Chronic diabetic foot ulcers (DFUs) remain one of the most consequential complications of diabetes, contributing to roughly 80% of nontraumatic lower-extremity amputations and carrying a five-year mortality rate that rivals many common cancers. Even with best-practice care—offloading, debridement, infection control, and vascular assessment—a substantial proportion of DFUs fail to heal within 12 weeks. This persistent treatment gap has driven sustained interest in adjunctive therapies that target one of the central biological problems of the diabetic wound: tissue hypoxia. Among these, topical oxygen therapy (TOT) has accumulated a growing body of high-quality evidence over the past decade and is now formally recognized in international guidelines.
Why Oxygen Matters in the Diabetic Wound
Wound healing is an oxygen-dependent process. Oxygen drives collagen synthesis, supports neutrophil oxidative killing of bacteria, promotes angiogenesis, and is required for fibroblast proliferation and epithelial migration. In diabetic patients, peripheral arterial disease, microvascular dysfunction, and tissue edema combine to produce a chronically hypoxic wound bed, often with transcutaneous oxygen pressures well below the threshold needed for healing. Topical oxygen therapy—delivered as continuous diffusion of oxygen (CDO) or as cyclical pressurized oxygen (such as the TWO2 device)—aims to raise local oxygen tension at the wound surface without requiring a hyperbaric chamber.
Evidence from Randomized Controlled Trials
Two pivotal sham-controlled, double-blind RCTs anchor the modern evidence base. Niederauer and colleagues (2018) randomized 146 patients with DFUs to active CDO or an identical placebo device. Healing rates were significantly higher in the CDO group (32.4% vs 16.7%, p=0.033), and time to 50% wound area reduction was almost halved (18.4 vs 28.9 days, p=0.001). The treatment effect was greatest in larger, more chronic, and weight-bearing wounds—precisely the ulcers most likely to fail conventional care.
The TWO2 study, published by Frykberg and colleagues in Diabetes Care in 2020, was a multinational, multicenter, double-blind RCT of cyclical pressurized topical oxygen as an adjunct to optimal standard care in refractory DFUs. At 12 weeks, 41.7% of ulcers in the active arm closed compared with 13.5% in the sham arm (odds ratio 4.57, p=0.010). The benefit persisted at one year, with 56% of active-arm ulcers closed compared with 27% of sham-arm ulcers (p=0.013). Importantly, all participants received best-practice offloading and wound care, indicating that topical oxygen offered additive benefit on top of guideline-based therapy.
Systematic Reviews and Meta-Analyses
Recent pooled analyses are broadly concordant. Thanigaimani and colleagues (2021) synthesized data from multiple trials and reported that topical oxygen significantly increased the likelihood of DFU healing, although effects on amputation and cost-effectiveness remained uncertain. A 2022 systematic review and meta-analysis by Sun and colleagues, focused on cyclical topical wound oxygen, similarly found a significant healing advantage in chronic DFUs. A broader 2024 meta-analysis by Putri and colleagues in the International Wound Journal, encompassing both RCTs and observational studies, again reported improved healing rates with topical oxygen across diverse wound types, including diabetic ulcers.
Heterogeneity remains a real limitation. Trials differ in oxygen delivery modality (continuous vs cyclical, pressurized vs ambient), duration of therapy, definitions of healing, and patient selection. Risk-of-bias assessments in the 2023 IWGDF systematic review classified one trial as low risk and three as having some risk, reflecting the early state of methodologic standardization in this field.
Guideline Recommendations
The 2023 update of the International Working Group on the Diabetic Foot (IWGDF) guidelines, published by Chen and colleagues in Diabetes/Metabolism Research and Reviews in 2024, issued a conditional supportive recommendation for the use of topical oxygen therapy as an adjunct in DFUs that have not healed despite best standard care. The same guideline gave conditional support to several other adjuncts, including sucrose octasulfate dressings, negative pressure wound therapy for postoperative wounds, placental-derived products, autologous leucocyte/platelet/fibrin patches, and hyperbaric oxygen. The IWGDF emphasized that adjuncts should be reserved for ulcers failing to progress with optimal standard care and used only where resources permit.
Clinical Takeaways
The current evidence supports topical oxygen therapy as a reasonable adjunct for hard-to-heal, non-ischemic or moderately ischemic DFUs that are not progressing despite offloading, debridement, infection control, and glycemic optimization. The most consistent benefits have been demonstrated in chronic Wagner grade 1–2 ulcers. Patient selection, adherence to home-based protocols, and continuation of all foundational wound care principles remain essential. Topical oxygen does not replace standard care, vascular evaluation, or treatment of infection—it complements them. As trial methodology matures and longer-term outcomes (amputation rates, recurrence, cost-effectiveness) accumulate, the precise place of topical oxygen in the DFU treatment hierarchy will continue to come into sharper focus.
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.
- Niederauer MQ, Michalek JE, Liu Q, Papas KK, Lavery LA, Armstrong DG. Continuous diffusion of oxygen improves diabetic foot ulcer healing when compared with a placebo control: a randomised, double-blind, multicentre study. Journal of Wound Care. 2018;27(Sup9):S30–S45.
- 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.
- Thanigaimani S, Singh T, Golledge J. Topical oxygen therapy for diabetes-related foot ulcers: A systematic review and meta-analysis. Diabetic Medicine. 2021;38(8):e14585.
- Sun X, Wang X, Zhao Z, et al. Efficacy of Topical Wound Oxygen Therapy in Healing Chronic Diabetic Foot Ulcers: Systematic Review and Meta-Analysis. Advances in Wound Care. 2022.
- Putri IL, Pramanasari R, Wungu CDK, et al. The efficacy of topical oxygen therapy for wound healing: A meta-analysis of randomized controlled trials and observational studies. International Wound Journal. 2024;21(3):e14960.
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