Abstract
Ozonated water and oil are emerging as potential dermatologic therapeutics, particularly for the treatment of various wounds. However, the safety of these liquids has not been extensively studied. The aim of this systematic review was to evaluate the risks of ozonated liquids to human skin tissue based on the available literature. We completed a structured search of five scientific databases and identified 378 articles for consideration. Based on pre‐established inclusion/exclusion criteria, nine studies were included in this review. Two studies specifically evaluated the cytotoxicity of ozonated liquids on human cells, five studies evaluated ozonated liquids in randomised controlled trials (RCTs), one was a post‐market surveillance study, and one was a crossover study in humans. None of the included studies found any significant human dermatologic risks associated with ozonated water or liquid. Because of the small sample size, however, additional short‐ and long‐term RCTs specifically designed to evaluate the dermatological risks of ozonated liquids are recommended.
Keywords: dermatologic agent, drug‐related side effects and adverse reactions, ozone, topical administration, wound healing
1. INTRODUCTION
Ozone (O3) is an inorganic and highly reactive gas composed of three oxygen atoms. It is both a natural and manufactured product with potent oxidative properties. O3 gas has been studied extensively over the years as a component of the atmosphere as well as in various industrial and commercial applications. Gaseous forms of O3 have been used in the preparation of organic compounds and for disinfection, deodorization, and decontamination in medical and industrial settings.
Liquid formulations of O3 include various ozonated oils and ozonated water. Ozonated oils are produced using an ozone generator and bubbling ozone gas into a natural oil for a specified duration in a reaction chamber followed by a controlled cooling process to stabilise the O3 within the product. 1 Ozonated water is a less stable product produced at the site of usage by one of two methods: coronal discharge, where an electrical discharge is applied to pure oxygen gas or air to create O3 gas, which is then incorporated with water, and by way of direct water electrolysis using low voltage applied to water flowing across a polymer membrane in a compact electrolytic cell. 2 The ozonated water rapidly decomposes upon contact with naturally occurring organic materials, returning to free oxygen and water while releasing the free radicals responsible for disinfection. 1 , 3
Ozonated liquids have been used in industrial and residential applications that exploit ozone's oxidising capabilities. 4 The broad applications for these liquid formulations have included everything from food preparation to decontamination of water pipes. O3 liquids have gained attention in the literature for many clinical applications, including wound care. In the international literature, there are many such references to the utilisation of ozonated liquids in clinical practice, 5 implying that these agents are widely used and accepted treatment modalities. A recent systematic review by Wen and colleagues 6 demonstrated that ozone therapy markedly accelerated the improvement of chronic wounds and reduced the amputation rate. Other studies that include liquid forms of O3 are often of small sample size and lack validation with large randomised controlled trials (RCTs); however, they have shown promising results in the management of venous stasis ulcers, 7 burns, 8 atopic dermatitis, 9 , 10 tinea pedis, 11 , 12 , 13 hand sanitation, 14 diabetic foot ulcers, 15 and other dermatologic conditions.
While the mechanisms of topical O3 therapy remain unclear in some clinical applications, antimicrobial action is thought to be because of its effect of blocking the enzymatic function of bacteria by oxidising glycoproteins and glycolipids. This oxidation of the phospholipids and lipoproteins of the bacterial cell envelope disrupts the cytosolic membrane integrity. 12 , 13
Although the clinical applications of ozonated liquids may suggest that they are safe for topical use, this is contrary to gaseous O3, which has known toxicities in high concentrations or over extended periods of time. It is well known that gaseous O3 is harmful to the human respiratory system. 16 , 17 , 18 , 19 On the other hand, there does not seem to be a consensus paper addressing the safety of topically applied ozonated liquids in humans. Therefore, this comprehensive systematic review sought to assess the possible risks of exposure of human skin tissue to ozonated liquids.
