Diabetes is a disorder of metabolism and of the circulation. Chronic metabolic irregularities linked to poor circulatory perfusion and nerve damage can affect a number of organ systems, including skin tissues. In this article, the focus is on factors in diabetes that can contribute to dermal breakdown, ulceration, and infection. Most importantly, it proposes a treatment modality, which, backed by solid experimental, and clinical data cumulated worldwide, shows great promise in the management of diabetes-related skin lesions.

The conditions surveyed include infected wounds, skin ulcers and gangrene. These wounds, in the context of diabetes, are notoriously difficult to resolve. Healing resistance is thus a well-recognized element of frustration in their clinical care.

In most of the above conditions, multiple factors play into healing resistance. Among them are circulatory impairments, neurological deficits, tissue injury, and immunological compromise. A central factor is the proliferation of infectious microorganisms that, by the variety of their families, their toxin-producing capacities, and their resistance to antibiotics, offer daunting obstacles to standard treatment regimens.

Approximately 15% of the estimated 20 million Americans afflicted with diabetes mellitus develop lower leg skin ulcers. Of those patients, 20% will eventually require amputations. Diabetes mellitus is the leading cause of nontraumatic lower extremity amputation in the United States (LeRoith 2003).

Factors contributing to skin lesions in diabetes:

Arteries and arterioles in chronic diabetes are prone to plaque buildup (Tesfaye 2005). The precise reason for this phenomenon is still elusive, yet it is well documented that Type II non-insulin dependent diabetes is linked to abnormal blood lipid profiles known as diabetic dyslipidemia (Goldberg 2004). Low-density lipoproteins particles are smaller in size and thus more apt to adhere to vessel walls, resulting in progressive vascular occlusion (Beckman 2002; Renard 2004). Lowered oxygen and nutrient supplies stress tissue resilience and impair recovery from injury (Chapnick 1996).

Poorly controlled diabetes is correlated with peripheral nerve dysfunction. The mechanisms of diabetic injury to neurons are poorly understood. Higher blood glucose level seem to promote oxidative stress in neurons, but much more complex mechanisms are implicated (Tomlinson 2002).

Diabetic neuropathy can involve motor, sensory, and autonomic system neurons. Sensory neuron malfunction is translated as loss of feeling, reflex loss, problems with limb position sense, tingling (paresthesias) and pain. Motor impairment shows as muscle weakness. Autonomic neuropathy alters local circulation (Boulton 2004, Bensal 2006).

Chronic and repeating pressure on the skin compresses dermal arterioles, inhibiting tissue perfusion. Tissue weakness leads to ulceration. Ulcers are fertile ground for pathogenic microorganisms, and surrounding tissues become prone to cellulitis. At times, the ulcer crater reaches the underlying bone, initiating osteomyelitis (Boulton 2000).

The oxygen atom exists in nature in several forms: (1) As a free atomic particle, singlet oxygen (0), it is highly reactive and unstable. (2) Oxygen (02), its most common and stable form, is colorless as a gas and pale blue as a liquid. (3) Ozone (03), has a molecular weight of 48, a density one and a half times that of oxygen, and contains a large excess of energy (03 g 3/2 02 + 143 KJ/mole). It has a bond angle of 127° ± 3°, resonates among several hybrid forms, is distinctly blue as a gas, and dark blue as a solid. (4) 04, a very unstable, rare, nonmagnetic pale blue gas readily breaks down into two molecules of oxygen.

Ozone, as a triatomic configuration of oxygen, possesses supreme oxidizing power derived from its marked tropism for extracting electrons from other molecules, simultaneously releasing one of its own oxygen atoms in the process.

Ozone’s capacity for inactivating microorganisms has been increasingly appreciated since the turn of the last century (Viebahn 1999). In the past few decades, ozone’s action against bacteria, viruses and fungi has sparked keen interest for its use, not only for purifying water supplies, but also for medical objectives.

Ozone/oxygen mixtures exert significant antimicrobial activity. As with many medications, however, ozone has a range of action that, in the terminology of pharmacokinetics, is referred to as a therapeutic window (Bocci 2005). Indeed, ozone applied in concentrations that are too low, has little therapeutic effect. Applied externally in high concentrations, ozone may become irritating and tissue-toxic.

