Review Article
An Overview of Ozone Therapy for Treating Foot Ulcers in Patients With Diabetes

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Abstract

Diabetic foot ulcer (DFU) is one of the most common and severe complications of diabetes mellitus, which is becoming increasingly prevalent throughout the world, with high mortality and morbidity. Because of the complex pathophysiological processes involved, DFU is difficult to treat effectively with traditional therapies. Ozone therapy, an emerging method, has been reported as potentially beneficial for closure of DFUs and may gradually move to the forefront of clinical practice. Possible mechanisms of action include antioxidant capacity, pathogen inactivation, vascular and endogenous growth factor modulation, and immune system activation. However, some researchers are skeptical about its safety, and clinical trials are lacking. This article reviews the current research and application of ozone therapy for DFUs.

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INTRODUCTION

Diabetes mellitus is a disease characterized by hyperglycemia and glycosuria, caused by impaired insulin function or secretion.1 Poor long-term management of blood glucose and high plantar pressure are responsible for diabetic foot ulcers (DFUs), one of the quintessential complications of diabetes mellitus, defined as full-thickness wounds that penetrate the dermis (the deep vascular and collagenous inner layer of the skin) and are located below the ankle in diabetic patients.2 It is

PATHOGENESIS, DIAGNOSIS AND CONVENTIONAL THERAPY FOR DFUS

Studies show that independent risk factors such as active smoking, obesity and hyperlipidemia predispose patients with type 2 diabetes to develop DFUs.9 DFUs associated with neuropathy and angiopathy are characterized by impaired wound healing and prolonged closure time.10 Diabetic neuropathy results in reduction or loss of sensation and foot dysmorphia, which subjects the foot to increased localized pressure, leading to callus and tissue injuries and eventual ulcer formation.10 Besides

Antioxidant Capacity

Besides creating hydrogen peroxide (H2O2), a reactive oxygen species (ROS) and a mixture of lipid ozonation products, this transient and moderate oxidative stress caused by ozone therapy has increased activation of the transcriptional factor mediating nuclear factor erythroid 2-related factor 2 (Nrf2) simultaneously.21 The Nrf2’s domain is responsible for activating the transcription of antioxidant response elements capable of promoting formation of antioxidant enzymes such as superoxide

PATHOGEN INACTIVATION

Bactericidal effects of ozone in vitro have been confirmed by a wide variety of studies. As a potent oxidant, ozone destroys bacterial cell walls by oxidizing phospholipids and lipoproteins on the cytosolic membrane and thereby destroying its integrity. As this occurs, accompanied by changes in the bacterial envelope's permeability, ozone infiltrates the microorganism to oxidize glycoproteins and glycolipids and damage enzymatic function, causing cell death and lysis.21 Specifically, a previous

HEMORHEOLOGY AND ENDOGENOUS GROWTH FACTOR MODULATION

Given the more efficient mitochondrial respiratory chain in the presence of ozone therapy, oxygen levels inside the cell increase as a result of transmembrane flow of oxygen.41 By facilitating the glycolytic rate, ozone autohemotransfusion increases adenosine triphosphate and 2,3-diphosphoglycerate in the cell. For this reason and because of the Bohr effect, the oxygen-bound hemoglobin is unloaded into ischemic tissues more easily, a direct consequence of rightward shift of the

IMMUNE SYSTEM ACTIVATION

The development of inflammatory responses in patients with DFUs is related to infections due to immunologically mediated acute phase reactions manifested by increased levels of amyloid A and C-reactive protein. Studies devoted to the influence of immune changes in the course of long-term diabetes showed significantly reduced chemotaxis of neutrophils and impaired phagocytic activity associated with reduced monocyte adhesion to vascular endothelium.50 In addition, it has been reported that

ADMINISTRATION SAFETY OF OZONE THERAPY

Offloading and debridement of the area around the DFU are important in initial therapy for neuropathic ulcerations, and proper footwear is essential to alleviate unnecessary pressure to the foot. Indications for ozone therapy for diabetic wounds are listed in Table 1. There are 2 forms of ozone therapy for wounds: topical treatment and systemic treatment. Topical treatment includes bagging, tenting, compresses, local injection and ozonized olive oil. Systemic treatment includes rectal

CONCLUSIONS

The mechanisms of action of ozone have not been elucidated completely, and the therapeutic window for ozone dosage has not been standardized to minimize the risk of toxicity. Adjunctive therapies should be applied with caution after conventional management strategies fail. More controlled clinical trials are warranted to demonstrate the comprehensive effects on DFUs.

Author Contributions

QW and QC conceived the concept of the review. QW wrote the manuscript. QC designed and formatted the table. QW and QC read, edited and reviewed the manuscript. All authors have read and agreed to the published version of the manuscript.

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    Conflict of Interest: All authors of this manuscript declare no conflicts of interest regarding the publication of this article.

    Funding: This project is funded by the Science and Technology Program of Sichuan Province (No. 2019YFS0085). The sponsors are not involved in design, execution or writing the study.

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