2. MATERIALS AND METHODS
2.1. Search strategy
To retrieve the list of studies on dermatologic risks of ozonated oil and water, a search was conducted in five 5 databases for all years up to September 2020: Web of Science Core Collection, Embase, Cochrane Library, Ovid MEDLINE(R) < 1946 to September 2020>, and Google Scholar. The search consisted of a combination of keywords and MeSH terms used in the title and the abstract as free‐text words (Appendix A). The terms used were associated with ozone in its topical form of oil, gel, ointment, emulsion, water, aqueous, or liquid, in combination with terms related to skin, skin absorption, dermatology, epidermis, epithelium, squamous, or cutaneous. We included proximity or adjacency operators (NEAR or ADJ) to connect search terms in the search string, which were also disaggregated using the truncation symbol (“*”), in most databases to capture different word endings. Limits were added to the searches to exclude non‐English papers and review articles. To discover additional relevant grey literature, we conducted equivalent searches in Google Scholar. The results from all databases used were aggregated and de‐duplicated for screening. All searches in this study were developed and executed by a medical librarian (M.R.).
2.2. Inclusion and exclusion criteria
Studies were included if they evaluated human cells, tissues, or patients who had ozonated water or oil applied topically for any duration. Required outcomes included any evaluation of risk of damage to skin tissue. Examples of risk defined a priori included cellular morphology change or destruction, tissue destruction, pathologic organ change, or antioxidant loss. Inflammatory biomarkers alone were not sufficient, given that there is no consensus from the literature confirming a universally accepted biomarker as an indicator of cellular injury. 20
Case studies and series, theoretical papers, review articles, and abstract‐only studies were excluded. There were no exclusion criteria based on publication date or study location; however, studies were required to be in English for evaluation.
2.3. Selection process
The four authors involved in screening articles (D.R., S.L., B.L., and K.B.) participated in two rounds of training with a sample of 20 articles in each training round to attain a high level of inter‐rater reliability prior to beginning the article screening process. To assess agreement amongst the four raters, interclass correlations (ICCs) were calculated using SPSS statistical package (IBM SPSS Statistics v. 27, RRID:SCR_019096, 2020). The interclass correlation coefficient using a two‐way mixed‐effects model with absolute agreement based on average measures indicated excellent interrater reliability, ICC = 0.90 (95% CI: 0.80–0.96).
Using the aforementioned criteria in the Covidence review manager software (Covidence, RRID:SCR_016484), the authors first screened study titles and abstracts, and then evaluated full‐text studies for inclusion. Two authors reviewed each study at all stages, with a third resolving any disputes.
2.4. Data extraction and risk of bias assessment
The authors collectively extracted basic information and results from the studies. Additionally, we evaluated the risk of bias relative to our desired outcomes using the Cochrane collaboration's risk of bias tool, 21 assigning low, high, or unclear risk for the following categories: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other bias. Two authors independently assessed the risk of bias for each article, using group consensus to resolve any disputes.
3. RESULTS
3.1. Literature search
The literature search returned a total of 378 studies for screening (Figure 1). Following title and abstract screening, 337 studies were deemed irrelevant as they did not meet pre‐determined study criteria. Of the 41 articles that were subject to full‐text review, an additional 32 studies were excluded because of incorrect study design, ozone type, or lacking sufficient information on risk‐related outcome variables. As a result, nine studies published between 2002 and 2020 were included in this systematic review.
FIGURE 1.
PRISMA diagram for study selection
3.2. Study characteristics
The characteristics and outcomes related to this systematic review of the studies included are listed in Table 1. Overall, the reviewed studies include five RCTs, 4 , 7 , 11 , 12 , 22 one crossover study, 14 one clinical trial, 13 and two in vitro studies. 23 , 24 A total of 2628 patients/volunteers participated in the studies included. Four of the nine studies were designed to examine cytotoxicity or adverse side effects of ozonated liquids (oils and water) on skin a priori. The remaining five studies reported adverse side effects of ozonated liquids on skin as a secondary outcome to wound healing or treatment.
TABLE 1.