Due to ozone's demarcated therapeutic range, ozone concentrations administered to the patient need to be carefully calibrated and controlled. Optimally therapeutic ozone/oxygen mixtures require state of the art quantitative (dosage, concentration), as well as qualitative (purity) controls currently available in contemporary ozone generation technologies, all predicated upon the evaluation of the lesions under treatment.

Ozone is a gas with a half-life of approximately one hour at room temperature. Medical ozone generation and delivery systems therefore require that ozone be created at the moment it is to be administered. Ozone, in this sense is not a drug that has a shelf life enabling it to be kept for long periods of time.

Ozone is created by applying energy to oxygen. The oxygen source should be pure and devoid of nitrogen or other impurities. The presence of too much nitrogen favors the production of tissue-toxic nitrogen oxides.

Importantly, the humidity level of the ozone/oxygen mixture enters into the treatment protocol. Indeed, in certain wounds, humidity added to the ozone/oxygen mixture, markedly enhances therapeutic results.

Bacteria fare poorly when exposed to ozone, a fact appreciated since the 19th century (Viebahn 1999). Ozone is a strong germicide needing only micrograms per liter for measurable action. At a concentration of 1 mg per liter of water at 1°C, ozone rapidly inactivates coliform bacteria, staphylococcus aureus, and Aeromonas hydrophilia (Lohr 1984). The inactivation rate for E. coli, takes place in relatively small concentrations of ozone, and is influenced by pH and temperature (Ivanova 1983).

At dosage concentrations used in external therapy, ozone essentially inactivates all bacterial species. This holds true for oxygen-dependent aerobic organisms, for oxygen-independent anaerobic bacteria associated with gangrene, and for facultative species that can function with or without oxygen. Spores and cysts are neutralized as well (Ishizaki 1986, Langlais 1986). Spores of Bacillus cereus and Bacillus megaterium are susceptible to ozone exposure (Broadwater 1973). Ozone’s universal antibacterial action makes it an agent of choice in the management of wound infections colonized by bacterial species belonging to diverse groups.

An incomplete list of bacterial families susceptible to ozone inactivation includes the Enterobacteriaceae, a large group whose natural habitat is the intestinal tract of mammals. These Gram-negative organisms include Escherichia coli, Salmonella, Enterobacter, Shigella, Klebsiella, Serratia, and Proteus. Other ozone-sensitive bacterial species include Streptococci, Staphylococci, Legionella, Pseudomonas, Yersinia, Campylobacteri, and Mycobacteria (Dyas 1983, Broadwater 1973).

The cell envelopes of bacteria are composed of intricate multilayers. Covering the bacterial cytoplasm to form the innermost layer of the envelope is the cytoplasmic membrane, made of phospholipids and proteins. Next, a polymeric layer built with giant peptidoglycan molecules provides bacteria with a stable architecture. In Gram-positive organisms, the pepticoglycan shell is thick and rigid. By contrast, Gram-negative bacteria possess a thin pepticoglycan lamella on which is superimposed an outer membrane made of lipoproteins and lipopolysaccharides. In acid-fast bacteria, such as Mycobacterium, up to one half of the capsule is formed of complex lipids (Parish 2005, Hogg 2005).

The most cited explanation for ozone's bactericidal effects centers on disruption of cell membrane integrity through oxidation of its phospholipids and lipoproteins. There is evidence for interaction with proteins as well (Mudd 1969). In one study exploring the effect of ozone on E. coli, evidence was found for ozone's penetration through the cell membrane, breaking the closed circular plasmid DNA, which would presumably diminish the efficiency of bacterial procreation (Ishizaki 1987).

Fungi are frequent inhabitants of chronically infected wounds. One study (Moussa 1999) found colonization by Candida and Aspergillus. Fungal organisms neutralized by ozone exposure include Candida, Aspergillus, Histoplasma, Actinomycoses, and Cryptococcus. The multilayered cell walls of fungi, composed of carbohydrates, proteins and glycoproteins, contain many disulfide bonds sensitive to ozone oxidation.

