**5. Plants with beneficial effect on wound healing, approved by the Committee on Herbal Medicinal Products (HMPC)**

Many plants and their extracts have great potential for the management and treatment of wounds. Natural agents induce healing and regeneration of the lost tissue by multiple mechanisms. The so-called phytomedicines are affordable and they cause minimal adverse effects. However, there is need for scientific standardization, validation and safety evaluation of plants of traditional medicine before these can be recommended for wound healing [49]. Therefore, an extensive research has been carried out in the area of wound healing and management through medicinal plants [38].

The following paragraphs outline some medicinal plants and their properties that exhibit wound healing activity.

*Achillea millefolium* (Family: *Asteraceae*)*.* Yarrow (a common name of the plant) has been known and used due to its healing effects by many cultures for hundreds of years [129]. Among its proven beneficial effects in wound healing are a good antibacterial activity against *Shigella dysenteriae* [130], moderate activities against *Streptococcus pneumoniae, Clostridium perfringens* and *Candida albicans,* and a weak antibacterial activity against *Mycobacterium smegmatis, Acinetobacter lwoffii* and *Candida krusei* [131]. Yarrow also has a proven anti-inflammatory effect [132].

*Aloe vera* (Family: *Liliaceae)*. *Aloe vera* has been used for medicinal purposes in several cultures for millennia: Greece, Egypt, India, Mexico, Japan and China [133]. 3500 years ago, Egyptians used this herb in treating burns, infections and parasites [134]. Its gel has the ability to heal different kinds of wounds including ulcers and burns by forming a protective coating on the affected areas and speeding up the healing process. Various constituents of *Aloe vera* stimulate wound healing and have anti-inflammatory activity [29].

*Chromolaena odorata* (Family: *Asteraceae*). The aqueous extract and the decoction from the leaves of this plant have been used throughout Vietnam for the treatment of soft tissue and burn wounds. It enhances haemostatic activity, inhibits wound contraction, stimulates granulation tissue and re-epithelization processes and can therefore be of much therapeutic value in

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*Commiphora myrrha* (Family: *Burseraceae*). Myrrh is among the oldest known traditional medicines used by humans, with a documented use even in the times of ancient Rome (found in texts written by Hippocrates). In addition, other cultures report its potential medical use. These include the Bible, as well as the Koran [148]. Various pharmacological activities of myrrh are reported (e.g. antibacterial and antifungal effects against several strains, as well as antiinflammatory, local anaesthetic and analgesic activities). Presently, it is cutaneous used in the form of a tincture in the treatment of minor wounds, abrasions and skin inflammations [35]. *Curcuma longa* (Family: *Zingiberaceae*). Turmeric possess anti-bacterial, anti-fungal, analgesic and anti-inflammatory activities [149]. Its anti-inflammatory properties, presence of vitamin A, as well as several proteins were shown to have a beneficial effect on the early formation of collagen fibres, which could be related to stimulation of fibroblastic activity [36]. As part of traditional medicines, fresh rhizome juice from turmeric is often used in treatment of fresh

*Echinacea* (Family: *Asteraceae*). *Echinacea* species and various preparations thereof have one of the longest reported histories of use in the American people's medicine [150]. The most used species include *E. purpurea, E. angustifolia*, *E. palida*, *E. simulata* and *E. paradoxa* [151]. The documented use of *Echinacea purpurea* dates back to 1787 and includes its use for external application in treatment of wounds, burns and insect bites [152]. Its more specific activities are an antimicrobial activity against *Vesicular Stomatitis virus, Escherichia coli, Pseudomonas aeruginosa, Aspergillus niger, Candida albicans, Staphylococcus aureus, Pseudomonas aeruginosa* [153], *Encephalomyocarditis virus, Vesicular Stomatitis virus* [154], *Saccharomyces cerevisiae, Candida shehata, Candida kefyr, Candida albicans, Candida steatulytica and Candida tropicalis* [42]. Echinacea extracts exhibit also pain reducing effects, which are related to an inhibitory effect on cyclooxygenase-I, cyclooxygenase-II [155] and 5-lipoxygenase [37]. The mentioned activities contribute also to its anti-inflammatory activity. All described properties (e.g. antimicrobial, pain reducing effects, anti-inflammatory activ-