Main characteristics of included studies
| Author | Study aims | Design | Participants | O3 Type | Comparator | Risk outcome variable | Results |
|---|---|---|---|---|---|---|---|
| Aghaei et al. (2019) Iran | Evaluate O3 oil + glucantime on leishmaniasis | RCT | 30 patients | O3 oil (0.5 ml/mm2, 2×/day for 8week) + glucantime (20 mg Sb5+/kg, 20 days) | glucantime (20 mg Sb5 + /kg 20 days) | self‐report of pain, erythema, and oedema | Transient burning sensation with O3 oil in some patients |
| Breidablik et al. (2019) Norway | O3 water vs. ABHR in hand disinfection | Crossover | 30 nursing students | O3 water 0.8 or 4 ppm (30 seconds) | ABHR (30 seconds) | self‐report of burning/dryness | O3 water = 0% burning, dryness ABHR = 20% burning, dryness |
| de Oliveira et al. (2017) Brazil | Cytotoxicity of O3 neem oil or O3 neem oil + H2O | in vitro | Human skin cell line HaCaT | O3 neem oil or O3 neem oil + H2O | neem oil 5‐Fluorouracil methotrexate | GI50 values a | No cytotoxicity of HaCaT cells with O3 neem oil, neem oil + H2O, or control neem oil |
| Esposito et al. (2020) Italy | Evaluate O3 oil‐based gel on wound healing | single‐blind RCT | 114 patients | O3 oil‐based gel (2×/day; 2‐3 week) | hyaluronic acid (2×/day; 2‐3week) | Physician assessed ASR | No adverse reaction to O3 oil‐based gel or hyaluronic acid |
| Kashiwazaki et al. (2020) Japan | Evaluate O3 water for cytotoxicity | in vitro | cultured human keratinocyte | O3 water 4 ppm (1, 3, or 15 min) | hand disinfectants or DDW | Damage to SC surface Damage below SC Cell survival | O3 H2O or DDW = no SC damage O3 H2O = no damage below SC O3 H2O ≥ 92.4% cell survival |
| Lu et al. (2018) China | Efficacy of O3 water and oil on tinea pedis | RCT | 60 patients | O3 water (30 min) + O3 oil (1×/day; 4 week) | naftinfine hydrochloride + ketoconazole | Investigator observation of ASR | O3 H2O + O3 oil = desquamation (n = 1 patient); no other ASRs |
| Menéndez et al. (2002) Cuba | Efficacy of O3 sunflower oil on tinea pedis | RCT | 200 patients | O3 sunflower oil (2×/day; 6 week) | ketoconazole (2×/day; 6 week) | Not specified | No side effects observed with O3 sunflower oil or ketoconazole |
| Menéndez et al. (2008) Cuba | Efficacy and ADR of O3 sunflower oil on tinea pedis | Open clinical trial | 2165 patients | O3 sunflower oil (2×/day; 6 week) | n/a | Biweekly clinical evaluation ADR (mild‐very severe) | 0.3% (n = 6) patients reported ADR (mild burning sensation, pruritus, and erythema) |
| Solovăstru et al. (2015) Romania | O3 sunflower oil + α‐bisphenol for venous leg ulcers | RCT | 29 patients | O3 sunflower oil + α‐bisphenol (1×/day; 30d) | TAU | Not specified | No report of pain or irritation in O3 and TAU groups |
GI50, the concentration for 50% maximum inhibition of cellular growth. Higher values indicate less inhibition and greater cell proliferation.
Abbreviations: ADR, adverse drug reactions; ASR, adverse skin reactions; DDW, deionised distilled water; GI50, concentration causing 50% cell growth inhibition; O3, ozone; SC, stratum corneum; TAU, treatment as usual.
