Topical oxygen therapy and singlet oxygen in wound healing: A scoping review

Abstract

The aim of this scoping review was to provide an overview of current research into topical oxygen therapies including the under‐researched singlet oxygen for wound healing. A scoping review was undertaken using five databases. After duplicates and ineligible studies were excluded, 49 studies were included for a narrative review. Out of the included 49 studies, 45 (91.8%) were published in the past 10 years (2013–2023) with 32 (65.3%) published in the past 5 years (2018–2023). Eight of the studies were systematic reviews and/or meta‐analysis and 18 were RCTs. The search identified zero human RCTs on singlet oxygen, but one human cohort study and five studies in animals. There is evidence that topical oxygen therapy may be useful for the treatment of chronic wounds, mainly diabetic foot ulcers. Singlet oxygen has shown potential, but would need further confirmation in controlled human trials, including more research to understand the bio‐properties.

1. INTRODUCTION

In the UK, 7% of the adult population is estimated to have a wound. ¹ Oxygen is vital for wound healing. Almost all phases in the healing process require oxygen, including the proliferation of keratinocytes and fibroblasts, collagen synthesis and angiogenesis. Tissues that are damaged, necrotic or infected also require extra oxygen consumption due to the presence of highly metabolically active immune cells. The high oxygen demand may therefore lead to areas within the wound with hypoxia. Important immune cells as neutrophils, may also lose their efficacy of bacterial cleansing in hypoxic areas. All these processes require a minimum of 25–100 mmHg pO₂. ² Effective wound management could incorporate improved oxygen supply as one of its strategies to deliver oxygen to the hypoxic tissue to aid skin regeneration. ² , ³ The most common oxygen therapy used for wound healing is hyperbaric oxygen therapy. Although hyperbaric oxygen therapy (systemic oxygen therapy) has been used for wound healing for more than six decades, ⁴ less is known about the impact of topical oxygen therapies on wound healing such as haemoglobin spray, oxygen dressings and continuous topical oxygen therapy. Topical oxygen therapy (TOT) can be defined as ‘the administration of oxygen applied topically over injured tissue by either continuous delivery or pressurised systems’. ⁵ Hyperbaric oxygen therapy is expensive, and patients are required to visit a hyperbaric clinic multiple times to receive treatment. TOT can address these disadvantages by offering oxygen therapy that can be delivered in patients' homes at reduced cost.

One of the under‐researched oxygen species is singlet oxygen. Singlet oxygen comprises of an oxygen molecule containing more energy than the oxygen humans typically breathe. Oxygen in its basic state has low energy, however, oxygen can be excited to a more reactive state called singlet state through energy transfer. In the singlet state, oxygen can better penetrate the membrane which was discovered in the 1930s. Singlet oxygen is a bio‐usable form of energised oxygen. Although singlet oxygen has been used to treat respiratory conditions, less is known about the potential of singlet oxygen for wound healing. Promising findings indicate that singlet oxygen may play a positive role in wound healing. ⁶

Several systematic reviews on topical oxygen therapies for wound healing have been identified, however, most focus on diabetic foot ulcers. ⁷ , ⁸ , ⁹ Although one systematic review ¹⁰ that was published in 2017 researched the effect of oxygen therapies in all wound types, there is a need for a study that would include recent developments in topical oxygen therapies. This scoping review aims to provide an overview of current research into topical oxygen therapies including the under‐researched singlet oxygen for wound healing.

1.1. Scoping review aim

The primary aim of this scoping review was to assess the extent of the literature on current uses of topical oxygen therapy for wound healing in humans and their clinical and cost outcomes.

The secondary aim was to understand the potential of singlet oxygen therapies for wound healing in humans and animals and their clinical and cost outcomes.

1.2. Scoping review objectives

• What types of topical oxygen therapies are being used in wound care in humans and what are the clinical, healthcare utilisation and cost outcomes of these treatments?

• How is singlet oxygen therapy being used in wound care in humans and animals and what are the clinical, healthcare utilisation and cost outcomes of singlet oxygen therapy?

• How are topical oxygen therapies including singlet oxygen being administered (including what technologies are being used to generate the topical oxygen therapies)?

2. METHODS

2.1. Information sources

The search was conducted using the following databases: MEDLINE (via Ovid), EMBASE (via Ovid), CINAHL (via EBSCO), Database of veterinary systematic reviews VetSRev (via the University of Nottingham) and the Cochrane Library. In addition, the reference lists of systematic reviews were hand‐searched for additional studies. The Participants/Concept/Context framework was used to inform the design of the primary objective and inclusion criteria.

2.2. Eligibility criteria

Articles published in English from the inception of the databases until 14th December 2022 were included if they investigated the use of topical oxygen therapies for wound healing in humans or the use of singlet oxygen for wound healing in humans and animals.

2.2.1. Topical oxygen therapies

This scoping review considered both experimental and quasi‐experimental study designs including randomised controlled trials (RCTs), non‐randomised controlled trials, before and after studies and interrupted time‐series studies. In addition, comparative observational studies (both prospective and retrospective) were considered for inclusion. In addition, systematic reviews and meta‐analyses that met the inclusion criteria were also considered, depending on the research question. Studies that reported on topical oxygen therapy for wound healing in humans were included.

2.2.2. Singlet oxygen

The inclusion criteria for studies researching singlet oxygen studies were wider and included observational and experimental study designs reporting on the use of singlet oxygen for wound healing in humans as well as animals.

2.3. Exclusion criteria

2.3.1. Topical oxygen therapies

Non‐comparative observational studies, literature reviews, editorials, comments, case‐reports and in vitro studies were excluded, including those not reporting on wound healing. Animal studies and studies that were unavailable in full‐text were excluded. Studies reporting on the use of topical hyperbaric oxygen were excluded.

2.3.2. Singlet oxygen

Literature reviews, editorials, comments and in vitro studies were excluded, including those not reporting on wound healing. Studies that were unavailable in full‐text were excluded.

2.4. Search strategy

Our search technique consisted of a combination of search terms that included various types of topical oxygen therapy and singlet oxygen, various wound types, wound healing and relevant study type (Appendix 1).

The term ‘reactive oxygen species’ was removed from the search strategy because of the large number of hits returning from all databases. In CINAHL, using the Mesh terms (MH ‘Wounds and Injuries+’) and (MH ‘Oxygen Therapy+’) generated too many hits and studies that were not relevant. Instead, we searched for the terms ‘wounds and injuries’ and ‘oxygen therapy’ as a major concept which generated studies more relevant to our topic of interest.

2.5. Selection and data collection process

Using Rayyan (https://www.rayyan.ai/), data were extracted from selected papers using a data extraction tool developed by the project team. Abstract and full‐text reviews were conducted by one reviewer.

2.6. Data items

The data extracted included specific details about participants, treatment mode, how was the treatment delivered, wound type, study design and key findings relevant to the review questions. A copy of the extraction form is provided (Appendix 2). No assumptions were made about missing or unclear information.

3. RESULTS

In total, the database searches identified 1690 articles. After duplicates were removed (n = 340), 1350 abstracts were reviewed. In total, 145 articles were included for a full‐text review. Forty‐four studies met the inclusion criteria. A hand search of reference lists of systematic reviews identified further 10 studies, of those five met the inclusion criteria. In total, 49 studies were included for narrative review (Figure 1).

FIGURE 1.

PRISMA diagram. ⁶³

Out of the included 49 studies, 45 (91.8%) were published in the past 10 years (2013–2023) with 32 (65.3%) published in the past 5 years (2018–2023). Almost a half of the studies included in this review focused on diabetic foot ulcers (n = 21), followed by infected wound (n = 5) and venous leg ulcers (n = 4). Eight of the studies were systematic reviews and/or meta‐analysis and 18 were RCTs. The studies were grouped depending on the type of study or mode of oxygen delivery, that is, findings from meta‐analyses and systematic reviews, continuous oxygen therapy, high‐pressure oxygen therapy, intermittent oxygen delivery, topical oxygen therapy with a variation on temperature, oxygen dressings, oxygen transfer and other forms of topical oxygen therapies (as summarised in Figure 2). This classification was created by the project team to group studies using a similar TOT method which helps us to better understand the significance of findings from each study within one category. Singlet oxygen was delivered via an aqueous solution, gel, membrane, nanosheet, nanorods or peptides. Table 1 shows the summary of all included studies.

FIGURE 2.

Designed classification of included topical oxygen therapies. ROS, reactive oxygen species; TOT, topical oxygen therapy.

TABLE 1.

Summary of included studies.

