Review
Skin Pharmacol Physiol 2011;24:113–126
DOI: 10.1159/000322643
Antioxidant Therapies for Wound Healing:
A Clinical Guide to Currently Commercially
Available Products
S.D. Fitzmaurice a R.K. Sivamani a R.R. Isseroff a, b
a
Department of Dermatology, University of California, Davis School of Medicine, Sacramento, Calif., and
b
Dermatology Wound Service, Department of Veterans Affairs Northern California Health Care System
Mather, Calif., USA
Key Words
Antioxidant ⴢ Wound healing therapy
Abstract
Many facets of wound healing under redox control require a
delicate balance between oxidative stress and antioxidants.
While the normal physiology of wound healing depends on
low levels of reactive oxygen species and oxidative stress, an
overexposure to oxidative stress leads to impaired wound
healing. Antioxidants are postulated to help control wound
oxidative stress and thereby accelerate wound healing.
Many antioxidants are available over the counter or by pre-
scription, but only one, Medihoney쏐, has been specifically
FDA approved for wound healing. Here we review the exist-
ing evidence for the use of antioxidants for wound healing,
with a review of the pertinent animal and clinical studies.
Natural products and naturally derived antioxidants are be-
coming more popular, and we specifically review the evi-
dence for the use of naturally derived antioxidants in wound
healing. Antioxidant therapy for wound healing is promis-
ing, but only few animal studies and even fewer clinical stud-
ies are available. Because only few products have undergone
FDA approval, the consumer is advised to scrutinize them for
© 2011 S. Karger AG, Basel
1660–5527/11/0243–0113$38.00/0
Fax +41 61 306 12 34
E-Mail karger@karger.ch Accessible online at:
www.karger.com www.karger.com/spp
Received: February 5, 2010
Accepted after revision: October 28, 2010
Published online: January 15, 2011
purity and contaminants prior to use, and this may require
direct contact with the companies that sell them. As a field
of science, the use of antioxidants for wound healing is in its
infancy, and future studies will better elucidate the role of
antioxidants in wound healing.
Copyright © 2011 S. Karger AG, Basel
Introduction
Wound healing proceeds through distinct yet overlap-
ping stages of coagulation, inflammation, reepithelializa-
tion and tissue remodeling after injury. The role of reac-
tive oxygen species (ROS) in these processes has been and
continues to be an area of evolving research. The previ-
ously held belief that oxidants were deleterious to healing
has recently been challenged. Current thinking supports
a positive role for prooxidants in the healing process when
the correct balance between oxidative and antioxidative
forces occurs. The proreparative actions of free radicals to
combat invading microorganisms and aid in cellular sig-
naling require that the tissue concentrations of these free
radicals be precisely controlled to avoid the cellular dam-
age that occurs with excess oxidative stress. Excellent re-
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Dr. R.R. Isseroff
University of California, Davis School of Medicine
Department of Dermatology, Dermatology Research
TB 192, 1 Shields Avenue, Davis, CA 95616 (USA)
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Tel. +1 530 752 8155, Fax +1 530 752 9767, E-Mail rrisseroff @ ucdavis.edu
views of the mechanism by which free radicals impact
upon wound healing have recently been published [1–3],
and therefore only a minimal discussion of the mecha-
nism ensues here, as the primary goal of this paper is to
review the evidence that supports the antioxidant treat-
ments currently available to the health care practitioner,
and their potential role in improving wound healing. A
host of over-the-counter ‘natural’ products are marketed
to consumers as antioxidants with prohealing activity.
The practitioner is often faced with a patient who is al-
ready using, or plans to use, one or many of these available
products. In this paper, we have assembled as a resource
for the clinician an evidence-based review of the antioxi-
dant products that are available as well as their mecha-
nisms of action and potential for improving wound repair.
Free radicals are highly unstable molecules, and ROS
are a form of free radicals that include the oxygen atom
as well as reactive molecules such as superoxides and per-
oxides. Although normally formed as a byproduct of me-
tabolism and reactive to invading organisms, overpro-
duction leads to an increased load of free radicals and
ROS known as oxidative stress. Antioxidants are impor-
tant mediators in regulating the damage that is poten-
tially incurred by biological molecules such as DNA, pro-
tein, lipids and body tissue in the presence of reactive spe-
cies. Antioxidants are beneficial in their ability to be
relatively unreactive as free radicals and therefore less
likely to propagate deleterious damage [4].
ROS are likely needed at some basal level for wound
healing. The importance of ROS to wound healing is il-
lustrated by studies demonstrating that total suppression
of oxidant production results in impaired healing, just as
excessive amounts of oxidants do. For example, nicotin-
amide adenine dinucleotide phosphate (NADPH) oxi-
dase plays a critical role in the leukocyte’s ability to pro-
duce the respiratory burst important in pathogen killing
[2]. Dysfunction of NADPH oxidase impairs the ability
to produce superoxide, resulting in subsequent compro-
mised wound healing in mice [2]. Likewise, while low
concentrations of hydrogen peroxide accelerate wound
closure in a murine model, the suppression of hydrogen
peroxide production by the in vivo transfer of catalase
results in a downregulation of vascular endothelial
growth factor (VEGF), with subsequent decreased angio-
genesis and impairment of healing [1].
ROS have also been implicated as important mediators
of cell signaling and inflammation in wound repair [2].
Platelet-derived growth factor, a chemotactic recruiter of
cells key to wound repair, has been shown to generate hy-
drogen peroxide and superoxide in human hepatoma
114 Skin Pharmacol Physiol 2011;24:113–126
cells [5] and human aortic smooth muscle cells [6], re-
spectively; the latter then induces other inflammatory
mediators such as nuclear factor-␬B and monocyte che-
moattractant protein-1 (MCP-1) [2, 6]. In MCP-1-defi-
cient mice, a decreased monocyte population at the
wound results in a decrease in hydrogen peroxide pro-
duction and subsequent decrease in wound angiogenesis
[1]. Treatment of skin wounds in MCP-1-deficient mice
with exogenous hydrogen peroxide at a low, but not at a
high dose was found to increase VEGF mRNA expression
and improve wound healing [1]. ROS-stimulated release
of VEGF was also found in human keratinocytes [7]. Hy-
drogen peroxide is implicated in the induction of neutro-
phil chemotaxis [8]. Additionally, hydrogen peroxide has
been shown to indirectly induce matrix metallopeptidase
1 via activator protein-1 [9]. Matrix metallopeptidase 1
degrades extracellular matrix proteins, thereby allowing
wound cells to migrate. All these studies underscore the
pro-wound effects of ROS when levels are controlled.
Although ROS production is physiologic, excessive
