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Introduction

Diabetic foot ulcers (DFUs) have become much more common in recent years. Currently, DFUs affect 18.6 million people each year and have a prevalence rate of 6.3%.^1,2 Notably, in addition to the high number of people with DFUs, the lifetime risk of lower limb amputation is high at around 19%, and the recurrence rate is higher in individuals with a history of amputation. The recurrence rate within one year after lower limb amputation is 40%. This rate increases proportionally over time, reaching 70% within three years and 75% after five years.^3,4

Therefore, because DFUs are common and complex, they require conventional treatment and effective adjuvant technologies to minimise complications, such as amputations. In this context, researchers and healthcare professionals specialising in wound care have been searching for more effective solutions to prevent, treat or assist in the healing of DFUs.^5,6

Ozone therapy is among the adjuvant therapies that have gained prominence in the literature. It stands out as a technology with promising results in treating difficult-to-heal wounds, such as ulcers. It is a therapeutic method involving the local and/or systemic application of ozone to damaged tissues or organisms. Ozone therapy has bactericidal, anti-inflammatory and analgesic properties. Ozone therapy stimulates the formation of eosinophils, increases collagen fiber production, improves tissue oxygenation and nutrient supply and has a hypoglycemic effect.^7,8

Studies^5,6 show that, due to its properties, ozone therapy optimises tissue repair, reduces wound size and healing time, and decreases the number of infections and amputations compared to standard therapy. Consequently, it decreases complications and healthcare costs while improving the quality of life of affected individuals.

Thus, ozone therapy is used in various fields of healthcare, such as dentistry, medicine and nursing, due to its therapeutic and clinical benefits. In nursing, ozone therapy is increasingly being integrated into care due to its adjuvant potential, primarily for wound care, chronic conditions and pain management.^9,10

Although previous reviews have examined the effectiveness of ozone therapy for DFUs, less attention has been given to the therapeutic parameters used in randomised controlled trials, such as route of administration, ozone concentration, exposure time, number of sessions, treatment duration and application devices.^11,12 Therefore, this review specifically identifies the therapeutic parameters reported in RCTs, providing a clinically oriented synthesis to support future protocol development, guide evidence-based practice and inform the design of more rigorous studies.

Based on the information above, this study aimed to identify scientific evidence related to therapeutic parameters for the use of ozone therapy in people with diabetes mellitus and foot ulcers.

Method

Study design

This is an integrative review, a methodology that assesses and synthesises current knowledge on a given topic.¹³

Methodological framework

The study followed these stages: theme identification and research question selection; literature search and definition of eligibility criteria; data extraction; critical analysis of included studies; integrative review data interpretation and presentation.¹⁴

Research question

The research question was developed based on the acronym PCC¹⁵ to guide the execution of the study. In the acronym, P stands for population (people with diabetes mellitus and foot ulcers), C stands for concept (therapeutic parameters related to the use of ozone therapy), and C stands for context (literature). Therefore, the research question written using the acronym is: “What is the scientific evidence regarding therapeutic parameters related to the use of ozone therapy in people with diabetes mellitus and foot ulcers?”

Eligibility criteria

We included RCTs that described therapeutic parameters for ozone therapy, either alone or in combination with dressings and related products, via local or systemic routes. There were no temporal or language restrictions on publication.

Although integrative reviews may include different study designs,¹⁵ the present review intentionally restricted inclusion to RCTs because the objective was to identify therapeutic parameters under controlled intervention conditions, thereby maximising the reliability and comparability of the extracted data.

Studies that included participants with lesions not related to diabetes, were conducted in animal models or in vitro, as well as review articles, abstracts, conference proceedings, editorials/letters, book chapters, series and case reports were excluded. Studies addressing other chronic wound etiologies, such as venous leg ulcers or pressure injuries, were also excluded because substantial differences in pathophysiology, vascular impairment, neuropathy, infection burden and healing dynamics may influence ozone therapy protocols and treatment response, limiting the applicability of findings to DFU.

Source of data extraction

Data extraction was carried out using the Base de Dados de Enfermagem (BDENF), Literatura Latino-Americana e do Caribe em Ciências da Saúde (LILACS), accessed through the Biblioteca Virtual em Saúde (BVS), as well as the National Library of Medicine (accessed through PubMed), Sciverse Scopus (Scopus), EMBASE, Web of Science and ScienceDirect. The last five databases were accessed through the Coordination for the Improvement of Higher Education Personnel Journals Portal.

The search strategy was developed using controlled terms extracted from the Descritores em Ciências da Saúde (DeCS) and Medical Subject Headings (MeSH). To encompass the largest possible number of studies, a combination of uncontrolled terms was employed. The authors defined the criteria after analysing the elements that comprise the research question and conducting a prior literature review on the subject, as detailed in Table 1.

