Chronic diabetic foot ulcers are, at a cellular level, often oxygen-starved wounds. Peripheral artery disease, microvascular dysfunction, tissue oedema and the metabolic demands of infection all conspire to lower the oxygen tension in the wound bed. Because oxygen is required for collagen cross-linking, angiogenesis, epithelial migration and the oxidative burst that neutrophils use to kill bacteria, low tissue oxygen is not a passive marker of a stalled wound — it is frequently one of the reasons the wound has stalled. That logic has driven decades of interest in supplementing oxygen directly, either systemically in a pressurised chamber or locally at the wound surface. The evidence for these two approaches has matured considerably over the past ten years, and it is worth examining what it actually shows.
Hyperbaric Oxygen Therapy: A Divided Evidence Base
Hyperbaric oxygen therapy (HBOT) involves breathing 100% oxygen at pressures above atmospheric, typically for 90-minute sessions repeated daily over several weeks. The dissolved oxygen fraction in plasma rises dramatically, temporarily raising oxygen delivery to tissue that perfusion alone cannot supply.
The most methodologically rigorous negative trial remains the double-blind, sham-controlled study by Fedorko and colleagues, published in Diabetes Care in 2016. One hundred and three patients with chronic Wagner grade 2–4 ulcers received 30 sessions of either HBOT or sham. At 12 weeks, criteria for major amputation were met in 11 of 49 HBOT patients versus 13 of 54 sham patients — no meaningful difference. Healing rates were similarly indistinguishable (20% versus 22%). The authors concluded that HBOT added nothing to comprehensive wound care in this population.
Pooled analyses tell a somewhat different story. A 2025 meta-analysis by Monami and colleagues in Acta Diabetologica, prepared to inform the Italian guidelines on diabetic foot syndrome, examined 51 randomised trials of adjuvant therapies. Across the eight HBOT trials, healing rates were significantly higher than standard care, and HBOT was one of only two interventions — alongside platelet-rich plasma and fibrin — associated with a reduced risk of major amputation (odds ratio 0.28, 95% CI 0.10–0.79). That benefit came at a cost: serious adverse events were more frequent in treated patients.
The tension between a well-conducted null trial and favourable pooled estimates largely reflects patient selection. HBOT is most plausibly useful where tissue hypoxia is the limiting factor and where perfusion cannot be restored surgically. In wounds that are small, well-perfused and failing for other reasons, additional oxygen has little to offer.
Topical Oxygen Therapy: Newer, and Increasingly Supported
Topical oxygen therapy delivers oxygen to the wound surface at or near atmospheric pressure using a portable device, often in the patient’s home. It avoids the systemic risks of chamber therapy and is considerably less resource-intensive.
The pivotal trial is the multinational, double-blind, sham-controlled TWO2 study by Frykberg and colleagues, published in Diabetes Care in 2020. Patients with refractory ulcers that had failed to heal under standard care were randomised to cyclical pressurised topical wound oxygen or sham, both alongside optimal standard care. At 12 weeks, 41.7% of actively treated ulcers had closed compared with 13.5% of sham-treated ulcers. At 12 months, 56% of the active arm remained closed versus 27% of the sham arm.
A systematic review and meta-analysis by Thanigaimani, Singh and Golledge in Diabetic Medicine (2021) pooled six randomised trials involving 530 participants and found topical oxygen roughly doubled the likelihood of healing (risk ratio 1.94), with the effect holding in the subset of trials judged to be at low risk of bias. The authors were appropriately cautious: effects on amputation and cost-effectiveness remain unclear, and funnel plots raised the possibility of publication bias.
How Guidelines Position These Therapies
The 2023 International Working Group on the Diabetic Foot (IWGDF) guideline on wound-healing interventions issued conditional supportive recommendations for both hyperbaric and topical oxygen therapy. The accompanying systematic review by Chen and colleagues rated the certainty of evidence for both as low — better than the “insufficient” rating assigned to most adjunctive therapies, but well short of the moderate certainty afforded to sucrose octasulfate dressings and the autologous leucocyte, platelet and fibrin patch.
Critically, the guideline frames these as options for wounds that have failed to heal despite best standard care, and only where resources permit. Oxygen therapy is not a substitute for the foundations of diabetic foot ulcer management: adequate perfusion, sharp debridement, effective offloading, infection control and glycaemic management. A wound left to bear weight, or one with untreated critical ischaemia, will not be rescued by oxygen delivered through any route.
Clinical Summary
Both hyperbaric and topical oxygen therapy have randomised evidence supporting improved healing of chronic diabetic foot ulcers, and both carry conditional support in the current IWGDF guideline. Topical oxygen has the more consistent recent trial data and a favourable safety profile; hyperbaric oxygen has a longer track record, a signal for amputation reduction in pooled analyses, a well-documented null trial, and a higher adverse event burden. Neither is a first-line intervention. Both are best understood as adjuncts reserved for wounds that remain unhealed despite well-executed standard care, with patient selection — particularly the presence of correctable tissue hypoxia — likely determining who benefits. The overall certainty of evidence remains low, and the field continues to need larger, better-designed trials with health-economic analysis.
References
- 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.
- Chen P, Vilorio NC, Dhatariya K, et al. Effectiveness of interventions to enhance healing of chronic foot ulcers in diabetes: A systematic review. Diabetes/Metabolism Research and Reviews. 2024;40(3):e3786.
- Fedorko L, Bowen JM, Jones W, et al. Hyperbaric oxygen therapy does not reduce indications for amputation in patients with diabetes with nonhealing ulcers of the lower limb: a prospective, double-blind, randomized controlled clinical trial. Diabetes Care. 2016;39(3):392–399.
- 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.
- 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.
- Monami M, Scatena A, Ragghianti B, et al. Effectiveness of most common adjuvant wound treatments for the management of hard-to-heal diabetic foot ulcers: a meta-analysis of randomized controlled trials. Acta Diabetologica. 2025;62(7):1081–1095.
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