production can be harmful. ROS are a normal byproduct
of cellular metabolism. It has been estimated that 2–5%
of the daily basal oxygen use in humans is converted to
ROS [2, 3]. Inflammatory cells produce ROS as a defense
against invading pathogens. The respiratory burst pro-
duced by neutrophils and other leukocytes such as mac-
rophages and monocytes creates large quantities of ROS
mainly through the enzyme complex NADPH oxidase
[10]. These ROS include the superoxide anion and the dis-
mutated, nonradical product hydrogen peroxide. ROS
play a role in cellular signaling through orchestration of
cytokines, growth factors and hormones vital for wound
repair [2, 11]. The nonradical metabolites such as hydro-
gen peroxide have the potential to be harmful at excessive
levels [11]. Multiple authors have noted that despite not
being a radical itself, hydrogen peroxide can cause severe
cell damage due to the generation of hydroxyl radicals in
the presence of metals such as copper and iron through
the Fenton and Haber-Weiss reactions [4, 11]. Radicals
have the potential to be damaging through lipid peroxi-
dation, protein modification and DNA modification.
Thus to control possible damage from physiologic gen-
eration of ROS, physiologic defenses have evolved.
Physiologic antioxidant defenses include the ROS-de-
toxifying enzymes superoxide dismutase (SOD), catalase,
glutathione peroxidases and peroxiredoxins [11]. Endog-
enous and exogenous low-molecular-weight antioxidants
such as glutathione, vitamin E, vitamin C and phenolic
are nonenzymatic defenders against ROS [11]. These low-
molecular-weight antioxidants ‘sacrifice’ themselves to be
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oxidized and become radicals themselves, though less re-
active and therefore less damaging than the radicals they
scavenge [4]. In a continuing chain reaction, antioxidants
work together to regenerate these ‘sacrificed’ antioxidants
to be available again in their reduced forms for cell defense
[12]. Abnormally low levels of these antioxidants have
been associated with impaired wound healing [11].
As interest in the use of antioxidants continues to
grow, several animal and human studies have already
shown the efficacy of these compounds in promoting
healing. Here we highlight antioxidant studies limited to
those products that are now available to the general pub-
lic as over-the-counter products.
Superoxide Dismutase
SOD is currently available over the counter as a nutri-
tional supplement (table 1), although it has not received
FDA approval for any indication. Interestingly, it is re-
ported that the oral formulations are not absorbed [13].
Parenterally administered SOD, however, has been tested
in multiple animal models of thermal wounds. In one
model, rats were treated intraperitoneally with 100 ml/kg
of bovine Cu/Zn-SOD after having received full-thick-
ness burns followed by excision and allograft [14]. Ani-
mals treated with Cu/Zn-SOD followed by allograft had
lower plasma thiobarbituric acid reactive (TBAR) metab-
olites, an index of lipid peroxidation, after injury than
animals that did not receive allografting or SOD treat-
ment, allografted but not SOD-treated animals, and ani-
mals that only received SOD treatment without allograft.
The SOD treatment itself was not able to make a signifi-
cant difference in TBAR metabolite levels in burned, not
grafted animals. This suggests that excision followed by
allograft was the more important component in this
study, keeping TBAR metabolite levels from rising after
injury. SOD treatment needed to be administered with
excision and allografting for positive effects to be seen.
A second murine model involving full-thickness burn
wounds assessed the ability of intravenous long-acting Cu/
Zn-SOD at a concentration of 10 mg/kg (poly butyl ester-
bound SOD) to affect plasma TBAR metabolite following
prewound administration [15]. SOD-treated animals had
significantly lower plasma TBAR metabolite levels 3 h after
burn compared to control (saline-treated) animals. Sur-
vival at 7 days after burn was significantly greater in the
SOD-treated animals as compared to control rats.
Topical formulations containing SOD include creams
and sprays (table 1), but these are generally marketed with
antiaging and antiwrinkle indications and have limited
clinical evidence to support efficacy in human wounds.
Antioxidant Therapies for Wound
Healing
One animal study evaluated three different methods of
delivering recombinant human Cu/Zn-SOD to a rabbit
partial-thickness burn wound: topically applied as lipo-
somally encapsulated hydrophilic gel emulsion at 0.1 mg/
cm2, topically applied as an enzyme gel suspension at
1 mg/cm2, or directly injected into the wound at a con-
centration of 1 mg/cm2 [16]. Only the topically applied
liposomally encapsulated SOD treatment was able to
reach statistical significance in its ability to decrease
wound edema in the first 3 days after burn as compared
to control animals, although all three delivery methods
of SOD treatment reached significance in decreasing
wound size. In a subsequent study involving rats, histo-
logical analysis was assessed for only the liposomally en-
capsulated SOD group against the wound histology of
nontreated controls. SOD-treated rats evidenced less der-
mal histological damage 7 days after injury, and the treat-
ment led to a 4 times higher number of animals with al-
most complete reepithelialization at 3 weeks compared to
control animals. These studies highlight the importance
which enzyme stability, route of delivery and vehicle ad-
ministration have for an antioxidant agent to be effective
in improving wound healing.
To our knowledge, no wound healing studies in hu-
mans in the USA have been performed with SOD, but a
few limited reports of human studies, performed without
controls, and animal studies suggest that topical applica-
tion may be more effective than systemic administration.
While some topical formulations are readily commercial-
ly available (table 1), it will be important to examine the
bioavailability of active SOD in the wound environment
and to determine its efficacy in healing. Future controlled
human studies will be needed to explore the true role of
exogenous SOD in wound healing.
Vitamin C (Ascorbic Acid)
Vitamin C has been highlighted in wound healing for
its role in collagen formation. The importance of vitamin
C is well known, in large part due to its widely known role
in scurvy, where a dietary deficiency leads to a lack of
structural blood vessel integrity and subsequent bleed-
ing. On the molecular level, vitamin C is needed for the
hydroxylation of the amino acids proline and lysine.
These hydroxylated products contribute to the stabiliza-
tion of the triple helix structure of collagen [17]. Although
a deficiency in vitamin C is known to lead to poor wound
healing, its beneficial role in supplementation has unfor-
tunately not been well studied in human trials.
Two blinded clinical studies evaluating vitamin C sup-
plementation in humans have been performed. The first,
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Skin Pharmacol Physiol 2011;24:113–126 115
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 Table 1. Commercially available antioxidants for wound healing

