Chronic diabetic foot ulcers (DFUs) remain one of the most consequential complications of diabetes mellitus. Even with appropriate offloading, debridement, infection control, and glycemic management, a substantial proportion of ulcers fail to close within 12 weeks of best standard care. Tissue hypoxia is a defining feature of these wounds, and over the past decade topical oxygen therapy (TOT) has emerged as an adjunctive intervention designed to address that hypoxia directly. The 2023 update of the International Working Group on the Diabetic Foot (IWGDF) guidelines now includes a conditional recommendation supporting its use in selected non-healing wounds.
Why Oxygen Matters in the Diabetic Wound
Oxygen drives many of the cellular processes that move a wound from inflammation toward closure: collagen synthesis, fibroblast proliferation, keratinocyte migration, angiogenesis, and the oxidative burst that helps resist bacterial colonization. In diabetic feet, microvascular disease, peripheral arterial disease, and biochemical changes at the wound bed combine to lower local tissue oxygen tension well below the thresholds required for these processes — even when palpable pulses are present. Persistent hypoxia stalls the healing cascade, suppresses extracellular matrix production, and impairs reepithelialization (Zhao et al., Science Advances, 2021).
Topical oxygen therapy delivers concentrated oxygen directly to the wound surface through a chamber, sleeve, or portable patch. Unlike hyperbaric oxygen, which requires a pressurized chamber and a hospital-based program, most TOT systems can be administered at home, often as overnight or continuous low-flow therapy. The two are mechanistically distinct and should not be conflated.
What the Clinical Trials Show
The TWO2 Study
The most influential randomized trial to date is the multinational, double-blind, sham-controlled TWO2 study published in Diabetes Care in 2020 (Frykberg et al.). Patients with chronic, non-healing DFUs that had failed to respond to standard care were randomized to either cyclical pressurized topical wound oxygen plus standard care or sham therapy plus standard care. At 12 weeks, 41.7% of ulcers in the active arm achieved complete closure compared with 13.5% in the sham arm (OR 4.57; 97.8% CI 1.19–17.57; p = 0.010). The advantage persisted at 12 months, with 56% closure in the active arm versus 27% in the sham arm (p = 0.013).
Multicenter Open-Label RCT
A separate multicentre, open-label, community-based RCT of 145 patients with IDSA grade 1–2 or Wagner grade 1–2 ulcers reported a healing rate of 44.4% with continuous TOT plus standard care versus 28.1% with standard care alone at 12 weeks (p = 0.044) (Serena et al., Journal of Wound Care, 2021).
Systematic Reviews and Meta-Analyses
A 2023 systematic review and meta-analysis in Advances in Wound Care (Carter, Frykberg, and colleagues) concluded that adjunctive TOT improves the likelihood of healing by approximately 60% at 12 weeks compared with standard care alone, with no signal of increased adverse events. A 2024 meta-analysis in the International Wound Journal (Putri et al.) reported a relative risk for healing of 1.63 (95% CI 1.33–2.00) favoring TOT, again without measurable increases in safety events. Larger ulcers (≥3–4 cm²) appeared to derive the greatest benefit.
Where Topical Oxygen Fits in Clinical Practice
The IWGDF 2023 wound healing guideline (Chen et al., Diabetes/Metabolism Research and Reviews, 2024) emphasizes that adjunctive therapies — including TOT, hyperbaric oxygen, sucrose octasulfate dressings, and autologous leucocyte/platelet/fibrin patches — should be reserved for ulcers that are not progressing despite optimal standard care. Foundational management still comes first: pressure offloading, sharp debridement, infection control, vascular assessment, and metabolic optimization. TOT is best understood as a targeted intervention for wounds whose physiology has stalled in a hypoxic state, not as a replacement for the basics of diabetic wound care.
The current evidence base does have limitations. Many trials are small or open-label, blinding is difficult given the visible nature of the devices, and study populations vary widely in ulcer chronicity, depth, and vascular status. Nevertheless, the consistency of effect across independent trials and meta-analyses has been sufficient to move TOT from experimental to guideline-supported.
Key Clinical Takeaways
Topical oxygen therapy addresses the physiological hypoxia that characterizes chronic diabetic foot ulcers. Randomized trials and meta-analyses suggest that adding TOT to optimal standard care increases the likelihood of complete healing at 12 weeks by roughly 50–60%, with a favorable safety profile. The 2023 IWGDF guidelines recommend it as a conditional adjunctive option for non-healing ulcers when standard care has failed and resources allow. Topical oxygen is not interchangeable with hyperbaric oxygen, and it is not a substitute for offloading, debridement, infection control, or revascularization when indicated.
References
- Frykberg RG, Franks PJ, Edmonds M, et al. A Multinational, Multicenter, Randomized, Double-Blinded, Placebo-Controlled Trial to Evaluate the Efficacy of Cyclical Topical Wound Oxygen (TWO2) Therapy in the Treatment of Chronic Diabetic Foot Ulcers: The TWO2 Study. Diabetes Care. 2020;43(3):616–624.
- Serena TE, Bullock NM, Cole W, et al. Topical oxygen therapy in the treatment of diabetic foot ulcers: a multicentre, open, randomised controlled clinical trial. Journal of Wound Care. 2021;30(Sup5):S7–S14.
- Carter MJ, Frykberg RG, Oropallo A, Sen CK, Armstrong DG, Nair HKR, Serena TE. Efficacy of Topical Wound Oxygen Therapy in Healing Chronic Diabetic Foot Ulcers: Systematic Review and Meta-Analysis. Advances in Wound Care. 2023.
- Chen P, Vilorio NC, Dhatariya K, et al. Guidelines on interventions to enhance healing of foot ulcers in people with diabetes (IWGDF 2023 update). Diabetes/Metabolism Research and Reviews. 2024;40(3):e3644.
- Zhao D, Su Y, Xia D, et al. Sustained oxygenation accelerates diabetic wound healing by promoting epithelialization and angiogenesis and decreasing inflammation. Science Advances. 2021;7(36):eabj0153.
- Putri IL, Adzalika LB, Pramanasari R, Wungu CDK. The efficacy of topical oxygen therapy for wound healing: A meta-analysis of randomized controlled trials and observational studies. International Wound Journal. 2024;21(6):e14960.
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