		Author	Sample size (N)	Type of TOT	How administered	Type of wound	Length of treatment	Outcomes	Type of study
Meta‐analyses and systematic reviews		Carter et al. (2023)	N = 4 RCTs	Topical oxygen therapy	?	Chronic diabetic foot ulcers	12 weeks	↑ Wound healing: at 12 weeks TOT versus SOC alone (RR: 1.59; 95% CI: 1.07–2.37; p = 0.021) (meta‐analysis of 4 RCTs) The difference between intervention versus SOC groups (complete wound healing) ranged from 5% to 27% (all rates had higher healing rates compared with SOC), but Driver reported stat. non‐sig.results These data support the use of TOT for the treatment of chronic Wagner 1 or 2 diabetic foot ulcers in the absence of infection and ischaemia	Systematic review and meta‐analysis
		Connaghan et al. (2021)	N = 8 articles (4 included for meta‐analysis)	Topical oxygen therapy	?	Chronic diabetic foot ulcers	?	↑ Wound healing: DFUs are >2 times more likely to heal with TOT than with SOC alone (meta‐analysis of 4 RCTs) (OR = 2.49; CI 95%: 1.59–3.90, p = 0.00001) ↓ Healing time: time to 50% DFU closure was significantly shorter in TOT versus sham: mean 18.4 days versus 28.9 days in the sham therapy group (p = 0.001) (1 study)	Systematic review and meta‐analysis
		Thanigaimani et al. (2021)	N = 6 RCTs involving 530 participants	Topical oxygen therapy	TransCu O2®, Natrox, Epiflo, cyclical topical wound oxygen therapy	Diabetes‐related foot ulcers	4–12 weeks (+12 months follow up 1 study)	↑ Likelihood of ulcer healing compared to controls (RR = 1.94; 95% CI: 1.19–3.17; NNT = 5.33) (meta‐analysis) The TOT effect on amputation and cost‐effectiveness remain unclear	Systematic review and meta‐analysis
		Sun et al. (2022)	N = 7 RCTs involving 614 participants	Topical oxygen therapy	Continuous diffusion of oxygen therapy (5 studies) and intermittent TOT (2 studies)	Diabetic foot ulcers	?	↑ Wound closure: Compared with the control group, the TOT group had a higher healing rate (RR = 1.63, 95% CI [1.33, 2.00]) ↓ Ulcer area: TOT reduced the ulcer area and improved healing durability and QoL (descriptive analysis) No effect on the occurrence of adverse events Unclear whether able to ↓ healing time The existing evidence suggests that TOT is effective and safe for chronic DFUs	Systematic review
		Ntentakis et al. (2021)	N = 40 studies (some animal or in vitro)	Dissolved oxygen	Dissolved oxygen in aqueous solutions: Dissolved oxygen solutions (17), O2 dressings (9), O2 hydrogels (11) and O2 emulsions (3)	Non‐healing wounds	Various	↑ Wound oxygenation: All technologies improved wound oxygenation, each to a variable degree. ↑ Wound healing: achieved at least one statistically significant outcome related to wound healing, mainly in epithelialisation, angiogenesis and collagen synthesis	Critical review (systematic review)
		Vas et al. (2020)	N = 6 studies (TOT)	Topical oxygen therapy	Transdermal continuous oxygen therapy, continuously diffused topical oxygen therapy, a portable oxygen concentrator, others not described	Chronic foot ulcers in diabetes	Up to 90 days	Effectiveness: The use of topical oxygen therapy or other gases does not seem to be more effective in ulcer healing when compared with best standard of care. Quality of evidence: low	Systematic review
		Nataraj et al. (2019)	N = 5 studies	Continuous topical oxygen, NATROX, Hyper‐Box	Continuous ambulatory topical oxygen therapy, NATROX oxygen delivery system, Hyper‐Box topical wound oxygen extremity chamber, transdermal continuous oxygen therapy, Hyper‐Box topical wound oxygen therapy system	Diabetic foot ulcers	Up to 12.8 weeks (90 days + follow‐up 2 years)	↑ Wound healing: The healing trajectory of the wounds was completely achieved in low‐grade ulcers (grade 1), whereas all high‐grade ulcers (grades 2, 3 and above) showed either 100% or 50% healing with a reduction in ulcer size and ulcer tissue depth CONCLUSION: Topical oxygen therapy facilitates wound healing dynamics among individuals with chronic diabetic foot ulcers	Systematic review
		de Smet et al. (2017)	N = 65 articles (17 TOT)	Oxygen therapy (including local oxygen)	Transdermal sustained oxygen delivery system (TWO2) + oxygen dressings	Chronic and acute wounds	5 years follow‐up	↑ Wound healing: 3/7 studies obtained positive outcomes, 1/7 found no significant differences and 3/7 evaluated several wound parameters, of which half proved positively (O2 dressings) ↑ Wound healing: 7/10 studies had at least one or more significant positive outcomes (TOT)	Systematic review
Continuous oxygen therapy		Al‐Jalodi et al. (2022)	N = 29 Adult	Natrox	Continuous oxygen therapy	Diabetic foot ulcers	12 months	↑ Wound healing: 85% (10/12) of treatment group versus 60% (6/10) control group remained healed at 1 year	RCT Unsure whether blinded Sample size calculation not included
		Serena et al. (2021)	N = 145 Adult	Natrox	Continuous oxygen therapy (delivers a pure oxygen flow rate of 15 mL/h)	Hard‐to‐heal diabetic foot ulcers	12 weeks	↑ Wound healing: complete closure 44.4% (treatment group) versus 28.1% (control group) (p = 0.044 ITT analysis) ↓ Mean wound size: 70.1% (SD: 45.5) (treatment group) versus 40% (SD: 72.1) (control group) (p < 0.005 PP analysis)	RCT Sample size (min. 120 evaluable subjects) Data blinded to group allocation
		Yu et al. (2016)	N = 20 Adult	Natrox	Continuous oxygen therapy	Diabetic foot ulcer	8 weeks	↑ Wound healing: full closure of Grade II 100% (treatment group) versus 0% (control group) ↓ Wound size: statistically significant difference between baseline versus week 8 (treatment group) ↑ Wound quality treatment versus control (increased exudate for the first two week)	RCT Unsure whether blinded Sample size calculation not included
	Potential overlap of these two studies	Driver et al. (2017)	N = 130 Adult	Transdermal continuous oxygen therapy	Transdermal continuous oxygen therapy (continuous administration of 98 + % oxygen to the wound site using a 15‐day device changed every 15 days)	Diabetic foot ulcers (1‐10 cm2)	12 weeks	↑ Wound healing: fully healed 34/61 wounds (56%) (TCOT group) versus 31/61 (49%) (control group) (PP) ↑ Wound healing: ≥65 years (PP): 14/17 (82%) healed (TCOT) versus 8/16 (50%) (control) (p = 0.049) ↓ Median time to complete closure: 63 days (TCOT group) versus 77 days (control group) (p > 0.05) (PP) ↓ Infection rates: 3 (5%) (TCOT) versus 10 (15%) (control)	RCT Triple blinded Sample size included (96 or n = 48 per arm = 80% power)
		Driver et al. (2013) a	N = 17 Adult	Epiflo	Transdermal continuous oxygen therapy (a continuous delivery of 3 mL/h of 99.8% pure oxygen 24/7)	Diabetic foot ulcers (0.5‐15 cm2)	4 weeks	↓ Wound size: average reduction 87% (55.7%–100%) (treatment) versus 46% (15%–99%) (control) (p < 0.05) ↓ CD68+ macrophage counts showed statistically significant reduction in response to TCOT compared to the control group (p < 0.01)	Randomised Clinical Study
		Niederauer et al. (2018)	N = 146 Adult	TransCu O2	Continuous diffusion of oxygen (continuously generate pure [>99.9%], humidified oxygen at flow rates of 3–15 mL/h directly to the wound bed)	Diabetic foot ulcers	12 weeks	↑ Wound healing: 195% of DFUs healed (CDO) arm compared with placebo (32.4% vs. 16.7% p = 0.033) ↓ Mean time to 50% DFU closure: 18.4 versus 28.9 days (p = 0.001) ↑ Relative performance: in more chronic wounds (p = 0.008) and in weight‐bearing wounds (p = 0.003) (did not vary with wound size (p = 0.80))	RCT Double‐blinded Placebo‐controlled Sample size calculated (100 or n = 50 per arm = 90% power)
	Interim results of RCT (Niederauer 2018)	Niederauer et al. (2017) b	N = 100 Adult	TransCu O2	Continuous diffusion of oxygen (continuously generate pure, humidified oxygen at flow rates of 3–15 mL/hr and deliver it directly to the wound bed)	Diabetic foot ulcers	12 weeks	↑ Wound healing: 46% (treatment) versus 22% (sham) (p = 0.02) ↑ Wound healing in more chronic wounds: 42.5% (treatment) versus 13.5% (sham) (p = 0.006) ↑ Rates of closure (100%): <50 days (treatment) versus >50 days (sham) (p < 0.001)	RCT
		Niederauer et al. (2015) c	N = 42 Adult	TransCu O2	Continuous diffusion of oxygen (delivers pure oxygen to the wound at low flow rates 3–10 mL/h)	Diabetic foot ulcers	12 weeks	↓ Days to closure: 9 (treatment) versus 3 (sham) (p = 0.03) ↑ Wound healing at 12 weeks: complete closure 11 (52.3%) (treatment) versus 8 (38.1%) (sham) (p = 0.54) The absolute performance in the Active arm appeared non‐inferior to other reimbursable wound treatment devices	Interim results from RCT
		Zulbaran‐Rojas et al. (2021)	N = 21 Adult	TransCu O2	Continuous diffusion of oxygen system (Humidified oxygen was delivered at 5 mL/hr in a pure continuous flow for 24 h per day)	Surgical wound (cervicotomy)	4 weeks	↓ >10% of scar length reduction at 4 weeks: 88.8% (treatment) versus 28.5% (control) (p = 0.008) showing a 40.4% smaller scar (15.7% versus 11.2%, d = 0.13, p = 0.72) compared to the CG	Proof of concept RCT Not blinded Sample size (n = 6 per arm = 80% power)