116
Antioxidant Formulation Brand name Manufacturer Notes

SOD oral A 250 mg tablets A GliSODin쏐 Power A Source Naturals A Mix of gliadin and SOD derived from cantaloupes
B 250 mg tablets B SOD B Puritan’s Pride B Cellulose coated to ease swallowing
SOD topical A Cream – 50,000 PIU A SOD Cream A Young Again Products A Other ingredients include 600,000 IU retinol and 1,000 IU vitamin E
Zn/Cu complexed SOD B SOD Skin Spray B Young Again Products acetate; the product’s caution states that it is not to be used in wounds
B Spray – 50,000 PIU C Superoxide dismutase C SupplementSpot B Contains SD alcohol that can irritate wounds; product’s caution states
Zn/Cu complexed SOD wrinkle cream that it is not to be used in wounds
C Cream – 100,000 PIU SOD C Other ingredients include 1,200,000 IU retinol and vitamin E;
the product’s caution states that it is not to be used on wounds
Vitamin E oral A 400 IU capsules A Vitamin E Liquid Softgels A Nature Made A Manufacturer cautions to consult a doctor prior to starting supplement if
B 400 IU capsules B Super E Complex B Twinlab there is a history of vascular disease, diabetes, pregnancy, bleeding
C 1,000 IU capsules C Natural Vitamin E C Swanson Health Products problems or upcoming surgery
B Contains a mixture of d-␣-, d-␤-, d-␦- and d-␥-tocopherols
C Label denotes that vitamin E is delivered as d-␣-tocopherol
Vitamin E A Oil – 28,000 IU A Pure E Oil A Colonial Dames A Label reports 100% pure vitamin E
topical B Cream – 25,000 IU B Vitamin E Cream B Jason Natural Cosmetics B Label reports the product is 70% organic; also contains avocado oil,
C Cream C Vitamin E Moisture Cream C The Body Shop sunflower seed oil, grapefruit seed extract
D Gel D Vea Lipogel D Vea C Manufacturer lists vitamin E, sorbitol and lanolin as the ‘key ingredients’

Skin Pharmacol Physiol 2011;24:113–126

D Advertized to sooth and protect against minor burns in babies and
support skin rejuvenation in adults
␣-Lipoic acid A 300 mg capsules A Alpha Lipoic Acid 300 A GNC A Bottle states: ‘supports antioxidant regeneration’
B Skin cream B Alpha Lipoic Acid Skin B Vitamin Shoppe B Bottle denotes external use only
Cream
Metronidazole A 250 mg tablets A Metronidazole A Cheap-supplier.com A A phone representative confirmed that no prescription was needed to
oral1 purchase oral metronidazole; reported the pharmaceuticals are supplied
from India
Metronidazole A 3% cream A Xin Fumanling Cream A Demodex Solutions A Marketed to kill Demodex mites and bacteria, diminish inflammation
topical and stop itching
Elemental A 30 mg capsules A Zinc Chelate A Nature’s Way A Label advertises zinc is delivered with an amino acid chelate for optimal
antioxidants B 2 mg tablets B Copper 2 B General Nutrition absorption
oral C 100 ␮g capsules C Selenium Centers (GNC) B Supplied as copper gluconate
C Swanson Health Products C Label advertises 100 ␮g of elemental selenium from selenomethionine
Elemental A 0.25% zinc pyrithione A DermaZinc Spa Cream A Dermalogix Partners A Label cautions that stinging may occur if applied to open lesions
antioxidants cream B Visibly Firm Night Cream B Neutrogena B Marketed to improve skin’s elasticity and restore firmness
topical B Active copper cream C Selsun Blue C Chattem Inc. C Advises against use on broken skin or inflamed areas
(copper tripeptide-1)
C 1% selenium sulfide lotion
␤-Glucan oral A 250 mg capsules A BetaRight Beta Glucan A Swanson Health Products A Label reports a minimum of 70% of ␤-glucan 1,3/1,6
B 3 mg capsules B NSC-24TM Beta Glucan B Nutritional Scientific B Inulin is used as filler and has FDA Generally Regarded As Safe (GRAS)
C 75–500 mg capsules C WGP쏐 Beta Glucan 1,3/1,6 Corporation (NSC) distinction

Fitzmaurice /Sivamani /Isseroff

D 250 mg capsules D Beta Glucan 1,3/1,6 C Life Source Basics, a C Cellulose is the only other ingredient
E Powder E CocoaGold with subsidiary of Biothera D Contains 150 mg calcium
Beta-Glucan D Source Naturals E Contains 100 mg of cocoa polyphenols; can lower blood sugar;
E Life Extension caution with concurrent insulin use

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 Table 1 (continued)

Antioxidant Formulation Brand name Manufacturer Notes

Healing
␤-Glucan A Cream A Skin Renewal Cream A Life Source Basics, a A Contains aloe and vitamin E that can also promote wound repair
topical B Cream – 1% B Beta Glucan Therapy Cream subsidiary of Biothera B Other ingredients include 600,000 IU retinol and 1,000 IU vitamin E
B Young Again Products acetate; the product’s caution states that it is not to be used in wounds
Curcumin/ A 500 mg capsules A Curcumin C3 Complex쏐 A Ageless Cures A Vegetarian capsule
turmeric oral B 900 mg capsules B Curcumin Complex B Swanson Health Products B Label advises against use during pregnancy or nursing; caution with
C 250 mg capsules C Curcumin C Solaray history of gall bladder disease
D 575 mg capsules D Turmeric Capsules D Greenbush Natural C Label advises against use during pregnancy, gall bladder obstruction,
Products hyperacidity or the presence of stomach ulcers; caution with nursing
D Certified as kosher; vegetarian

