By Windy Cole, DPM
When you think back to your early studies in General Biology you may recall memorizing the steps of the Krebs Cycle. It is through this process of aerobic respiration that most living things generate energy. In aerobic organisms, cells utilize oxygen (O2) as a final electron acceptor to synthesize high-energy adenosine triphosphate (ATP) from adenosine diphosphate (ADP). This ATP is what fuels most cellular processes. Wounded tissues exhibit an increased energy demand leading to a hypermetabolic state.1 Therefore, wound healing is heavily reliant on attaining adequate levels of oxygenation within the injured tissues. Oxygen is essential to multiple wound healing processes including oxidative killing of bacteria, cellular signaling and proliferation, collagen deposition, and angiogenesis.2
The Antimicrobial Effects of Oxygen
Oxygen is a necessary component for control of bacterial burden during the inflammatory phase of wound healing. After tissue injury has occurred, chemical signals such as histamine are released. These stimuli induce migration of monocytes and neutrophils into the wound site. These cells then produce reactive oxygen species (ROS) by the process of a respiratory burst. ROS are responsible for the oxidative killing of bacteria that protects the wound from infection.2 Without adequate local tissue oxygenation, the respiratory burst is impaired, resulting in increased susceptibility to infection. Hohn et al conducted a study in which they determined that skin wounds of rabbits exposed to air containing low oxygen concentrations had more elevated levels of Staphylococcus Aureus than skin wounds of rabbits exposed to air containing high levels of oxygen.3 Local tissue oxygen levels are a determining factor in the microbial contamination of wound tissues.
Growth Factor Regulation
ROS in low levels plays a role in both cellular signaling and growth factor release. Growth factors use various mechanisms such as fibroblast migration and keratinocyte proliferation to stimulate healing. Acute hypoxia stimulates growth factor production, but chronic hypoxia inhibits or eliminates it.4 Siddiqui and colleagues investigated the proliferation of fibroblasts in varying environments. They compared cells grown in a hypoxic environment (1% O2) vs standard culture conditions (20% O2). The results of the study showed cell proliferation was 3 times slower with exposure to 1% oxygen versus 20% oxygen. The investigators concluded that chronically low levels of local oxygen were detrimental to growth factor production and led to decreases in fibroblast proliferation.5
Fibroblasts are responsible for the synthesis of collagen fibers. Collagen is the most abundant protein produced in the human body. Deposition of collagen is a fundamental step in the wound healing process as it provides a natural scaffold or substrate for new tissue growth. The formation of the collagen triple helix is O2 dependent. Without the triple helix, procollagen is non-functional. It is these extracellular cross-linkages that are ultimately responsible for the tensile strength needed in prolonged wound healing.6 Hunt and colleagues used a rabbit model to track the rate and density of collagen formation with changes in oxygen levels. The results demonstrated that exposure to hyperoxic environments accelerated collagen synthesis.6
The formation of new blood vessels, or angiogenesis, is critical in wound healing. This neovascularization provides channels for active cells, nutrients and O2 to travel to the wounded tissues. Vascular endothelial growth factor (VEG-F) is a major angiogenic stimulus. Initially, hypoxia acts as a stimulus to VEG-F. However, prolonged hypoxia inhibits VEG-F formation and function and obstructs neovascularization.7 Topical oxygen therapy has been shown to increase both VEG-F levels as well as angiogenesis.
A 2008 study by Gordillo et al evaluated outcomes in 1,854 outpatient wound clinic patients who were screened for non-randomized enrollment into either hyperbaric oxygen therapy treatment (HBOt) or topical oxygen (TO) for the treatment of their chronic wounds. The investigators determined that there were no significant changes in wound measurements in the HBOt patient group. However, the TO treatment group did exhibit a noticeable decrease in overall wound dimensions. Tissue biopsies were obtained from wounds in both treatment arms. There was an increase in VEG-F found within the TO group. Overall, the investigators concluded that TO showed better wound healing benefits compared to HBO.7
It has been the author’s experience that continuous topical oxygen therapy (cTOT) offers an effective non-invasive chronic wound treatment that may speed healing by improving microcirculation and oxygenated hemoglobin as demonstrated by the case in Figures 1 and 2.
Case Patient: 85 y.o. male with a left lower leg venous ulcer of 62-weeks duration; ABI: 1.07
Past Medical History: Peripheral Vascular Disease; Venous Insufficiency; Venous Stasis Dermatitis; Non-Insulin Dependent Diabetes Mellitus; Degenerative Joint Disease; Hypertension
Previous failed wound therapies: Alginate; Foam and Compression Dressings; Iodine; Silver Dressing; Collagen; Medihoney; Santyl
Oxygen is an important biomarker when determining a wound’s ability to heal. As demonstrated above, oxygen is essential for all phases of wound healing. The oxygen gradient in wounded tissue is unequal. Supply may not meet demand. This is especially true in patients suffering from small vessel disease. Although the etiology of non-healing chronic wounds is multi-factorial, hypoxia is a common component in a vast majority of cases. Chronic wounds continue to pose a challenge to clinicians. For many years hyperbaric oxygen therapy (HBOt) has been employed to deliver high-pressure 100% oxygen to the tissue in the hopes of increasing wound oxygenation. HBOt relies on adequate arterial perfusion in order to transfer oxygen to the wounded tissue. The advent of newer technologies can now enable small, portable battery-powered oxygen generators to allow cTOT to be applied directly to the wound base at normospheric pressure. cTOT is a novel treatment that could prove to be a more cost-effective alternative to HBOt as it may potentially be applied to a broader cross-section of patients, including some that may not be eligible for HBOt.
Windy Cole, DPM, serves as Medical Director of the Wound Care Center, University Hospitals Ahuja Medical Center and Adjunct Professor and Director of Wound Care Research at Kent State University College of Podiatric Medicine, both in Cleveland, Ohio. She is a dedicated healthcare advocate with interests focused on medical education, diabetic foot care, wound care, limb salvage, clinical research and humanitarian efforts. Dr. Cole has published extensively on these topics and is a sought-after speaker both nationally and internationally. Dr. Cole also serves as a member of the Editorial Advisory Board for LER.
- Tandara AA, Mustoe TA. Oxygen in wound healing–more than a nutrient. World J Surg. 2004;28(3):294–300.
- Rodriguez PG, Felix FN, Woodley DT, Shim EK. The role of oxygen in wound healing: a review of the literature. Dermatol Surg. 2008;34(9):1159–1169.
- Hohn DC, MacKay RD, Halliday B, Hunt TK. Effect of O2 tension on microbicidal function of leukocytes in wounds and in vitro. Surg Forum. 1976;27(62):18–20. Bishop A. Role of oxygen in wound healing. J Wound Care. 2008;17(9):399–402.
- Bishop A. Role of oxygen in wound healing. J Wound Care. 2008;17(9):399–402.
- Siddiqui A, Galiano RD, Connors D, Gruskin E, Wu L, Mustoe TA. Differential effects of oxygen on human dermal fibroblasts: acute versus chronic hypoxia. Wound Repair Regen. 1996;4(2):211–218.
- Hunt TK, Pai MP. The effect of varying ambient oxygen tensions on wound metabolism and collagen synthesis. Surg Gynecol Obstet. 1972;135(4):561–567.
- Gordillo GM, Sen CK. Revisiting the essential role of oxygen in wound healing. Am J Surg. 2003;186(3):259–263.