Diabetes
The Potential of Hyperbaric Oxygen Therapy in Treating Diabetic Foot Ulcers
Introduction
Hyperbaric Oxygen Therapy (HBOT) consists of breathing oxygen at a pressure higher than local atmospheric pressure for multiple sessions for the treatment or prevention of specific diseases. As per the European Code of Good Practice (Kot et al.), there is a general consensus that the term HBOT can only be applied when the partial pressure of oxygen in breathing mixture exceeds 1.5 absolute atmosphere (ATA) for a minimum period of 60 minutes (excluding compression and decompression).
HBOT is an adjunctive treatment that may enhance wound healing and reduce the risk of amputation in patients with diabetic foot ulcers (DFUs). Approximately 15–25% of patients with diabetes will develop a foot ulcer during their lifetime, and these wounds are often difficult to manage because of impaired healing mechanisms associated with diabetes, including peripheral vascular disease, neuropathy, and infection. Conventional treatment approaches for DFUs – for example, offloading, debridement, and infection control – often prove insufficient in cases of chronic ulcers. In these cases, HBOT may enhance wound healing and reduce the risk of amputation in patients with non-healing DFUs by increasing oxygen delivery to hypoxic tissues, thereby promoting healing and reducing infection.
Benefits of HBOT for Patients with DFUs
Patients with non-healing wounds may experience a range of benefits from HBOT that improve outcomes and quality of life.
Decreased risk of amputation: Some studies have shown lower major amputation rates in severe cases of non-healing wounds and DFUs following HBOT (Kaya et al., 2009; Brouwer et al., 2020; Kumar et al., 2020; Sharma et al., 2021), although some studies have shown no clear benefit (Margolis et al., 2013; Fedorko et al., 2016).
Accelerated wound healing: HBOT can improve the closure rates of chronic wounds (Kranke et al., 2015), including DFUs (Kessler et al., 2003; Löndahl et al., 2010), thus reducing the risk of complications and shortening hospital stays.
Decreased chronic pain: DFUs are associated with chronic pain (Ghadeer et al., 2025), and HBOT may reduce pain in many conditions (Sutherland et al., 2016), including DFUs (Pasek et al., 2022).
Quality of life: Diabetic patients with ulcers affecting the lower extremities report significant effects on their quality of life (Brod et al., 1998; Ghadeer et al., 2025). By accelerating wound healing and reducing the risk of complications, HBOT has been reported to enhance patients’ quality of life (Lopes et al., 2024).
Side Effects and Risks of HBOT
HBOT is generally well tolerated, and serious side effects are rare (Camporesi, 2014; Zhang et al., 2023). Reported side effects are typically mild and reversible, including middle ear barotrauma and transient myopia. Serious complications, such as oxygen toxicity seizures or pulmonary barotrauma, are rare.
However, a number of studies have reported that HBOT decreases blood glucose levels in patients undergoing treatment for DFUs (Baitule et al., 2021), and blood sugar should be monitored during hyperbaric treatment of diabetic patients.
In one clinical trial, a substantial proportion of patients eligible for HBOT could not be treated because of their unfavourable overall medical condition (Santema et al., 2018).
Mechanisms of Action of HBOT
During HBOT at OxyGeneration, patients are treated with near-pure oxygen in a chamber in which the pressure is higher than atmospheric pressure (2 ATA) for 1.5 hours for multiple sessions. HBOT may facilitate the resolution of ulcers through several mechanisms, primarily by enhancing oxygen delivery to tissues.
Enhanced oxygenation: Due to inflammation and disruption of the vasculature, chronic wounds, such as ulcers, are often hypoxic. HBOT increases the amount of dissolved oxygen in plasma, enhancing oxygen delivery to wounds and enhancing healing (Cannellotto et al., 2024).
Angiogenesis: Angiogenesis is impaired in chronic wounds of diabetic patients, which leads to chronic hypoxia and impaired micronutrient delivery (Okonkwo & DiPietro, 2017). HBOT may stimulate angiogenesis by inducing the release of pro-angiogenic factors (Huang et al., 2020), and in patients with DFUs, VEGF levels are increased following HBOT (Semadi, 2019).
Anti-inflammatory effects: Chronic inflammation is a hallmark of non-healing wounds (Acosta et al., 2008; Wang et al., 2022). HBOT exerts anti-inflammatory effects in patients with chronic diabetic wounds by decreasing the levels of pro-inflammatory mediators and increasing growth factors (Capó et al., 2023), including in patients with DFUs (Semadi, 2019; Pérez-Vielma et al., 2024).