Antioxidant Therapies for Wound

Curcumin/ A Cream A AC3 Max Curcumin Derma A Ageless Cures A Will temporarily stain skin and will stain clothing
turmeric B Cream Cream B Vicco B Option to have cream with or without sandalwood oil
topical B Turmeric Skin Paste
EGCG/green A Lotion A Green Tea Lotion A Abra Therapeutic Personal A Contains many other extracts in the formulation, including aloe, vitamin
tea topical Care E and fruit oils
Proanthocy- A 100 mg capsules A Grape Seed Extract A Natural Factors A Contains 95% proanthocyanidins
anidins oral B 100 mg capsules B Grape Seed Extract B Thompson B Contains 95% proanthocyanidins; vegetarian capsules
C 100 mg capsules C Grape Seed Extract C Nature’s Answers쏐 C Contains 95% proanthocyanidins; vegetarian capsules
D 50 mg capsules D GrapenolTM D Solaray D Contains bioflavonoid complex derived from lemons
Propolis oral A 500 mg capsules A Bee Propolis A Puritan’s Pride A Label advises caution during pregnancy, and avoidance if there is a
B 400 mg capsules B Phytoflora쏐 Propolis B Uniflora쏐 Health Foods history of allergy to bees or bee products
C 500 mg capsules C Standardized Bee Propolis C Beehive Botanicals쏐 B Manufactured from Brazilian green propolis
C Contains Propol 2000쏐, which is manufactured by a proprietary process;
manufactured in Wisconsin, USA, from reddish-brown propolis
Propolis topical A Cream A Propolis Cream with A Uniflora Health Foods A Propolis origin is Brazil; contains aloe vera, beeswax and calendula oil
B Cream Aloe Vera B Eclectic Institute Inc. B Contains several other extracts
C Cream B Goldenseal-Propolis Cream C Eco-Beauty Organics C Contains several other extracts
C Propolis HautCreme
Honey topical A Wound and burn dressing A MedihoneyTM Dressing A Derma Sciences A FDA approved; contains active Leptospermum honey; not to be used in
children younger than 18 months

PIU = Pyrogallol inhibition units; EGCG = epigallocatechin gallate.

1 Oral and topical metronidazole are available by prescription only in the USA; the 2 internationally produced items listed in the table have been made available without a prescrip-

tion to the best of our knowledge.