3.3. Cell culture assays
Two studies 23 , 24 examined the cytotoxicity of ozonated liquids on skin cells. In the study by Kashiwazaki et al., 24 ozonated water (4 ppm; up to 15‐minute exposure time) was found to have no cytotoxic effects on a normal thickness stratum corneum of cultured epidermis as compared with other hand disinfectants (ie, 1% CHG‐E, 0.2% benzalkonium chloride, 83% ethanol, and 0.5% povidone‐iodine) that destroyed or damaged the stratum corneum. Ozonated water also produced no morphological changes to keratinocytes below the stratum corneum compared with the other hand disinfectants that produced condensed nuclei and vacuolar cells. However, in a “sensitive skin” model, in which cells were cultured for a shorter period producing an immature stratum corneum and other layers, ozonated water did produce vacuolar cells albeit fewer than those produced by other hand disinfectants (ozonated water = 5 versus 83% ethanol = 10, 0.2% benzalkonium chloride = 29, povidone‐iodine = 15, CHG = 19 and CHG‐E = 16). Compared with control (deionised distilled water), which demonstrated a 100% cell survival rate after 15 minutes of application, ozonated water performed well with ≥92.4% cell survival after 15 minutes. Cell survival rates for the other hand disinfectants decreased below 20% at 15 minutes of application. The study by de Oliveira et al. 23 compared ozonated neem oil and ozonated neem oil plus water to pure neem oil on human keratinocyte cells (HaCaT). Neem oil and neem oil plus water was reacted at concentrations of 63 mg L−1 O3/O2 for 2, 4, 6, 8, 10, and 12 hours. The ozonated neem oil and ozonated neem oil plus water demonstrated low values of cytotoxicity (GI50 range = 325.37 to 164.52) on HaCaT cell lines compared with the positive control, 5‐Fluorouracil (GI50 = 6.82) but lower than pure neem oil (GI50 > 600) and methotrexate (GI50 > 500). a
3.4. Randomised controlled trials (RCTs)
Five RCTs were included in this review. 4 , 7 , 11 , 12 , 22 The primary aim of these RCTs was wound healing or treatment of skin disease and the assessment of adverse skin effects was secondary. A total of 433 patients participated in the RCTs. All five studies evaluated a form of ozonated oil although one study included the use of ozonated water washes and baths along with ozonated oil 11 and one study combined ozonated oil with glucantime. 22 Two studies used physician observation to assess adverse skin effects, 4 , 11 one used patient self‐report 22 and two studies did not specify the process by which adverse skin effects were assessed. 7 , 12 Three studies reported no adverse skin effects (eg, pain, burning, irritation) of ozonated oils. 4 , 7 , 12 Aghaei et al. 22 reported a brief burning sensation following application of ozonated oil in “some” patients. Lu et al. 11 reported desquamation of skin in one of 60 patients in their trial and no other adverse skin effects from ozonated oil.
3.5. Clinical trials
Two articles reported on clinical trial or crossover studies. 13 , 14 Breidablik et al. 14 conducted a crossover trial on 30 nursing student volunteers with ozonated water (0.8 ppm or 4 ppm) and alcohol‐based hand rub (ABHR) to assess hand decontamination. No students reported burning or dryness with ozonated water but 20% reported burning or dryness with ABHR use. Menéndez et al. 13 evaluated ozonated sunflower oil on 2165 patients in an open clinical trial to treat tinea pedis. Patients were evaluated for adverse skin effects at regular study intervals and 0.3% (n = 6) experienced mild levels of burning sensations, pruritus, and/or erythema from ozonated oil use.
3.6. Assessment of the risk of bias
Figure 2 summarises the results of the risk of bias assessment using the Cochrane collaboration's risk of bias tool. 21 Seven of the nine studies reviewed had at least one bias category rated as having a high bias risk. Only one study had low risk of bias ratings in every category except selective reporting bias, which was rated as high. 4 Two studies had a mixture of high risk and unclear risk ratings. 7 , 13 Two studies had a mixture of low risk and unclear risk ratings. 23 , 24 The remaining four studies had a mixture of high, low, and unclear risk of bias in the domains assessed. 11 , 12 , 14 , 22
FIGURE 2.
Risk of bias, assessed as low (L), high (H) or unclear (−)
4. DISCUSSION
This is the first systematic review conducted to evaluate the potential risks of liquid forms of O3 on human skin tissue. There is increasing interest in the utilisation of O3 because of the growing evidence that O3 has antimicrobial, 25 immunologic, 26 and therapeutic activities. 27 Therefore, it is necessary to have a better understanding of the dermatologic safety of these agents. The preliminary evidence suggests that ozonated liquids are well tolerated and pose no significant dermatological risks.