Collagen synthesis: The hypoxic and inflammatory microenvironment of skin wounds may affect collagen remodelling and delay wound healing. HBOT promotes the proliferation and activity of fibroblasts (Huang et al., 2020) and increases collagen synthesis, promoting wound repair (André‐Lévigne et al., 2016; Růžička et al., 2021).
Antimicrobial effects: Diabetic foot ulcers are frequently complicated by infection (Del Core et al., 2018). HBOT inhibits the growth of anaerobic bacteria and enhances the ability of leukocytes to kill bacteria (Memar et al., 2019), and HBOT is recommended for patients who have a DFU associated with infection (Hanley & Manna, 2023).
Clinical Evidence Supporting HBOT of DFUs
The clinical efficacy of adjunctive HBOT in treating DFUs is supported by many studies, clinical trials, and meta-analyses, although some studies have shown conflicting results. HBOT is approved by the US FDA as a treatment for DFUs, as well as by the European Committee on Hyperbaric Medicine (ECHM) (Mathieu et al., 2017) and the Undersea and Hyperbaric Medical Society (UHMS) (Huang, 2024).
1. Systematic reviews and meta-analyses: Several meta-analyses of clinical trials for HBOT (typically 100% O2, 2–3 ATA, 45–120 mins, 4–50 sessions) of DFUs concluded that HBOT reduces the wound area and is effective as an adjunctive treatment for DFUs (Brouwer et al., 2020; Cruz et al., 2022; Sharma et al., 2021; Golledge & Singh, 2019; Zhang et al., 2022; Oley et al., 2024; Damineni et al., 2025). However, other reviews and meta-analyses found that HBOT has no benefits in the treatment of DFUs compared to standard care alone (Health Quality Ontario, 2017; Lalieu et al., 2020; Mackay et al., 2025). In all these reviews and meta-analyses, confidence was limited by trial design weaknesses and inconsistent findings.
For example, a systematic review and meta-analysis by Brouwer et al. (2020) concluded that adjuvant HBOT improves the major amputation rate, but not wound healing, in patients with a DFU and peripheral arterial occlusive disease (PAOD). In contrast, several systematic reviews and meta‐analyses (Golledge & Singh, 2019; Sharma et al., 2021; Cruz et al., 2022; Zhang et al., 2022) of HBOT for DFUs found that HBOT improves healing in addition to reducing the amputation rate.
A recent systematic review (Damineni et al., 2025) of six studies showed that the majority indicated reduced major amputation rates, improved ulcer healing rates, and decreased ulcer size and depth with adjunctive HBOT for DFUs compared to standard care alone. However, selection bias from inconsistent patient allocation was an issue in many of the studies.
In contrast, several reviews found that the evidence is insufficient to draw any conclusions regarding the clinical efficacy or cost-effectiveness of adjunctive HBOT versus standard wound care alone for the treatment of DFUs (Health Quality Ontario, 2017; Lalieu et al., 2020; Mackay et al., 2025). For example, in a systematic review of seven studies of HBOT for non-ischaemic DFUs, HBOT did not accelerate wound healing or prevent major or minor amputations in patients with DFU without PAOD (Lalieu et al., 2020).
The recent literature review of Mackay et al. (2025) concluded that despite encouraging clinical research findings, there remains a lack of strong clinical evidence of the benefits of HBOT for DFUs. The authors also suggested that hyperglycaemia, hypoxia, chronic inflammation, peripheral neuropathy, and vascular dysfunction may all adversely affect DFU healing, indicating that patient selection is critical.
The inconsistency in results may be due to mixed patient cohorts, including differences in ulcer severity. To determine which patients with DFUs benefit from HBOT, Oley et al. (2024) performed a systematic review and meta-analysis of HBOT for DFUs based on Wagner grading. The authors concluded that there was moderate-quality evidence that adjunctive HBOT improved DFU wound healing for Wagner grades 2, 3, and 4, prevented minor and major amputations for grades 3 and 4, respectively, and prevented operative debridement in grade 2 wounds.
2. Clinical trials: Clinical trials of HBOT for DFUs have been ongoing for over 30 years (Leslie et al., 1988; Doctor et al., 1992; Faglia et al., 1996). Many randomised controlled trials (RCTs) have reported benefits of HBOT for DFUs, including accelerated healing and a lower rate of amputation.
