Diabetic Wound Management:
by Gérard V. Sunnen, M.D.
A Key Ingredient is Missing
© March 2007
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
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
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 as a drug
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
Ozone generation and administration
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.
Ozone’s actions on wound pathogens
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
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
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
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
Ozone’s cutaneous physiological effects
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
Ozone, when added to oxygen, however, has properties
that clearly transcend oxygen administration alone. The
two properties invoked are:
- Ozone’s extremely broad range of antipathogenic
- 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.
Diabetic skin conditions benefited by ozone therapy:
Wounds with a potential for infection
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
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
Poorly healing wounds
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
Diabetic leg ulcers
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
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
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
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.
The practice of external ozone therapy in diabetic
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
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
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.
Advantages of topical ozone therapy in diabetes
- 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
- 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.
- 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.
- External ozone application to superficial
tissues whose blood supply is reduced enhances
tissue blood and oxygen perfusion.
- There is evidence that ozone, via its oxidizing
properties, inactivates bacterial toxins. Toxins,
whose function is to destroy tissues, provide
bacteria with colonizing advantage.
- 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
- Externally applied ozone/oxygen mixtures are
entirely compatible with systemically administered
antibiotics, as they are with debridement and other
local wound care procedures.
Disadvantages of topical ozone therapy in diabetes
- Ozone/oxygen mixtures are not transportable and
need to be created at the site and time of
- Ozone/oxygen mixtures need to be administered
serially in diabetic wounds. This may translate, in
many circumstances, to daily applications until the
- 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
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