Ozone therapy for diabetic foot.

Diabetic foot ulcers (DFU) are a burden to the diabetic community. With increasing medical bills, to unsuccessful treatment, those suffering from DFUs can use alternative therapeutics. First seen in the mid-1800s, ozone (O3) is thought to be unstable, due to inherent molecular nature. With the help of pharmaceutical science, various O3 treatments have flourished in the medical community to help those suffering from DFUs. Promising results are seen through numerous studies. Usually, a mixture of both O2 and O3 is seen in pressurized machines as administered to the foot ulcer. Foot ulcers, specifically DFUs, need to be assessed, cleaned, and treated as fast as possible for the fastest results. Results such as amputation can be seen if the foot is not attended to as soon as possible. With fast growing clinical trials in O3 therapy and quick administration of the O3, O3 therapy may be on the rise to be at the forefront of treating DFUs. Compelling evidence is seen in clinical trials, but more must be done to fully understand the role of O3 in DFUs.

INTRODUCTION

Foot ulcers have an incidence of 4–10% in patients diagnosed with diabetes mellitus and a lifetime incidence of around 25%.1 Furthermore, it is clear that patients that present diabetic foot ulcers (DFU) are hospitalized more often than without DFU. Amputations can be attributed to ischemia, infection, neuropathy, faulty wound healing, ulceration, gangrene, and initial minor trauma.2 Recurrent infections in patients suffering from type 2 diabetes mellitus (T2DM) coupled with high plantar pressure are a major determining factor for DFUs.3 Common treatments of DFU is debridement, offloading areas of friction and other conventional wound managements.4 If treatment is delayed, the neuropathic and vascular complication of DFU can lead to gangrene or even amputation.5 Not only is foot problems of diabetic patients seen as a major factor when considering morbidity, there seems to be a cost burden with heavy expenditure associated with treatment for the diabetic foot (DF).6 The use of ozone (O3) within the medical community has begun in the mid 19th century.7 Medicinal application of O3 is met with great discourse due to its inherently unstable nature. However, it is believed that O3 can be initiated to pharmaceutical science with great therapeutic benefit to specific biological systems and not just serve as an esoteric approach.8 O3 has been seen to be used in many medicinal applications ranging from uses in dentistry to proper sterilization of medical instruments.79 Beneficial effects of O3 has been seen in orthopedics, mucosal and cutaneous infections.10 Future effects can show O3 therapy being used to treat heart failure.11 Furthermore, there is growing evidence that O3 can be used to treat DFUs. A study showed that O3 treatment via rectal insufflation can improve glycemic index along with preventing oxidative stress in diabetic rats.12 Efficacy can be measured by how well the wound has closed in DFU after O3 treatment has been administered.13 Herein we review the evidence for possible use of O3 therapy on DFU.

CLASSIFICATION OF DIABETIC FOOT ULCERS

There are several different ways to assess the severity of a DFU. The most common classification system surfaced in the 1970s named the Meggit-Wagner classification, summarized in .14 The Meggit-Wagner classification system has been around the longest, however, some researchers believe it lacks overall substance to describe the ischemia and possible complications. In the early 1990s a more profound classification system, developed by the University of Texas, surfaced and is summarized in .15 Although these two classification systems are both very much used today, it is believed that the Meggit-Wagner classification is too simple and the University of Texas classification is too complex. That is until Amit Jain proposed a new classification based on infective and non-infective complications as depicted in .16

