Review

Skin Pharmacol Physiol 2014;27:303310

DOI: 10.1159/000357477

Received: December 17, 2012

Accepted after revision: November 20, 2013
Published online: June 27, 2014

Skin Wound Healing and Phytomedicine:

A Review
Nader Pazyar a Reza Yaghoobi a Esmail Rafiee a Abolfath Mehrabian a Amir Feily b
a Department

of Dermatology, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, and b Department of

Dermatology, Jahrom University of Medical Sciences, Jahrom, Iran

Abstract
Skin integrity is restored by a physiological process aimed at
repairing the damaged tissues. The healing process proceeds in four phases: hemostasis, inflammation, proliferation and remodeling. Phytomedicine presents remedies,
which possess significant pharmacological effects. It is popular amongst the general population in regions all over the
world. Phytotherapeutic agents have been largely used for
cutaneous wound healing. These include Aloe vera, mimosa,
grape vine, Echinacea, chamomile, ginseng, green tea, jojoba, tea tree oil, rosemary, lemon, soybean, comfrey, papaya,
oat, garlic, ginkgo, olive oil and ocimum. Phytotherapy may
open new avenues for therapeutic intervention on cutaneous wounds. This article provides a review of the common
beneficial medicinal plants in the management of skin
wounds with an attempt to explain their mechanisms.
2014 S. Karger AG, Basel

2014 S. Karger AG, Basel

16605527/14/02760303$39.50/0
E-Mail karger@karger.com
www.karger.com/spp

Introduction

Skin wound is characterized by an injury made on the

skin due to trauma, tear, cut or contusion [1]. Wound
healing is a physiological process which restores skin integrity and is aimed at repairing the damaged tissues. The
process of skin wound healing proceeds in four phases:
hemostasis, inflammation, proliferation and remodeling
[2]. Cytokines promote healing by different pathways such
as stimulating the production of basement membrane
components, preventing dehydration, increasing inflammation and accelerating granulation tissue formation [3].
Hemostasis results from platelet activation and the subsequent production of platelet-derived growth factor
(PDGF), transforming growth factors (TGFs), fibroblast
growth factors (FGFs) and vascular endothelial growth
factor (VEGF) [4]. Inflammation occurs by fibrin clot formation and the degranulation of aggregated platelets that
release chemotactic factors essential for the recruitment of
leukocytes, principally neutrophils, as well as bone marrow-derived stem cells or fibrocytes in the wound. Neutrophils produce elastase and collagenase as well as tumor
necrosis factor (TNF)- and interleukin-1 (IL-1) that will
recruit fibroblasts and epithelial cells [5]. Monocytes arrive at the wound and differentiate into macrophages.
Amir Feily
Honari Clinic, Department of Dermatology
Motahari Street
Jahrom (Iran)
E-Mail dr.feily@yahoo.com

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Key Words
Inflammation Herbal medicine Phytomedicine Review
Topical application Treatment Wound healing Skin
Dermatology

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DOI: 10.1159/000357477

Methods
An extensive literature search from two databases, PubMed
and ISI Web of Science, was performed. A total of 89 references
regarding preclinical studies as well as clinical trials were included.
The criteria used were as follows: (1) English language and (2) publication date from 2000 to October 2013. The main search terms
used were wound healing, herbal medicine, mimosa, aloe vera,
grape seed, echinacea, chamomile, ginseng, green tea, jojoba, tea
tree oil, rosemary, lemon, soybean, comfrey, papaya, oat, garlic,
ginkgo, olive oil and ocimum.

Results

Aloe vera
Aloe vera is a tropical herb which is grown in hot and
dry climates and largely distributed in Asia, Africa and
other tropical regions [15]. A. vera gel is obtained from
the mucilaginous part of the center of the leaf. It has been
used for many centuries and comprises the major ingredient in various commercial skin and wound care products. A. vera gel contains vitamins A, B, C and E, enzymes,
polysaccharides, amino acids, sugars and minerals [3]. It
has been reported that glycoprotein fraction isolated
from A. vera is an effective component in healing via cell
proliferation and migration [15]. In an in vivo animal
study the effects of topical application of A. vera gel were
examined on sutured incisions in Wistar rats. It increased
the mean number of fibroblasts and blood vessel sections
and the mean thickness of the regenerating epithelium by
4 days after surgery. This study suggests that topical administration of A. vera gel can be a good treatment for
surgical incisions [16].
Mimosa
Notably, aqueous extracts of Mimosa tenuiflora are
widely used for wound healing and burns in Middle and
South America. Some researchers reported that M. tenuiflora induced specific enhancement of dermal fibroblast
activity in vitro [17]. It should be considered that this experimental study is not reproducible in animal or human
models. Another study demonstrated that the ointment
containing 2% (w/w) methanolic and 2% (w/w) total
aqueous extract of Mimosa pudica could be effective in
wound repair in rats [18].
Grape Vine
Grape (Vitis vinifera) seed extract exhibits anti-inflammatory and antioxidant features [19]. It has been explained that topical application of grape seed proanthoPazyar /Yaghoobi /Rafiee /Mehrabian /Feily