*Euphorbia hirta* (Family: *Euphorbiaceae*). The aqueous extract of the plant shows analgesic, anti-inflammatory activities and an inhibitory action on platelet aggregation. Ethanolic extract

*Ginkgo biloba* (Family: *Ginkgoaceae*). Ginkgo leaf extracts have been therapeutically used for hundreds of years [156]. Its pharmacological activities include an increase in blood fluidity, anti-oxidative activity, membrane stabilization, improvement in cognition, and wound healing promotion. Various ginkgo preparations have been shown to improve granulation tissue breaking strength, as well as promote epithelization without influence on wound

*Helianthus annuus* (Family: *Asteraceae*). In traditional medicine, the sunflower herb is used by Indian tribes for treating inflammation of the eyes, sores, tiger bites, and to treat bone

of the entire herb was found to possess significant wound healing activity [38].

the wound healing, minimizing post-burn scar contracture and deformities [147].

wounds, bruises and also leech bites.

contraction [45].

ity) present beneficial effects of *Echinacea* for wound healing [37].

*Angelica sinensis* (Family: *Apiaceae*). Chinese angelica is widely used in Chinese traditional medicine. Its isolate has been found to stimulate wound healing and increase the strength of the healed wounds [135].

*Avena sativa* (Family: *Poaceae*). The oats has been known for more than 4000 years as a food and the traditional medicinal usage has been documented since the twelfth century. For cutaneous use, mostly fruits of *Avena* are prepared as 'colloidal oatmeal' described in the USP 30 (1990) [136]. *In vitro* investigations are indicative of an anti-inflammatory activity of several oat fruit preparations. Pasta made with oat's flour mixed with beer yeast is used on infected ulcers and wounds, and to facilitate wound healing [137].

*Azadirachta indica* (Family: *Meliaceae*). Neem has been used in India for over two millennia for many medicinal properties, particularly for skin diseases. Products made from neem trees possess anti-bacterial, anti-fungal, anti-viral and anti-inflammatory activities. Neem oil aids the building of collagen, promotes wound healing and maintains the skin elasticity. It also keeps the wound moist during the healing process. All mentioned mechanisms accelerate wound healing [138].

*Calendula officinalis* (Family: *Asteraceae*). *In vitro* pharmacological studies confirmed its anti-viral, anti-genotoxic and anti-inflammatory properties [32]. Pot marigold was shown to possess also an antimicrobial activity against *Bacillus subtilis, Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Candida albicans* [139], *Sarcina lutea, Klebsiella pneumoniae* and *Candida monosa* [140]. Different preparations of pot marigold are known (e.g. suspensions or tinctures) for topical use to reduce inflammation, as well as to control bleeding [141]. It was also shown to inprove the healing of poorly healing wounds [142].

*Cedrus deodara* (Family: *Pinaceae*). Deodar possesses anti-inflammatory, anti-microbial, astringent and wound healing activities and is therefore particularly useful in treatment of infected wounds [33].

*Centella asiatica* (Family: *Mackinlayaceae*). Extensive research has been conducted regarding its use in the treatment of leprosy and several other skin conditions, including the treatment of various wounds. For example, centella was used in the treatment of experimentally induced open wounds in rats. In this study, its aqueous extract increased collagen content and the overall thickness of the freshly formed epithelium [143]. Apart from the mentioned, the topical use of its aqueous extract increased proliferation of various cells, improved collagen synthesis at the wound site (all mentioned was proven by increased DNA and protein synthesis in the tested cells), through an increased collagen content in the granulation tissue, and in an improved tensile strength [144]. All mentioned confirms the potential of *Centella asiatica* to promote wound healing and to facilitate repair of the connective tissues [145].

