Jordi | Journal of Oral Diagnosis Online Submission Review an Article SOBEP - Sociedade Brasileira de Estomatologia e Patologia Oral
Volume 2 - 2017

Original Article

DOI: 10.5935/2525-5711.20170032

Ozone therapy influence in the tissue repair process: A literature review

Júlia dos Santos Vianna Néri1; Erielma Lomba2; Alexandre Melo Karam3; Silvia Regina de Almeida Reis4; Antônio Márcio Teixeira Marchionni5; Alena Ribeiro Alves Peixoto Medrado6

1. Master in Stomatology from Bahiana School of Medicine and Public Health (Assistent teacher of Bahia Adventist School), Salvador, BA, Brazil
2. Graduation student of Bahia Adventist College (Graduation student of Bahia Adventist College) , Salvador, BA, Brazil
3. Master in Implantodology from University Center of Educacional Fundation of Barretos (Dentist cirurgion), Barretos, SP, Brazil
4. PhD in Pathology at Berlin's Free University. Associate Professor of Bahiana School of Medicine and Public Health - Salvador, Bahia, Brazil
5. PhD in Laser from Federal University of Bahia (Adjunct teacher of Bahiana School of Medicine and Public Healt), Salvador, BA, Brazil
6. PhD in Human Pathology at Federal University of Bahia (Adjunct Professor of Bahiana School of Medicine and Public Health), Salvador, BA, Brazil

Corresponding authors: Alena Ribeiro Alves Peixoto Medrado

Article received on June 7, 2017.
Article accepted on July 14, 2017.



INTRODUCTION: The ozone therapy is a bio-oxidation therapy, based on a gaseous mixture with oxygen and ozone. It can be considered an alternative therapeutic tool the treatment of many systemic and locals diseases. It induces acute oxygenation stress and is not deleterious, which allows the restoration of oxidation and reduction balance. Within the therapeutic effects, it has been associated to the improvement metabolism and the peripheral tissue oxygenation. In addition, ozone is an important antimicrobial agent against bacteria, fungi, protozoa and viruses. In Dentistry, the ozone therapy has been used in several clinical situations due to its mechanisms of action.
OBJECTIVES: The purpose of this literature review is to discuss the chemical and physical properties of ozone and its mechanisms of action in tissue repair.
METHODS: It is a narrative review based on research articles searched in Pubmed and LILACS database, from December 2015 to May 2016. The following descriptors in English: "ozone", "oxidative stress" and "tissue repair" used. Finally, 36 articles were included in this narrative literature review.
RESULTS AND CONCLUSION: The use of ozone as treatment seems to be promising in health areas, including dentistry due to its biological and biochemical properties. However, there is a need for more methodologically adequate studies so it can be safely and efficiently applied.

Keywords: Ozone; Soft Tissue Injuries; Wound Healing.



Tissue repair involves progressive biochemical and cellular mechanisms in a complex sequence and is initiated at the time of trauma or illness. In the face of any injury, it is through repair that the body recovers and restores its balance1,2. Since the last century, the use of ozone therapy has been proposed in the literature because it is able to influence the oxy-reduction equilibrium. It is considered an alternative treatment for many acute and chronic diseases3-6.

Ozone, which formula is O3, is a powerful oxidant, and when in contact with organic fluids causes the formation of reactive oxygen molecules (O2). These molecules influence cellular metabolism, which may be beneficial to tissue repair, in addition to its potent antimicrobial effect6.

Some other properties of ozone therapy are already described in the literature. It stimulates and regulates the immune system and increases biosynthesis of some organic molecules. Its bio-energetic, antihypoxic, analgesic and hemostatic properties have also been highlighted in literature3,7. The aerobic process, increased vasodilators secretion, such as nitric oxide (NO), and acceleration of tissue regeneration have been cited by Seidler et al., in 20088. In addition, ozone therapy is easily systemic or local applied for properly qualified professionals, has low cost, no side effects and has restricted intolerance or contraindication6.

The only way that ozone cannot be administer by inhalation, as it is a toxic gas to the lungs. There is still much debate and controversy regarding the appropriate therapeutic dose and its effectiveness, because in very low or very high concentrations, it may be useless or bring adverse effects to the individuals6.

There are several chronic or acute lesions that affect the oral cavity, both linked to systemic and local changes. Thus, the study and use of a therapeutic agent such ozone, with several beneficial properties for humans, is an important tool in the treatment of these oral diseases.

The aim of this narrative review is to discuss the chemical and physical characteristics of ozone as well as its mechanisms of action in tissue repair.