Protozoa

Protozoan organisms are often found in chronically infected wounds. Species disrupted by ozone include Giardia, Cryptosporidium, and free-living amoebas, including Acanthamoeba, Hartmonella, and Negleria. Several authors have demonstrated ozone’s capacity to penetrate through the walls of Giardia cysts causing fatal structural damage (Widmer 2002, Wickramanayake 1984).

Oxygen has long been established as beneficial in many pathological conditions, forming the basis for the use of hyperbaric oxygen treatment for carbon monoxide poisoning, decompression sickness, gas gangrene and stroke, among others. Oxygen under pressure, applied to infected tissues, inhibits the proliferation of anaerobic bacteria and stimulates local circulation (Wunderlich 2000).

Ozone, when added to oxygen, however, has properties that clearly transcend oxygen administration alone. The two properties invoked are:

1. Ozone’s extremely broad range of antipathogenic action and,
2. The vasodilation of arterioles promoting tissue oxygenation and the delivery of nutrients and immunological factors to compromised tissues; and the vasodilation of veins, increasing venous outflow and the removal of toxins.

This category addresses wounds that are not yet infected but have a high probability for eventual infection. Post-surgical wounds, injuries such as abrasions, contusions and lacerations are salient examples.

The use of topical ozone therapy in these cases may be solely preventive, aimed at inhibiting the proliferation of potentially infective organisms. Preventative topical ozone therapy may thus stave off the development of potentially disastrous infectious complications.

Wounds healing in an indolent manner are apt to regress if treatment continuity is interrupted.

In these wounds, anaerobic bacteria - bacteria that do not need oxygen for their growth (e.g., Bacteroides, Clostridium) - may be active at deeper levels of the dermis, insulated from the influence of oxygen. While anaerobic bacteria are responsible for many devastating infections including gas gangrene, aerobic bacteria normally found on skin surfaces such as Staphylococcus epidermis, Corynebacteria, and Propionobacteria, given propitious circumstances, are capable of remarkable aggressive infectivity.

Diabetic ulceration is accelerated by poor circulation and neuropathy. One study (Anandi 2004) reported bacterial culture results for 107 patients with diabetic foot lesions. They included E. coli, Klebsiella, Pseudomonas, Proteus, Enterobacter, Clostridium perfringens, Bacteroides, Prevotella, and Peptostreptococcus.

The treatment of diabetic ulcers requires a multidisciplinary approach, including surgical, topical, and systemic interventions when indicated (Cavanagh 2005, Kruse 2006). Topical antibiotics often fail to penetrate far enough into the wound and frequently cause secondary dermatitis and allergy in their own right (De Groot 1994). For this reason, they are not generally recommended. Systemic antibiotics, prescribed for infections transgressing ulcer borders, can only address a portion of the spectrum of microorganisms cultured from such wounds. Bacterial resistance is common (e.g., ß-lactam antibiotic resistance, as in methicillin-resistant staphylococcus).

Ozone applications in diabetic ulcers provide essential dual functions of topical broad-spectrum coverage and circulatory stimulation. In addition, ozone, via multiple serial applications and higher dose ranges, is able to further its penetration into deeper tissue layers where anaerobic bacteria are apt to reside.

Gas gangrene, also known as necrotizing fascitis, myositis, and myonecrosis is feared because of its rapid evolution leading to the galloping breakdown of affected tissues (Chapnick 1996, Falanga 2002)).

Several bacterial species are implicated in this process, the most common being Clostridium and toxin-producing Group A Streptococcus families. Other bacterial species implicated in gas gangrene include E. coli, Proteus, Staphylococcus, Vibrio, Bacteriodes, and Fusiforms (Caballero 1998). Gas gangrene may become a fatal complication of diabetic and decubitus ulcers.

Anaerobic and facultative bacteria feed on sugars and glycogen, produce lactic acid, and gases such as methane, carbon dioxide, and hydrogen. Their life threatening toxins cause severe tissue breakdown, hemolysis, renal failure, and shock.