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a double-blind placebo-controlled trial from 1974, was
done in hospitalized surgical patients with pressure sores.
The treatment group, who received 500 mg of ascorbic
acid twice daily, had an 84% mean reduction in wound
area compared to 42.7% in the placebo group [18]. The
rate of wound healing in the treatment group was statisti-
cally significantly improved at 2.47 cm2 per week com-
pared to 1.45 cm2 per week in the placebo group. Anoth-
er study set out to repeat this trial in 1995 in a multicenter
blinded randomized trial, though with a control group
that received 10 mg of ascorbic acid twice daily and a
treatment group that received 500 mg ascorbic acid twice
daily [19]. This study was unable to demonstrate a differ-
ence in wound healing between the two groups as as-
sessed by the percent change in wound surface area and
healing velocity in centimeters per week.
The conflicting findings on the impact of vitamin C
supplementation on wound healing between these two
studies make it difficult to form an evidence-based rec-
ommendation. Although the treatment group of the
study by Taylor et al. [18] had a strikingly greater im-
provement in wound healing, their results are limited by
a lower number of subjects and lower power to their study.
The placebo group in the Taylor study [18] received no
vitamin C supplementation and had levels of ascorbic
acid at the low end of the normal range. However, the
control group in the study by ter Riet et al. [19] received
10 mg ascorbic acid twice daily, a treatment that may have
corrected any possible low level of vitamin deficiency that
would have made wound healing differences between
treatment and control groups discernible. If true, this
would support the argument that increased doses of sup-
plementation do not have any greater impact on wound
healing than low-dose supplementation. Study compari-
son is further complicated by a considerably larger initial
mean wound size of 16 cm2 in the Taylor study [18] as
compared to 1.4 cm2 in the ter Riet study [19]. The Taylor
study subjects [18] were hospitalized surgical patients,
whereas the ter Riet study [19] subjects were primarily
from skilled nursing facilities and presumably had more
comorbidities found in this type of patient population. It
seems safe to say that correction of vitamin C deficiency
is crucial for wound healing, but it remains to be proven
that supplementation, whether at a low or high dose, can
further improve healing.
Vitamin D
Although vitamin D is well known to activate nuclear
receptors and regulate phosphorus and calcium homeo-
stasis, it can also have antioxidant properties [20]. Studies
118 Skin Pharmacol Physiol 2011;24:113–126
investigating the role of vitamin D in bone fracture repair
are abundant, but only a few studies investigated its role
in skin wound repair. A study involving mice showed that
intraperitoneal injection of cholecalciferol resulted in
faster reepithelialization of acute wounds and greater
wound rupture strength [21]. In another study, topically
applied 1,25(OH)2-vitamin D3 increased the rate of acute
full-thickness wound closure [22]. However, pretreat-
ment of wounds with calcipotriol did not affect the reep-
ithelialization in comparison to no pretreatment [23]. Al-
though the total number of studies is limited, these stud-
ies suggest that pretreatment with vitamin D analogs may
not affect wound healing, but treatment after wounding
may be beneficial. However, there are no human studies
that investigated the role of vitamin D and its analogs in
wound healing. Furthermore, none of the aforemen-
tioned studies investigated the antioxidant capabilities of
vitamin D, and the link between vitamin D, antioxidant
status and wound healing will need to be better explored
in future studies. At the present time, evidence support-
ing a role for vitamin D in human skin wound healing is
too limited to propose its use for this indication in clini-
cal medicine.
Vitamin E
Vitamin E has long been known to possess antioxidant
properties, but only few studies have evaluated its role in
wound healing. There are two subfamilies of vitamin E,
the tocopherols and the tocotrienols [24], with tocotri-
enols postulated to be more potent antioxidants. Both to-
copherols and tocotrienols are available over the counter
in both oral and topical preparations. Raxofelast is a wa-
ter-soluble vitamin E analog synthetically developed in
the laboratory [25], and it is not currently available over
the counter.
Several animal studies have evaluated the role of oral-
ly or parenterally administered vitamin E in wound heal-
ing. One study in rats evaluated the role of either vitamin
E subfamily by comparing the wound healing properties
of ␣-tocopherol against palm vitamin E extract, which is
rich in tocotrienols [26]. Streptozotocin-induced diabetic
mice were excision wounded and treated orally with ei-
ther vitamin E subfamily at 200 mg/kg and compared to
controls that were fed olive oil. Mice treated with palm
vitamin E extract had faster wound closure rates, in-
creased glutathione peroxidase and SOD enzyme activi-
ties, and decreased levels of MDA when compared to the
␣-tocopherol- or control-treated mice.
A recent study evaluated the role of topical vitamin E
in the treatment of surgical incision wounds in children
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[27]. Children were either treated topically with petrola-
tum jelly as control or with a topical vitamin E formula-
tion. Children pretreated and posttreated with the topical
vitamin E formulation showed decreased scar formation
and keloid formation during wound healing. Although
this result is promising, this study did not use an ade-
quate control since the topical vitamin E formulation also
contains castor oil and palmitate, which have been used
to accelerate wound healing in other studies [28, 29]. The
control used was petrolatum, which serves as an adequate
control to isolate the effects of topical vitamin E. There-
fore, although vitamin E is promising, the current evi-
dence is not yet convincing that topical vitamin E (to-
copherol) is useful for surgical incision wounds, especial-
ly in light of another study that did not show effectiveness
for vitamin E where proper controls were used [30].
␣-Lipoic Acid
␣-Lipoic acid (LA) is an antioxidant that is fat and wa-
ter soluble, and is available as an over-the-counter oral
supplement and as a component of topical preparations.
It is proposed to both scavenge ROS and contribute to the
regeneration of other antioxidants such as vitamin E,
ascorbate and coenzyme Q10. In one study, the antioxi-
dant effect of LA in patients with chronic wounds receiv-
ing hyperbaric oxygen (HBO) therapy was assessed in 20
patients [31]. The theoretical basis for the combination
treatment is that LA would scavenge ROS generated by
HBO therapy. The patients were randomized to 1 month
of 600 mg oral LA per HBO treatment, or placebo plus
daily HBO treatment. Lipid peroxidation was inhibited
throughout the study in the LA-treated group. The total
antioxidant status of the plasma was slightly increased in
the LA-treated group compared to controls after 20 HBO
treatments. The wound size decreased in approximately
50% of the placebo group and 80% of the LA treatment
group at 40 days after the start of HBO treatment. The
authors concluded that HBO treatment can induce oxida-
tive damage that is repaired by an adaptive cellular re-
sponse, and speculated that, in chronic wounds, there is
an excessive oxidant stress that is better treated with the
additional antioxidant power of LA. However, it is un-
clear how much LA would improve wound healing in a
setting that does not involve HBO, and this will require
further studies of LA alone on wounds.
Metronidazole
Metronidazole is a nitroimidazole antibiotic that is
used primarily against anaerobic bacteria and protozo-
ans. As an orally administered drug, it is used to treat
Antioxidant Therapies for Wound
Healing
trichomoniasis, amebic dysentery or amebic liver abscess,
or some anaerobic bacterial infections. Topically it is used
for treating vaginal infections with protozoa such as
Trichomonas vaginalis, Amoeba and Giardia, and for ro-
sacea. Although both oral and topical formulations cur-
rently are available by prescription only in the USA, there
are some foreign formulations that are marketed as avail-
able without prescription (table 1). Because this drug is
frequently used to treat anaerobic infection in burn
wounds, one study evaluated its role as an antioxidant.
Equal concentrations (180 mg/kg) of vitamin C in dis-