The present study is a narrative literature review and it was based on research articles searched in Pubmed and LILACS database, from December 2015 to May 2016. It was used intersection of the following descriptors in English: "ozone", "oxidative stress" and "tissue repair".

The selection of the articles was based on the titles that addressed how the ozone therapy can influence wound healing, and its biological effects, including the role of reactive oxygen species and the general aspects of the ozone. Its clinical applicability and outcomes, as well as cellular changes induced by its administration considered.

First, it was collected the summaries that were available in database. 76 articles were found in Pubmed and 34 in LILACS. Only articles that provided evidence about the use of ozone in Dentistry and its therapeutic potential on tissue repair were selected. The following inclusion criteria were stablished: articles relevant to the theme, written in English and that had been published between 1987 to 2015. Articles that did not have fully abstracts were excluded from the study.

After prior examination, only 36 articles were included in this narrative literature review.


Physical and chemical properties of ozone

Ozone has a molecular weight of 47.98 g/mol, and is a gas composed of three oxygen atoms, present in abundance in the upper atmosphere. At room temperature, it has a strong odor, a blue color and has the ability to filter harmful ultraviolet rays, which plays a fundamental role in maintaining the biological balance of the biosphere4,9. Normally, the concentration of ozone in atmospheric air rotates around 0.1 ppm10. O3 is one of the most important oxidants present in nature and is considered the third most powerful oxidant after fluoride and persulfate. It can act as a precursor of many radicals. It is highly reactive with organic compounds and highly thermodynamically unstable because, depending on the conditions of temperature and pressure, it easily decomposes by exothermic reaction in pure oxygen, with short survival (40 minutes at 20 °C). Therefore, it cannot be stored and should be used quickly8,11,12.

In nature, its formation occurs through the combination of oxygen in the air, along with influencing factors such as ultraviolet (UV) radiation, electric shocks and intense physical stress in water9. Artificially, it is necessary a generator capable of promoting electric discharges for ozone formation. Through a high voltage gradient, these specific generators produce O3 from the passage and photo dissociation of dioxygen in oxygen atoms (O2 → 2O), which react with other dioxygen molecules, forming the ozone (O2 + O → O3)3. Depending on its concentration, pressure and temperature, O3 dissolves physically in pure water.

Some of its molecules decompose rapidly, in a matter of seconds, and the other part remains stable for hours, with a half-life about 10 hours (at pH = 7 and 20oC). So, it can remain in water for a few days, if stored in a tightly closed glass vessel13,14. In addition to ozonized water, ozone can also be mixed with oils by means of electric discharges. When ozonized, the unsaturated acids present in the oils form ozonizes, and hydrolysis of these can generate aldehydes, ketones and hydrogen peroxides (H2O2), which are responsible for triggering biochemical reactions in living tissues13,14.

Tissue repair

Skin integrity and mucous membranes function as a flexible mechanical barrier, which is intended to protect humans from infections. When this barrier is broken, either by surgery or trauma, there is a need for repair of connective tissue and regeneration of epithelium, through an intriguing healing process that begins immediately after injury15. The repair can occur through two mechanisms: By first intention, when the tissues are approximated, or by second intention, characterized when the lesion is extensive and infected, with great tissue destruction and uncounted edges16. Immediately after injury, there is extravasation of substances from the blood, derived from injured vessels, which have the purpose of filling the lesion. This extravasation is mainly composed of platelets, fibrin and fibronectin, which act in the release of inflammatory signaling substances, such as cytokines and coagulation system proteins, which eventually trigger the inflammatory response cascade in association with prostaglandins, interleukins (IL) and NO17. All stages of repair are coordinated by growth factors and specific cytokines18. Initially, there is vasodilation of adjacent vessels, with exudative phenomena and defense cells, mainly polymorph nuclear leukocytes, which arrive at the site in an attempt to destroy the external agent or remove cellular debris. Neutrophils then secrete cytokines, with the goal of attracting other cells, such as leukocytes and fibroblasts.

Fibroblasts differentiate into myofibroblasts and migrate to the lesion after two or three days, and through their contractile capacity, promote a retraction of the wound, which can reach 50 to 70% of the initial size. Over time, they secrete substances that fill the injured area, corresponding to extracellular matrix substances, such as hyaluronic acid and type III collagen.

Within 3 to 5 days, takes place granulation tissue deposition. It is a rich tissue fulfilled by vascular endothelial growth factors (VEGF), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), epithelial growth factor (EGF), and transform growth-beta factor (TGF-β). The granulation tissue is composed of neoformed vessels, leukocytes, macrophages and fibroblasts18-20.