		He et al. (2021)	N = 120 Adult	A micro‐oxygen supply device (Greens O‐4–3)	Continuous diffusion of oxygen (a micro‐oxygen supply device was used to generate high‐purity oxygen, continuous delivery to the centre of the wound at a constant flow rate)	Diabetic foot ulcers	8 weeks + 1 year follow up	↑ Wound healing: completely healed in 72.5% (combination) versus 42.5% (MWD) versus and 47.5% (CDO) ↓ Mean wound healing times: 76.42 ± 32.78 days (MWD) versus 75.52 ± 25.62 (CDO) versus 48.39 ± 13.32 days (combination) (p < 0.05) ↓ Amputation rate during 12 months: 15% (MWD) versus 12.5% (CDO) versus 0% (combination)	Clinical trial
		Wang and Yu (2020)	N = 76 Adult	Oxygen‐irrigated wound negative pressure	Oxygen‐irrigated wound negative pressure (oxygen delivered at flow rate [3 L/min], temperature [27°C], humidity [65.0%] and 24 h' continuous oxygen treatment for 14 days)	Various (incision, PUs, trauma, other)	14 days	↓ Healing time, total treatment cost, & dressing replacement frequencies in the experimental group lower than in the control group (all p < 0.05) ↓ Wound area and depth at 7, 10, 14 days: treatment versus control (all p < 0.01) ↓ PUSH scores at 7, 10, 14 days: treatment versus control (all p < 0.01) ↑ Granulation tissue at 7, 10, 14 days: treatment versus control (all p < 0.01)	Clinical trial
		Tang et al. (2021)	N = 20 Adult	Natrox	Continuous oxygen therapy (delivers a pure oxygen flow rate of 15 mL/h)	Diabetic foot ulcers	3 months	↑ Wound healing: wound closure of >75% observed in 14/20 (70.0%) patients ↓ Wound area: a 91.3% (±SD) wound area reduction by 3 months from baseline ↑ Tissue granulation ↑ DFS‐SF mean scores (significant improvements between baseline and 3 months of the ‘leisure’ and whether ‘bothered by the ulcer care’ components)	Observational clinical trial
		Altinbas and Sahsivar (2022)	N = 64 Adult	Transdermal continuous oxygen therapy	Transdermal continuous oxygen therapy (continuous delivery of oxygen for 15 days)	Venous leg ulcers	45 days	↑ Wound healing: fully healed 28/32 (TWOT) versus 1/32 (control) (p < 0.001) ↓ Wound area (cm2): 6.72 ± 3.35 (TWOT) versus 27.72 ± 14.66 (control) (p < 0.001)	Prospective comparative study
High pressure oxygen therapy		Frykberg et al. (2020)	N = 73 Adult	TWO2 (HyperBox; AOTI Ltd, Galway, Ireland)	Cyclical topical wound oxygen (operates by inflation of a single use extremity chamber over the patient's limb using a 10 L/min oxygen concentrator, home treatment for 90 min daily 5×/week)	Chronic diabetic foot ulcers	12 weeks	↑ Wound healing: closure rate 41.7% (treatment group) versus 13.5% (sham group) (p = 0.010) ↓ Wound area: the mean (SD) absolute reduction in ulcer area from baseline 1.97 (2.75) cm2 (treatment) versus 0.40 (1.75) cm2 (sham) ↑ Closure at 12 months post‐enrolment: 56% (treatment) versus 27% (sham) (p = 0.013) ↓ Ulcer recurrence at 12 months: 1/15 (6.7%) healed ulcers (treatment) versus 2/5 (40%) healed ulcers (sham)	RCT Double‐blinded Sample size calculated based on previous research (n = 73)
		Azimian et al. (2015)	N = 100 Adult	Transdermal wound oxygen therapy (high pressure)	Transdermal wound oxygen therapy (direct application of humidified high pressure 10 L/min oxygen to the wound site for 20 min, 3×/day for 12 days)	Pressure ulcers	12 days	↑ Wound healing: complete closure at 12 days 16/50 (treatment) versus 1/50 (control) (p < 0.001) ↓ Mean wound area: 13.36 ± 7.07 (treatment) versus 31.81 ± 3.94 (control) (p < 0.001)	RCT Single‐blinded Sample size (n = 50 per arm = 80% power)
		Blackman et al. (2010)	N = 28 Adult	TWO2	Cyclical topical wound oxygen (60‐min treatment 5×/week, pressure cycles between 5 and 50 mb)	Diabetic foot ulcers	Follow up 24 months	↑ Wound healing: complete epithelialisation 14/17 (82.4%) (TWO2) versus 5/11 (45.5%) (control) (p = 0.04) ↓ Median time to closure: 56 days (TWO2) versus 93 days (control)	Prospective, controlled study
	Potential overlap of these two studies	Tawfick and Sultan (2013)	N = 132 Adult	TWO2	Cyclical topical wound oxygen (the limb was placed in the AOTI Hyper‐Box for 180 min twice daily under pressure of 50 mbars, with oxygen supplied at 10 L/min with continuous humidification)	Refractory venous leg ulcers	12 weeks + 36 months follow up	↑ Wound healing at 12 weeks: 76% healed (TWO2) versus 46% (control) (p < 0.0001) ↓ Median time to full healing: 57 days (TWO2) versus 107 days (control) (p < 0.0001) ↓ Recurrence at 36 months: 3/51 (TWO2) versus 14/30 (control) ↓ Infection: 11/24 MRSA‐positive ulcers became negative by 5 weeks versus 0/19 (control) (p < 0.001) ↓ Pain scores: from 8 to 3 by 13 days (TWO2)	Prospective comparative study
		Tawfick and Sultan (2009) d	N = 83 Adult	TWO2	Cyclical topical wound oxygen (the affected limb was placed in the AOTI Hyper‐Box for 180 min 2× daily under pressure of 50 mbar, O2 at 10 L/min with continuous humidification)	Refractory venous leg ulcers	12 weeks	↑ Wound healing: completely healed 80% (TWO2) versus 35% (conventional compression dressings) (p < 0.0001) ↓ Median time to full healing: 45 days (TWO2) versus 182 days (CCD) (p < 0.0001) ↓ Mean ulcer surface area at 12 weeks: 96% (TWO2) versus 61% (CCD) ↓ Pain scores: from 8 to 3 by 13 days (TWO2)	Parallel observational comparative study
		Yellin et al. (2022)	N = 91 + 111 unmatched controls and 70 + 70 PSM matched controls	TWO2	Cyclical topical wound oxygen	Diabetic foot ulcers	360 days	↓ Hospitalisation and/or amputation within 360 days of initial wound documentation: Among propensity score‐matched cohorts of 140 DFU patients (70 TWO2, 70 NO TWO2), compared with NO TWO2, 82% fewer TWO2 patients were hospitalised (7.1% vs. 40.0%, p < 0.0001) and 73% fewer TWO2 patients had amputations (8.6% vs. 31.4%, p = 0.0007) Logistic regression (matched cohorts) showed nearly 9× higher risk of hospitalisation and 5× amputation for NO TWO2 versus TWO2	Retrospective cohort study
		Singh et al. (2020)	N = 86 Adult	Topical pressurised oxygen therapy	Topical pressurised oxygen therapy (3 L/min for 90 min/day)	Various (acute traumatic, chronic infected)	14 days	↑ Sterile cultures of infected wounds after treatment: 72% (21/29) (indigenous NPWT), 79% (15/19) (conventional NPWT) and 85% (6/7) (indigenous NPWT with TPOT) ↓ Mean wound area and depth reduction was 35.4% and 38.9% for indigenous NPWT; 39.3%, 40.4% for indigenous NPWT with oxygen therapy and 40.2%, 42.3% for conventional NPWT	Comparative study
Intermittent O2 delivery		Ahmadinejad et al. (2020)	N = 80 Paediatric	Transdermal wound oxygen therapy	Transdermal wound oxygen therapy (local oxygen at flow rate of 10 L/min for 20 min 2×/day through sterile coating that covered the entire ulcer)	Pressure ulcer Stage 3	2 weeks	↓ Surface area at 2 weeks: decreased by 3.60 cm2 (49%) (intervention) versus 1.37 cm2 (20%) (control) (p < 0.0001) ↓ Exudation at 2 weeks: reduced by 97% (intervention) versus 77.5% (control) (p < 0.0001) PUSH scores at 2 weeks: decreased in 100% of the patients (intervention) versus 92.5% (control) (p < 0.0001)	Double‐blinded clinical trial
		Ansari et al. (2022)	N = 60 Adult and paediatric	Sheet connected to oxygen cylinder	Sheet covering wound connected to an oxygen cylinder (the sealed cover was filled with O2 at the rate of 5‐6 L/min, treatment for 5 days of 60 min/day + 3‐day break)	Trauma (traffic related accidents)	1–3 weeks	↓ Percent wound area at final follow up: 34 ± 9.7% (VAC) versus 11.3 ± 3.8% (TOT) (p < 0.05) ↑ Epithelialisation: TOT improvement in epithelialisation compared to VAC at last follow up (p < 0.05)	Pilot, non‐randomised prospective study
		Yu et al. (2021)	N = 64 Adult	Cup connected to oxygen device	The wound was covered by a cup with holes to deliver oxygen (O2 device was connected with O2 content of 100%, O2 flow 6–8 L/min, wound treated with blowing O2 for 30 min; intermittent O2 blowing maintained for 12+ h every day)	Superficial malignant tumours and ulcer infection	7 days	↓ Dressing change frequency: 19.96 ± 3.50 (intervention) versus 30.75 ± 3.71 (control) group (p < 0.05) ↓ Number of times of blood oozing: 11.09 ± 2.62 (intervention) versus 17.90 ± 3.58 (control) (p < 0.05) ↓ VAS scores: 2.25 ± 0.67 (intervention) versus 3.84 ± 0.76 in (control) (t = 8.843, p < 0.0001) ↑ Wound healing: 93.75% (intervention) versus 65.63% in (control) (Z = −3.024, p = 0.002)	Retrospective analysis
Temperature		Anirudh et al. (2021)	N = 20 Adult	KADAM	Topical oxygen at a controlled temperature of 42°C a concentration of 93% (± 3%), and a flow rate of 1 L/min	Diabetic foot ulcers	6 weeks + 5 days (40 days)	↓ Mean (SD) wound area baseline‐end of treatment: 2.72 (0.57) vs 1.54 (0.95), reduction −1.18 (treatment) (p = 0.019) versus 3.05 (0.68) vs 2.94 (1.05), reduction −0.1 (p = 0.646) (control) ↑ QoL baseline‐6 weeks: The reduction in the IVDP‐QoL score 7.5 (95% CI, 3.23, 11.77) (intervention) versus 4.44 (95% CI:−9.75, 18.64) (control)	Pilot RCT Single‐blinded Sample size (n = 375, 80% power for a full RCT, this is a pilot RCT)