*Chamomilla recutita* (Family: *Asteraceae*). Chamomile has been used for centuries as an antimicrobial, antioxidant, anti-inflammatory agent, as a mild astringent and a healing medicine [34]. It helps in wound drying and it accelerates epithelization. Chamomile aids wound management also through increased granulation tissue weight, hydroxyproline content, rate of wound contraction and wound-breaking strength [146].

*Chromolaena odorata* (Family: *Asteraceae*). The aqueous extract and the decoction from the leaves of this plant have been used throughout Vietnam for the treatment of soft tissue and burn wounds. It enhances haemostatic activity, inhibits wound contraction, stimulates granulation tissue and re-epithelization processes and can therefore be of much therapeutic value in the wound healing, minimizing post-burn scar contracture and deformities [147].

affected areas and speeding up the healing process. Various constituents of *Aloe vera* stimulate

*Angelica sinensis* (Family: *Apiaceae*). Chinese angelica is widely used in Chinese traditional medicine. Its isolate has been found to stimulate wound healing and increase the strength of

*Avena sativa* (Family: *Poaceae*). The oats has been known for more than 4000 years as a food and the traditional medicinal usage has been documented since the twelfth century. For cutaneous use, mostly fruits of *Avena* are prepared as 'colloidal oatmeal' described in the USP 30 (1990) [136]. *In vitro* investigations are indicative of an anti-inflammatory activity of several oat fruit preparations. Pasta made with oat's flour mixed with beer yeast is used on infected

*Azadirachta indica* (Family: *Meliaceae*). Neem has been used in India for over two millennia for many medicinal properties, particularly for skin diseases. Products made from neem trees possess anti-bacterial, anti-fungal, anti-viral and anti-inflammatory activities. Neem oil aids the building of collagen, promotes wound healing and maintains the skin elasticity. It also keeps the wound moist during the healing process. All mentioned mechanisms accelerate wound

*Calendula officinalis* (Family: *Asteraceae*). *In vitro* pharmacological studies confirmed its anti-viral, anti-genotoxic and anti-inflammatory properties [32]. Pot marigold was shown to possess also an antimicrobial activity against *Bacillus subtilis, Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Candida albicans* [139], *Sarcina lutea, Klebsiella pneumoniae* and *Candida monosa* [140]. Different preparations of pot marigold are known (e.g. suspensions or tinctures) for topical use to reduce inflammation, as well as to control bleeding [141]. It was

*Cedrus deodara* (Family: *Pinaceae*). Deodar possesses anti-inflammatory, anti-microbial, astringent and wound healing activities and is therefore particularly useful in treatment of infected

*Centella asiatica* (Family: *Mackinlayaceae*). Extensive research has been conducted regarding its use in the treatment of leprosy and several other skin conditions, including the treatment of various wounds. For example, centella was used in the treatment of experimentally induced open wounds in rats. In this study, its aqueous extract increased collagen content and the overall thickness of the freshly formed epithelium [143]. Apart from the mentioned, the topical use of its aqueous extract increased proliferation of various cells, improved collagen synthesis at the wound site (all mentioned was proven by increased DNA and protein synthesis in the tested cells), through an increased collagen content in the granulation tissue, and in an improved tensile strength [144]. All mentioned confirms the potential of *Centella asiatica* to

*Chamomilla recutita* (Family: *Asteraceae*). Chamomile has been used for centuries as an antimicrobial, antioxidant, anti-inflammatory agent, as a mild astringent and a healing medicine [34]. It helps in wound drying and it accelerates epithelization. Chamomile aids wound management also through increased granulation tissue weight, hydroxyproline content, rate of

promote wound healing and to facilitate repair of the connective tissues [145].

wound contraction and wound-breaking strength [146].

wound healing and have anti-inflammatory activity [29].

ulcers and wounds, and to facilitate wound healing [137].

also shown to inprove the healing of poorly healing wounds [142].

the healed wounds [135].

134 Herbal Medicine

healing [138].

wounds [33].