 

Table 1. Controlled descriptors and keywords

 

The search strategy, which used the Boolean operators “AND” and “OR,” was applied in July 2024 and updated in November 2025, as shown in Table 2. The study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to record the process of identifying, screening, determining eligibility and including scientific studies¹⁶.

 

Table 2. Databases and search strategies used to compile the integrative review.

 

The search strategy was intentionally restricted to DFU because the objective of the review was to identify therapeutic parameters specifically applied to this population. Therefore, prioritising specificity was considered essential to ensure the clinical applicability of the findings to people with DFUs.

Study screening and selection

A paired search was conducted in the databases, and the scientific documents were transferred to the Rayyan platform in Research Information Systems file format. Two researchers independently assessed and selected the articles found in the databases.

Subsequently, a duplicate document check was performed, during which only one copy of each document was kept and duplicates were excluded. The screening process was carried out in two phases: first, the titles and abstracts of the articles were read, and the theme and study design were analysed; second, the articles were read in full to determine eligibility.

Disagreements between reviewers during the screening process were resolved by consensus through discussion among the reviewers regarding study eligibility.

Data collection

In accordance with the previously established eligibility criteria, scientific documents on the subject were analysed using a data analysis and extraction instrument.¹⁷ The variables of interest included: the title, authors, and year of publication; professional category; objective; sample; country and language; level of evidence; number of weekly sessions; route of administration; application device; application time; ozone dose/concentration; treatment time; ozone generator equipment; and main results. The data were compiled into two tables in Microsoft Word^®.

We used the classification of the level of evidence of the included studies, as proposed by Melnyk and Fineout-Overholt,¹⁸ which defines the following levels: meta-analysis of controlled and randomised studies (Level I); experimental study (Level II); quasi-experimental study (Level III); descriptive/non-experimental study or with a qualitative approach (Level IV); case report or experience (Level V); consensus and expert opinion (Level VI).

The JBI RCTs checklist was chosen to assess the methodological quality of the evidence.¹⁹ This tool assesses the quality of a study’s design, conduct, and analysis to determine the risk of bias. The use of recognised critical appraisal tools is recommended in integrative reviews because it enhances methodological robustness and increases confidence in the interpretation of review findings.²⁰

Data synthesis

The main results of the studies included in the final sample were examined and synthesised. They were then organised into tables to make the results easier to understand and present.

Results

The database search yielded 474 documents, of which 167 were excluded after a duplicate analysis. After reviewing the titles and abstracts, an additional 299 documents that did not meet the eligibility criteria were excluded. Eight articles were selected for a full reading of the text. After a thorough reading, two articles were excluded. Ultimately, six articles were deemed eligible for inclusion in the integrative review sample, as illustrated in Figure 1.

 

Figure 1. Illustrative flowchart of the study screening and selection process,
adapted from the Preferred Reporting Items for Systematic Reviews and
Meta-Analyses recommendations.¹⁶

 

The six articles included in the integrative review are described in Table 3. The articles were published in the following years, one in each year: 2023, 2020, 2019, 2014, 2011 and 2005. The studies were conducted in several countries, including Poland, Iran, China, Israel and Cuba. They were published in English (n=5) and Chinese (n=1). Concerning the level of evidence classification, all studies were classified as Level II.

 

Table 3. Characterisation of the studies included in the review by title, author, year, objective, sample, country, language and level of evidence (n=6).

 

The majority of the research aimed to assess the effectiveness of ozone therapy in treating people with diabetes mellitus and foot ulcers. A total of 597 people diagnosed with diabetes were included in the study.

The assessment of methodological quality (Table 4) revealed that two studies (33.33%) adequately described the randomisation process (Q1), and only one study (16.67%) clearly presented allocation information (Q2). Furthermore, three of the assessed articles (50%) discussed the similarity between the groups (Q3). All six articles (100%) had insufficient information on patient blinding regarding treatment (Q4), and only one (16.67%) mentioned blinding of the professionals administering treatment (Q5).

 

Table 4. Critical analysis of the methodological quality of studies according to the JBI.

 

All studies were unclear about blinding outcome assessors (Q6). All of the studies provided clear information on whether treatment groups were treated equally, except for the intervention of interest (Q7). However, only two articles (33.33%) presented information on follow-up (Q8). Patient analysis was performed according to randomisation in all six of the investigated articles (Q9), and outcome measurements between treatment groups were well described (Q10). All studies lacked clarity about the reliability of outcome measurements (Q11). Four studies (66.7%) employed adequate statistical analyses (Q12). All of the analysed study designs were considered adequate (Q13).