tilled water, vitamin E in emulsion, and metronidazole in
gum acacia were orally administered daily to rats with
partial-thickness burn wounds for comparison of antiox-
idant capacity [32]. From previous work, the study inves-
tigators had determined malondialdehyde (MDA) levels
to be highest at 48 h after burn, and as such chose this as
the time point to evaluate the effect of treatment on MDA
levels. All three treatments decreased 48-hour MDA levels
to below normal versus burn control and nonburned ani-
mals, though vitamin C had the greatest capacity to do so.
All three treatments decreased the time to complete epi-
thelialization after burn by a similar length of time of ap-
proximately 2 days quicker than untreated controls. The
authors concluded that all three treatments tested had an-
tioxidant capability, evidenced by the ability to suppress
postburn elevated MDA levels. Metronidazole produced
results most similar to those of vitamin E, assumed to be
a known antioxidant. Additionally demonstrated was that
the degree of greatest MDA lowering, produced by vita-
min C, did not correlate with the fastest reepithelializa-
tion. Topical cream formulations of metronidazole are
also being evaluated for improvement of burn wound
healing, with initial positive results [33]. Pharmacy-com-
pounded metronidazole gels have also been found to be
helpful in decreasing the offensive odor of chronic wounds
in small uncontrolled studies [34].
Elemental Antioxidants
Elements and trace minerals are available to consum-
ers as purified oral and topical supplements or often in
combination products. Oral products are often marketed
as immune supplements and antioxidants important for
the health of specific organs such as the prostate, heart
and liver. Topical preparations are marketed for a range
of applications from antiaging to treatment for skin irri-
tation and minor wounds. One study tested a triad treat-
ment with 3.75 mg copper, 375 ␮g selenium and 37.5 mg
zinc given intravenously for its impact on wound healing
and its capacity as an antioxidant in a prospective, ran-
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domized, placebo-controlled trial in burn patients [35].
Copper, selenium and zinc were stated to have been cho-
sen for their reported depletion in burn patients second-
ary to significant exudative losses. Infusion was complet-
ed over 12 h daily for 14 or 21 days, respectively, given
20–60% or 160% of the body surface area was burned. At
study completion, wound tissue in the treatment group
had increased levels of Se and Zn as compared to controls.
In the Cu/Se/Zn-treated subjects, tissue glutathione, glu-
tathione reductase and glutathione peroxidase levels were
higher than baseline values at a statistically significant
level, and higher than the levels in the subjects treated
with vehicle only, though not at a statistically significant
level. Maxwell [4] nicely summarized the antioxidant role
of glutathione peroxidase, glutathione and glutathione
reductase. Glutathione peroxidase removes hydrogen
peroxide among other antioxidants at the expense of glu-
tathione. Glutathione reductase then regenerates gluta-
thione using NADPH. That these were elevated in the
treatment group highlights a potentially increased anti-
oxidant reserve. Improved wound healing, as noted by
decreased grafting requirements, occurred in the treat-
ment group. Plasma trace elements, Cu and Se, increased
in the treatment group compared to controls, though
measurement of plasma inflammatory markers and oxi-
dant mediators such as interleukin-6, interleukin-10,
SOD, glutathione peroxidase and total antioxidant status
did not change. The author of the study comments that
despite not noting any toxicity to the patients, he found
that supplementation values were much higher than rec-
ommended by the American Burn Association, and that
the safety of their use was not known.
Improvement in wound healing following an oral di-
etary supplement containing the triad of arginine, vita-
min C and zinc was assessed in a second clinical trial of
16 patients with pressure ulcers [36]. The authors’ interest
in arginine supplementation was based on the implied
role of the amino acid in protein synthesis, collagen de-
position, cell proliferation, immune cell function and as
a substrate for nitric oxide (NO) production. Patients ran-
domized to a standard hospital diet, a standard hospital
diet plus 72 mg vitamin C and 7.5 mg Zn, or a standard
diet plus 9 g arginine, 500 mg vitamin C and 30 mg Zn
were blindly evaluated using the clinical Pressure Ulcer
Scale for Healing score as a marker of ulcer improvement.
The group randomized to the arginine-containing diet
had improved wound healing following 2 and 3 weeks of
supplementation compared to baseline status and had
greater wound healing compared to the other two groups
at 3 weeks. Notably, in the group randomized to supple-
120 Skin Pharmacol Physiol 2011;24:113–126
mentation with vitamin C and Zn, there was no change
in Pressure Ulcer Scale for Healing score over 3 weeks
despite the augmented diet. Unfortunately, there are
many limiting factors in this study to confound the re-
sults. As a result of the randomization process, the argi-
nine-supplemented group had an overall lower BMI. The
authors of the study note that due to this BMI discrep-
ancy, this group may have benefited more from the di-
etary supplement than the other groups. Looking at di-
etary records, the arginine-supplemented group con-
sumed the greatest percentage of daily recommended
energy intake, may have had better overall nutrition dur-
ing the study and, subsequently, improved wound heal-
ing. Additionally, for the group supplemented with vita-
min C and Zn only, protein intake was only 63% of the
estimated need. The energy and protein deficiency in this
group may especially obscure the interpretation of results
regarding supplementation with vitamin C and Zn.
The Cochrane review of available randomized con-
trolled trials and controlled clinical trials found that Zn
supplementation in chronic arterial or venous ulcers did
not show evidence of improved healing efficacy [37]. An-
other Cochrane review found only one study with enough
power to support the positive effect of a mixed nutrition-
al supplement containing additional calories, zinc and vi-
tamin C on preventing pressure ulcers, and even less sup-
porting evidence for the use of zinc supplementation in
the treatment of pressure ulcers [38]. To date, the studies
assessing the efficacy of elemental supplements have un-
fortunately been characterized by low power, multiple
confounding variables, and short treatment and follow-
up courses. There is little evidence for their positive effect
on wound healing, although they have few adverse ef-
fects. If tolerable and not contraindicated in the light of
other comorbidities, it seems that there may be little harm
in elemental supplementation, although the benefits for
wound healing are unclear at this time.
Natural Products for Antioxidant Wound Healing
There is great consumer interest these days in ‘natural
products’, which include compounds derived from fruits,
plants and herbs. Indeed, these contain a rich diversity of
antioxidants [39] and are widely available and used for a
multitude of cutaneous ailments. Preclinical studies have
shown their promise for use in wound healing because
they are versatile as antioxidant and antimicrobial sourc-
es [40]. However, only two natural products, Medihoney쏐
and ␤-glucans, have been critically evaluated by the FDA,
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and only Medihoney has been evaluated specifically for
wound healing. We review a few of the natural products
that have been studied for wound healing that are also
available over the counter.
␤-Glucan
␤-Glucans are glucose polymers found in the cell
wall of yeast, fungi and cereal plants that have previ-
ously been approved by the FDA for use against coro-
nary heart disease. It is currently promoted as a dietary
oral supplement and in topical creams and lotions for
antiaging purposes and wound healing. ␤-Glucans are
proposed to have antioxidant properties and have been
studied in rats for their role in burn wound healing [41].
␤-Glucan was administered as either 3.75 mg topical
ointment or enterally at 50 mg/kg to rats with partial-
thickness burn wounds. Both groups of treated animals
had lower serum tumor necrosis factor- ␣ levels than
control animals. MDA levels in tissue, an indicator of
lipid peroxidation, were higher in the burn-injured
animals than in controls. Only topical ␤-glucan was
able to significantly decrease MDA tissue levels. ␤-Glu-