Each of the nine studies included in this systematic review, regardless of study design, assessed the adverse effects of liquid forms of O3 on human skin tissue. None of the studies found significant evidence of risk with the use of ozonated liquids. Only two studies of those reviewed were designed to specifically evaluate the microscopic cytotoxicity of ozonated neem oil or ozonated water on a human epidermal cell model. 23 , 24 Neither study found any evidence of cytotoxic effects of liquid forms of O3 at concentrations up to 4 ppm on human skin cells. Five studies aimed to evaluate the efficacy of liquid forms of O3 in clinical therapeutic applications and provided information on post hoc examination or patient self‐report of side effects. 4 , 7 , 11 , 12 , 22 Three of the five studies found no indications of adverse effects from ozonated liquids. Of the 433 participants in these studies, only one patient reported desquamation and an unclear number of patients reported a transient burning sensation upon application. One clinical efficacy paper had safety and evaluation of adverse drug reactions (ADR) as its primary endpoint. 13 This study evaluated a branded ozonated sunflower oil in a Phase IV open clinical trial for the treatment of tinea pedis. Of the 2165 patients who completed the trial, only six patients reported any ADR, and these were rated as mild by the study participants. The final study 14 examined the efficacy of ozonated water compared with alcohol‐based hand rubs (ABHR) in hand disinfection in a crossover design. None of the 30 participants reported adverse effects with the ozonated water, while 20% of participants reported burning sensations and dryness with the ABHR.
Although our systematic review found no evidence of significant short‐term dermatologic risks of ozonized liquids, there are noteworthy limitations to the studies included in this review that limit firm conclusions about the long‐term safety of the liquid forms of O3 on human skin. Sample sizes in most of the clinical studies on human populations were small (N range = 29–1264; median = 60). 4 , 7 , 11 , 12 , 13 , 14 , 22 The formulation, concentration, and exposure duration of liquid O3 on skin varied across the studies. The study design used (e.g., in vitro, RCT, open clinical trial) and the outcome variables measured varied widely across the nine studies included in this review. While over half the studies were RCTs, procedures of randomization and blinding were not applied or were unclearly applied to the methods of assessing adverse risk variables. 7 , 12 , 22 Moreover, only a few studies, regardless of design, specified a priori hypotheses about adverse effects and clearly delineated adverse risk assessment methods. 13 , 14 , 23 , 24 Many of the papers lacked objective and clear rating systems for adverse risk variables and deferred to subjective assessments of side effects by clinicians who may not have been blinded to group membership. 7 , 11 , 12 , 13 , 22 Finally, there was an absence of longitudinal data with either continuous or intermittent use of O3 in each of the studies. The longest treatment interval in any of the trials was only 6 weeks. 12 , 13
This systematic review has some additional limitations. Unfortunately, there is very little high‐quality literature available on assessing risks and side effects of the liquid forms of O3 in human tissue. The poor reporting of study methodology made it difficult to assess the quality of the studies and the risk of bias across studies was found to be highly variable. Moreover, meta‐analysis could not be conducted because of the range of methods used, lack of clear outcome variables in some cases, and the reporting of only qualitative outcome data of adverse risk in others.
While this review highlights the need for additional thorough research on topical ozone that is well‐controlled, longitudinal, and specifically designed to evaluate risk, there is already growing interest in medical applications of liquid O3. Notably, ozonated water was anecdotally used on a large scale for hand hygiene in a Giardiasis outbreak in Norway in 2004 14 and has several described uses in the field of dentistry. 28 The lack of reported adverse effects from these and other international uses, in combination with the outcomes reported in this systematic review, point to ozonated water's seemingly high safety profile when used topically.
5. CONCLUSION
The results of this systematic review suggest a low likelihood of significant short‐term risk to topically applied O3 liquids. However, the small numbers of studies, high incidence of selective reporting bias, and short follow‐up times indicate the need for higher‐quality RCTs to confirm the safety and tolerability of ozonated liquids on human skin.
CONFLICTS OF INTEREST
BRL, DJR, SAL, and KNB were compensated through an unrestricted grant from 3Oe Scientific, Inc. BRL also serves on the medical advisory board of and holds equity in 3Oe Scientific, Inc. RML is compensated by and holds equity in 3Oe Scientific, Inc.