Table 5 shows the therapeutic parameters and main results from the studies. The number of weekly sessions reported in the included studies was as follows: five (A1), two (A3), seven (A4 and A6), and four in the first phase of treatment and two in the second phase (A5). The application routes were topical (A1–A6) and systemic (A3 and A6). The application devices were an ozone bag (A1–A6), rectal insufflation (A3 and A6), and an ozonised oil solution for subcutaneous injection (A3). The application time for the ozone bag was 30 minutes for A1, A2, A3, and A4; 26 minutes for A5; and 60 minutes for A6. Oil applications occur every 12 hours.

 

Table 5. Characterisation of the articles included in the integrative review according to therapeutic parameters and main results.

 

The following concentrations were used in relation to ozone concentration, as reported by the authors: 40mg/L (A1), 35mg/L (A2), 52mg/L (A4), 80mg/L and 40mg/L (A5), 50mg/L (topical) and 60mg/L (systemic) (A6). Treatment time was established as follows: 30 sessions for A1, 20 sessions for A3, A4, and A6, 32 sessions for A5, and three weeks for A2. Different types of ozone generator equipment were used.

Incomplete reporting of therapeutic parameters was observed in some studies. Specifically, A2 did not report the frequency of weekly treatment sessions, whereas A3 did not provide detailed information regarding ozone concentration or generator characteristics. These reporting limitations hindered direct comparison across protocols and restricted a more comprehensive assessment of the consistency and applicability of the reported therapeutic parameters.

After topical application of ozone using an ozone bag to the lesion, the articles demonstrated that ozone therapy reduced the lesion area (A1, A2, A4 and A6) and was effective in healing DFUs (A5). It also had analgesic (A1, A2) and antimicrobial (A2) effects, stimulated growth factor production in wounds (A2, A4), decreased amputation rates (A3), reduced C-reactive protein levels and increased collagen production in lesions (A4). Additionally, systemic ozone application decreased fasting blood glucose levels and erythrocyte sedimentation rate (A3), blood glucose levels and insulin resistance and reduced hospitalisation time and treatment costs (A6).

Discussion

This review adds to the existing literature by focusing not only on the clinical effects of ozone therapy, but specifically on the therapeutic parameters reported in RCTs involving DFUs. This parameter-focused approach allowed the identification of recurring patterns in ozone therapy protocols while also highlighting substantial heterogeneity across studies.

Based on the analysed therapeutic parameters, most studies reported daily application, topically, using an ozone bag for 30 minutes, totaling 20 sessions. The ozone concentrations most frequently reported ranged from 35 to 60mg/L, while higher concentrations, such as 80mg/L, were restricted to specific treatment phases. The main benefits of ozone therapy for DFU were reduced lesion area, analgesic and antimicrobial effects via topical application and reduced fasting blood glucose levels and insulin resistance via systemic application. However, the current evidence remains insufficient to establish optimal treatment protocols because direct comparisons between different parameter combinations were not performed.

Regarding the number of weekly applications, it was established that daily application without interruption was necessary. In contrast, a study conducted in Poland adopted a frequency of five sessions, excluding Saturdays and Sundays.⁷ This finding may be related to the residual effect of ozone, which triggers lasting responses in the antioxidant and immune systems, as well as modulating inflammation.

Another important therapeutic parameter is the route of administration. In this regard, the primary route employed in the analysed studies was topical. Kadir et al⁸ supported this finding when they used the same method to analyse the effectiveness of ozone in healing DFU. Local application allows the ozone to act directly on the lesion. Furthermore, this method provides a prolonged residual effect due to its more effective healing and antimicrobial action.^26,27

The ozone bag is the method of choice for the topical application of ozone. A study of 50 patients with DFUs used this method as part of its clinical protocol.²⁸ A factor that explains its greater use is the lower probability of adverse events and better patient acceptance of the treatment.

As for the duration of each treatment session, most of the analysed studies opted for a 30-minute session. Qin et al²² used the same exposure time for the lesion to ozone in their research. According to the literature, the use of ozone for prolonged periods may result in oxidative tissue damage or delayed healing.²⁹

In addition to the duration of the intervention, the total number of sessions must be established. Therefore, half of the included studies reported 20 treatment sessions. A study reported that patients with DFU treated with this number of sessions achieved significantly shorter healing time and lower amputation rates.²² Thus, this quantity enhances these effects by avoiding unnecessary discomfort and prolonging treatment.

In this context, the reported ozone concentration was found to range from 35 to 80mg/L. However, studies^28,30 show that ozone therapy with concentrations between 35 and 60mg/L effectively promoted ulcer healing. However, it is worth noting that high concentrations can generate toxic effects on tissues, which may delay the healing process or cause local irritation.