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They phagocyte the remaining matrix debris, pathogens

and neutrophils and secrete cytokines such as TGF- and
VEGF [6]. Macrophages participate in the phagocytosis
and release PDGF, TGF-, -FGF, TNF-, IL-1 and IL-6
that help the proliferative phase of healing. Lymphocytes
are the last cells to be infiltrated but are essential in IL-2
production, which helps recruit fibroblasts [5].
Epithelialization involves keratinocytes by migration
and proliferation from the wound edges and by differentiation of stem cells from the remaining hair follicle bulbs
[7]. Epithelialization is helped by EGF, keratinocyte
growth factors and TGF- [5]. Angiogenesis is triggered
by migration, proliferation, alignment and tube formation of endothelial cells sprouting from the parent vessel
to other vessels. The process of angiogenesis is related to
the expression of angiogenic factors such as VEGF and
PDGF [7]. In remodeling, inflammatory cells leave and
fibroblasts continue to synthesize collagen bundles and
further covalent cross-linking of collagen molecules [5].
Wound repair disorders commonly result from biofilm formation on wound surfaces requiring conscientious wound hygiene. Conventional liquid antiseptics are
not often sufficient and sustainable because the borders
and the surrounding of chronic wounds are frequently
composed of sclerotic tissue, impeding an effectual penetration of these products [8]. Tissue-tolerable plasma
has been reported to be highly efficient in decreasing the
skin bacterial load [9]. According to an in vivo animal
study conducted on enucleated contaminated eyes from
slaughtered pigs, the efficacy of tissue-tolerable plasma
was higher than that of PVP-iodine and polyhexanide
[10]. Recently, Lademann et al. [11] demonstrated that
human skin treatment with tissue-tolerable plasma led to
74% elimination of the bacterial load in infected skin.
According to the WHO definition, herbal agents incorporate as active components plant parts or herb materials in the crude or processed state, as well as certain excipients, i.e. solvents, diluents or preservatives [12]. Phytotherapy is popular amongst the general population and
is extensively used for the intervention and prevention of
various diseases [13]. Almost 4 billion people worldwide
use plants as medicines since nothing else is affordable or
available [3]. The actual and perceived relative safety of
natural products is one of the main reasons for their popularity with the general public [14]. Recently, topical and
systemic herbal agents have been widely used for wound
repair. The present review attempts to introduce herbal
remedies and their mechanisms of action in healing skin
wounds and also provides useful information for the development of more effective wound repair drugs.

Echinacea
Echinacea and its constituent echinacoside seem to
have effective anti-inflammatory and wound-healing effects [21]. Echinacoside is a caffeoyl conjugate of Echinacea with known antihyaluronidase properties. Rousseau
et al. [22] investigated the wound-healing effects of Echinacea and the antihyaluronidase effect was tested on vocal folds from larynges of pigs. They randomly received a
topical application of 300, 600 or 1,200 mg of standardized Echinacea on the injured side. Results showed a favorable outcome of antihyaluronidase therapy on acute
vocal fold wound healing.
Chamomile
The dried flowers of chamomile (Matricaria recutita)
incorporate abundant terpenoids and flavonoids contributing to its medical features [23]. Chamomile extract and
decoction has been used for the treatment of wounds [24].
Interestingly, recent studies have suggested that chamomile caused complete wound healing faster than corticosteroids. There is also an antiulcerogenic effect of chamomile due to its antagonistic action on H2 receptors. Histamine receptor antagonists stimulate skin barrier
restoration and the 5-hydroxytryptamine -2 (5-HT2) receptor antagonists promote wound healing [25]. It merits
note that chamomile has been reported to have opioid-like
properties. Topical opioids accelerate wound repair and
potentiate platelet aggregation for starting the healing process. Some researchers [23] evaluated the efficacy of topical chamomile to enhance wound healing on 14 patients
who underwent dermabrasion of tattoos. They showed
that chamomile is statistically efficacious in producing
wound drying and in speeding re-epithelialization.
Ginseng
Ginseng has been used for thousands of years in traditional medicine. The term ginseng generally refers to
Panax ginseng and it is regarded in a high position on the
list of the best-selling medical herbs in the world [2628].
Kimura et al. [29] reported that ginsenosides (the main
active ingredients of ginseng) exhibited the potential for
healing burn wounds when intravenously infused into
rats. This may be due to the promotion of angiogenesis
during skin wound repair via an increase of hypoxia-inducible factor-1 expression in keratinocytes and the
stimulation of VEGF production. Additionally, the inWound Healing and Phytomedicine