*Commiphora myrrha* (Family: *Burseraceae*). Myrrh is among the oldest known traditional medicines used by humans, with a documented use even in the times of ancient Rome (found in texts written by Hippocrates). In addition, other cultures report its potential medical use. These include the Bible, as well as the Koran [148]. Various pharmacological activities of myrrh are reported (e.g. antibacterial and antifungal effects against several strains, as well as antiinflammatory, local anaesthetic and analgesic activities). Presently, it is cutaneous used in the form of a tincture in the treatment of minor wounds, abrasions and skin inflammations [35].

*Curcuma longa* (Family: *Zingiberaceae*). Turmeric possess anti-bacterial, anti-fungal, analgesic and anti-inflammatory activities [149]. Its anti-inflammatory properties, presence of vitamin A, as well as several proteins were shown to have a beneficial effect on the early formation of collagen fibres, which could be related to stimulation of fibroblastic activity [36]. As part of traditional medicines, fresh rhizome juice from turmeric is often used in treatment of fresh wounds, bruises and also leech bites.

*Echinacea* (Family: *Asteraceae*). *Echinacea* species and various preparations thereof have one of the longest reported histories of use in the American people's medicine [150]. The most used species include *E. purpurea, E. angustifolia*, *E. palida*, *E. simulata* and *E. paradoxa* [151]. The documented use of *Echinacea purpurea* dates back to 1787 and includes its use for external application in treatment of wounds, burns and insect bites [152]. Its more specific activities are an antimicrobial activity against *Vesicular Stomatitis virus, Escherichia coli, Pseudomonas aeruginosa, Aspergillus niger, Candida albicans, Staphylococcus aureus, Pseudomonas aeruginosa* [153], *Encephalomyocarditis virus, Vesicular Stomatitis virus* [154], *Saccharomyces cerevisiae, Candida shehata, Candida kefyr, Candida albicans, Candida steatulytica and Candida tropicalis* [42]. Echinacea extracts exhibit also pain reducing effects, which are related to an inhibitory effect on cyclooxygenase-I, cyclooxygenase-II [155] and 5-lipoxygenase [37]. The mentioned activities contribute also to its anti-inflammatory activity. All described properties (e.g. antimicrobial, pain reducing effects, anti-inflammatory activity) present beneficial effects of *Echinacea* for wound healing [37].

*Euphorbia hirta* (Family: *Euphorbiaceae*). The aqueous extract of the plant shows analgesic, anti-inflammatory activities and an inhibitory action on platelet aggregation. Ethanolic extract of the entire herb was found to possess significant wound healing activity [38].

*Ginkgo biloba* (Family: *Ginkgoaceae*). Ginkgo leaf extracts have been therapeutically used for hundreds of years [156]. Its pharmacological activities include an increase in blood fluidity, anti-oxidative activity, membrane stabilization, improvement in cognition, and wound healing promotion. Various ginkgo preparations have been shown to improve granulation tissue breaking strength, as well as promote epithelization without influence on wound contraction [45].

*Helianthus annuus* (Family: *Asteraceae*). In traditional medicine, the sunflower herb is used by Indian tribes for treating inflammation of the eyes, sores, tiger bites, and to treat bone fractures [157]. The alcoholic extract of the whole plant of *Helianthus annuus* applied on the excised wounds of rats led to a significant reduction of the healing period which was indicated by earlier appearance and higher accumulation of mucopolysaccharides [158].

*Hydnocarpus wightiana* (Family: *Achariaceae*). The oil from chaulmoogra seeds has been widely used in Indian and Chinese traditional medicine [159]. The wound healing effect is substantiated by improved collagenation and strength of scar tissue, as well as by promoted epithelization [160].

**Figure 5.** Overview of medical plants traditionally used in wound healing and their pharmacological activities (all plant images were obtained using the Google search engine with the enabled option for 'free use, share and modify').

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fractures [157]. The alcoholic extract of the whole plant of *Helianthus annuus* applied on the excised wounds of rats led to a significant reduction of the healing period which was indi-

cated by earlier appearance and higher accumulation of mucopolysaccharides [158].

