According to the Wound Healing Society, wounds are physical injuries that result
in an opening or break of the skin that causes disturbance in the normal skin
anatomy and function (Strodtbeck, 2001). They result
in the loss of continuity of epithelium with or without the loss of underlying
Wounds represent a significant burden on the patients and health care professionals
worldwide. They not only affect physical and mental health of millions of patients
but also impose significant cost on them. Current estimates indicate that worldwide
nearly 6 million people suffer from chronic wounds (Kumar
et al., 2007). Unhealed wounds constantly produce inflammatory mediators
that produce pain and swelling at the wound site. Wounds are a substrate for
infection and prolong the recovery of injured patients. Chronic wounds may even
lead to multiple organ failure or death of the patient (Roberts
et al., 1998).
Wound healing is a normal biological response to the injury that sets into
motion a sequence of events. Although wound healing is a familiar process but
its underlying biology is very complex and it is still only partially understood
(Sherratt and Dallon, 2002).
Many medicinal plants have been reported to possess wound healing activity and found useful in the treatment of wounds. This article outlines types of wound, factors affecting wound healing, mechanism of wound healing and properties of some medicinal plants that exhibit wound healing activity. The paper presents discussion of some patents relating to herbal products for wound healing management.
CLASSIFICATION OF WOUNDS
Wounds are classified as open and closed wounds on the basis of underlying cause of wound creation and as acute and chronic wounds on the basis of physiology of wound healing.
Open wounds: Through an open wound blood escapes the body and bleeding
is clearly visible. Open wounds can be further classified into various types
(Schultz, 1999) according to the object that causes the
Incised wounds: It is an injury with no tissue loss and minimal tissue damage. It is caused by a sharp object such as a scalpel or knife. Bleeding in such cases can be profuse, so immediate action should be taken.
Laceration wounds or tear wounds: This is nonsurgical injury in conjuction with some type of trauma, resulting in tissue loss and damage.
Abrasions or superficial wounds: Abrasion is caused by a sliding fall onto a rough surface. During abrasions the topmost layer of the skin i.e., epidermis is scraped off that exposes nerve endings resulting in a painful injury. Blood loss similar to a burn can result from serious abrasions.
Puncture wounds: They are caused by an object puncturing the skin, such as a nail or needle. Chances of infection in them are common because dirt can enter into the depth of the wound.
Penetration wounds: Penetration wounds are caused by an object such as a knife entering and coming out from the skin.
Gunshot wounds: They are caused by a bullet or similar projectile driving into or through the body.
Closed wounds: In closed wounds blood escapes the circulatory system but remains in the body. This is visible in the form of bruises. Closed wounds have fewer categories, but are just as dangerous as open wounds.
Contusions or bruises: Bruises are caused by a blunt force trauma that damage tissue under the skin.
Hematomas or blood tumor: They are caused by damage to a blood vessel that consequently causes blood to collect under the skin.
Crush injury: Crush injury is caused when great or extreme amount of force is applied on the skin over a long period of time.
Acute wounds: Acute wound is a tissue injury that normally proceeds
through an orderly and timely reparative process that results in sustained restoration
of anatomic and functional integrity (Lazarus et al.,
1994). Acute wounds are usually caused by cuts or surgical incisions and
complete the wound healing process within the expected time frame. However,
various physiologic and mechanical factors may impair the healing process and
wound fails to proceed through the usual stepwise progression of healing. It
results in the development of chronic wound that takes much longer time to heal.
Chronic wounds: Chronic wounds are wounds that have failed to progress
through the normal stages of healing and therefore enter a state of pathologic
inflammation (Menke et al., 2007). Chronic wounds
either require a prolonged time to heal, do not heal, or recur frequently (Krishnan,
2006). These wounds are a major cause of physical disability.
Local infection, hypoxia, trauma, foreign bodies and systemic problems such as diabetes mellitus, malnutrition, immunodeficiency or medications are the most frequent causes of chronic wounds. Some common examples of chronic wounds are diabetic foot ulcer, pressure ulcer and the venous leg ulcer.
FACTORS AFFECTING WOUND HEALING
Wound healing is a normal biological process in the human body. Many factors
can adversely affect this process and lead to improper and impaired wound healing.
