Topical oxygen therapy induces vascular endothelial growth factor expression and improves closure of clinically presented chronic wounds

Abstract

1. Chronic wounds, especially in diabetics, represent a serious threat to human health. 2. Correcting a compromised state of tissue oxygenation by the administration of supplemental O(2) is known to benefit wound healing. Beyond its role as a nutrient and antibiotic, O(2) supports wound healing by driving redox signaling. 3. Hyperbaric oxygen (HBO) therapy is widely used and approved by Center for Medicare and Medicaid Services to treat specific ulcerations. The current literature supports the notion that approaches to topically oxygenate wounds may be productive. 4. 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. 5. In total, 1854 patients were screened in outpatient wound clinics for non-randomized enrolments into the HBO (n = 32; 31% diabetic) and TO (n = 25; 52% diabetic) studies. 6. Under the conditions of the present study, HBO treatment seemed to benefit some wounds while not benefiting others. Overall, HBO did not result in statistically significant improvements in wound size in the given population over the time monitored in the present study. 7. However, TO significantly improved wound size. Among the three O(2)-sensitive genes (VEGF, TGFbeta1 and COL1A1) 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. There was no significant change in the expression levels of any of genes studied in patients in the HBO study. This establishes a link between VEGF gene expression and healing outcome for TO therapy. 8. Taken together, the present study provides evidence demonstrating that TO treatment benefits wound healing in patients suffering from chronic wounds. Treatment with TO is associated with an induction of VEGF expression in wound edge tissue and an improvement in wound size.

Figure 1

Wound etiology and locations for patients enrolled in the HBO and topical oxygen studies.

Figure 2. Wound closure in response to HBO treatment

Analysis of the effects of HBO on wound closure was based on a model which included the cubed root of the initial volume as a covariate and the best fit was determined to be linear using fractional polynomials. The untransformed results are shown here. The diagonally dashed line of reference represents no change in wound volume in response to treatment. Observations (black dots) on or above the dashed line represents no benefit in wound size in response to treatment. Observations plotted below the dashed line of reference represent that the treatment improved wound closure outcome. The solid line represents the linear regression model based on wound closure data. The solid line was tested to be statistically not significantly different from the reference dashed line (p-value = 0.150, R² = 0.068)

Figure 3. Wound closure in response to topical oxygen treatment

Analysis of the effects of topical oxygen on wound closure was conducted as described in the legend of Figure 2. The solid line represents the linear regression model based on wound closure data from the topical oxygen study. The solid line was tested to be significantly different from the reference dashed line (p-value < 0.001, R² = 0.414) indicating that topical oxygen treatment improved wound closure.

Figure 4. Scatter plot illustrating individual data points plotting topical oxygen induced changes in VEGF gene expression in the time period specified on the y-axis against changes in wound volume over the entire study period

Both the VEGF ratio and the wound volume ratio were log transformed. The number against each data point represent the age of the respective patient in years. a, VEGF changes during the time period T₀ (initial) to T₁ (interim); b, VEGF changes during the time period T₁ (interim) to T₂ (final); and c, VEGF changes during the time period T₀ (initial) to T₂ (final) i.e the entire study duration.

Figure 5. Scatter plot illustrating individual data points plotting changes in HBO-induced VEGF gene expression in the time period specified on the y-axis against changes in wound volume over the entire study period

Both the VEGF ratio and the wound volume ratio were log transformed. The number against each data point represent the age of the respective patient in years. a, VEGF changes during the time period T₀ (initial) to T₁ (interim); b, VEGF changes during the time period T₁ (interim) to T₂ (final); and c, VEGF changes during the time period T₀ (initial) to T₂ (final) i.e the entire study duration.