**4.1. Groups of plant-derived molecules with beneficial effects on wound healing**

When we describe the beneficial effects of plant-derived molecules on human health, mostly it is the secondary plant metabolites, producing pharmacological and/or toxicological effects, that we are discussing [48]. Secondary metabolites are produced within the plants and are regarded as by-products of biochemical reactions in the plant cells. As such, these molecules are not part of any crucial daily functioning of the plant, hence are not important for the plants main biosynthetic and metabolic routes that yield products with major significance for the plant growth and/or development [50]. Although this means that these molecules are not key to the plants basic functions, this does not mean that they do not importantly contribute to the success of the plants overall survival in its ecosystem. For example, several of them play important roles in the living plants´ protection, attraction or signalling [51]. It seems that most plant species are capable of producing at least some of these compounds. But before we describe the most important groups of these secondary metabolites, let us first define the related term bioactive compounds. By definition, bioactive compounds in plants are compounds, produced by plants having pharmacological or toxicological effects in man and animals [52].

At the moment, we know over 8000 different structures of plant phenolic compounds. Due to this huge number of compounds, it is important to use an effective classification system for their distinction. The most commonly used to distinguish phenolic compounds, groups them initially into flavonoid and non-flavonoid compounds. Both main groups are further divided

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Most likely the largest class of polyphenolic compounds found in nature are flavonoids [63]. Over 4000 structurally unique flavonoids were already identified from various plant sources [64]. Primarily, flavonoids were recognized as pigments responsible for many colors that occur in autumn, since they can provide various hues of yellow, orange and red in flowers, vegetables, nuts, seeds, fruits, etc., as well as the color of tea and red wine [65]. Several studies have shown that many plants contain therapeutic amounts of flavonoids [66]. These were (and still are) used in traditional medicine as anti-inflammatory, pain reducing, healing promoting, anti-allergic agents and others [67]. Most of the pharmacological effects found in flavonoids can be related to their (almost common) strong antioxidant activity [68]. They also act as free radical scavengers, can chelate metals, and are able to interact with enzymes, have an action on adenosine receptors and interfere with bio-membranes [69]. Among the main motivations for this review are several studies reporting different flavonoids with beneficial

The core molecular structure of flavonoids consists of two aromatic rings connected by a three carbon bridge [70]. In plants, flavonoids often occur in association with sugar moieties

as presented in **Figure 3**.

properties for wound-healing [47].

**Figure 3.** A diagram showing the classification of phenolic compounds.

*4.1.1.1. Flavonoids*

Bioactive compounds in plants can be classified considering different criteria. A presentation based on clinical function—their pharmacological or toxicological effects—is relevant for the clinician, pharmacist or toxicologist. The botanical approach on the other side considers the plant, from which they originate [53]. Finally, the biochemical approach seems to be the most commonly used. The latter is based on their classification according to the metabolic (biochemical) pathway, by which they are produced [54]. Using this approach, groups are more clearly understandable to most readers with at least basic knowledge in chemistry. The list of possible products is quite long, but since the focus of this chapter is on the ones with a beneficial effect on wound healing, we will focus on the groups, which could benefit the latter also in future clinical applications. The final subchapter summarizes some of the other groups, which might attract more researchers in the future.

#### *4.1.1. Phenolic compounds*

Phenolic compounds present secondary metabolites that are known to contribute to several plant functions [55]. Apart from the important functions in relation to the plant host organism, phenolic metabolites (mostly called polyphenols in literature) are among the most important plant-derived molecules with a versatile range of potential beneficial biological properties on the human health [56]. Phenolic compounds were shown to possess beneficial effect on the human health, regardless of the type of intake/application [57]. For example, skin application can alleviate symptoms and inhibit the development of various skin disorders [58]. Because, in nature, there is an abundant source of various polyphenols with proven effect on the skin and due to the already proven low toxicity for many of them, these type of compounds have a great potential in wound healing, including treatment of various skin damage (e.g. wounds and burns) [55]. Polyphenols present an important source for future applications in wound care, ranging from reduction of minor skin problems (e.g., wrinkles, acne) [59] to more severe ones, such as cancer [60].

There are many available studies describing the potential of phenolic compounds to be used in treatment of various skin disorders, including reports about their beneficial influence on wound healing [61]. Phenolic compounds are among the most known plant secondary metabolites mostly due to their broad spectrum of biological properties [62]. The latter were shown to be related to their molecular structure, which consists of the main core, formed by at least one phenol ring, in which hydrogen is usually replaced by a more active moiety (e.g. hydroxyl, methyl or acetyl) [55]. The variability in their biological properties and activities is related to the type and degree of the substitutes on the phenol ring. Since many of the natural phenolic compounds contain more than one phenol ring, such compounds are often called polyphenols [62].

At the moment, we know over 8000 different structures of plant phenolic compounds. Due to this huge number of compounds, it is important to use an effective classification system for their distinction. The most commonly used to distinguish phenolic compounds, groups them initially into flavonoid and non-flavonoid compounds. Both main groups are further divided as presented in **Figure 3**.