Oxygen dressings		Moffatt et al. (2014)	N = 100 Adult	Oxyzyme/Iodozyme wound dressing	Oxygenating hydrogel dressing (While the dressing is in contact with the wound surface, the hydrogen peroxide is converted to water and dissolved oxygen by serum catalase in the wound)	Venous and mixed ulcers	12 weeks + 24 weeks follow up	Healing at 12 weeks: 49.1% (control) versus 44.7% (treatment) QoL: little difference between the groups ↑ Wound healing in patients with high protease activity (treatment) (HR = 1.35, 95% CI 0.63, 2.87) (p = 0.44) ↓ Dressing changes: 14.8 (treatment) versus 10.0 (control) (p = 0.033) ↓ Mean costs per patient: £436 (treatment) versus £525 (control)	RCT Not blinded Sample size calculation not included
		Lairet et al. (2014)	N = 17 Adult	OxyBand dressing	Oxygen‐diffusion dressing OxyBand (the dressing comes prefilled with high levels of oxygen between the layers)	Skin‐graft donor sites (2) in burn patients	Until healed	↓ Mean time to healing: 9.3 ± 1.7 days (OxyBand) versus 12.4 ± 2.7 days (Xeroform) (P < 0.001) ↓ Pain scores postoperative days 4–12: 0.6–0.4 (OxyBand) versus 1.6–1.4 (Xeroform) (both p < 0.05) No difference in the cosmetic outcome of the wounds at 30 to 45 days postoperatively	Single‐centre, prospective, randomised, controlled, open‐label study
Oxygen transfer		Jonker et al. (2021)	N = 79 Adult (38 randomised)	Granulox	10% carbonylated haemoglobin spray applied twice weekly	Foot ulcer	12 weeks	Comparison of the median % ulcer size reduction at baseline—12 weeks: 100% (control) versus 48% (treatment) (p = 0.21) Complete healing: 8/14 healed (control group) versus 4/15 healed (treatment group) (p = 0.14)	RCT Unsure whether blinded Sample size calculation not included
		Arenbergerova et al. (2013)	N = 72 Adult	10% haemoglobin solution	Aqueous 10% solution (10% carbonylated haemoglobin)	Venous leg ulcers	13 weeks	↓ Wound size: 53% (treatment group) ↓ Average mean wound size between both groups at the beginning and end of the study (treatment group p > 0.0001) ↑ Wound quality (by day 91 ↓ necrotic tissue 48% vs. 17%) ↓ Mean reduction in pain intensity day 0–91 (68% (p < 0.01) in treatment group, 7% (p > 0.05) in control group)	Prospective, randomised, single blind, monocentric study
		Hunt et al. (2018)	N = 200 Paediatric and adult	Granulox	10% carbonylated haemoglobin spray	Sloughy wounds	26 weeks	↑ Healing: 94% healed (treatment group) compared with 63% (control group) ↓ Mean slough coverage (by week 4: 1% in treatment groups vs. 29% on control group) (p < 0.001) ↓ Exudate: no high or moderate exudate 94% (treatment group) versus 67% (control group)	Comparative study (Cohort compared with retrospective controls)
	Potential overlap of these two studies	Hunt and Elg (2017)	N = 100 Paediatric and adult	Granulox	10% carbonylated haemoglobin spray	Chronic wounds	26 weeks	↑ Healing: at 26 weeks: 90% completely healed (treatment group) versus 38% (control group) ↓ Mean healing time: 6.6 weeks (treatment group) versus 11.4 weeks (control group) ↓ Mean pain VAS scores: by week 4, 86% (treatment group) versus 16% (control group) ↓ Mean slough coverage: by week 4, 100% wounds slough‐free (treatment group) versus 32% (control group)	Retrospective cohort study
		Hunt and Elg (2016) e	N = 35 Adult	Granulox	10% carbonylated haemoglobin spray	Diabetic foot ulcers	28 weeks	↓ Wounds size: at 28 weeks 95% (treatment group) versus 63% (control group) (p < 0.05) ↓ Pain: at 12 weeks 100% pain‐free (treatment group) versus 33% pain‐free (control group) ↓ Slough levels: after 4 weeks 100% slough‐free (treatment group) versus 10% mean reduction (control group) (p < 0.001)	Cohort compared with retrospective controls
Other		Otaviano et al. (2021)	N = 73 Adult	Topical oxygen jet therapy	Jet (gas leaves the reservoir dry, at a 150 mmHg pressure and 15 L/min flow, treatment for 4–10 min depending on the wound size)	Infected surgical wounds	10 days	↑ Wound healing: PUSH scale day 1 to day 10: 11.4 to 7.7 (treatment group) versus 10.3 to 10.0 (control group) (p < 0.001) ↓ VAS pain scores: 3.8 to 2.8 (treatment group) versus 3.8 to 2.8 (control group)	RCT Unsure whether blinded Sample size (n = 29 per arm = 80% power)
		Song et al. (2021)	N = 112 Adult	Micro‐oxygen therapy (Zhengzhou Runyuan Medical Instrument Co., Ltd., China)	Topical oxygen therapy on the basis of negative‐pressure wound therapy with the use of a micro‐oxygen therapy instrument (oxygen flow rate was 3 L/min, temperature was between 27 and 28°C, humidity was 65%; oxygen was given constantly each day for 2 weeks)	Chronic traumatic wounds	2 weeks + follow up 3 months	↑ Wound healing (PUSH): exudate volume within 24 h, pressure ulcer area, type of the wound tissue all decreased (lower in intervention group) (all p < 0.05) ↑ Granulation from day 3–14: higher in intervention group versus control (all p < 0.05) ↓ Culture‐positive rate after treatment: lower in the intervention group than in the control group (p < 0.05) ↑ Healing rate at 3 months: 89.29% (50/56) (intervention) versus 73.21% (41/56) (control) (p < 0.05) ↓ Healing time at 3 months: 27.34 ± 5.68 (intervention) days versus 33.47 ± 6.83 days (control) (p < 0.05)	RCT Unsure whether blinded No sample size calculation included
		Onouye et al. (2000)	N = 3 Adult	Oxygen mist	Mist (93% oxygen delivered at a rate of 15 L/min) (half face) + occlusive dressing (half face)	CO2 laser resurfacing	5 days	↓ Crusting observed on the half of the face treated with the oxygen mist (p < 0.05)	Retrospective case series
		Tang et al. (2020)	N = 53 Adult	Topical oxygen therapy (unspecified device)	Topical oxygen therapy (continuously generate pure, humidified O2 at flow rates of 3–15 mL/hr and deliver it to the wound bed via tubing, typically 90‐min 1×/day)	Malignant fungating wounds	6 days	↓ Odour and exudation TOT versus non‐TOT (p < 0.05) ↓ Haemorrhage cases: after TOT, the number reduced to 10 (p < 0.05) ↑ QoL: TOT had a higher QLQ‐C30 score (p < 0.05) No significant difference in VAS pain scores	Retrospective observational case series
Singlet oxygen		Kammerlander et al. (2011)	N = 73 Adult	Singlet oxygen	ActiMaris: a hypertonic (3%) ionised (pH 9.8) sea water solution	Stagnating wounds	42 days	↑ Healing: at 42 days 33% wounds healed and 58% improved (>20% reduction in size) ↓ Signs of critical colonisation & infection: 42% wounds infected at baseline versus 0% at 42 days ↓ Offensive odour: offensive odour resolved in all cases, with a mean score of 1.2 (SD ± 0.96) ↑ QoL: Day 0 mean score 4.2 (±3.8) versus 1.8 (±1.6) at day 42	Clinical evaluation (cohort study)
		Ding et al. (2021)	N = 15 Mice (5 groups)	Singlet oxygen	Singlet oxygen generation by DhaTph‐membrane under natural light irradiation	Infected wounds with Staphylococcus aureus	14 days	↓ Bacterial survival rate (IBU@DhaTph‐membrane under sunlight) ↓ % wound area (IBU@DhaTph‐membrane under sunlight)	In vivo study
		Ye et al. (2022)	N =? 3 groups Mice	Reactive oxygen species incl. singlet oxygen	Two‐Dimensional Pd@Ir bimetal nanosheet	Surgical wounds infected with MRSA	10 days	↓ Wound area: reduced to ∼13% (Pd@Ir group) versus ∼31% (Pd NS control group) and ∼50% (PBS control group) Biocompatible and biosafe: negligible damage to the liver and kidney functions of mice	In vivo study
		Gong et al. (2022)	N =? 4 groups Mice	Reactive oxygen species incl. singlet oxygen	Zn2GeO4:Cu2+ (ZGC) persistent luminescence nanorods	Surgical wounds infected with MRSA	9 days	↓ Relative wound area: wound area of control groups no treatment (21.5%), blank MNs (19.3%), ZGC@MNs treatment (17.5%) were 4.3, 3.9 and 3.5 times larger than the ZGC@MNs under pre‐illumination treatment group (5.0%) System toxicity: MNs and ZGC@MNs caused negligible lesion to organs	In vivo study
		Zhu et al. (2021)	N =? 5 groups Mice	Singlet oxygen	L‐Arg‐rich amphiphilic dendritic peptide	Subcutaneous abscesses	10 days	↑ Qualitative wound parameters (scab formation) ↑ Bacteria elimination: the combination of PDT and NO achieved a significant synergistic therapeutic effect No apparent biotoxicity due to Ce6@Arg‐ADP + laser was observed	In vivo study
		Li et al. (2021)	N =? 4 groups Mice	Reactive oxygen species (assuming singlet oxygen)	Spirulina platensis hydrogel + laser therapy producing ROS	Escherichia coli and S. aureus infected wound	6 days	↑ Wound closure in the SP gel + laser group versus other groups ↓ Wound area: decreased to 62.1% (SP gel + laser group) versus 92.3% (control group) Biosafety: liver and kidney function indexes were within the normal range	In vivo study