can treatment, both topical and systemic, was able to
reverse the burn-induced decrease in tissue glutathione.
Myeloperoxidase (MPO) activity was used as an indica-
tor of tissue neutrophil infiltration. Both topical and
systemic ␤-glucan treatment were able to acutely (6 h
after injury) suppress MPO levels, though only the top-
ical administration was able sustain the decrease in
MPO levels for up to 48 h after injury. Tissue histology
demonstrated lower total damage in ␤-glucan-treated
groups compared to placebo treatments. Oxidative
damage was demonstrated in this study by increased tis-
sue MDA and MPO levels and decreased glutathione
levels. Systemic inflammation was demonstrated by in-
creased serum tumor necrosis factor- ␣ levels after burn.
␤-Glucan demonstrated its ability to defend against ox-
idative stress by combating the change in the measured
parameters as well as by aiding wound healing. No hu-
man studies have specifically evaluated the role of ␤-
glucans in wound healing. The potential of ␤-glucans
has been recognized for antiaging and wrinkle treat-
ment, and it is hoped that rigorous clinical trials will be
able to demonstrate their efficacy in human skin wound
healing with expansion of the indications for the use of
this modality.
Curcumin
Curcumin is an extract from the naturally occurring
spice turmeric. Turmeric has been used for centuries to
Antioxidant Therapies for Wound
Healing
treat many different ailments as part of the Indian Ay-
urvedic medicine system, and it possesses potent anti-
oxidants [42]. Curcumin is available over the counter in
oral and topical formulations, although the FDA has not
formally evaluated it. Curcumin has been tested in sev-
eral animal models of wound healing; however, no hu-
man clinical studies have yet been performed.
Curcumin has been studied in radiation-induced
wounds since radiation-induced toxicity is at least in part
mediated by the production of oxygen-derived free radi-
cals. The ability of curcumin to alter healing in full-
thickness wounds in mice given whole-body gamma ra-
diation or sham irradiation was assessed [43]. Mice were
treated with a single oral dose of 10 mg/kg curcumin or
placebo prior to radiation administration. Curcumin-
treated mice had greater wound contraction as compared
to the placebo-treated mice in the irradiated animals as
well as in the sham-irradiated group. The collagen con-
tent approximated from hydroxyproline levels was high-
er in the curcumin-treated group than in placebo-treated
mice following irradiation, though these levels where un-
able to reach the hydroxyproline content in the sham-ir-
radiated group. Both the irradiated and the sham-irradi-
ated groups had greater nitrate and nitrite concentrations
after irradiation with curcumin treatment. Nitrite and
nitrate are end products of NO synthesis and are an esti-
mation of NO production. NO has been proposed to be
necessary for many elements of wound healing.
Curcumin has also been investigated in animal exci-
sional wounds. Rats were topically treated with physio-
logic saline or 40 mg/kg/day of curcumin for 12 days pri-
or to tissue analysis [44]. Tissue samples at 1 week after
wounding in curcumin-treated rats had lower catalase,
higher SOD and higher glutathione peroxidase tissue ac-
tivity compared to controls. Tissue peroxide levels in the
treated animals were significantly lower during the first
week compared to controls, though by 12 days, control
animal levels decreased to a value not significantly differ-
ent from those of treated animals. From these results it
appears that curcumin may act as an antioxidant in the
earlier stages of healing and may inhibit the rise in oxi-
dant status seen in untreated wounds. Curcumin-treated
animals had greater wound contraction than controls,
and less time to complete reepithelialization.
Although there are no human studies of curcumin and
wound healing, clinical studies for other indications have
shown very few side effects, even when given in large dos-
es [45, 46]. There is some evidence for the positive effects
of curcumin in animal studies and anecdotally in hu-
mans, though clinical evidence is lacking. The potential
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usefulness of this modality as a therapy in wound healing
would be greatly enhanced by rigorous clinical trials in
human subjects.
Epigallocatechin Gallate
Epigallocatechin gallate (EGCG) belongs to a group
known as catechins, naturally occurring polyphenolic
compounds, and is an important component of green tea.
EGCG is available as an oral over-the-counter supple-
ment and as a topical ointment marketed as Veregan쏐. No
human studies have evaluated the role of EGCG in wound
healing, but EGCG has been examined in various other
human trials for other indications. One animal study
tested EGCG in a rat incisional wound model [47]. In this
study, epicatechin-3-gallate was intradermally tested in
unsutured full-thickness incisional rat wounds against a
saline control. Treated animals received 1 prewound dose
of 0.04 mg EGCG followed by equal doses daily for 1 week
after wounding. The group treated with epicatechin-3-
gallate had better histological wound healing as assessed
by a blinded investigator at 2 and 3 weeks after injury. Us-
ing the immunohistochemical endothelial cell marker
CD31, it was shown that the treated group had peak levels
at day 1 compared to the control group that peaked at day
7 after wounding. Tissue VEGF protein levels similarly
paralleled the expression of CD31 in both treated and
control animals. From these results it was speculated that
the EGCG treatment had the ability to enhance angio-
genesis and accelerate the course of wound healing. How-
ever, it is difficult to extend this study to excisional
wounds or ulcers without specific studies. Human clini-
cal trials would better assess how EGCG functions in
acute and chronic wounds. Recent studies have shown
that EGCG blocks and decreases the activity of some an-
ticancer agents [48], and systemic therapy should be per-
formed with caution in patients that are also receiving
anticancer therapies.
Proanthocyanidins
Proanthocyanidins are polyphenolic bioflavonoids
that are found in many common foods including berries,
grapes, apples, chocolate and cinnamon spices [49]. The
most potent sources were noted to be grape seeds and cin-
namon. Proanthocyanidins are available over the counter
as health supplements in powder and capsule formula-
tions.
Grape seed proanthocyanidin extract (GSPE) has been
said to have redox-active properties. GSPE treatment ap-
plied topically was assessed in mice with full-thickness
excisional wounds left to heal by secondary intention
122 Skin Pharmacol Physiol 2011;24:113–126
[50]. Wounds treated with 2.5 mg GSPE daily had greater
wound contraction and closure after 5 days as measured
by digital imaging compared to placebo-treated controls
at all time points from day 1 to day 11 after injury. Histo-
logical analysis of GSPE-treated wounds showed in-
creased formation of epidermis and granulation tissue
with better structural organization compared to control
(nontreated) wounds on the same mouse. Wound edge
tissue of GSPE-treated wounds had greater VEGF protein
staining, and the study investigators deduced that the
GSPE likely mediates VEGF expression. Proanthocyani-
dins remain yet to be investigated in human wound heal-
ing studies, though the positive effects shown in animal
models are encouraging.
Propolis
Propolis is collected from the hives of honeybees and
is a resinous material that honeybees use as a sealant, an-
tibacterial and antifungal [51, 52]. Many factors are re-
sponsible for the composition of propolis as it is created
from a variety of botanical and nonbotanical materials
that are collected by each particular honeybee species.
Variation in the composition can be due to geography,
honeybee species or collection from different hives, and
variation can be noted within the same hive. Neverthe-
less, it has been shown that propolis contains several an-
tioxidants including caffeic acid phenethyl ester (CAPE)
[53]. Propolis is available in both oral and topical formu-
lations and has been marketed for numerous indications
including treatment of minor burns and canker sores and
as an antiinflammatory mediator in various conditions.
Likely the potencies and combination of compounds
within in each formulation vary tremendously. Propolis
has been examined in only a few studies in animals and
humans.
One study in rats investigated the use of topical prop-
olis for the treatment of excisional wounds in streptozo-