A thorough understanding of these factors and their influence on wound healing
is essential for developing better therapeutic options for wound treatment (Kerstein,
Improper diet: Wound healing is an anabolic process that requires both
energy and nutritive substrates. It is reported that serum albumin level of
3.5 gm/dl or more is necessary for proper healing (Hanna
and Giacopelli, 1997). Protein is essential for collagen synthesis on wound
site. A state malnutrition may provide an inadequate amount of protein and this
can result in the decreased rate of collagen synthesis wound tensile strength
or an increased chance for infection (Albritton, 1991;
Rosen and Cleary, 1991).
Infection at the wound site: Wound infection is probably the most common
reason for impaired wound healing (Lazarus et al.,
1994). Staphylococcus aureus, Streptococcus pyogenes, Corynebacterium
sp., Escherichia coli and Pseudomonas aeruginosa are some
important organisms causing wound infection (Kumar et
Insufficient oxygen supply and tissue perfusion to the wound area: Adequate
blood supply and tissue perfusion is extremely important for proper wound healing.
Excessive pain, cold or anxiety can cause local vasoconstriction and increased
healing time (Cuzzell and Stotts, 1990). Smoking and
use of tobacco decrease tissue perfusion and oxygen tension in wounds (LaVan
and Hunt, 1990).
Drugs: Many drugs are known to impair wound healing. Chemotherapeutic
drugs used in cancer are the largest group well known to delay wound repair
(Franz et al., 2007). Systemic glucocorticoids
interfere in the normal healing process by reducing collagen synthesis and fibroblast
Elderly age: Elderly age is found associated with delayed wound healing.
It is reported that fibroblast growth and activity diminishes and collagen production
and wound contraction are slowed in injured older individuals (Sherman,
Diabetes and other disease conditions: Diabetic patients are more susceptible
to wound infection. In a study wound infection rate was found 11% higher in
diabetic patients than in the general patient population (Greenhalgh,
2003). Acute and chronic liver diseases are also associated with delays
in wound healing. Patients with altered immune function have an increased susceptibility
to wound infection.
THE WOUND HEALING MECHANISM
Wound healing is a complex process in which the skin or the affected organ
repairs itself after injury. In normal conditions the outermost layer of the
skin i.e., epidermis and the inner or deeper layer i.e., dermis exists in steady-state
equilibrium and forms a protective barrier against the external environment.
If this protective barrier is broken due to any injury the normal physiologic
process of wound healing is immediately instigated. Upon injury to the skin,
a set of complex biochemical events takes place in a closely organized cascade
to repair the damage. Within few minutes after the injury, platelets aggregate
at the injury site to form a fibrin clot. This clot acts to control the active
bleeding and to achieve hemostasis. The entire wound healing process that begins
at the moment of injury can continue for even months or years.
There are three main phases of wound healing viz., inflammatory phase, proliferative
phase and remodeling phase. These phases are briefly described here.
Inflammatory phase: The inflammatory phase starts immediately after
the injury that usually lasts between 24 and 48 h and may persist for up to
2 weeks in some cases (Li et al., 2007). The
inflammatory phase launches the hemostatic mechanisms to immediately stop blood
loss from the wound site. Clinically recognizable cardinal signs of inflammation,
rubor (redness), calor (warmth), tumor (swelling), dolor (pain) and functio
laesa (loss of function) appear as the consequence. This phase is characterized
by vasoconstriction and platelet aggregation to induce blood clotting and subsequently
vasodilatation and phagocytosis to produce inflammation at the wound site.
Proliferative phase: The second phase of wound healing is the proliferative
phase that lasts upto 2 days to 3 weeks after the inflammatory phase. This phase
comprises of three steps viz., granulation, contraction and epithelialisation.
In the granulation step fibroblasts form a bed of collagen and new capillaries
are produced. Fibroblasts produce a variety of substances essential for wound
repair including glycosaminoglycans and collagen (Stadelmann
et al., 1998). Under the step of contraction wound edges pull together
to reduce the defects. In the third step fresh epithelial tissues are formed
over the wound site.
Remodeling phase: This phase lasts for 3 weeks to 2 years. New collagen
is formed in this phase (Madden and Peacock, 1968; Prockop
et al., 1979). Tissue tensile strength is increased due to intermolecular
cross-linking of collagen via vitamin C-dependent hydroxylation. The scar flattens
and scar tissues become 80% as strong as the original tissue.