Abbreviations: CCD, conventional compression dressings; CDO, continuous diffusion of oxygen; CG, control group; CI, confidence interval; DFU, diabetic foot ulcers; DFS‐SF, diabetic foot ulcer scale ‐ short form; HR, hazard ratio; MRSA, methicillin‐resistant Staphylococcus aureus; MWD, moist wound dressing; NNT, number needed to treat; NPWT, negative pressure wound therapy; OR, odds ratio; PBS, phosphate‐buffered saline; PDT, photodynamic; PP, per protocol; PSM, propensity score matched; PUs, pressure ulcers; PUSH, pressure ulcer scale for healing; RCT, randomised controlled trial; ROS, reactive oxygen species; RR, relative risk; SOC, standard of care; SP, spirulina platensis; TOT, topical oxygen therapy, VAC, vacuum assisted closure; VAS, visual analogue scale.

^a Potential overlap with RCT by Driver et al. (2017).

^b Interim results of RCT by Niederauer et al. (2018).

^c Interim results of RCT by Niederauer et al. (2018).

^d Results possibly included in a larger study by Tawfick and Sultan (2013).

^e Results possibly included in a larger study by Hunt and Elg (2017).

3.1. Findings from meta‐analyses and systematic reviews

Eight systematic reviews including three meta‐analyses were included in this scoping review. All three meta‐analyses focused on diabetic foot ulcers. The results from the meta‐analyses showed that TOT compared to standard of care (SOC) alone leads to improved wound healing (RR: 1.59; 95% CI: 1.07–2.37; p = 0.021), ¹¹ diabetic foot ulcers are more than two times more likely to heal with TOT than with SOC alone (OR = 2.49; CI 95%: 1.59–3.90, p = 0.00001) ⁸ and increased likelihood of diabetic‐related ulcer healing compared to controls (RR = 1.94; 95% CI: 1.19–3.17). ⁷ Out of the eight systematic reviews, six studies focused on diabetic foot ulcers, one study on chronic and acute wounds ¹⁰ and one study on non‐healing wounds. ¹² Overall, there was evidence supporting the effectiveness of topical oxygen therapy (TOT) for the treatment of wounds.

Seven systematic reviews ⁷ , ⁸ , ⁹ , ¹⁰ , ¹¹ , ¹² , ¹³ concluded that TOT improves various aspects of wound healing such as reduction in ulcer size and depth, ⁹ improved wound oxygenation ¹² and increased wound closure. ¹³ A study by de Smet et al. ¹⁰ concluded that within the included 10 TOT studies, seven reported at least one or more significant positive wound outcomes in chronic or acute wounds, or both. A variety of wound outcomes was reported by the 10 included studies which included observational as well as experimental studies. Findings from a recent systematic review ⁷ indicate that the impact of TOT on amputation rates and cost‐effectiveness remains unclear. Only one systematic review ¹⁴ that included four RCTs and two cohort studies, reported less promising results on wound healing. The authors concluded that TOT does not seem to be more effective in diabetic foot ulcer healing when compared with best standard of care, with quality of evidence being assessed as low. The inclusion criteria of this study however differed from the other systematic reviews because the authors also included studies researching topical hyperbaric oxygen (of those two studies, one RCT reported no apparent reduction in the ulcer area at 14 days). ¹⁵

Reviews reporting adverse events mostly described that TOT was well‐tolerated. Adverse effects were reported by all but two reviews, ⁹ , ¹⁰ although three reviews reported that adverse effects were reported but no further information was available. ⁸ , ¹² , ¹⁴ Sun et al. ¹³ concluded that TOT had no effect on the occurrence of adverse events. Carter et al. ¹¹ reported that adverse events were similar in both groups (TOT and standard of care) for all studies. Thanigaimani et al. ⁷ was the only study that reported serious adverse events (requirement for amputation, mortality rates), however it was not clear whether any were related to TOT.

