated Bax:Bcl‐2 ratio in the older rats, it seems that aging also results in a higher susceptibility to cell death after ischemic injury because of lower baseline VEGF receptor signaling levels leading to unhindered activation of the apoptotic pathways. This helps to explain the results of studies showing that subdermal VEGF administration improves the survival rate of ischemic skin flaps …”

“…This helps to explain the results of studies showing that subdermal VEGF administration improves the survival rate of ischemic skin flaps. [32][33][34] VEGF may not be solely responsible for accelerated tissue repair. Circulating levels and mobilization of other cytokines and growth factors (eg, basic fibroblast growth factor, platelet-derived growth factor, transforming growth factor beta, interleukins) into the flap areas as well as a balance of matrix metalloproteinases and tissue inhibitor of metalloproteinase expression play accompanying roles in regulating anti-apoptotic, proliferative, migratory, and proangiogenic activities of wound-bed cells.…”

Effects of Muscone on Random Skin Flap Survival in Rats

“…18 In the random skin flap model, application of VEGF improved flap survival through increasing angiogenesis and blood supply to the flap. 19,20 In our previous research, we found that traditional Chinese medicines, such as Huáng Qí injection and vinpocetine, have positive effects to promote the survival of random skin flap as well as stimulate the expression of VEGF. 21,22 In the present study, muscone also improved VEGF expression in the random skin flap model.…”

Thermal Assisted In Vivo Gene Electrotransfer

“…GET of skin is a simple and direct method for gene therapy and can be accomplished in a minimally invasive way. Several approaches with potential therapeutic or prophylactic applications have been evaluated including wound healing [16-18], ischemia [19-21], infectious disease vaccines [22-25] and cancer vaccines and therapies [5, 8, 26]. To date, sixty-eight clinical trials are being enrolled, are ongoing, or are completed using GET (clinicaltrials.gov “electroporation”, “electrotransfer”).…”