These impressively destructive wounds demand emergency ozone application as an important adjunct to their multidisciplinary interventions.

In every case, an individual assessment has to be made relative to the skin lesion under treatment. Noted in this evaluation are the size (diameter and depth) of the lesion, and in deeper lesions, the involvement of dermal tissues, ligaments, muscle and bone. Also, the presence of purulence and necrosis, the relative health of surrounding tissues, and adjacent circulatory competence.

Ozone therapy is always individualized to incorporate these clinical observations. Accordingly, ozone concentrations are adjusted, as are lengths and frequencies of treatment, all recalibrated as treatment progresses.

In the practice of external ozone application, a specially designed ozone-resistant envelope is used to enclose the area being treated. A precise fitting of the envelope is needed in order to ensure a constant ozone/oxygen concentration within the envelope milieu and a proper containment of the gas. Ozone will thus be prevented from escaping into the ambient environment, reducing respiratory exposure to treating personnel.

The ozone concentrations prescribed during the course of treatment, the duration and frequency of individual sessions, and the lengths of the overall course of therapy are all predicated upon the evolution of the specific medical condition under treatment. In extensive wet ulcers and burns, for example, initial topical ozone concentrations need to be low in order to prevent excessive systemic ozone absorption. With gradual epitheliazation of the ulcer wound, applied ozone concentrations will require corresponding adjustments.

1. The ease of administration of this therapy. Once the principles of ozone dynamics and the art of adapting ozone dosages and treatment protocols are mastered by the clinician, topical oxygen/ozone therapy can safely be applied to a broad range of diabetes-related afflictions.
2. Ozone is an effective antagonist to an enormous range of pathogenic organisms. In this regard, ozone cannot be equaled. It inactivates aerobic, facultative, and anaerobic bacterial organisms, a wide spectrum of viruses, and a comprehensive range of fungal and protozoan pathogens. To replicate this therapeutic action, ulcerative conditions would have to be treated with an assortment of various systemic antibiotic agents. In the context of accepted contemporary medical practice, this is not feasible.
3. External ozone therapy, applied in a timely fashion, may obviate the need for systemic antipathogen therapy, thus saving the patient from all the side effects and organ stresses this option entails. External ozone is both a preventive, acute care, and chronic care therapeutic agent.
4. External ozone application to superficial tissues whose blood supply is reduced enhances tissue blood and oxygen perfusion.
5. There is evidence that ozone, via its oxidizing properties, inactivates bacterial toxins. Toxins, whose function is to destroy tissues, provide bacteria with colonizing advantage.
6. Ozone exerts its anti pan-pathogenic actions through entirely different mechanisms than conventional antibiotic agents. The latter must be constantly upgraded to surmount pathogen resistance and mutational change. Ozone, on the other hand, presents a direct and powerful oxidative challenge that any and all pathogens are incapable of circumventing.
7. Externally applied ozone/oxygen mixtures are entirely compatible with systemically administered antibiotics, as they are with debridement and other local wound care procedures.

1. Ozone/oxygen mixtures are not transportable and need to be created at the site and time of administration.
2. Ozone/oxygen mixtures need to be administered serially in diabetic wounds. This may translate, in many circumstances, to daily applications until the lesion resolves.
3. Ozone/oxygen mixtures, applied externally, have limited penetrability. While they possess panpathogenic power on ulcer surfaces, their therapeutic action has limited range at greater depths of ulcer boundaries.

Topical ozone/oxygen therapy has shown effectiveness and safety in healing diabetic skin afflictions. In this article, the following are cited: Wounds with potential for infection, infected wounds, poorly healing wounds, diabetic leg ulcers, decubitus ulcers and gangrene.

Ozone possesses unique physico-chemical attributes enabling it to exert potent antipathogenic activity. Applied to the adjunctive treatment and management of diabetic leg lesions, ozone can tip the balance from chronic failure to resolution. There is one crucial element missing from contemporary therapeutic regimens for diabetic skin lesions: Ozone

Suggested Reading and References

Gérard V. Sunnen M.D.
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