APPENDIX A. SEARCH STRATEGY
Web of Science Core Collection
Search: September 20, 2020
| ID | Search history | Results |
|---|---|---|
| #1 |
TS=(ozon* NEAR/5 topical) Indexes=SCI‐EXPANDED, SSCI, A&HCI, CPCI‐S, CPCI‐SSH, BKCI‐S, BKCI‐SSH, ESCI, CCR‐EXPANDED, IC Timespan=All years |
57 |
| #2 |
TS=(ozon* NEAR/5 cream*) Indexes=SCI‐EXPANDED, SSCI, A&HCI, CPCI‐S, CPCI‐SSH, BKCI‐S, BKCI‐SSH, ESCI, CCR‐EXPANDED, IC Timespan=All years |
6 |
| #3 |
TS=(ozon* NEAR/5 gel*) Indexes=SCI‐EXPANDED, SSCI, A&HCI, CPCI‐S, CPCI‐SSH, BKCI‐S, BKCI‐SSH, ESCI, CCR‐EXPANDED, IC Timespan=All years |
121 |
| #4 |
TS=(ozon* NEAR/5 oil*) Indexes=SCI‐EXPANDED, SSCI, A&HCI, CPCI‐S, CPCI‐SSH, BKCI‐S, BKCI‐SSH, ESCI, CCR‐EXPANDED, IC Timespan=All years |
485 |
| #5 |
TS=(ozon* NEAR/5 ointment* ) Indexes=SCI‐EXPANDED, SSCI, A&HCI, CPCI‐S, CPCI‐SSH, BKCI‐S, BKCI‐SSH, ESCI, CCR‐EXPANDED, IC Timespan=All years |
4 |
| #6 |
TS=(ozon* NEAR/5 emulsion* ) Indexes=SCI‐EXPANDED, SSCI, A&HCI, CPCI‐S, CPCI‐SSH, BKCI‐S, BKCI‐SSH, ESCI, CCR‐EXPANDED, IC Timespan=All years |
17 |
| #7 |
TS=(ozon* NEAR/5 water ) Indexes=SCI‐EXPANDED, SSCI, A&HCI, CPCI‐S, CPCI‐SSH, BKCI‐S, BKCI‐SSH, ESCI, CCR‐EXPANDED, IC Timespan=All years |
5,786 |
| #8 |
TS=(ozon* NEAR/5 aqueous) Indexes=SCI‐EXPANDED, SSCI, A&HCI, CPCI‐S, CPCI‐SSH, BKCI‐S, BKCI‐SSH, ESCI, CCR‐EXPANDED, IC Timespan=All years |
1,464 |
| #9 |
TS=(ozon* NEAR/5 liquid*) Indexes=SCI‐EXPANDED, SSCI, A&HCI, CPCI‐S, CPCI‐SSH, BKCI‐S, BKCI‐SSH, ESCI, CCR‐EXPANDED, IC Timespan=All years |
509 |
| #10 |
#9 OR #8 OR #7 OR #6 OR #5 OR #4 OR #3 OR #2 OR #1 Indexes=SCI‐EXPANDED, SSCI, A&HCI, CPCI‐S, CPCI‐SSH, BKCI‐S, BKCI‐SSH, ESCI, CCR‐EXPANDED, IC Timespan=All years |
7,838 |
| #11 |
TS=(skin) Indexes=SCI‐EXPANDED, SSCI, A&HCI, CPCI‐S, CPCI‐SSH, BKCI‐S, BKCI‐SSH, ESCI, CCR‐EXPANDED, IC Timespan=All years |
590,642 |
| #12 |
TS=dermat* Indexes=SCI‐EXPANDED, SSCI, A&HCI, CPCI‐S, CPCI‐SSH, BKCI‐S, BKCI‐SSH, ESCI, CCR‐EXPANDED, IC Timespan=All years |
164,173 |
| #13 |
TS= cutaneous Indexes=SCI‐EXPANDED, SSCI, A&HCI, CPCI‐S, CPCI‐SSH, BKCI‐S, BKCI‐SSH, ESCI, CCR‐EXPANDED, IC Timespan=All years |
152,168 |
| # 14 |
TS=squamous Indexes=SCI‐EXPANDED, SSCI, A&HCI, CPCI‐S, CPCI‐SSH, BKCI‐S, BKCI‐SSH, ESCI, CCR‐EXPANDED, IC Timespan=All years |
158,962 |
| #15 |
TS=epithel* Indexes=SCI‐EXPANDED, SSCI, A&HCI, CPCI‐S, CPCI‐SSH, BKCI‐S, BKCI‐SSH, ESCI, CCR‐EXPANDED, IC Timespan=All years |
541,749 |
| #16 |
TS=epiderm* Indexes=SCI‐EXPANDED, SSCI, A&HCI, CPCI‐S, CPCI‐SSH, BKCI‐S, BKCI‐SSH, ESCI, CCR‐EXPANDED, IC Timespan=All years |
207,483 |
| #17 |
#16 OR #15 OR #14 OR #13 OR #12 OR #11 Indexes=SCI‐EXPANDED, SSCI, A&HCI, CPCI‐S, CPCI‐SSH, BKCI‐S, BKCI‐SSH, ESCI, CCR‐EXPANDED, IC Timespan=All years |