cin-induced diabetic rats [54]. The diabetic rats had
slower rates of wound closure and higher wounded skin
MPO activity, which normalized when treated with top-
ical propolis. Another study investigated the use of
CAPE. Rats with full-thickness incisional wounds, su-
tured after wounding, were treated intraperitoneally
with 10 ␮mol/kg CAPE or saline placebo daily for up to
2 weeks [55]. Tissue levels of MDA, glutathione, NO,
SOD and catalase activity, measured by the rate of hydro-
gen peroxide decomposition, were assessed. The treat-
ment group had increased tissue levels of glutathione at
7 and 14 days, and decreased MDA and SOD activity at
1 and 2 weeks after injury compared to controls. The in-
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vestigators speculated that the increased levels of gluta-
thione in treated animals may have been due to an inhi-
bition of glutathione depletion as it is a coenzyme for
glutathione peroxidase. There may have been a decreased
requirement for glutathione peroxidase in the CAPE-
treated animals. Likewise, the decreased level of SOD in
the treated animals was speculated to be a product of de-
creased induction in the lower oxidative stress environ-
ment created by CAPE treatment. Wound histology of
the CAPE-treated group displayed better vascularization
and connective tissue formation compared to placebo-
treated controls. Although the authors claimed faster
reepithelialization, reapproximated incision wounds are
not optimal for studying reepithelialization, and an ex-
cisional wound model would be superior to assess reepi-
thelialization.
One clinical study in humans evaluated the use of
topical propolis for the treatment of partial-thickness
(second-degree) burns in comparison to topical silver
sulfadiazine [52]. No differences were found in microbial
colonization between the two treatment groups. The
propolis-treated wounds were clinically observed to close
2 days earlier in comparison to silver sulfadiazine, al-
though no tests for statistical significance were reported.
The authors note that the number of patients in the study
was low and suggest future studies with an increased
number of patients to improve the analysis. Propolis was
not noted to have any side effects in the study, but it is
known to cause rare cases of allergic contact dermatitis
[56]. Preliminary studies indicate promise in the use of
propolis for wound healing, but larger clinical studies
will be necessary to more clearly define its efficacy and
its side effect profile.
Honey
Honey, in general, contains a rich combination of an-
tioxidants [57, 58] with a mixture of osmotically active
agents and antibacterial components. A Cochrane evi-
dence-based review of honey concluded that honey may
be beneficial to acute wounds but not to long-standing
wounds such as venous leg ulcers [59]. Honey is readily
available over the counter, and in 2007 the FDA ap-
proved Medihoney for topical wound therapy. Medi-
honey is the only naturally derived product that has re-
ceived FDA approval specifically for the treatment of
wounds. Medihoney contains manuka honey and un-
dergoes processing to ensure its sterility. It is produced
by bees that gather nectar from only one flower type,
those that grow on the manuka bush (Leptospermum
scoparium), which is native to New Zealand. A recent
Antioxidant Therapies for Wound
Healing
clinical study of Medihoney showed that honey had a
trend toward faster wound healing rates, but the study
was underpowered and did not show a statistically sig-
nificant advantage over an unspecified standard therapy
[60]. Of note, the majority of the wounds treated in this
trial were leg ulcers, which were likely chronic in nature,
and these had been shown in the Cochrane review to be
less responsive to honey therapy than acute wounds [59].
Medihoney is not without side effects since some people
may develop a contact dermatitis. Although Medihoney
is sterilized, honey is known to contain spores from
Clostridium botulinum, and this product should not be
used in children less than 18 months of age. Honey is
considered widely for use in wound healing and it seems
to have a beneficial role in acute wounds, but its benefits
with chronic wounds are less certain. Larger clinical
studies would help overcome the weakness of earlier un-
derpowered studies. Honey is used widely for wound
healing therapy.
Role of FDA Approval
There is a growing interest in the use of antioxidant
therapies for wound healing. Wound healing therapies
have a considerable market, estimated to be from USD 7
to 10 billion. Although some of these therapies require a
physician’s prescription, many inexpensive wound heal-
ing products are touted in the over-the-counter market.
To make it to the over-the-counter market, wound heal-
ing therapies must first gain clearance from the FDA.
There are three ways in which this can happen, either by
a new drug application, an abbreviated new drug applica-
tion, or by satisfying the requirements laid out by an FDA
over-the-counter drug monograph.
The most time-consuming application process is the
new drug application since this requires a considerable
amount of data to establish safety and efficacy. An abbre-
viated new drug application is allowed when a newly mar-
keted product is shown to have an active ingredient, dos-
age form, characteristics and intended use identical to
one that is already approved. Therefore, an abbreviated
new drug application must significantly mimic an exist-
ing over-the-counter drug product. The third way to
achieve FDA approval is to satisfy the criteria that are laid
out in an FDA monograph. FDA monographs are stan-
dards that provide the marketing conditions for some
over-the-counter drug products including the active in-
gredients, labeling and other general requirements. The
FDA has issued a monograph for oral wound healing
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agents, but no specific monograph exists for cutaneous
wound healing apart from oral wound healing. As a re-
sult, over-the-counter wound healing products require
submission of either a new drug application or an abbre-
viated new drug application unless they have an oral
wound healing equivalent. New drug applications re-
quire significant time and cost [61]. Furthermore, abbre-
viated new drug applications are not feasible since exist-
ing FDA-approved, topical antioxidant-based wound
healing therapies are rare.
The only product reviewed here that has received FDA
approval specifically for wound healing therapy is Medi-
honey. Most of the antioxidants and over-the-counter
products reviewed here are considered health supple-
ments for wound healing that ‘do not intend to diagnose,
treat, cure, or prevent disease’. Therefore, they do not re-
quire FDA approval prior to being marketed to the con-
sumer. The same is true for nutraceuticals or botaniceu-
ticals (naturally derived products) since they are market-
ed as health supplements. In these cases, it will be left to
the consumer to research the product and judge the safe-
ty prior to usage.
animal and clinical studies are complicated by the mul-
tiple types of wounds assessed, concurrent treatment
with multiple agents and multiple routes of administra-
tion. Very few products have FDA approval specifically
for wound healing. A prudent approach is to use products
that do not have many side effects since efficacy data are
limited due to the low number of studies. For products
that have not been evaluated by the FDA, the consumer
is advised to perform extra research to ensure that the
purity and contaminant testing are within regulated lim-
its prior to use of the product. With the exception of clin-
ically known adverse effects such as the risk of botulinum
toxin poisoning from honey in young children, it is al-
most impossible to say what the potential liability is for
recommending the use of these products without more
clinical evidence. Consumers should be advised to first
evaluate for skin irritation or allergy in a localized healthy
area before use within a wound. The field of antioxidants
continues to expand rapidly, and future animal and clin-
ical studies will better elucidate the role of antioxidants
in wound healing therapy.

Acknowledgements
Conclusion
This work was supported in part by grants 06-NCA-004 from
the Shriners Hospital for Children, and VA Merit Award 9301 to
The field of antioxidants for wound healing therapies R.R.I., and Active Naturals Institute award to R.K.S. and R.R.I.
is growing, but there are a limited number of clinical tri-
als to provide evidence for their use. Interpretations of the

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