SOME MEDICINAL PLANTS USEFUL IN WOUND HEALING
Medicinal plants are important sources of new chemical substances that have beneficial therapeutic effects. Extensive research has been carried out in the area of wound healing management through medicinal plants. Recent studies with significant findings involving Alternanthera sessilis, Morinda citrifolia, Lycopodium serratum, Sesamum indicum, Catharanthus roseus, Cecropia peltata, Euphorbia hirta, Ginkgo biloba, Clerodendrum serratum, Pterocarpus santalinus, Lawsonia alba, Napoleona Imperialis, Kaempferia galangal Radix paeoniae, Prosopis Cineraria and Trigonella foenum-graecum are emphasized here.
Alternanthera sessilis: Alternanthera sessilis Syn. Alternanthera
triandra belongs to Amaranthaceae plant family. It is a prostrate herb mainly
used as a lactagogue and febrifuge. The seeds of the plant contain many fatty
acids such as myristic, palmitic, stearic, oleic and linoleic acid (Hosamani
et al., 2004). Leaves of the plant were reported to have wound healing
activity by Jalalpure et al. (2008). They studied
wound healing activity of the chloroform extract of the plant through excision,
incision and dead space wound models. The test group of animals showed significant
wound healing activity as compared to the control group in all the models.
Morinda citrifolia: Morinda citrifolia L., the noni
(Rubiaceae) is an evergreen shrub. The leaves, fruits and roots of the plant
are very nutritious. Blanco et al. (2006) reported
the nutritional and therapeutic properties of the noni fruit. The ethanolic
extract of the plant leaves in an oral dose of 150 mg/kg/day was used by Nayak
et al. (2007) to evaluate the wound healing activity in an experiment
on rats. Reduction in the wound area was found to be 71% in the test animals
as compared to 57% in the controls. Significantly lower complete epithelialization
time was observed in test animals than in the control animals.
Lycopodium serratum: Lycopodium serratum (Lycopodiaceae)
is commonly known as Club moss. The plant is used to increase efficiency of
learning and memory and in the treatment of Alzheimers disease. The plant
is reported to contain many alkaloids (Takayama et al.,
2003). Wound healing activity of aqueous and ethanolic leaf extracts
of L. serratum was studied by excision, incision and dead space wound
models on rats (Manjunatha et al., 2007). As
compared to the aqueous extract and controls the ethanolic extract showed significant
decrease in the period of epithelialisation and an increase in wound contraction
rate, tissue breaking strength and hydroxyproline content at the wound site.
Sesamum indicum: Sesamum indicum L. is a member of family
Pedaliaceae. Sesame oil obtained from the seeds of the plant is highly nutritive
as it is a rich source of natural oxidants such as sesamin and sesamol (Rajeswari
et al., 2010).
The methanolic extract of roots of Sesamum indicum was obtained and
was incorporated in gel and ointment bases. These preparations were evaluated
for in vivo wound healing activity on rats using excision wound model (Dhumal
and Kulkarni, 2007). The test preparations exhibited faster contraction
of wound diameter as compared to the control. The ointment showed a comparable
wound healing potential to the povidone-iodine ointment.
Catharanthus roseus: Catharanthus roseus plant is a key
source of monoterpenoid indole alkaloids, vinblastine and vincristine which
are found useful in the treatment of cancer (Magnotta
et al., 2006). In a study ethanolic extract of Catharanthus roseus
flowers in a dose of 100 mg/kg/day demonstrated to possess wound healing property
(Nayak et al., 2006).
Cecropia peltata: Cecropia peltata (Cecropiaceae) leaves
are used traditionally in Mexico to treat a variety of disorders including type
2 diabetes. Infusion prepared by the dried leaves of the plant is drunk as agua
de uso (Andrade-Cetto and Vázquez, 2010). Aqueous
and ethanolic leaf extracts of this plant were screened for wound healing properties
(Shivananda, 2006). Wound areas reduced statistically
significantly in all treatment groups as compared to respective controls (p<0.001).
Protein, hydroxyproline and hexosamine contents were increased significantly
in extract treated animals as compared with the controls.
