Oxygen is the raw material of wound repair. Fibroblast proliferation, collagen cross-linking, angiogenesis, and the oxidative burst neutrophils use to kill bacteria are all oxygen-dependent. In the diabetic foot, where peripheral arterial disease and microvascular dysfunction frequently combine to leave wound tissue hypoxic, this creates an obvious therapeutic target. Two very different technologies have been built on that premise — systemic hyperbaric oxygen therapy (HBOT), in which the patient breathes 100% oxygen inside a pressurised chamber, and topical oxygen therapy, delivered directly to the wound surface. After three decades of trials, the evidence for each is more nuanced than the underlying physiology would suggest.
What Hyperbaric Oxygen Therapy Actually Does
During HBOT, patients breathe 100% oxygen at roughly two to three times atmospheric pressure, typically for 90 to 120 minutes per session, five days a week, over several weeks. The pressure dramatically increases the amount of oxygen dissolved in plasma, raising arterial oxygen tension far beyond what haemoglobin alone can carry. Proposed mechanisms include stimulation of angiogenesis, improved leucocyte bactericidal function, reduced oedema through vasoconstriction, and mobilisation of stem progenitor cells (Benedict Mitnick and Johnson-Arbor, Clinics in Podiatric Medicine and Surgery, 2019).
HBOT is an adjunct. It does not substitute for debridement, offloading, infection control, or revascularisation. Where a wound is ischaemic because of a correctable arterial lesion, restoring blood flow remains the primary intervention.
The Randomised Evidence: Short-Term Signal, Long-Term Uncertainty
The Cochrane review of HBOT for chronic wounds pooled twelve randomised trials involving 577 participants, ten of which enrolled people with diabetic foot ulcers. Among five trials with 205 participants, HBOT increased the rate of ulcer healing at six weeks (risk ratio 2.35, 95% CI 1.19–4.62), but this benefit was no longer apparent at one-year follow-up. There was no statistically significant reduction in major amputation (risk ratio 0.36, 95% CI 0.11–1.18). The authors noted that the included trials had design and reporting flaws that limited confidence in the pooled estimates (Kranke et al., Cochrane Database of Systematic Reviews, 2015).
The largest trial in ischaemic diabetic wounds, DAMO2CLES, randomised 120 patients with diabetes and an ischaemic leg ulcer to standard care with or without HBOT. At twelve months, limb salvage was achieved in 53 of 60 HBOT patients versus 47 of 60 controls (risk difference 10%, 95% CI −4 to 23), and complete healing occurred in 30 versus 28 (risk difference 3%, 95% CI −14 to 21) — neither statistically significant. Notably, 35% of patients assigned to HBOT could not complete the treatment protocol; those who did complete it had significantly better amputation-free survival, a finding that is hypothesis-generating rather than confirmatory (Santema et al., Diabetes Care, 2018).
An overview of eleven systematic reviews applying AMSTAR-2, ROBIS, and GRADE found no high-quality evidence supporting HBOT in this population, and concluded that routine application to all diabetic foot ulcers — particularly non-ischaemic ulcers — is not supported. The authors described a potential signal for healing and amputation reduction confined to ischaemic ulcers, tempered by the low methodological quality of the underlying reviews (Wenhui et al., Diabetes Research and Clinical Practice, 2021). A more recent meta-analysis of adjuvant therapies conducted for the Italian diabetic foot guidelines pooled eight HBOT trials and reported both higher healing rates and a lower risk of major amputation (Mantel-Haenszel odds ratio 0.28, 95% CI 0.10–0.79), alongside a higher rate of serious adverse events (Monami et al., Acta Diabetologica, 2024).
How Guidelines Have Resolved the Conflict
The 2023 update of the International Working Group on the Diabetic Foot (IWGDF) wound healing guideline reflects this mixed picture with a deliberately narrow recommendation: consider hyperbaric oxygen as an adjunct in neuro-ischaemic or ischaemic diabetes-related foot ulcers where standard care alone has failed and where the resources to deliver it already exist. The recommendation is conditional and based on low-certainty evidence. The guideline does not support routine use across all diabetic foot ulcers, nor its use for the sole indication of treating a foot infection (Chen et al., Diabetes/Metabolism Research and Reviews, 2024).
Topical Oxygen: A Separate Question
Topical oxygen is often conflated with HBOT but is a distinct modality with its own evidence base. The multinational, double-blind, sham-controlled TWO2 trial evaluated cyclical pressurised topical wound oxygen as an adjunct to standard care in refractory diabetic foot ulcers. At twelve weeks, 41.7% of ulcers in the active arm closed versus 13.5% in the sham arm (odds ratio 4.57, 97.8% CI 1.19–17.57); at twelve months, 56% versus 27% remained closed (Frykberg et al., Diabetes Care, 2020). Because topical oxygen can be delivered at home without chamber infrastructure, its cost profile differs substantially, and modelling based on the TWO2 outcomes has suggested favourable cost-effectiveness (Kerr et al., Journal of Diabetes and Its Complications, 2025).
Clinical Summary
Oxygen-based adjuncts occupy a specific and limited place in diabetic foot ulcer care. The evidence for systemic HBOT points to short-term acceleration of healing that has not consistently translated into durable healing or clear amputation reduction, with the most plausible benefit confined to ischaemic and neuro-ischaemic wounds that have failed optimal standard care. Topical oxygen has produced more consistent randomised healing data in refractory ulcers but a smaller overall evidence base. Neither displaces the fundamentals — sharp debridement, effective offloading, infection management, revascularisation where indicated, and glycaemic control — and both carry resource, adherence, and adverse-event considerations relevant to any decision about their use.
References
- Kranke P, Bennett MH, Martyn-St James M, Schnabel A, Debus SE, Weibel S. Hyperbaric oxygen therapy for chronic wounds. Cochrane Database of Systematic Reviews. 2015;(6):CD004123. doi:10.1002/14651858.CD004123.pub4
- Santema KTB, Stoekenbroek RM, Koelemay MJW, et al. Hyperbaric oxygen therapy in the treatment of ischemic lower-extremity ulcers in patients with diabetes: results of the DAMO2CLES multicenter randomized clinical trial. Diabetes Care. 2018;41(1):112–119. doi:10.2337/dc17-0654
- Wenhui L, Changgeng F, Lei X, Baozhong Y, Guobin L, Weijing F. Hyperbaric oxygen therapy for chronic diabetic foot ulcers: an overview of systematic reviews. Diabetes Research and Clinical Practice. 2021;176:108862. doi:10.1016/j.diabres.2021.108862
- 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. doi:10.1007/s00592-024-02426-7
- 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. doi:10.1002/dmrr.3644
- 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. doi:10.2337/dc19-0476
- Benedict Mitnick CD, Johnson-Arbor K. Atypical wounds; hyperbaric oxygen therapy. Clinics in Podiatric Medicine and Surgery. 2019;36(3):525–533. doi:10.1016/j.cpm.2019.02.008
- Kerr M, Wild D, Edmonds M, Boulton AJM. Cost effectiveness of topical wound oxygen therapy for chronic diabetic foot ulcers. Journal of Diabetes and Its Complications. 2025;39(5):109016. doi:10.1016/j.jdiacomp.2025.109016
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