3.2. Continuous oxygen therapy

Continuous oxygen therapy delivers 98%–100% oxygen to the wound bed continuously at a rate of 3 to 15 mL/h. Patients are required to wear a small portable device that is attached to the wound 24 h a day for a pre‐defined number of days. Of 49 included studies, 13 researched the use of continuous oxygen therapy for the treatment of various wound types, with diabetic foot ulcers (DFU) being the most common type (n = 10), followed by venous leg ulcer (n = 1), surgical wounds (n = 1) and various wounds (n = 1). Four studies used Natrox, four used TransCu O₂, two used non‐specified transdermal continuous oxygen therapy, one used Epiflo, one used a micro‐oxygen supply device and one used oxygen‐irrigated wound negative pressure.

Nine out of the 13 studies were undertaken as RCTs, although two RCTs ¹⁶ , ¹⁷ were interim findings of a larger RCT using TransCu O₂ in DFUs. ¹⁸ This review therefore only reports findings from the final RCT to prevent double‐counting. Findings form the RCT show that improved wound healing in DFUs was seen at 12 weeks: a significantly higher proportion of DFUs healed in the treatment arm compared with placebo (32.4% vs. 16.7%, p = 0.033) and the time to 50% DFU closure was significantly shorter in patients that received CDO therapy (mean 18.4 vs. 28.9 days, p = 0.001). ¹⁸ Yu et al. ¹⁹ conducted an RCT in 20 patients demonstrated that the use of Natrox resulted in 100% healing rates in the Grade II diabetic foot ulcers treatment group compared to 0% in the control group at 8 weeks. A Randomised Clinical Study by Driver et al. ²⁰ using Epiflo in 17 patients with diabetic foot ulcers concluded that there was a statistically significant difference in the average wound size reduction of 87% (55.7%–100%) in the treatment group compared with 46% (15%–99%) in the control group (p < 0.05) at 4 weeks. Driver et al. ²¹ conducted an RCT 4 years later that evaluated the transdermal continuous oxygen therapy in 130 patients with DFUs. Their findings showed that at 12 weeks 54% of wounds in the treatment group fully healed compared with 49% in the control group although the findings were not statistically significant (p = 0.4167). An RCT of 145 patients with DFUs using Natrox ²² compared complete wound closure at 12 weeks and reported a closure in 44.4% TOT group compared with 28.1% standard of care group (SOC) (p = 0.044). A recent RCT into diabetic foot ulcers conducted by Al‐Jalodi et al. ²³ reported that in the Intention to Treat analysis, 18 patients healed in the SOC group at 12 weeks (28.1%) compared with 36 in SOC Plus TOT (44.4%) (p = 0.044). Further, the authors reported 85% of TOT group remained healed at 1 year compared to 60% of the control group.

He and colleagues ²⁴ conducted a clinical trial using a micro‐oxygen supply device (Greens O‐4–3) in DFU which led to significantly decreased mean wound healing times when using a combination of standard care and continuous oxygen therapy (p < 0.05). An observational study by Tang et al. ²⁵ reported a 91.3% wound area reduction by 3 months from baseline using Natrox in diabetic foot ulcers.

Other studies investigated the efficacy of continuous TOTs on surgical wounds, ²⁶ venous leg ulcers ²⁷ and various wound types ²⁸ with all three reporting a positive impact of TOT on wound healing. A proof‐of‐concept RCT ²⁶ into surgical wounds using TransCu O₂ reported a > 10% of scar length reduction at 4 weeks (88.8% of the intervention compared to the control group 28.5%, d = 0.48, p = 0.049). A randomised clinical trial conducted by Wang and Yu ²⁸ used oxygen‐irrigated wound negative pressure which showed statistically significant results in decreasing wound area and depth (all p < 0.01) and increasing granulation tissue (p < 0.01) when comparing the treatment and control groups in‐patients with various wound types (16 incision cases, 11 IV‐degree pressure sore cases, 9 trauma cases and 2 other cases). Results from a prospective comparative study ²⁷ showed that transdermal continuous oxygen therapy for venous leg ulcers increased wound closure (p < 0.001) and decreased wound area (p < 0.001) in the treatment group compared to controls.

3.3. High‐pressure oxygen therapy

Seven studies employed high‐pressure oxygen therapy which was delivered at high pressure of between 5 and 50 mbar. The most commonly used device was the TWO2 device (n = 5) which delivers oxygen via a chamber, the other two studies used a non‐specified topical pressurised oxygen therapy. Two of the seven included studies were undertaken as RCTs. An RCT by Frykberg et al. ²⁹ of 73 patients with diabetic foot ulcers using TWO2 HyperBox showed increased closure rate of 41.7% in the treatment group compared with 13.5% in the sham group (p = 0.010) at 12 weeks. An RCT conducted by Azimian et al. ³⁰ applied an unidentified high‐pressure transdermal wound oxygen therapy with a direct application of humidified high‐pressure 10 L/min oxygen to the wound site for 20 min, three times a day for 12 days for the treatment of 100 grade II‐IV pressure ulcers resulted in increased complete closure at 12 days in 16/50 pressure ulcers in the treatment group compared to 1/50 pressure ulcers in the control group (p < 0.001). A prospective, controlled study ³¹ in diabetic foot ulcers showed statistically significant difference in complete epithelisation when comparing the treatment and control groups (82.4% vs. 45.5%, respectively, p = 0.04). Further, two comparative studies using TWO2 for the treatment of venous leg ulcers demonstrated a statistically significant decrease in Methicillin‐resistant Staphylococcus aureus (MRSA) infection rate of venous leg ulcers although no information was provided on how the infection was measured ³² ; and complete healing of ulcers at 12 weeks in 80% of the TWO2 group compared to 35% of the conventional compression dressings group (p < 0.0001). ³³ A comparative study by Singh et al. ³⁴ compared the effectiveness of indigenous negative pressure wound therapy (NPWT) with conventional NPWT, and indigenous NPWT with added topical pressurised oxygen therapy. The results show that patients who received indigenous NPWT with added topical pressurised oxygen therapy achieved the highest mean wound area and depth reduction, and increased sterile cultures of infected wounds after treatment. A matched cohort study by Yellin et al. ³⁵ concluded that the control group (no TWO2) had nearly nine times higher risk of hospitalisation and five times higher risk of amputation compared with the TWO2 group.

3.4. Intermittent oxygen delivery

Intermittent oxygen delivery category was created for studies who did not deliver oxygen continuously but intermittently. Oxygen was delivered at flow of 10 L for 20 min twice a day through sterile coating that covered the entire ulcer, ³⁶ 5‐6 L for treatment for 5 days of 60 min a day followed by a 3‐day break through a sheet covering wound connected to an oxygen cylinder, ³⁷ and 6‐8 L for 30 min with intermittent O₂ blowing maintained for 12+ h every day via a cup with holes. ³⁸ Three studies were identified that used an intermittent oxygen delivery. Of those, one study focused on paediatric patients only while another study included both adult and paediatric patients. A double‐blinded clinical trial ³⁶ of stage III pressure ulcers in 80 children showed that at 2 weeks the wound surface area decreased in 95% of patients in the intervention group compared to 77.5% of the patients in the control group (p < 0.0001), the amount of drainage in the intervention group was reduced by 97% compared to 77.5% in the control group (p < 0.0001), the PUSH score decreased in 100% of the treatment group patients compared to 92.5% in the control group (p < 0.0001). A non‐randomised prospective study of 60 traffic‐related traumatic wounds in adults and children ³⁷ that compared VAC with TOT found that TOT led to a decreased percent wound area and increased epithelisation (both p < 0.05). A retrospective analysis study by Yu et al. ³⁸ used a cup with holes to deliver oxygen to superficial malignant tumour ulcer wounds. The results showed that the treatment group compared to the control group experienced a higher total effective rate of treatment (93.75% compared to 65.63% p = 0.002), lower frequency of dressing change (times) of 19.96 ± 3.50 in the treatment group compared to 30.75 ± 3.71 in the control group (p < 0.05) and lower VAS scores 2.25 ± 0.67 compared to 3.84 ± 0.76 (p < 0.0001).

3.5. Topical oxygen therapy—temperature

One pilot RCT ³⁹ used the KADAM device to deliver topical oxygen at a controlled temperature of 42°C, a concentration of 93% (± 3%) and a flow rate of 1 L/min for the treatment of grade III pressure ulcers. The comparison of the treatment and control group showed a reduced mean wound area in the treatment group (p = 0.019) and improved quality of life from baseline to week 6. The IVDP‐QoL score in the intervention group was 7.5 (95% CI: 3.23, 11.77) compared to 4.44 (95% CI: −9.75, 18.64) in the control group.