1,536,098 |
| #18 |
#17 AND #10 Indexes=SCI‐EXPANDED, SSCI, A&HCI, CPCI‐S, CPCI‐SSH, BKCI‐S, BKCI‐SSH, ESCI, CCR‐EXPANDED, IC Timespan=All years |
152 |
| #19 |
LA=English Indexes=SCI‐EXPANDED, SSCI, A&HCI, CPCI‐S, CPCI‐SSH, BKCI‐S, BKCI‐SSH, ESCI, CCR‐EXPANDED, IC Timespan=All years |
57,086,694 |
| #20 |
#19 AND #18 Indexes=SCI‐EXPANDED, SSCI, A&HCI, CPCI‐S, CPCI‐SSH, BKCI‐S, BKCI‐SSH, ESCI, CCR‐EXPANDED, IC Timespan=All years |
145 |
| #21 |
DT=Review Indexes=SCI‐EXPANDED, SSCI, A&HCI, CPCI‐S, CPCI‐SSH, BKCI‐S, BKCI‐SSH, ESCI, CCR‐EXPANDED, IC Timespan=All years |
1,844,020 |
| #22 |
#20 NOT #21 Indexes=SCI‐EXPANDED, SSCI, A&HCI, CPCI‐S, CPCI‐SSH, BKCI‐S, BKCI‐SSH, ESCI, CCR‐EXPANDED, IC Timespan=All years |
132 |
EMBASE
Search: September 20, 2020
| ID | Search history | Results |
|---|---|---|
| #1 | ozon* NEAR/5 topical | 71 |
| #2 | ozon* NEAR/5 cream* | 8 |
| #3 | ozon* NEAR/5 gel* | 44 |
| #4 | ozon* NEAR/5 oil* | 249 |
| #5 | ozon* NEAR/5 ointment* | 6 |
| #6 | ozon* NEAR/5 emulsion* | 10 |
| #7 | ozon* NEAR/5 water | 1,877 |
| #8 | ozon* NEAR/5 aqueous | 510 |
| #9 | ozon* NEAR/5 liquid* | 145 |
| #10 | #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 | 2,702 |
| #11 | ‘skin’/exp | 392,363 |
| #12 | ‘epithelium’/exp | 364,143 |
| #13 | ‘epithelium cell’/exp | 545,341 |
| #14 | ‘skin absorption’/exp | 7,972 |
| #15 | Skin | 1,172,031 |
| #16 | epithel* | 698,306 |
| #17 | epiderm* | 368,087 |
| #18 | squamous | 249,632 |
| #19 | cutaneous | 241,406 |
| #20 | dermat* | 805,698 |
| #21 | #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 | 3,067,578 |
| #22 | #10 AND #21 | 186 |
| #23 | english:la | 31,846,543 |
| #24 | #22 AND #23 | 164 |
| #25 | review/it | 2,634,943 |
| #26 | #24 NOT #25 | 152 |
Cochrane Library
Search: September 20, 2020
| ID | Search history | Results |
|---|---|---|
| #1 | (ozon* NEAR topical) | 32 |
| #2 | (ozon* NEAR cream*) | 4 |
| #3 | (ozon* NEAR gel*) | 13 |
| #4 | (ozon* NEAR oil*) | 33 |
| #5 | (ozon* NEAR ointment*) | 1 |
| #6 | (ozon* NEAR emulsion*) | 0 |
| #7 | (ozon* NEAR water) | 55 |
| #8 | (ozon* NEAR aqueous) | 6 |
| #9 | (ozon* NEAR liquid*) | 2 |
| #10 | #1 OR #2 OR #3 OR #4 OR #6 OR #7 OR #8 OR #9 | 115 |
| #11 | MeSH descriptor: [Skin] explode all trees | 4,366 |
| #12 | MeSH descriptor: [Epithelium] explode all trees | 4,093 |
| #13 | MeSH descriptor: [Epithelial Cells] explode all trees | 1,996 |
| #14 | MeSH descriptor: [Skin Absorption] explode all trees | 285 |
| #15 | skin:ti,ab,kw | 55,803 |
| #16 | epithel*:ti,ab,kw | 10,207 |
| #17 | epiderm*:ti,ab,kw | 7,484 |
| #18 | squamous:ti,ab,kw | 9,923 |
| #19 | cutaneous:ti,ab,kw | 11,915 |
| #20 | dermat*:ti,ab,kw | 19,957 |