For example, in a prospective randomised study of HBOT in 14 patients with non-ischaemic chronic DFUs (Wagner grades 1–3), HBOT (100% O2, 2.5 ATA, 90 mins, 20 sessions) doubled the mean healing rate of DFUs compared with patients treated with standard care alone while the therapy was ongoing (Kessler et al., 2003).
In a single-centre RCT of HBOT for patients with DFUs of Wagner grades 2–4, complete healing of the index ulcer was achieved in 52% of patients in the HBOT (100% O2, 85 mins, 2.5 ATA, 40 sessions) group compared to 29% in the placebo group at the one-year follow-up (Löndahl et al., 2010). Similarly, HBOT of 28 patients with DFUs (Wagner grades 2–4), HBOT (100% O2, 2.4 ATA, 90 mins, 36 sessions) was associated with decreased healing times and lower rates of amputation and debridement (Kumar et al., 2020).
In a non-blinded RCT, 13 patients with DFUs (Wagner grades 2–4) treated with HBOT (100% O2, 2.5 ATA, 90 mins, 35 sessions) showed accelerated healing compared with patients treated with standard care alone (Lopes et al., 2024). HBOT also led to a greater improvement in quality-of-life dimensions, including functional capacity and pain.
Other studies that have shown positive benefits include Abidia et al. (2003), Duzgun et al. (2008), Ma et al. (2013), Chen et al. (2017), Hisamuddin and Zahiruddin (2019), and Salama et al. (2019), which have indicated improved healing and decreased rates of amputation in patients with ischaemic or non-ischaemic DFUs.
In contrast to the studies showing positive results for HBOT of DFUs, several studies have reported that adjunctive HBOT has no advantage over standard care alone. For example, a prospective double-blind RCT of 113 patients with DFUs of Wagner grades 2–4 found that HBOT (100% O2, 2 ATA, 90 mins, 30 sessions) did not reduce the number of patients who met the criteria for major amputation and did not facilitate wound healing (Fedorko et al., 2016).
In a longitudinal observational cohort study of 793 patients with a DFU, the authors concluded that HBOT neither improved wound healing nor prevented amputation (Margolis et al., 2013). However, in the cohort of patients treated with HBOT, the mean wound size and the proportion of patients with Wagner grades ³3 were significantly greater than in patients who did not undergo HBOT, suggesting patient selection bias, i.e. patients with more severe DFU were more likely to undergo HBOT.
The DAMO2CLES study, a major multicentre, randomised, parallel-group superiority trial in the Netherlands and Belgium, concluded from an intention-to-treat analysis of patients with diabetes and ischaemic lower-extremity ulcers (primarily DFUs) that adding HBOT (100% O2, ~2.5 ATA, 90 mins, ≤40 sessions) to standard care did not result in statistically significant benefits in terms of limb salvage or wound healing (Santema et al., 2018). However, in a per-protocol analysis, although not statistically significant, 92% of patients who underwent HBOT until complete closure of the wound or completed ≥30 sessions had no amputations versus 67% in the standard care group (See Table 2 in Santema et al. (2018)). The authors also noted that a substantial proportion of the patients who were eligible for HBOT could not be treated because of their unfavourable overall medical condition.
It has been suggested that the contradictory results in these studies may be due to grouping patients with and without PAOD together (Lalieu et al., 2022), indicating that patient selection is critical. Also of note, Erdoğan et al. (2018) showed that HBOT for DFUs had higher levels of efficacy in patients with Wagner grades 3 and 4 ulcers compared to those with grade 2 or 5 ulcers. Other issues in the published studies include differences in the glycaemic control and level of ischaemia in patients, as well as weaknesses in the study design.
Conclusion
Although there is mixed evidence for the efficacy of HBOT for DFUs, by enhancing oxygen delivery, angiogenesis and wound healing, reducing inflammation, and exerting antimicrobial effects, adjunctive HBOT may significantly improve wound healing of DFUs and reduce the need for amputation in appropriately selected patients. HBOT for DFUs is generally safe, and as well as the potential benefits regarding healing and lower amputation rates, HBOT is associated with decreased pain and improvements in patients’ quality of life, potentially further benefitting patients with DFUs.
Overall, the balance of evidence indicates that HBOT may be beneficial for patients with adequate glycaemic control and Wagner grade 3–4 DFUs, particularly when chronic wounds are associated with infection or PAOD, although patients with lower-grade DFUs may also benefit from HBOT.