Topical Oxygen Therapy for Diabetic Foot Ulcers: A Review of the Current Evidence
Diabetic foot ulcers (DFUs) remain one of the most consequential complications of diabetes mellitus, affecting roughly one in three people with diabetes during their lifetime and preceding the majority of non-traumatic lower-limb amputations. Despite optimal standard care — debridement, offloading, infection control, glycaemic optimisation, and revascularisation when indicated — a substantial proportion of DFUs fail to heal within 12 weeks. Over the past decade, topical oxygen therapy (TOT) has emerged as one of the better-studied adjunctive modalities for these refractory wounds, and the 2023 update to the International Working Group on the Diabetic Foot (IWGDF) wound-healing guideline now provides a conditional positive recommendation for its use.
Why Oxygen Matters in Diabetic Wound Healing
Wound repair is highly oxygen-dependent. Adequate tissue oxygen tension is required for collagen synthesis, angiogenesis, fibroblast proliferation, and the oxidative burst that allows neutrophils to kill bacteria. In people with diabetes, the wound bed is often hypoxic because of microvascular disease, peripheral arterial disease, glycation-related changes in haemoglobin oxygen affinity, and the metabolic demands of chronic inflammation. Localised hypoxia stalls healing at the inflammatory phase and is associated with persistent biofilm and wound chronicity (Sen, Advances in Wound Care, 2019).
Hyperbaric oxygen therapy (HBOT) raises systemic oxygen delivery but requires a specialised chamber, carries risk in patients with certain cardiac and pulmonary conditions, and is logistically demanding. Topical oxygen therapy was developed as a wound-bed-targeted alternative: pure oxygen is delivered directly to the ulcer at the bedside or in the home, often through a sealed chamber, a sleeve, or a small portable diffusion device.
Modalities of Topical Oxygen Delivery
Three principal TOT delivery formats are studied in the literature. Continuous diffusion of oxygen (CDO) systems use a small portable concentrator to deliver low-flow oxygen continuously through a tube into a sealed dressing. Cyclical pressurised topical wound oxygen (TWO2) systems intermittently pressurise an extremity chamber with humidified oxygen. Higher-flow chamber-based systems deliver short pressurised oxygen treatments in a clinic setting. Each system raises peri-wound and wound-bed oxygen tension, but evidence quality varies by device and study (Carter et al., Advances in Wound Care, 2023).
Evidence from Randomised Controlled Trials
The most rigorous evidence comes from the TWO2 Study, a multinational, multicentre, randomised, double-blind, placebo-controlled trial published by Frykberg and colleagues in Diabetes Care (2020). Two hundred and twenty patients with chronic, non-healing DFUs received standard care plus either active cyclical pressurised topical oxygen or a sham device for 12 weeks. At 12 weeks, complete wound closure was achieved in 41.7% of the active arm versus 13.5% of the sham arm. At 12 months, 56% of active-arm ulcers were closed compared with 27% in the sham arm (P = 0.013), suggesting a durable healing benefit rather than a short-term effect alone.
A subsequent multicentre, open-label randomised trial of continuous diffusion oxygen reported by Serena and colleagues in the Journal of Wound Care (2021) found 12-week closure in 44.4% of patients receiving standard care plus TOT versus 28.1% with standard care alone. A 2023 systematic review and meta-analysis by Carter, Frykberg, Oropallo, Sen, Armstrong, Nair and Serena pooled the available randomised evidence and confirmed that adjunctive TOT significantly increased the probability of wound closure compared with standard care, with a favourable safety profile and no increase in adverse events.
The 2023 IWGDF Guideline Position
The IWGDF 2023 update on interventions to enhance healing of foot ulcers in people with diabetes (Chen et al., Diabetes/Metabolism Research and Reviews, 2024) reviewed the available evidence and issued a conditional positive recommendation for topical oxygen therapy as an adjunct to best standard of care in non-healing DFUs. The guideline panel emphasises three caveats. First, TOT is an adjunct, not a replacement for offloading, debridement, infection control, and vascular assessment. Second, it should be considered in wounds that have failed to progress on best standard care for several weeks. Third, evidence is strongest for cyclical pressurised and continuous diffusion systems, and the panel notes ongoing uncertainty about which patient subgroups benefit most.
Practical Clinical Considerations
Patient selection appears to matter. Most randomised data are in Wagner grade 1 and 2 ulcers without untreated critical limb ischaemia or active deep infection. Adequate macrocirculation should be confirmed before initiating TOT, because oxygen delivered topically cannot compensate for an occluded inflow vessel. Adherence is also important: continuous diffusion systems generally require daily home use, while pressurised systems require structured treatment cycles.
Conclusion
Topical oxygen therapy has moved from an experimental adjunct to a guideline-supported option for selected non-healing diabetic foot ulcers. Randomised and meta-analytic evidence suggests meaningful improvements in wound closure rates at 12 weeks and, in the case of cyclical pressurised therapy, sustained benefit at one year. Like all advanced wound therapies, TOT performs best when integrated with optimal offloading, sharp debridement, infection management, vascular assessment, and metabolic control. Clinicians and patients evaluating its use should base decisions on wound characteristics, comorbidities, and access to specific delivery systems rather than on TOT alone.
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;12(1):1–16.
- 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.
- Sen CK. Human wound and its burden: updated 2020 compendium of estimates. Advances in Wound Care. 2019;8(2):39–48.
- Edmonds M, Lazaro-Martinez JL, Alfayate-Garcia JM, et al. Sucrose octasulfate dressing versus control dressing in patients with neuroischaemic diabetic foot ulcers (Explorer): an international, multicentre, double-blind, randomised, controlled trial. The Lancet Diabetes & Endocrinology. 2018;6(3):186–196.
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