3.6. Oxygen dressings

Two studies were identified to use an oxygen dressing, namely the Oxyzyme dressing and the OxyBand dressing. The Oxyzyme is an oxygenating hydrogel dressing containing glucose oxidase to make hydrogen peroxide and a halide to make iodine. Upon the contact with the wound surface, the hydrogen peroxide is converted to water and dissolved oxygen by serum catalase in the wound. The OxyBand is a multilayer dressing that is prefilled with pure oxygen that is continuously released into the wound bed. OxyBand acts as an oxygen‐emitting reservoir. Although the Oxyzyme/Iodozyme RCT by Moffatt et al. ⁴⁰ showed no statistically significant difference in healing rates at 12 weeks compared to standard care (49.1% control vs. 44.7% treatment), Oxyzyme decreased the frequency of dressings changes (p = 0.033) and reduced mean costs per patients £436 (treatment group) compared to £525 (control group). Results from a single‐centre, prospective, randomised, controlled, open‐label study conducted by Lairet et al. ⁴¹ in 17 patients with foot ulcers showed that OxyBand reduced mean time to healing (9.3 ± 1.7 days in the OxyBand group compared to 12.4 ± 2.7 days in the Xeroform group) (p < 0.001) and pain scores on postoperative days 4 and 12 (both p < 0.05).

3.7. Oxygen transfer

For the purpose of this review, oxygen transfer refers to oxygen delivery from gas to the surface of the wound using a spray. In total, five studies evaluated the effectiveness of a haemoglobin spray for wound healing. Four studies evaluated Granulox (Infirst Healthcare) and one study evaluated an aqueous 10% solution containing 10% carbonylated haemoglobin as does Granulox. Each study researched the use of a haemoglobin spray for different wound types, that is, foot ulcers, venous leg ulcers, sloughy wounds, diabetic foot ulcers and chronic wounds which makes comparisons challenging. An RCT by Jonker et al. ⁴² researched the twice‐weekly use of Granulox for the treatment of foot ulcers but did not find that Granulox led to favourable healing at 12 weeks. The control arm that received standard care achieved higher healing rates: 8/14 healed in the control group compared with 4/15 healed in the treatment group (p = 0.14). Moreover, the median percentage ulcer size reduction between the start and 12 weeks was 100% in the control group compared with 48% in the treatment group (p = 0.21). Two studies comparing a cohort with retrospective controls ⁴³ , ⁴⁴ reported significantly improved wound healing: decrease in wound size in the treatment group compared to the control (p < 0.05) and decrease in mean slough coverage (p < 0.001). A retrospective cohort study ⁴⁵ showed that Granulox led to decreased healed rates with 90% of the treatment group completely healed compared with 38% of the control group at 26 weeks (p < 0.001). In addition, the mean time to complete wound healing was 6.6 weeks (range: 3–22) in the haemoglobin spray group compared with 11.4 weeks (range: 3–25) in the control group (p = 0.01). A prospective, randomised, single‐blinded, monocentric study ⁴⁶ that applied an aqueous solution with 10% carbonylated haemoglobin reported a positive outcome on wound healing of venous leg ulcers at 13 weeks. Their findings showed that the mean reduction in wound size at 13 weeks was 53.4% in the treatment group (p > 0.0001) with 1/33 venous leg ulcers increasing in size. In contrast, 17/31 participants in the control group showed an increase in wound size with the remaining 14/31 participants showing only a slight decrease in wound size. The treatment group displayed higher levels of pain reduction measured by visual analogue scale of 68% from baseline to day 91 (p < 0.01) compared to 7% in the control group (p > 0.05). The authors however do not report ITT analysis results or offer any comparison of difference in outcomes between the treatment and the control group.

3.8. Other forms of topical oxygen therapies

Topical oxygen therapy was delivered in other modes such as oxygen jet, ⁴⁷ oxygen mist, ⁴⁸ topical oxygen therapy on the basis of negative‐pressure wound therapy with the use of a micro‐oxygen therapy instrument, ⁴⁹ and an unspecified topical oxygen therapy delivered at 3–15 mL/h ⁵⁰ (Tang et al. 2020). Results from two RCTs ⁴⁷ , ⁴⁹ showed that the TOT treatment group had improved pressure ulcer scale for healing (PUSH) scores compared to the control group (both p < 0.05). The remaining two studies were retrospective case series that reported less crusting on the half of the face treated with the oxygen mist (p < 0.05), ⁴⁸ reduced odour and exudation (p < 0.05) and improved quality of life (p < 0.05) in TOT group compared to non‐TOT group. ⁵⁰

3.9. Singlet oxygen

Singlet oxygen is one of the reactive oxygen species that carries higher energy than normal oxygen. In this review, six studies were identified that used singlet oxygen for wound healing although none of these was undertaken as an RCT. Only one was conducted on humans and the remaining five on mice. The one study on humans evaluated the clinical effectiveness of singlet oxygen in cleansing and disinfecting stagnating wounds with ActiMaris, a hypertonic, ioinised sea water solution in 73 participants. ⁶ The following wound types were included: venous leg ulcer (n = 25), mixed leg ulcer (n = 13), surgical wound (n = 10), DFU (n = 8), post infection (n = 4), trauma (n = 5), pressure ulcer (n = 4), arterial leg ulcer (n = 1) and other wound type (n = 3). The results showed that 90.4% of the stagnating wounds healed and improved within the treatment period of 42 days from baseline. At baseline, almost a half of the wounds (42%) showed clinical signs of critical colonisation (a term that lacks international standardisation) and 16% of infection as confirmed by a wound swab, infection was eradiated at day 42. In addition, the effect of ActiMaris on peri‐wound skin inflammation was assessed using a four‐point scale, based on a modified Physician Global Assessment scale. At day 0, peri‐wound skin inflammation was present in all of the included wounds, with a mean score of 3.6 (SD ± 3.12) on the four‐point scale. At day 42, peri‐wound skin inflammation had resolved in 60% (n = 44), with a mean score of 1 (SD ± 1.02); was minimal in 33% (n = 23), with a mean score of 1.7 (SD ± 1.14); and was moderate in 7% (n = 6), with a mean score of 2.8 (SD ± 2.62). As this was a cohort study, there was no control group. The authors also report results from a follow‐up study of 1158. Of the 33% (n = 386) of patients that had wounds with symptoms and signs of critical colonisation and/or infection at day 0, 28% (n = 108) had resolved within 14 days of treatment. Eradication of infection was confirmed by comparing wound cultures taken on days 0 and 14, together with the clinical picture of symptoms and signs. No adverse events were reported when performing wound cleansing and/or wound disinfection with ActiMaris.

Five in vivo studies ⁵¹ , ⁵² , ⁵³ , ⁵⁴ , ⁵⁵ focused on infected wounds in mice. All but one study ⁵¹ included a small or unclear sample size. Singlet oxygen was delivered via a membrane (singlet oxygen generation by DhaTph‐membrane under natural light irradiation), nanosheet (two‐Dimensional Pd@Ir bimetal nanosheet), peptide (L‐Arg‐Rich Amphiphilic Dendritic Peptide), nanorods (Zn₂GeO₄:Cu₂+ (ZGC) persistent luminescence nanorods) and hydrogel (Spirulina platensis hydrogel + laser therapy producing ROS). The study by Li et al. ⁵⁵ does not specifically mention singlet oxygen, but the authors use the more generic term, reactive oxygen species (ROS). However, on analysing their methods used, it is clear that the ROS they refer to is indeed singlet oxygen therefore this study was included in the analysis. The study by Ding et al. ⁵¹ utilised two membranes and various types of light to compare their impact on wounds infected with S. aureus by detecting the secretion of inflammatory cytokines. The use of the DhaTph‐membrane under natural light irradiation resulted in little secretion which would indicate its photodynamic antibacterial performance. All mice treated with the DhaTph‐membrane survived and gained weight 7 days after the infection. The study by Ye et al. ⁵² investigated the effect of Two‐Dimensional Pd@Ir Nanosheets, that can generate singlet oxygen and hydroxyl radicals, and compared them with two control groups using phosphate‐buffered saline and Pd nanosheets for the treatment of MRSA‐infected wounds in mice. Their findings showed that the wound area in the group treated with the singlet oxygen‐generating Pd@Ir nanosheets was reduced to ∼13% compared with two control groups in which the wounds decreased to ∼31% (Pd nanosheet group) and ∼50% (phosphate‐buffered saline group) at ninth day of treatment. From the publication, it remains unclear whether these findings are statistically significant or not. Moreover, the skin tissues of the sacrificed mice were analysed and mice treated with the Pd@Ir nanosheet showed the least number of remaining bacterial colonies. The authors concluded that the Pd@Ir Nanosheets have a potential to improve the healing of infected wounds due to their ability to generate singlet oxygen and hydroxyl radicals.