136 Herbal Medicine

**Figure 5.** Overview of medical plants traditionally used in wound healing and their pharmacological activities (all plant images were obtained using the Google search engine with the enabled option for 'free use, share and modify').

*Hydnocarpus wightiana* (Family: *Achariaceae*). The oil from chaulmoogra seeds has been widely used in Indian and Chinese traditional medicine [159]. The wound healing effect is substantiated by improved collagenation and strength of scar tissue, as well as by promoted epithelization [160].

*Hypericum perforatum* (Family: *Hypericaceae*). Under its traditional names St. John's Wort, this plant has a long history of safe and effective use as part of various folk and herbal remedies. With proven anti-inflammatory [39], antiseptic [161], analgesic, astringent and antibacterial activities [43], it seems an ideal candidate for use in wound treatment. The latter has been confirmed also in different studies, which include its healing promoting action, when used externally on minor wounds [162], as well as through the positive effects of *Hypericum perforatum* tincture on epithelization, an increase in the wound contraction rate and an improved granulation tissue breaking strength [163].

The chemo-preventive properties of many phytochemicals are well known and have been already proven beneficial in treating various disorders, including skin diseases. Different phytochemicals can contribute to the skin protective mechanisms by quenching free radicals and reducing inflammation through the inhibition of cellular and humoral immune responses. In the last decades, several strong research groups performed extensive research with the aim of identifying specific compounds from plant extracts and their molecular targets. This will provide a sound foundation for future clinical trials in the development of phytochemicals as

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Various plants produce secondary metabolites and other products that have beneficial effects on wound healing, including the enhancement of the skins natural repair mechanisms. Due to the possibility to produce different plant preparations for topical use, these have a huge potential in future therapeutic approach in wound care. Recent developments of novel extraction technologies, newly found knowledge about traditional use of various plants, as well as our steadily improving knowledge about wound healing physiology importantly contribute to the popularization of studies of herbs and herbal materials from the physiological and therapeutic point of view. This in turn contributes also to a steadily increasing number of herbal products for wound treatment. Considering also the increasing number of clinical studies related to the safety and therapeutic efficacy of herbal products, many more herbs have a bright future either in curative or preventative uses in wound healing. Based on our present knowledge, future studies should aim at the isolation and identification of specific active substances from plant extracts, which could also disclose compounds with better therapeutic value. Finally, the combination of traditional and modern knowledge seems to be the best approach to produce novel effective therapeutic interventions for wound healing with a significantly improved treatment efficacy, lowered

The authors acknowledge the financial support from the Slovenian Research Agency for research core funding No. P2-0118 and P3-0036, and for the financial support through the

potentially important therapeutic agents.

**7. Conclusions**

side effects and costs.

**Acknowledgements**

**Conflict of interest**

projects No. Z2-8168 and J2-7413.

The authors declare no conflict of interest.

*Jasminum auriculatum* (Family: *Oleaceae*). The juice of the leaves of *Jasminum auriculatum* was found to promote wound healing through improved tensile strength in the early phase of healing [164] and due to acceleration of mucopolysaccharide accumulation [165].

*Pterocarpus santalinus* (Family: *Fabaceae*). The wood of the red sanders possesses astringent and tonic properties. Ethanolic extract of the leaf and stem bark of *Pterocarpus santalinus* has demonstrated significant decrease in the period of epithelialisation, an increase: in the rate of wound contraction, the extent of collagenation, in the skin breaking strength, of the granulation tissue dry weight, and of the hydroxyproline content [38].

*Rosmarinus officinalis* (Family: *Lamiaceae*). Rosemary is used for wound treatment. It reduces inflammation and enhances wound contraction, re-epithelization, and regeneration of granulation tissue, angiogenesis and collagen deposition [40].

*Tridax procumbens* (Family: *Asteraceae*). The juice of *Tridax procumbens* promotes wound healing by accelerating epithelization and collagenization, resulting in the retardation of scar formation and granulation [166].

**Figure 5** presents a summary of plants with proven beneficial effect on wound healing.