| #21 | #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 | 99,330 |
| #22 | #10 AND #21 | 24 |
Ovid MEDLINE(R) < 1946 to September Week 2 2020>
Search: September 20, 2020
| ID | Search history | Results |
|---|---|---|
| #1 | (ozon* adj5 topical).tw. | 33 |
| #2 | (ozon* adj5 cream*).tw. | 1 |
| #3 | (ozon* adj5 gel*).tw. | 28 |
| #4 | (ozon* adj5 oil*).tw. | 133 |
| #5 | (ozon* adj5 ointment*).tw. | 4 |
| #6 | (ozon* adj5 emulsion*).tw. | 5 |
| #7 | (ozon* adj5 water*).tw. | 1,093 |
| #8 | (ozon* adj5 aqueous).tw. | 315 |
| #9 | (ozon* adj5 liquid*).tw. | 92 |
| #10 | 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 | 1,572 |
| #11 | exp skin/ | 224,315 |
| #12 | exp epithelium/ | 249,477 |
| #13 | exp Epithelial Cells/ | 555,767 |
| #14 | exp Skin Absorption/ | 11,709 |
| #15 | "epithel*".tw. | 429,540 |
| #16 | squamous.tw. | 116,200 |
| #17 | epidermis.tw. | 35,045 |
| #18 | dermat*.tw. | 143,470 |
| #19 | cutaneous.tw. | 135,488 |
| #20 | skin.tw. | 469,690 |
| #21 | 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 | 1,774,400 |
| #22 | English.lg. | 22,429,920 |
| #23 | Review.pt. | 2,473,191 |
| #24 | 10 and 21 | 82 |
| #25 | 22 and 24 | 73 |
| #26 | 25 not 23 | 67 |
Google Scholar
Search: September 14, 2020
Exclude patents
Exclude citations
(skin OR “Skin Absorption” OR “Epithelial Cells” OR Epithelium OR Epidermis OR squamous) (“systematic review” OR “Randomised Controlled Trial” OR “Clinical Trial” OR meta‐analysis) intitle:“Ozone oil” OR “Ozonated oil” OR “ozonised oil” OR “ozonized oil”
Total results: 104
(skin OR “Skin Absorption” OR “Epithelial Cells” OR Epithelium OR Epidermis OR squamous) (“systematic review” OR “Randomised Controlled Trial” OR “Clinical Trial” OR meta‐analysis) intitle:“Liquid ozone” OR “Aqueous ozone” OR “Ozone water” OR “ozonized water” OR “Ozonated water”
Total results: 87
(skin OR “Skin Absorption” OR “Epithelial Cells” OR Epithelium OR Epidermis OR squamous) (“systematic review” OR “Randomised Controlled Trial” OR “Clinical Trial” OR meta‐analysis) intitle:“topical ozone” OR “Ozone emulsion” OR “Ozone ointment” OR “Ozone cream” OR “Ozone gel”
Total results: 12
Leon BR, Romary DJ, Landsberger SA, Bradner KN, Ramirez M, Lubitz RM. Risks of ozonated oil and ozonated water on human skin: A systematic review. Int Wound J. 2022;19(7):1901‐1910. doi: 10.1111/iwj.13760
Funding information This study was funded by an unrestricted grant from 3Oe Scientific, Inc., a technology company evaluating human applications for aqueous ozone.
DATA AVAILABILITY STATEMENT
Data sharing not applicable ‐ no new data generated
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Data sharing not applicable ‐ no new data generated