Euphorbia hirta: Euphorbia hirta (Euphorbiaceae) is a
weed commonly found in tropical countries and has been used traditionally for
cough, asthma, bronchitis bowel complaints, worm infestation, kidney stones,
bronchial affections and conjunctivitis (Loh et al.,
2009). The aqueous extract of the plant shows analgesic, anti-pyretic, anxiolytic,
sedative, anti-inflammatory activities and also inhibitory action on platelet
Ethanolic extract of the entire herb of Euphorbia hirta was employed
for exploring its wound healing activity in an investigation (Jaiprakash
et al., 2006). Wistar Albino rats were used in the experiment and
excision wounds, incision wounds and dead space wounds were studied. It was
found that the ethanolic extract of the entire herb of E. hirta possesses
significant wound healing activity.
Ginkgo biloba: Ginkgo biloba is used as an herbal medicine
from the ancient times. In recent experiments the plant has been reported to
be effective in ischemic brain injury, cerebrovascular insufficiency, cognitive
speed, dementia and Alzheimers disease, peripheral vascular disease and
aging damages (Satoh and Nishida, 2004).
Healing suppressant effect of cyclophosphamide by Ginkgo biloba was
evaluated by Bairy et al. (2006). Cyclophosphamide
significantly reduced (p<0.05) and Ginkgo biloba significantly increased
(p<0.05) the breaking strength and hydroxyproline content of granulation
tissue. This effect of Ginkgo biloba may be attributed to its antioxidant
Clerodendrum serratum: The roots and leaves of Clerodendrum serratum (Bharngi) have great medicinal value. It is found useful in cephalalgia, ophthalmia, glandular swellings and in wound healing.
Ethanolic extracts of root and leaves of Clerodendrum serratum were
obtained and their wound healing potency was evaluated on Albino rats (Vidyai
et al., 2005). The results showed higher wound healing potency of
the root extract as compared to the leaf extract. On comparison with the control
both the extracts demonstrated significant wound healing potency.
Pterocarpus santalinus: Pterocarpus santalinus L. belongs
to the family Fabaceae. The wood of the plant possess astringent, tonic and
diaphoretic properties. A paste of the wood is used externally in inflammations
and headache (Kameswara et al., 2001). The wound
healing potency of ethanolic extracts of leaf and stem bark of Pterocarpus
santalinus was evaluated by Manjunatha et al. (2005).
The extracts demonstrated significant decrease in the period of epithelialisation,
increase in the rate of wound contraction, skin breaking strength, granulation
tissue dry weight, hydroxyproline content and breaking strength of granulation
tissue. Histopathological study of granulation tissue also evidenced the increased
collagenation when compared to control group of animals.
Lawsonia alba: Lawsonia alba (Lynthraceae) has been shown
to possess antimicrobial, antifungal and antitubercular activities. Its bark
is reported to be useful in jaundice and in the enlargement of the spleen (Ahmed
et al., 2000).
Wound healing potential of the leaf extract of Lawsonia alba was evaluated
through oral and topical routes of administration. Results indicated that the
extract exhibited better efficacy upon topical administration as compared to
the oral administration (Mandawade and Patil, 2003).
Napoleona imperialis: Napoleonaea imperialis is a Nigerian
folklore medicinal plant. Chah et al. (2006)
demonstrated antibacterial and wound healing properties of this plant in rats.
In another experiment Esimone et al. (2005) prepared
an herbal ointment of the methanolic extract of Napoleona imperialis and
evaluated its wound healing effect by the excision wound model on guinea pigs.
The result of the experiment indicates that Napoleona imperialis extract
possess a better wound healing property as compared to the standard antibiotic
used as control.
Kaempferia galanga: This medicinal plant has been extensively
used for treatment of various disorders including hypertension, rheumatism and
asthma (Zakaria and Mustafa, 1994). In Thailand the rhizome
of Kaempferia galanga (Zingiberaceae) is traditionally used for relieving
toothache, abdominal pain, muscular swelling and rheumatism (Ridtitid
et al., 2008).
In a study conducted by Shanbhag et al. (2006)
ethanolic extract of Kaempferia galanga was obtained and its effect in
dexamethasone suppressed wound healing was studied in Wistar rats. When Kaempferia
galanga extract was coadministration with dexamethasone a significant reduction
in the epithelialization time with an increase in tissue breaking strength and
percentage of the wound contraction was observed.
