TOPICAL OXYGEN THERAPY INDUCES VASCULAR ENDOTHELIAL GROWTH FACTOR EXPRESSION AND IMPROVES CLOSURE OF CLINICALLY PRESENTED CHRONIC WOUNDS

Chronic wounds, especially in diabetics, represent a serious threat to human health. Correcting a compromised state of tissue oxygenation by the administration of supplemental O2 is known to benefit wound healing. Beyond its role as a nutrient and antibiotic, O2 supports wound healing by driving redox-signaling. HBO (hyperbaric oxygen) therapy is widely used and approved by CMS to treat specific ulcerations. The current literature supports that approaches to topically oxygenate wounds may be productive. Here, we present the results of two simultaneous studies testing the effects of HBO and portable topical oxygen (TO) therapies. These two therapeutic approaches have several contrasting features. A total of 1854 patients were screened in outpatient wound clinics for non-randomized enrollments into the HBO (n=32, 31% diabetic) and TO (n=25, 52% diabetic) studies. Under the conditions of the current study, HBO treatment seemed to benefit some wounds while not benefiting the others. Overall, HBO did not result in statistically significant improvements in wound size in the given population over the time monitored in this study. TO significantly improved wound size. Among the three (VEGF, TGFβ1 and COL1A1) O2-sensitive genes studied in wound-edge tissue biopsies, TO treatment was associated with higher VEGF165 expression in healing wounds. Expression of the other genes mentioned was not affected by TO. All of the genes studied did not significantly change in expression in patients of the HBO study. This work establishes a link between VEGF gene expression and healing outcome for TO therapy. Taken together, this report presents evidence demonstrating that TO treatment benefits wound healing in patients suffering from chronic wounds. TO treatment is associated with induction in VEGF expression in the wound edge tissue and improvement in wound size. Keywords: redox, wound therapy, wound care, tissue repair, wound patient, topical therapeutics, skin, translational research Introduction Hypoxia, caused by disrupted vasculature as well as complicating vasculopathies and other systemic limitations, limits wound healing. Correcting a compromised state of tissue oxygenation by the administration of supplemental O2 benefits wound healing in the peri-operative and outpatient settings 1. Clinical trials have shown that keeping patients warm and administering supplemental O2, both of which enhance wound oxygenation, decreases the rate of wound infection in surgical patients and shortens the average length of hospitalization 2,3. Beyond its role as a nutrient and antibiotic, O2 supports wound healing by driving redox-sensitive gene expression and signal transduction which influences a wide array of healing responses 4–6. Clinical use of O2 to promote wound healing began in the 1960’s with administration of systemic HBO to treat wounds 7. Today, HBO therapy is approved by the Center for Medicare and Medicaid Services in the United States to treat specific ulcerations. Our own laboratory has noted beneficial effects of HBO therapy in restoring wound healing that was impaired by psychological stress8. Encouragingly, recent reports have demonstrated that HBO therapy may mobilize bone marrow-derived endothelial progenitor cells which could benefit the healing of chronic wounds affected by diabetes and peripheral arterial disease 9. On the down side, HBO poses the threat of oxygen toxicity in specific cases 10–12. This risk may be managed by adopting a personalized approach for HBO therapy where the treatment specifically aims at addressing wound hypoxia on a case by case basis. Although HBO is a clearly promising mode of wound therapy, it requires extensive facilities which may not be available to all patients. Furthermore, a population of wound patients may simply not qualify or consent to receive HBO therapy. The approach to topically oxygenate wounds using a variety of approaches is distinct from the conventional HBO therapy in many ways. For example, topical approaches do not involve high pressure, are not systemic in nature and therefore do not pose the uncommon risk of systemic oxygen toxicity 13. The hypothesis that wounds may benefit when oxygenated topically is supported by the current literature13–16. Among many known growth factors, VEGF is believed to be the most prevalent, efficacious and long-term signal that is known to stimulate angiogenesis in wounds 17. This work represents the side-by-side presentation from the result of two simultaneous studies testing the effects of HBO therapy and topical oxygen (TO) therapy, respectively. The goals were to examine changes in wound closure outcomes and in the expression of oxygen-sensitive genes including VEGF in biopsies collected from the wound-edge tissue.