Topical Oxygen Therapy for Diabetic Foot Ulcers: What the Evidence Now Shows

Introduction

Diabetic foot ulcers (DFUs) remain one of the most challenging complications of diabetes mellitus, with a lifetime incidence of roughly 19–34% in people living with diabetes and a five-year mortality after ulceration that rivals many common cancers. A central pathophysiologic problem in chronic DFUs is local tissue hypoxia: high glucose levels, microvascular disease, and impaired angiogenesis combine to deprive the wound bed of the oxygen required for fibroblast proliferation, collagen synthesis, leukocyte oxidative killing, and neovascularization. Over the past decade, topical oxygen therapy (TOT) — the delivery of supplemental oxygen directly to the wound surface, distinct from systemic hyperbaric oxygen therapy (HBOT) — has emerged as an evidence-based adjunct for refractory DFUs.

What Topical Oxygen Therapy Is — and How It Differs From HBOT

Topical oxygen therapy delivers near-100% oxygen to the wound surface at low pressure, either through a sealed extremity chamber (cyclical pressurized TWO₂), a continuous diffusion device worn under the dressing (CDO), or a portable system using oxygen-generating dressings. Unlike HBOT, which delivers systemic oxygen at 2–3 atmospheres in a multiplace or monoplace chamber, TOT acts locally, can typically be administered at home, and avoids the cardiopulmonary considerations and resource intensity of hyperbaric facilities. The 2023 IWGDF guideline on wound healing interventions recognizes both modalities as separate adjuncts and notes that the evidence base for topical oxygen has expanded substantially in recent years (Chen et al., 2024).

The Evidence: Recent Randomized Controlled Trials

The TWO₂ Study (Frykberg et al., 2020)

This multinational, multicenter, double-blind, sham-controlled RCT randomized patients with chronic, refractory Wagner grade 1–2 DFUs to cyclical pressurized topical wound oxygen plus optimal standard of care (SOC) versus sham plus SOC. At 12 weeks, complete closure occurred in 41.7% of the active arm versus 13.5% of the sham arm (odds ratio 4.57; P = 0.010). After adjustment for University of Texas grade, the odds ratio rose to 6.00 (P = 0.004). At 12 months, 56% of active-arm ulcers were healed versus 27% in the sham arm (P = 0.013), suggesting both improved closure and durability of healing.

Continuous Diffusion of Oxygen (Serena et al., 2021)

In a multicenter, open-label RCT of 145 patients with Wagner 1–2 or IDSA mild–moderate DFUs, the addition of continuous diffusion oxygen to SOC improved 12-week healing from 28.1% to 44.4% (P = 0.044). Mean wound-area reduction was 70% with TOT versus 40% with SOC alone (P = 0.005, per-protocol). A separate one-year follow-up of CDO-treated ulcers reported lower recurrence rates compared with SOC alone, supporting durability of the wound-closure benefit (Al-Jalodi et al., 2022).

Systematic Reviews and Meta-Analyses

A 2023 systematic review and meta-analysis by Carter and colleagues in Advances in Wound Care pooled randomized data on cyclical pressurized topical oxygen and reported a statistically significant increase in healing compared with SOC alone (risk ratio 1.59; 95% CI 1.07–2.37; P = 0.021). A broader 2024 meta-analysis in the International Wound Journal (Putri et al.) examining TOT across chronic wound types — including DFUs — likewise found favorable effects on closure rates and wound-area reduction relative to standard care.

Where TOT Fits in Clinical Practice

The 2023 IWGDF guideline issues a conditional, supportive recommendation that topical oxygen “can be considered as an adjunct therapy to standard of care where standard of care alone has failed,” alongside similar conditional recommendations for sucrose octasulfate dressings, negative pressure wound therapy for post-operative wounds, placental-derived products, autologous leukocyte-platelet-fibrin patches, and HBOT in neuro-ischemic ulcers (Chen et al., 2024). Two practical principles flow from the evidence:

• Optimize the basics first. Adjuncts such as TOT should layer on top of meticulous standard care: sharp debridement, infection control, vascular assessment and revascularization where indicated, glycemic optimization, and pressure offloading. None of the trials showing benefit removed these elements; rather, oxygen was added after ulcers failed to progress on best SOC.
• Reserve for non-healing wounds. The strongest data come from chronic, refractory DFUs that have stalled despite weeks of appropriate care. TOT is not currently indicated as first-line monotherapy for fresh, uncomplicated ulcers.

Limitations of the Current Evidence

Despite encouraging signals, the evidence base has heterogeneity in device type (cyclical vs. continuous), dosing protocols, ulcer severity, and outcome definitions. Several included trials are open-label, and head-to-head comparisons among different oxygen-delivery modalities are limited. Cost-effectiveness data, particularly outside the United States, remain modest. Larger pragmatic trials in moderate-to-severe and ischemic ulcers are still needed.

Clinical Summary

Topical oxygen therapy has accumulated meaningful randomized evidence over the past decade as an adjunct to standard care for chronic, hard-to-heal diabetic foot ulcers. Both cyclical pressurized (TWO₂) and continuous diffusion modalities have demonstrated improved 12-week closure rates, with at least one large RCT showing durable benefit at 12 months. Current international guidance positions TOT as a reasonable consideration for refractory Wagner 1–2 ulcers when best standard of care has failed to achieve healing, provided debridement, offloading, infection control, and vascular optimization are already in place.

References

1. 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.
2. 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.
3. Al-Jalodi O, Serena TE, Sabo MJ, et al. A multicenter clinical trial evaluating the durability of diabetic foot ulcer healing in ulcers treated with topical oxygen and standard of care versus standard of care alone 1 year post healing. International Wound Journal. 2022;19(7):1838–1842.
4. 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(4):177–186.
5. Putri NM, 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(4):e14960.
6. 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.

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