The remodeling corresponds to the final phase of the repair, in association with biosynthesis and degradation of damaged substances, through metalloproteinase, whose secretion is influenced by several stimuli, such as PDGF and FGF, cytokines, IL-1 and Tumor necrosis factor alpha (TNF-α). Type III collagen is replaced by much more resistant collagen type I, which confers tension to the newly formed tissue21. At the end of the repair process, myofibroblasts and same fibroblasts disappear by apoptosis, mainly induced by NO19,20. In 2005, Kandler et al.21 reported the need for a balance between the production of reactive oxygen species (ROS) and their neutralization in the healing process. A study by Sen et al.1, in 2002, demonstrated that H2O2 induce the expression of VEGF in macrophages and keratinocytes, acting on angiogenesis, and stimulating collagen production, which corroborates the idea that tissue repair is subject to oxidation and reduction, known as redox control.

According to Sem and Roy2, in 2007, oxygen is considered as a fundamental agent in tissue repair. Hemostasis, inflammation, re-epithelialization, vascularization and nitric oxide activity are sensitive to redox balance. Therefore, the study of ROS in repair is fundamental for the investigation of new therapies. Thus, ozone therapy, acting in the redox balance and in the correct concentration, can be effective in the treatment of wounds6.

Ozone therapy and tissue repair

When in contact with organic fluids such as saliva, plasma, urine and lymph, ozone interacts intensely with all tissue components. This interaction depends on its concentration, and can react with polyunsaturated fatty acids, antioxidants, cysteine, glutathione, and albumin, even with carbohydrates, enzymes, deoxyribonucleic acid (DNA) and ribonucleic acid (RNA).

All these reagents act as donor electrons and are oxidisable, and participate in the ozonation process and the consequent formation of ROSs and lipid oxidation products (LOPs). These molecules are responsible for the biochemical actions of ozone, and function as biochemical regulators of inflammation at distinct times and physiological concentrations13,14. Of these molecules, ROS are characterized by being highly unstable, rapidly forming, immediate action and half-life less than one second. They are derived from the oxygen molecule, generated by endogenous and exogenous sources and function as signaling molecules of innumerable cellular processes. Through interactions with cellular components and depending on the concentration of ozone in the tissue, these molecules can trigger biological effects that are either therapeutically or detrimental to health13,14.

During normal metabolism, osteoclasts, platelets, lymphocytes, neutrophils, monocytes and fibroblasts can induce the formation of ROS. When in excess, these reactive oxygen species can trigger damage to cellular constituents, extracellular components and affect the metabolism of the cells responsible for extracellular matrix synthesis, fundamental in tissue repair, which leads to apoptosis and cellular necrosis22.

Hydrogen peroxide is the main ROS. It is characterized as a potent oxidizer, and has the ability to activate different biochemical pathways. It functions as an ozone messenger with distinct cellular effects14. In cellular components, as in erythrocytes, H2O2 generated by ozone can alter glycolysis, with increased energy formation and consequent improvement of O2 transport to tissues. In neutrophils and leukocytes, it stimulates the synthesis of cytokines and interleukins, which are beneficial to immunosuppressed patients. In platelets, there is an increase in platelet activity, which leads to an improvement in autacoids and growth factors release13,14. Bocci23, since 1996, has already reported that ozone therapy can accelerate tissue repair.

On the other hand, LOPs are molecules that are distributed easily through the tissues, which are more diffused, more stable, and have the function of minimizing potential toxicities. They characterized as long-distance late messengers, and their metabolism mainly regulated through glutathione transferase and aldehydes dehydrogenases. Its production occurs after the oxidation of the polyunsaturated fatty acids of the cell membrane14. These are important molecules, capable of generating acute oxidative processes and function as signals of other existing oxidative stresses when in a low concentration13,14. When the living tissue is attacked by oxidative stress, activation of release systems of antioxidant agents occurs, which corresponds to the first line of defense of living tissue. Among the compounds of this release system of antioxidants, are the enzymes superoxide dismutase, glutathione peroxidase, glutadionereductase, catalase and hemeoxygenase-I.

Through the action of these enzymes, there is an increase in the release of stem cells by bone marrow cells, beneficial to tissue reconstitution, as well as increased NO production, fundamental in angiogenesis, through endothelial cells13,14. Valacchi et al.10,24 in 2002 and 2003, observed increased expression of hemeoxygenase-I, involved in cell proliferation and apoptosis, and metalloproteinase that participate in the balance between synthesis and reabsorption of the extracellular matrix when the skin was exposed to ozone.

Patients often report the sensation of well-being and euphoria during treatment with ozone therapy, and this can be explained by the account of the LOPs, because they stimulate the endocrine and central nervous system, with consequent improvement of metabolism, hormonal production and neurotransmitters release13,14.