Although concentration ranges were reported, the available studies did not directly compare different ozone concentrations under similar clinical conditions. Consequently, no conclusions can be drawn regarding dose–response relationships or the superiority of specific concentration ranges. Future studies should be specifically designed to compare ozone doses while controlling treatment duration and frequency of application.

Safety reporting was limited across the included studies. Although no major adverse events associated with ozone therapy were described, the available evidence was insufficient to establish safety thresholds or determine the concentration limits associated with optimal risk–benefit profiles. Standardised reporting of adverse events should be encouraged in future RCTs.

The main benefits of topically applied ozone were identified as the reduction of lesion area, an analgesic effect and the stimulation of growth factor production. These findings are consistent with those of previous studies.^7,22,29 Ozone can stimulate the healing process by inducing mild, controlled oxidative stress, which increases cell regeneration and growth factor secretion.³¹ Similarly, ozone is effective in reducing inflammation, increasing local oxygenation and relieving pain by promoting a favourable tissue environment.³²

Similarly, the systemic application of ozone is notable for its benefits, such as reducing fasting blood glucose and insulin resistance. Izadi et al³³ support this finding. This application method has been found to reduce blood glucose levels, contributing to the healing process since hyperglycemia impairs it.²⁶

The available evidence also did not allow a robust assessment of associations between specific therapeutic parameters and clinical outcomes. Differences in administration route, ozone concentration, session frequency, treatment duration and outcome definition limited direct comparison across studies. Therefore, the observed clinical benefits cannot be attributed to any individual therapeutic parameter.

Limitations should be considered when interpreting these findings. Only a small number of RCTs were identified, and considerable heterogeneity was observed regarding ozone concentration, administration route, treatment duration, session frequency, outcome measures and reporting practices. In addition, incomplete reporting of therapeutic parameters in some studies limited protocol comparison and precluded assessment of dose-response relationships. The available evidence also did not permit robust evaluation of parameter-outcome associations or the identification of optimal therapeutic protocols.

Nevertheless, the included studies showed convergence regarding some therapeutic parameters. Accordingly, the findings should be interpreted as a descriptive synthesis of the therapeutic characteristics most frequently reported in the literature rather than as evidence supporting a standardised clinical protocol.

Future RCTs should focus on comparing specific therapeutic parameters, including ozone concentration, exposure time, treatment duration, session frequency and administration route. Particular attention should be given to dose–response relationships, safety thresholds and parameter-outcome associations, which remain insufficiently explored in the current literature. Standardised reporting of intervention protocols and clinical outcomes will be essential for developing evidence-based ozone therapy protocols for DFUs.

Conclusions

This review identified the therapeutic parameters most frequently reported for ozone therapy in the treatment of DFU. The most commonly reported protocols involved topical ozone application using an ozone bag for approximately 30 minutes per session, over approximately 20 treatment sessions, with ozone concentrations ranging from 35 to 60mg/L. Although treatment frequency varied among studies, daily application was the most frequently reported regimen. These protocols were generally associated with favorable clinical outcomes; however, substantial heterogeneity and incomplete reporting across studies prevented the identification of optimal therapeutic parameters. Therefore, the findings should not be interpreted as a standardised clinical protocol.

Future RCTs should compare ozone concentrations, treatment durations, session frequencies, and administration routes, while adopting standardised reporting of therapeutic parameters, adverse events, and clinical outcomes to support the development of evidence-based protocols for DFUs.

Author contributions

Conceptualisation: Galvão and Araújo.
Methodology: Galvão, Brandão and Lima.
Investigation: Galvão, Brandão and Lima.
Data analysis and interpretation: Galvão, Brandão, Lima, Silvestre, Santos and Araújo.
Writing – original draft: Galvão, Brandão, Lima and Araújo.
Writing – review and editing: Galvão, Brandão, Lima, Silvestre, Santos and Araújo.
Supervision: Araújo.

Conflict of interest

The authors declare no conflicts of interest.

Ethics statement

Ethics approval was not required because this study is a review of previously published data and did not involve human participants, animals, or identifiable personal data.

Funding

This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

Author(s)

João Wesley da Silva Galvão*¹, Maria Girlane Sousa Albuquerque Brandão¹, Ainoã de Oliveira Lima¹,
Ruth Carolina Queiroz Silvestre¹, Joelita de Alencar Fonseca Santos², Thiago Moura de Araújo^1
1Institute of Health Sciences, University of International Integration of Afro-Brazilian Lusophony, Redenção, Ceará, Brazil
²Center for Health Sciences, Federal University of Piauí, Teresina, Piauí, Brazil

*Corresponding author email wesleygalvao@aluno.unilab.edu.br

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