MOLECULAR GENETICS OF DIABETIC FOOT ULCERS

The Intelectin 1 (ITLN1) gene encodes a protein known as omentin. Inherently, omentin has endothelial vasodilator activity and anti-inflammatory actions.17 For this reason, it is believed to be a protective factor in DFUs since they are vascular complications. Mrozikiewicz-Rakowska et al.18 sought to evaluate the association of the allelic variant, rs2274907, of the ITLN gene and the occurrence of DF in patients diagnosed with T2DM. A study with 670 individuals was done; 204 individuals had T2DM with DF, 299 had T2DM with no signs of DF, and 167 individuals served as a healthy control. Mrozikiewicz-Rakowska et al.18 found that neuropathy, ischemic heart disease, retinopathy, obesity, active smoking, and hyperlipidemia were all seen more frequently in patients with T2DM and DF than with T2DM and no DF. Furthermore, allele A of the rs2274907 variant was seen at a more frequent rate in the DF group than the healthy control. His team concluded the variant is associated with increased prevalence of DF.18 He also found that allele A is sex-specific and is present in men. Therefore, men with single-nucleotide variants (SNV) are at risk for DF. Individuals present with DFU have overexpressed pro-inflammatory cytokines. The cytokines seen present are: tumor necrosis factor α (TNF-α), chemokines (e.g., CCL2), stromal cell-derived factor 1 (SDF-1), and interleukins (IL) 1 and 6.19 Dhamodharan et al.20 studied the role and genotyped IL-6 (rs1800795), TNF-α (rs1800629), and SDF-1 (rs361525) SNVs in DFU. This study showed that IL-6-174 CC and GC genotypes protected against diabetes, but not no association with DFU was found. TNF-α-308 AA and GA was correlated with increased susceptibility towards diabetes and DFU. SDF-1-801 AA and GA role was similar to that IL-6-184 CC and GC with protection against DFU as well. This was studied via serum levels of IL-6, TNF-α, and SDF-1 variants, along with other diabetogenic markers.20

DIAGNOSIS OF DIABETIC FOOT ULCERS

Patients presented with DFUs are at risk for having peripheral arterial disease (PAD). Furthermore, nearly 50% of patients present with DFU are also present with PAD.21 A common physical examination for diabetic patients with foot ulcers is the use of ankle brachial pressure-systolic (ABI-s). The use of the ABI-s test is to understand how severe PAD has advanced in patients with DFUs. However, diabetic patients tend to have calcified lower limb arteries, disrupting the systolic pressure in the arteries after the contraction of the heart. ABI-s can be falsely elevated due to the calcified lower limb arteries. A study shows that instead of performing ABI-s one can perform ankle brachial pressure-diastolic (ABI-d). Asbeutah et al.22 had a size of 51 patients present with DFUs, 26 of which came present with calcified lower limbarteries and 25 of which did not present calcification. Another 25 persons were used as a control. Simply enough, both ABI-s and ABI-d were measured bilaterally via a brachial and ankle oscillometric pressure. The use of analysis of variance (ANOVA) showed statistical significance among people with the use of ABI-s and ABI-d leading to the conclusion that ABI-d may be a better tool for patients with DFUs with calcified arteries.22 More studies have been done to see whether other forms of non-invasive vascular assessment can be performed to asses PAD more significantly. Common device-based diagnostic testing for patients with DFU and possible PAD includes color duplex ultrasonography, MR angiography, radiography, capillaroscopy, phlebography, continuous wave Doppler (CWD) and toe-brachial index (TBI).23 Some researchers believe that ABI testing is not as effective as others such as CWD or TBI. A study was done where 117 participants were recruited with only 72 present with diabetes and 45 without diabetes. All patients received diagnostic testing via ABI, TBI, and CWD from the right lower limb. To properly assess accuracy a color duplex ultrasonography was used. Tehan et al.24 determined that CWD was both the most sensitive and most specific in determining the presence PAD in patients with diabetes than TBI or ABI. Another study ruled out against ABI because of the significant limitation it places on diabetic patients presented with critical limb ischemia.25

APPLYING OZONE TO DIABETIC FOOT ULCERS Table 4)