When there is overproduction of ROS, oxidative stress occurs, which is the cause of many diseases, such as cancer (CA), and consequently there is worsening of these diseases evolution. It is fundamental that the therapeutic dose of ozone in the tissues is respected, so as not to make it a toxic agent. However, the therapeutic use tends to be beneficial to the organism, since it represents an acute, non-toxic oxidative stress, which consequently induces modifications at the cellular level capable of reversing another preexisting oxidative stress14,25.

Ozone therapy can, when in therapeutic doses, act as a non-toxic "therapeutic shock" to the body because it tends to restore the balance of the redox state through changes in the physiological response, which may be useful in the treatment of metabolic, inflammatory, infectious and neoplastic diseases14,23. Schulz et al.26, in 2008, used ozone therapy from peritoneal insufflation of rabbits with advanced stage of squamous cell carcinoma. The authors observed that six of the seven surviving rabbits had total remission of the tumor with absence of local or distant metastasis. These data corroborate the idea that ozone therapy may be effective in the treatment of neoplasms. The authors suggested that, although the exact mechanism of action of ozone for tumor regression is still uncertain, peritoneal O3/O2 insufflation is considered a promising strategy in cancer therapy.

In a study carried out by Re et al.27 in 2008, it was proven that ozone is capable of promoting the increase and preservation of endogenous antioxidant systems, thus promoting an oxidative precondition. Similar results were found in the study by Gracer et al.28 in 2005, which described that the application of ozone in inflamed tissue may favor the synthesis of extracellular matrix, as well as cell proliferation and metabolic normalization. Traina6, in 2008, evaluated tissue repair in rat wounds, and ozone provided a greater reduction in wound area and tissue formation. In 2000, Cardoso et al.29 observed that ozonized water can attenuate the appearance and severity of gastric ulcers, as well as the edema of induced dermal lesions, as it acts as a modulator of the inflammatory process by the induction of oxidative stress. Martinez-Sanchez et al.30 in 2005, evaluated adult diabetic patients who had foot ulcers located at the extremities of the body and observed that in relation to the group treated with antibiotics, the group that received ozone therapy had a decrease of lesion area and perimeter, as well as a statistically significant difference in relation to the healing time.

Patel et al.31, in 2011, evaluated the effects of ozonized oil on the healing of wounds on the palate. 18 patients were divided between the test group (n=8) and the control group (n=10) and were treated with 2mL ozonized oil and a placebo one, respectively, in the same concentration daily for 1 week. The authors observed that, in the test group, there was an improvement in wound size when compared to control.

The authors also evaluated epithelial keratinization, regeneration and degeneration through the cytological technique, where the surface of the sterilized interproximal brush was firmly supported on the wound and rotated for collection of cellular material. There was a significant improvement of the ozone group in relation to epithelial regeneration.

In 2009, Kim et al.32 carried out a study with the objective of evaluating the therapeutic effect of ozonized oil on wound healing in pigs. The ozone group obtained a significant reduction of wounds in relation to the control group. The tissues were stained, showing the increase in the intensity of collagen fibers and fibroblasts in the ozone group. Immunohistochemically, increased expression of PDGF, TGF-β and VEGF was observed.

In another study, where ozonation of platelet-rich plasma samples was performed, the results demonstrated the increase of IL-8, which allows the leukocytes to exit the circulation into the tissues in order to facilitate the phagocytosis of bacteria and necrotic tissue of ulcers and wounds. It may be a plausible justification for the acceleration of tissue repair in patients with chronic ulcers and treated with systemic ozone therapy. In addition to IL-8, the results also demonstrated an increase in growth factors, such as PDGF, transforming growth factor beta1 (TGF-β1) and IL33. In 2006, Lim et al.34 found that the exposure of dermal wounds to ozone increased the activity of factor nuclear kappa B (NF-κB), an important immunomodulatory of inflammation, as well as the expression of TGF-β, which is fundamental for remodeling tissue. Similar results described by Huth et al.35 These authors observed that aqueous ozone influenced the NF-κB system, which corroborates with the idea that ozone does indeed play an anti-inflammatory role and immunomodulatory.

Ozone therapy has been strongly related to increased expression of nitric oxide. If there is NO deficiency, this may negatively influence tissue repair and its role related to collagen synthesis, through regulation of fibroblasts36.


Although ozone therapy shows to be a promising and effective treatment in different areas of dentistry because of its peculiar properties, such as its oxidative and antimicrobial potential, more researches, with adequate methodological designs, randomized samples and standardized methods that support their use in a safe and permanent manner, are need.


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