Radix paeoniae: Radix paeoniae (Paeonaceae) is used to
treat amenorrhea, traumatic injuries, epistaxis, inflammation, boils and sores
and to relieve pain (He et al., 2004).
Aqueous extract of the roots of Radix paeoniae was screened for wound
healing by excision, incision and dead space wound models on Wistar rats. Parameters
studied were tissue breaking strength, epithelialisation, wound contraction
and granulation tissue dry weight. The test group demonstrated significant wound
healing activity as compared to Nitrofurazone ointment treated control group
(Malviya et al., 2009).
Prosopis cineraria: Prosopis Cineraria (Mimosaceae) is
an evergreen, small, throny, irregularly branched tree. Aqueous paste of bark
of the tree when applied externally disinfects wounds and promotes healing (Anonymous,
1914). The tree is also found to possess anti-inflammatory, analgesic and
anti cancer activity (Vishnoi et al., 2005) and
useful in boils and skin diseases (Parveen et al.,
Trigonella foenum-graecum: Trigonella foenum - graecum (Papilionaceae),
commonly known as Fenugreek is a very useful medicinal plant. Seeds of the plant
show wound healing activity (Taranalli and Kuppast, 1996).
Fenugreek is found useful for its antihyperlipidemic activity (Issarani
and Nagori, 2006). Fenugreek seeds are rich in polysaccharide galactomannan
(Toppo et al., 2009) that has exhibited significant
wound healing property (McAnalley et al., 1995).
Issarani and Nagori (2004) demonstrated that Fenugreek
galactomannan is as a potential bioactive molecule for conducting advance research
in the area of wound healing management.
SOME PATENTS ON HERBAL PRODUCTS FOR WOUND TREATMENT
Patents are store houses of the latest technical information. Although patented
products are excluded to be made or used commercially by others before the patent
expiration (Nagori and Mathur, 2008, 2009)
still patent reviews are useful in many ways. Patent reviews provide a comprehensive
knowledge of the latest technical advances in a particular subject area. They
help researchers to identify potential areas for conducting new research work
and developing better products and methods. Such reviews help manufacturers
to avoid falling in patent infringement litigation by designing alternative
products and methods (Nagori and Mathur, 2009).
A review of some patents that relate with the use of medicinal plants in wound healing management is done here. This review provides an insight on the recent technological advances that have taken place in the area of wound management.
Topical gel matrix: Costa et al. (2008)
developed a gel matrix for wound healing, in which a plant oil extract is entrapped.
According to their patent such plant oil may be pine, clove, coriander or Sweet
Birch oil. The gel matrix comprises of about 15% w/w polyethylene glycol-150,
about 37.4-45% w/w ethoxydiglycol, 1-6% w/w polysorbate surfactant and a bio
compatible liquid carrier.
Pharmaceutical compositions comprising an extract of Euphorbia prostrata:
A novel composition comprising of an extract of the plant Euphorbia prostrate
was patented (Jain et al., 2008). This composition
contains pharmaceutically acceptable carrier optionally with therapeutic agents
useful for the treatment of wounds.
Herbal composition for cuts, burns and wounds: A novel herbal composition
for treatment of cuts, burns and wounds was developed (Pushpangadan
et al., 2008). The patented composition comprises extracts of any
of the plant Utleria solicifolia, Jatropha curcas, Clerodendrum infortunatu
and Centella asiatica. The herbal composition was found capable of
causing at least 70% wound contraction in 10 days.
Gel based cosmetic and wound healing formulation and method: Knapp
and DiSalvo (2007) patented a gel-based cosmetic and wound-healing formulation
and methods for making this formulation. The formulation comprises of live yeast
cell extract, pigment and a gel.
Topical wound dressing and method of making same: A patent on topical
wound dressing and method of making the same was granted to Leber
(2006). In this wound dressing a gauze pad is impregnated with tannin extract
derived from Black pekoe tea.
Herbal extract having therapeutic activity on injuries and pharmaceutical
composition and health food containing the same: A pharmaceutical composition
for treating injuries was developed by Hong (2006). The
composition contains a mixture of extracts of Astragali radix, Ginseng
radix, Carthami flos, Angelicae gigantis radix, Cnidii
rhizoma, Rehmanniae radix preparata, Paeoniae radix and
Cinnamomi cortex spissus.