A study demonstrated that ozonated water, along with ozonated oils, can be used as a disinfectant and healing stimulant.1026 This can reap great benefit for individuals suffering from DFUs. Furthermore, O2–O3 treatment can improve vascular endothelial growth factor (VEGF), transforming growth factor-β (TGF-β), and platelet-derived growth factor (PDGF) levels.27 The aforementioned growth factors, specifically, TGF-β, seem to increase in patients with DFUs and can heal the localized gangrene and tissue remodeling.282930 O3 causes platelets to aggregate, along with the release of the specific growth factors (e.g., PDGF, TGF-β, and IL-8) which is known to heal wounds rapidly.28 Furthermore, O3, when applied to DFUs, eliminates pathogens and the O2 promotes proliferation of fibroblasts. This helps rebuild the intercellular matrix, healing the area around the DFU.30 Bulynin et al.31 demonstrated that O3 has antibacterial properties and developed a new method for treatment via hydropressive treatment of wounds. A stream of ozonized fluids is generated under a pressure of 350 ATM and an “OZh-2” apparatus is used. The wound is cleansed rapidly, reduces chance of infection, and period of treatment.31 One study showed that the use of hyperbaric oxygen therapy can ameliorate dermal wound healing.32 Travagli et al.30 believe that the accelerated trend of wound closure in a young population may be due to O2 tension by O3 in the surrounding wound area that acts as an antibacterial substance to decrease bacterial infection. In the late 20th century, a team of German scientists used O3 on skin ulcers caused by diabetes. They used a polythene-bag for 25 minutes on average with a concentration ranging from 10 to 80 μg/mL. The different concentrations aforementioned were used with how severe the ulcers were. As the patients’ ulcers healed, a lower concentration of O3 was used.33 Záhumenský et al.3435 stated that offloading and debridement of the area around the DFU is a key step in beginning therapy for neuropathic ulceration. Furthermore, the healing process can be accelerated by O3, however, one should wear proper footwear to alleviate unnecessary pressure to the foot. In non-healing wounds, a combination of O2-O3 therapy might be of benefit. A study showed that it can heal and reduce the pain due to the inherent disinfectant properties and scavenging properties of endogenous oxygen free radicals.36 O2-O3 is recognized as a disinfectant because it is known to inactivate bacteria by destroying their envelope through oxidation of specific proteins and lipids. Moreover, interferon, TNF, and IL-2 activate the immune system.73637 This can explain why a reduction in infection is seen when O3 therapy is used for DFUs. A few studies showed that when patients come present with orthopedic wounds, O3 therapy can be applied after initial conventional treatment.3839

SAFETY OF OZONE THERAPY

The utility and safety of intralesional O3 injection in the treatment of chronic wounds has not yet been reliably assessed.44 Though O3 therapy is typically safe without adverse reactions,45 it may be toxic if administered outside its therapeutic window.46 Because intralesional O3 injection has not yet been used in any of the studies involving DFUs, its safety has not yet been ascertained. These injections may inadvertently drive the superficial infection into the deeper tissue.44 Moreover, O3 therapy is not recommended for deep, heavily infected or necrotic wounds.35

Uzun et al.44 described a case of a diabetic patient who developed severe foot necrosis and infection after receiving intralesional O3 injections for a non-healing wound. Major complications that have been linked to O3 injections for lumbar disc herniation45 include vitreo-retinal hemorrhages,47 ventral and dorsal root injury,48 vertebrobasilar stroke,49 pyogenic discitis, and ventral epidural abscess,50 and fulminant septicemia and death.51 Skin irritation may follow topical O3 application while respiratory irritation may occur due to gas emitted from the generator.35 In O2-O3 therapy via autohemotransfusion for psoriasis, Marchetti et al.52 described a fatal gas embolism.

When tested in pregnant rats, teratogenic or embriotoxic effects (i.e., fetal malformations) of O3 administered via rectal insufflation have not been identified.53 In the end, to prove the inocuity of O3, more controlled clinical trials are warranted.

PREVENTIVE CARE

Common measures individual can take to prevent DFUs is to get an annual DF screening along with care intervention, especially those at high risk of DF complications.54 Another measure, limited to individuals who have experienced ulceration, is nerve decompression surgery. It can prevent further ulceration along with amputation.55 PAD is a major complication of DF and can determine the prognosis of healing. According to the Eurodiale study group, a neuropathic ulcer shift to neuro-ischemic ulcer is quite often. Assessing PAD via imaging and revascularization can dramatically reduce health risks if treated appropriately and on time.56 Diabetic neuropathic ulcers can be managed by removing calluses, controlling infection, and reducing the amount of weight placed on the afflicted foot.57 Many physicians agree that one of the greatest ways to decrease rates of mortality and morbidity among those who suffer from DF complications is early recognition.58 Holistic care is available across the world via Multi-Disciplinary Foot Clinics.59 Callus formation in DF patients serves a high level of predictability of ulcer formation. One can remove such calluses via urea-based preparations.60 It behooves patients to consider preventative measures because a study has showed individuals with DFUs have a poor health-related quality of life.61

CONCLUSION

The purpose of this review is to provide the scientific community with up-to-date clinical trials, peer-reviewed studies, and compelling evidence on O3 therapy in the treatment of DFUs. Further studies with a larger sample size would corroborate existing evidence.

Table 1

Meggit-Wagner classification system for diabetic foot ulcer14

Table 2

University of Texas classification system for diabetic foot ulcer15

Table 3

Amit Jain's classification system for diabetic foot ulcer16

Table 4

Studies testing ozone for diabetic wound care