crease of IL-1 resulting from the accumulation of macrophages in the burn wound is another mechanism. The
production of IL-1 within the wound bed stimulates the
secretion of secondary inflammatory cytokines such as
IL-6, IL-8 and PGE2 [30].
Green Tea
Green tea contains high amounts of polyphenols, with
the major polyphenolic compound being epigallocatechin-3-gallate [31]. These influence the character of
TGF-1 in fibroblast-populated collagen gel contraction.
It is thought to be due to myofibroblast differentiation
and connective tissue growth factor gene expression. Accordingly, green tea potentially accelerates wound recovery [32].
Jojoba
Jojoba (Simmondsia chinensis) is an arid perennial
shrub grown in some areas of America and Africa and is
rich in liquid wax [33]. An in vitro study on human keratinocytes and fibroblasts indicated that jojoba liquid wax
provoked collagen I synthesis in fibroblasts, while no effect was detected on the secretion of matrix metalloproteinase-2 and matrix metalloproteinase-9. Therefore, it
could be used in the treatment of wounds in clinical settings [34].
Tea Tree Oil
Tea tree oil (Melaleuca alternifolia) has antimicrobial
and anti-inflammatory features and is reputed to have
wound renewal properties [3537]. It has been recognized that cooling is a useful method to decrease tissue
injury and increase wound healing. Jandera et al. [38]
compared the cooling and healing effect of tea tree oil hydrogel with tap water as a coolant in a porcine model.
They observed that Melaleuca was effective in the cooling
of burn wounds and the rate of healing increased with its
application and that tap water had similar properties.
Rosemary
Rosemary (Rosmarinus officinalis) oil is one of the famous essential oils extensively used in aromatherapy
[39]. In an in vivo study two full-thickness round wounds
were created in the dorsal area of diabetic BALB/c mice.
Topical application of essential oil of R. officinalis was
used on wounds of diabetic mice for 3 days. Decreased
inflammation, increased wound contraction, re-epithelialization, regeneration of granulation tissue and angiogenesis, as well as collagen deposition, were detected in
the treated wounds [40].
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cyanidin extract promotes wound restoration. It strongly

upregulates oxidant, TNF- and inducible VEGF expression in human keratinocytes [20].

Soybean
Researchers have investigated the immune system of
burn patients who had earlier received soy suspension.
Importantly, they reported that soy caused all populations of immune-competent cells to be activated mainly T-helper lymphocytes taking part in reparative processes, antibody synthesis and production of anti-inflammatory cytokines [43]. Anthocyanins from black soybean
seed coat possess antioxidant and anti-inflammatory
properties. It has been identified that anthocyanins enhance wound healing in Sprague-Dawley rats. Anthocyanins enhance wound healing due to cytoprotective properties, angiogenesis enhancement and anti-inflammatory
effect [44].
Comfrey
Comfrey (Symphytum officinale L.) root is traditionally used for the topical therapy of contusions. Allantoin
is regarded as the pharmacological active compound in
this herbal agent [45]. The allantoin, 5-ureide-hydantoin,
has been documented to possess numerous pharmacological activities, including the removal of necrotic tissue,
stimulating cell mitosis and the promotion of epithelial
stimulation [2]. Recently, Arajo et al. [46] have shown
that allantoin at 5% in soft lotion oil/water (O/W) emulsion possessed a wound restoration effect compared with
the control groups; nevertheless, it is not as intense as explained in the literature. The healing mechanism stimulated by allantoin occurs via the regulation of inflammatory reactions and stimulus to the proliferation of fibroblasts and extracellular matrix production. In an
experimental study, the wound-healing activity of leaf extracts of comfrey was evaluated. Three topical formulations, carbomer gel, glycero-alcoholic solution and O/W
emulsion (soft lotion) were compared. The O/W emulsion was shown to be the vehicle most effective in inducing healing activity. This could be evidenced from day 3
to 28 by an increase in collagen deposition from 40 to
240% and a reduction in cellular inflammatory infiltrate
from 3 to 46%. However, 8% prepared extract in emulsion
presented the best efficacy [47].