Wound healing antiscarring topical composition of centella and ginseng:
Mini et al. (2002) invented a wound healing antiscarring
topical composition of Centella and Ginseng. It comprises of centella whole
extract (0.01-1% by weight) and ginseng extract (0.01-0.5% by weight) with pharmaceutically
Antipruritic composition and wound-healing-promoting composition: Tsuchida
et al. (2006) developed an antipruritic and a wound healing promoting
composition which comprises Sasa albo-marginata extract in an amount 1%-10%
by weight as expressed in terms of the solid content thereof. The composition
is reported to show an excellent wound healing promoting effect.
Nutraceutical treatments for diabetic and non diabetic wound healing:
A method for improving wound healing in a mammal was developed by Chien
and Bagchi (2008). The method involves administering an effective amount
of two or more of the following substances: chromium, zinc, berry extract, Polygonum
cuspidatum extract, L-arginine, chlorophyll and aloe vera to the
patient. It is claimed to improve wound healing.
Topical wound care product containing hyssop extract: A new composition
for treating wounds containing hyssop extract combined with glycerol, salt,
saccharides and water was discovered to be effective in promoting healing of
wounds (Reichert, 2008).
Composition having wound curing promotive effect: A new skincare preparation
for external use, a pharmaceutical and a wound masking material comprising herbal
extract were prepared by Yamamoto et al. (2009)
in Japan. The preparation is claimed to be safe after long term use and was
found useful for diabetic patients.
Extract of Stewartia koreana and use there of: The extract of
Stewartia koreana promotes migration and multiplication of endothelial
cell and shows excellent effect in angiogenesis and wound healing (Kim
et al., 2010). A pharmaceutical composition for promoting angiogenesis
or tissue regeneration and a cosmetic for improving wrinkles containing Stewartia
koreana extract was developed.
Herbal medicinal composition for curing external wound and bedsore and method
of manufacturing medicine from the composition: A new herbal medicinal composition
for curing an external wound and a bedsore was prepared by Chuang
et al. (2009). The composition contains herbal medicinal materials
such as dried ginger root, dried aconiti tuber and cinnamon bark as the effective
Wound healing ointment: A novel ointment composition comprising Eleutherococcus
senticosus (Siberian ginseng) extract useful in the treatment of
wound and burns was prepared and patented (Vladimirovich
et al., 2009).
Wound healing agent containing momordicae semen extract: Momordicae
semen extract possess wound healing efficiencies. A topical transdermal
formulation comprising Momordicae semen extract was developed (Bongcheol
et al., 2009). The formulation was capable of reducing the time required
for wound treatment and wound closure.
Compound catechu ointment for healing wound and preparation method thereof:
The patent relates to a new compound Catechu ointment used for wound
healing and a method of preparing such ointment (Yimu, 2009).
Heidouba extract and preparation method and pharmaceutical use thereof:
An herbal preparation containing Huidouba extract was developed by Lirong
et al. (2009). The preparation was found useful in the treatment
of trauma, incised wound, scalds and burn injuries.
A process for the preparation of a novel herbal anti-maggot and topical
care composition: Agarwal (2009) prepared a novel
herbal anti-maggot and topical care composition in the form of cream, lotion
and aerosol spray. The composition contains the distillates of Cedrus, Eucalyptus
and Firms mixed with the extract of Curcuma.
A composition for the treatment of burns, cuts and like wounds: Compositions
and a method for fast healing of wounds, lesions, bed sores fissures, burns,
cuts and ulcers were developed by Lulla and Cipla Ltd. (2008).
The herbal based compositions are in the foam of creams, lotions, gels or ointments
or the like.
Wound healing is a biological process that begins with trauma and ends with scar formation. The goals of wound care include reducing risk factors that inhibit wound healing, enhancing the healing process and lowering the incidence of wound infections. Many medicinal plants have been found useful in wound healing. Medicinal plants provide leads to find therapeutically useful compounds, thus more efforts should be made towards isolation and characterization of the active principles and elucidation of the relationship between structure and activity. The combination of traditional and modern knowledge can produce better drugs for wound healing with fewer side effects.