The study by Gong et al. ⁵³ investigated the use of Zn₂GeO₄:Cu₂+ nanorod‐loaded microneedle patches in MRSA‐infected wounds in mice. The prepared nanorods were loaded into dissolvable microneedle patches that allowed them to penetrate biofilms and continuously release singlet oxygen. The results from in vivo experiments are missing in the paper, therefore we are unable to make any conclusions about the effectiveness of the Zn₂GeO₄:Cu₂+ nanorod‐loaded microneedle patches.

Zhu et al. ⁵⁴ investigated a versatile PDT‐driven controllable NO generation system (Ce6@Arg‐ADP) that was developed with l‐Arg‐rich amphiphilic dendritic peptide (Arg‐ADP) as a carrier. The system produces massive NO without affecting the production of singlet oxygen and the system was developed for NO/PDT synergistic treatment of subcutaneous abscesses and to promote wound healing of MRSA‐infected subcutaneous abscesses in mice. The findings from the study show that the combination of photodynamic and NO gas therapy using L‐Arg‐rich amphiphilic dendritic peptide as a donor has a potential to improve the treatment of subcutaneous abscesses based on the results from the bacterial viability test on day 10 compared to the other four groups. The findings suggest that the combination of NO and singlet oxygen may exert synergistic antibacterial and biofilm eradication effects.

A study by Li et al. ⁵⁵ researched the use of a bioactive living hydrogel including a photosynthetic bacteria spirulina platensis (SP) that can generate oxygen to relieve acute and chronic tissue hypoxia.

SP is believed to have antibacterial activities because it contains large amounts of chlorophyll, a natural photosensitiser able to produce ROS (including singlet oxygen) under laser irradiation. The SP hydrogel in combination with laser irradiation was applied to mice with S. aureus infected wounds and compared to three control groups using untreated control, chitosan and SP gel without laser irradiation. On day 6, the group treated with SP gel in combination with laser irradiation showed a significantly improved percentage of relative wound area (∼40%) compared to the SP gel and chitosan groups (∼60%), and control group (∼80%). These findings would suggest that SP gel in combination with laser irradiation is suitable for the treatment of infected wounds.

No, or negligible, biotoxicity was reported by four out of five in vivo studies ⁵² , ⁵³ , ⁵⁴ , ⁵⁵ with one study not investigating biosafety. ⁵¹

4. DISCUSSION

Oxygen plays a vital role in wound healing. ⁵⁶ In some phases of the wound healing process, wounds benefit from hypoxia. However, certain wounds, typically of chronic nature, often lack oxygen which contributes to delayed healing. ⁵⁷ , ⁵⁸ Effective wound management could incorporate improved oxygen supply as one of its strategies to deliver oxygen to the hypoxic tissue to aid skin regeneration. ² , ³ Oxygen therapies can be delivered systemically or locally. Systemic oxygen therapies include hyperbaric and inspired oxygen therapy. Hyperbaric oxygen therapy has been used for wound healing for several decades ⁵⁹ , ⁶⁰ and is delivered via a high‐pressure chamber which cannot be easily transported. To address the issue, other ways of oxygen delivery have been researched in recent years. Topical oxygen therapy (TOT) may offer a useful alternative to the systemic oxygen therapy. ⁵ Chronic and non‐healing wounds represent a significant burden to the healthcare service due to high treatment costs. The prevalence of chronic wounds in the UK is estimated to be rising annually which emphasises the need for finding effective treatment methods. ⁶¹

The number of recent studies published within the last 5 years would imply that topical oxygen therapies for wound healing are becoming an area of interest. Findings from this scoping review show that TOTs have been used in various mode of administration (as shown in Figure 2), and indicate that there is a growing evidence of the effectiveness of TOT as an adjunctive modality for wound healing, especially in diabetic foot ulcers although recent studies show promising results of using TOT for treating pressure ulcers, ³⁰ , ³⁶ infected surgical wounds, ⁴⁷ chronic traumatic wounds, ⁴⁹ skin graft sites ⁴¹ and venous leg ulcers ⁴⁶ although this study should be interpreted with caution as no comparison of the difference between the treatment and control group is offered. There was a variety of included studies from controlled to observational study designs in the included meta‐analyses and systematic reviews which makes comparison challenging. The majority were neither placebo‐controlled nor double‐blinded, which may have a significant impact on the overall study results. Further, study heterogeneity in terms of length and frequency of treatment and type of TOT does not allow for a meaningful comparison. Some studies used a non‐identified TOT or TOT developed for the particular study which further add to the issue of interpreting results from heterogeneous studies. A systematic review by Vas et al. ¹⁴ did not report favourable outcome of TOT, however, the authors also included studies using hyperbaric topical oxygen therapies unlike other studies. This further demonstrates the difficulty of making meaningful comparisons. More research is needed to better understand the impact of TOT on wounds of various aetiologies.

The review identified limited evidence of the impact of TOT on cost‐effectiveness. Similarly, a meta‐analysis and systematic review by Thanigaimani et al. ⁷ concluded that the impact of TOT on cost‐effectiveness remains unclear although the authors stated that three studies concluded that TOT would be cost‐effective compared to hyperbaric oxygen therapy. Interim results from an RCT by Niederauer at el. ¹⁷ concluded that the absolute performance in the TransCu O₂ arm appeared non‐inferior to other reimbursable wound treatment devices. An RCT by Moffatt et al. ⁴⁰ demonstrated that the use of Oxyzyme dressings resulted in decreased mean costs per patient. Although cost‐effectiveness was not one of the aims of the study, findings from a retrospective cohort study by Yellin et al. ³⁵ suggest that patients that were not treated with TWO2 had nine times higher risk of hospitalisation and five times higher risk of amputation compared to the group treated with TWO2 which would imply that TOT may lead to reduced costs as hospitalisation significantly increases associated treatment costs. More research is needed to better understand the cost implication of using TOT for the treatment of wounds.

There is limited evidence of the use of singlet oxygen for wound healing. No RCTs were identified that would investigate the role of singlet oxygen for wound healing. Findings from a cohort study in humans wound imply that singlet oxygen might have potential to aid wound healing. ⁶ However, the chosen study design and lack of control group make it challenging to understand how singlet oxygen affects wound healing in humans. Recent animal studies show that singlet oxygen may be effective in the treatment of infected wounds in mice, ⁵¹ , ⁵² , ⁵³ , ⁵⁴ , ⁵⁵ however, singlet oxygen was delivered via a variety of ways which makes comparisons difficult. More research is needed to better understand the role of singlet oxygen and its impact on wound healing in animals as well as humans.

Adverse events or a judgement of the quality of the evidence were not formal aims of this review. This would be important to include in future studies. Another limitation of this study is the availability of one reviewer only. Although the recommended use of two independent reviewers to conduct screening strengthens the reliability of the study, the approach is labour intensive. When conducting rapid reviews, single screening could be considered as an appropriate methodological shortcut. ⁶²

To conclude, there is evidence that topical oxygen therapy (TOT) may be useful for the treatment of chronic wounds, mainly diabetic foot ulcers. The impact of TOT on other wound types is less researched and requires more attention. The cost–benefit of using TOT remains unclear although their limited evidence suggesting that the use of TOT could lead to cost savings. The role of singlet oxygen in wound healing remains unclear although the findings from one cohort study would suggest that singlet oxygen helps to reduce critical colonisation and infection which is echoed by recent mice studies on infected wounds. It would appear that singlet oxygen has the potential to aid wound healing, however, more research is needed to understand the bio‐properties of singlet oxygen.

FUNDING INFORMATION

The study was jointly funded by SOE Health Ltd and the University of Nottingham.

CONFLICT OF INTEREST STATEMENT

MS was funded by SOE Health Ltd and the University of Nottingham to undertake this study. NS is a managing director of SOE Health Ltd. EB has no conflict of interest in relation to this review. CJM has no conflict of interest in relation to this review. YW has no conflict of interest in relation to this review. SK has no conflict of interest in relation to this review.

Supporting information

Data S1. Supporting information.

Sýkorová M, Moffatt CJ, Stentiford N, Burian EA, Katsuhiro S, Wei Y. Topical oxygen therapy and singlet oxygen in wound healing: A scoping review. Int Wound J. 2024;21(4):e14846. doi: 10.1111/iwj.14846

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available from the corresponding author upon reasonable request.