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Papaya
It has been found that papaya preparations accelerate
wound repair and decrease the severity of regional inflammation in rats with burn wounds. The positive effect
of this herb is related to the inhibition of bacterial catalase
and an advance in the efficiency of intracellular bacterial
killing. Additionally, antioxidant action of papaya reduces the risk of oxidative damage to tissues [48]. According
to an animal study, ethanol extract of Carica papaya seed
(50 mg/kg/day) was evaluated for its wound-healing activity in Sprague-Dawley rats using an excision wound
model. The hydroxyproline content was higher with the
granulation tissue. Histological analysis of granulation
tissue showed the deposition of well-organized collagen.
The extract exhibited antimicrobial activity against Salmonella choleraesuis and Staphylococcus aureus [49].
Oat
Oat bran is a particularly good source of B complex
vitamins, vitamin E, protein, fat and minerals [50]. Oat
(Avena sativa) has been recognized as having a wound
renewal effect. Some investigators examined the n-hexane, ethyl acetate, ethanol and water extracts of A. sativa
for wound repair on the skin of rats. Notably, they observed healing activity with the ointment formulation of
the ethanol extract at 1% concentration. The histopathological finding supported the outcome of wound models
[51]. Furthermore, an in vitro study on a skin model revealed that a spray containing Rhealba oat extract modulated re-epithelialization on a newly formed epithelium
[52].
Garlic
Garlic (Allium sativum) has long been used in traditional and complementary medicine [53]. Ejaz et al. [54]
assessed the influence of aged garlic solution on the
wound healing of chicken skin; 90 chicks were topically
exposed to various concentrations of aged garlic solution
for 6 consecutive days. An enhancement in the new loosely packed collagen and maturation of collagen fiber were
seen. Histological examination revealed the intensive
dose-dependent neovascularization in wounds treated
with aged garlic solution.
Ginkgo
Ginkgo biloba is believed to be the oldest living tree
species [55]. Bairy et al. [56] evaluated G. biloba extract
on the healing suppressant property of cyclophosphamide. They clarified that G. biloba elevated the breaking
strength and hydroxyproline amino acid of granulation
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Lemon
Lemon is a good source of vitamin C (ascorbic acid)
[41]. The effects of vitamin C have been evaluated on
wound healing of diabetic Wistar rats. Vitamin C hastens
cutaneous wound healing by its antioxidant and antiapoptotic mechanisms through a good drug delivery system [42].

Olive Oil
Importantly, olive oil phenolics have antioxidant properties higher than those of vitamin E on lipids and DNA
oxidation. They are able to prevent endothelial dysfunction by decreasing the expression of cell adhesion molecules and increasing nitric oxide production [57]. It has
been observed that topically applied ozonated olive oil
could stimulate acute skin wound repair in guinea pigs due
to the high expression of PDGF, TGF- and VEGF [58].
Ocimum
Ocimum is a well-known plant in Indian medicine and
exhibits different therapeutic effects such as repair properties and cytokine induction. An in vivo animal study on
Wistar albino rats showed the application of 10% Ocimum
sanctum aqueous extract in petroleum jelly caused an increase in the rate of epithelization and wound contraction
[59]. O. sanctum may be advantageous in the management
of abnormal healing such as keloids and hypertrophic
scars [60]. Udupa et al. [61] examined the ethanolic extract of O. sanctum in normal healing and dexamethasone-suppressed healing in albino rats. Interestingly, they
reported that wounds epithelialized faster and the rate of
wound contraction increased compared to control
wounds. Moreover, an increase in granulation tissue and
hydroxyproline content was observed. See table1 for a list
of the common herbs in cutaneous wound healing. Other
herbal remedies in wound healing are listed in table2.

Discussion

To our knowledge, this is the first review to survey

common medicinal plants and their mechanisms of action in wound management in the field of dermatology.
Cutaneous healing is a multistage event that depends on
the activation, recruitment or activity of different cells including keratinocytes, endothelial cells, fibroblasts and
inflammatory cells [76]. In the last decade there has been
a fast-growing use of herbal agents which has captured
the attention of scientists with a role in plant investigation
[77]. Notably, more than 80% of the population in developing countries rely on the use of herbal therapies [78]
and it has been estimated that 9.612.1% of US adults
regularly use them [79]. In recent years there has been an
exponential growth in the use of herbal remedies. These
Wound Healing and Phytomedicine

Table 1. List of the common herbs in cutaneous wound healing

A. vera [16]
Mimosa [17]
Grape vine [20]
Echinacea [22]
Chamomile [23]
Ginseng [29]
Green tea [32]
Jojoba [34]
Tea tree oil [38]
Rosemary [40]

Lemon [42]
Soybean [44]
Comfrey [47]
Papaya [49]
Oat [52]
Garlic [54]
Ginkgo [56]
Olive oil [58]
Ocimum [61]

Table 2. Other herbal drugs in wound healing

Herbal drug

Mechanism

Calendula officinalis

Neovascularization/epithelialization [62 64]

Centella asiatica

Procollagen type III synthesis

[65]

Angelica sinensis

Fibroblast proliferation [66]

Astragali radix

Fibroblast-proliferating activities of NF3 [67]

Boehmeria nivea

Effect on macrophages by
inhibiting p38 and JNK [68]

Chenopodium ambrosioides

Inhibition of NO, PGE2,

TNF- [69]

Polygonum

Increased fibroblasts, TGF-1

[70]

Aristolochia bracteolatancrease

Increase of super oxide dismutase and catalase [71]

Hypericum perforatum L.

Fibroblast collagen production [72]

Aspilia africana

Arresting wound bleeding,

inhibiting microbial growth
[73]

Dragons blood

Wound contraction, formation of collagen and epithelium [74]

Siam weed (Chromolaena)

NF-B pathway [75]

agents are gaining popularity both in developing and developed countries because of low cost, natural origin and
fewer side effects [80, 81]. Interestingly, numerous drugs
used in conventional medicine were originally derived
from plants [82]. Active ingredients are described as constituents of herbal medicine with therapeutic activity and
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tissue in wounds and reversed the healing suppressant effect of cyclophosphamide. This may be due to its antioxidant activity.

include carbohydrates, glycosides, lignanoids, alkaloids,

amino acids, peptides, proteins and enzymes [83]. Many
studies have already mentioned the biological activities of
natural preparations such as the induction of the immune
system and anti-inflammatory, antioxidant, antimicrobial, antimutagenic, anticancer and antiulcer effects [84].
Phytomedicine has been widely studied in chronic diseases such as hypertension [85], diabetes mellitus [86],
cancer [87], epilepsy [88] and chronic cutaneous disorders [89]. Importantly, promising results come from the
advantages of phytopreparations in the management of
wound restoration. It has been recognized that anti-inflammatory, antioxidant and antimicrobial activity of
herbal agents contribute to the process of healing. They
stimulate the production of critical cytokines such as
PDGF, FGF, VEGF, TGF- and IL-1 to accelerate reepithelialization, angiogenesis, granulation tissue formation, proliferation of fibroblasts and collagen deposition
in the wounds. Additionally, they may be valuable in the
handling of abnormal healing such as keloids and hypertrophic scars.
Inevitably, some limitations need to be pointed out in
the assessment of phytotherapy in wound management.
Despite widespread use and recent enthusiasm for herbalism, there is much still unknown about the plants in the
treatment of wounds. It seems the most important limitation is the paucity of preclinical and clinical studies. There
are only few investigations related to the role of herbal
remedies in skin wound healing, and their mechanisms

have been inadequately understood. Another limitation

is the complexity of chemical constituents and phytochemical studies. Herbs must be analyzed biochemically
to identify the main component that may be effective. The
investigation of their clinical effects requires study using
the assessments of histological and histochemical changes. One problem with using phytotherapeutic agents is
that there is limited controlled evidence and mechanisms
of action are a matter of debate. Notably, very few research studies have been carried out on a particular compound which shows the healing activity. Further studies
on plants and their mechanisms are needed in order to
find alternative ways for the clinical management of
wound restoration. Clinicians are required to be well informed regarding the use and safety of plants in order to
present the best care and consideration for the patients.
Medical herbalism may be our source of drugs in the future, with fewer side effects and better bioavailability for
wound recovery. Topical or systemic use of phytotherapeutic agents should be kept in mind, especially when
treating patients with resistant or chronic skin ulcers, either as monotherapy or as an adjunct to other medications for healing.

Disclosure Statement
The authors have no conflicts of interest to declare.

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