### *4.1.1.1. Flavonoids*

contribute to the success of the plants overall survival in its ecosystem. For example, several of them play important roles in the living plants´ protection, attraction or signalling [51]. It seems that most plant species are capable of producing at least some of these compounds. But before we describe the most important groups of these secondary metabolites, let us first define the related term bioactive compounds. By definition, bioactive compounds in plants are compounds, produced by plants having pharmacological or toxicological effects in man

Bioactive compounds in plants can be classified considering different criteria. A presentation based on clinical function—their pharmacological or toxicological effects—is relevant for the clinician, pharmacist or toxicologist. The botanical approach on the other side considers the plant, from which they originate [53]. Finally, the biochemical approach seems to be the most commonly used. The latter is based on their classification according to the metabolic (biochemical) pathway, by which they are produced [54]. Using this approach, groups are more clearly understandable to most readers with at least basic knowledge in chemistry. The list of possible products is quite long, but since the focus of this chapter is on the ones with a beneficial effect on wound healing, we will focus on the groups, which could benefit the latter also in future clinical applications. The final subchapter summarizes some of the other groups, which

Phenolic compounds present secondary metabolites that are known to contribute to several plant functions [55]. Apart from the important functions in relation to the plant host organism, phenolic metabolites (mostly called polyphenols in literature) are among the most important plant-derived molecules with a versatile range of potential beneficial biological properties on the human health [56]. Phenolic compounds were shown to possess beneficial effect on the human health, regardless of the type of intake/application [57]. For example, skin application can alleviate symptoms and inhibit the development of various skin disorders [58]. Because, in nature, there is an abundant source of various polyphenols with proven effect on the skin and due to the already proven low toxicity for many of them, these type of compounds have a great potential in wound healing, including treatment of various skin damage (e.g. wounds and burns) [55]. Polyphenols present an important source for future applications in wound care, ranging from reduction of minor skin

There are many available studies describing the potential of phenolic compounds to be used in treatment of various skin disorders, including reports about their beneficial influence on wound healing [61]. Phenolic compounds are among the most known plant secondary metabolites mostly due to their broad spectrum of biological properties [62]. The latter were shown to be related to their molecular structure, which consists of the main core, formed by at least one phenol ring, in which hydrogen is usually replaced by a more active moiety (e.g. hydroxyl, methyl or acetyl) [55]. The variability in their biological properties and activities is related to the type and degree of the substitutes on the phenol ring. Since many of the natural phenolic compounds contain more than one phenol ring, such compounds are often called

problems (e.g., wrinkles, acne) [59] to more severe ones, such as cancer [60].

and animals [52].

126 Herbal Medicine

might attract more researchers in the future.

*4.1.1. Phenolic compounds*

polyphenols [62].

Most likely the largest class of polyphenolic compounds found in nature are flavonoids [63]. Over 4000 structurally unique flavonoids were already identified from various plant sources [64]. Primarily, flavonoids were recognized as pigments responsible for many colors that occur in autumn, since they can provide various hues of yellow, orange and red in flowers, vegetables, nuts, seeds, fruits, etc., as well as the color of tea and red wine [65]. Several studies have shown that many plants contain therapeutic amounts of flavonoids [66]. These were (and still are) used in traditional medicine as anti-inflammatory, pain reducing, healing promoting, anti-allergic agents and others [67]. Most of the pharmacological effects found in flavonoids can be related to their (almost common) strong antioxidant activity [68]. They also act as free radical scavengers, can chelate metals, and are able to interact with enzymes, have an action on adenosine receptors and interfere with bio-membranes [69]. Among the main motivations for this review are several studies reporting different flavonoids with beneficial properties for wound-healing [47].

The core molecular structure of flavonoids consists of two aromatic rings connected by a three carbon bridge [70]. In plants, flavonoids often occur in association with sugar moieties

**Figure 3.** A diagram showing the classification of phenolic compounds.

as glycosides [70]. The main sources of flavonoids in the diet are fruits and vegetables. They occur also in certain grains, seeds, and spices, as well as in wine, tea, coffee, cocoa, and herbal essences [71]. All flavonoid compounds contain phenol-groups, which in general induces an antioxidant activity [72]. Other actions are diverse-several structures reduce inflammation or carcinogenicity [73].

been used to treat bites [82]. There are also reports describing its anti-depressant activity, as well as its effect on smooth muscles (acting as a muscle relaxant) [83]. Several researchers have performed many different studies in relation to the potential beneficial effect of lavender oil in various wound care applications [83]. One of these studies, conducted by Kane et al., reports about the significantly reduced pain intensity after aromatherapy using lavender oil during dressing changes in treatment of vascular wounds when compared with control therapies [84]. Another study showing a potential use of lavender oil in wound care is the study by Hartman and Coetzee [85]. They studied the effect of lavender and chamomile essential oils on wound healing in five patients with chronic wounds in a timespan of months. The wounds were graded using the US National Pressure Ulcer Advisory Panel (NPUAP) guidelines based on depth and visual characteristics [85]. The treatment protocol used in this study includes a treatment with a 6 wt.% solution of two drops of lavender oil and one drop of German chamomile, which were applied directly onto the wound, and subsequently covered with a gauze. Their result was that the wounds treated with the oils healed more quickly compared to the control wounds without the additional treatment using the essential oils, which were

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The wound healing aiding properties of chamomile (*Matricaria chamomilla* L.) oil, derived from chamomile flowers, were investigated also by Glowania et al. [86]. This double-blind study included 14 patients in which chamomile oil, when added to standard dressings, significantly improved the weeping and drying associated with dermabrasion wounds [86]. Another study that reports evaluation of potential positive effects on wound healing is a review of the bioactivity of chamomile, conducted by McKay et al. [87]. They found a moderate antimicrobial and a significant antiplatelet activity *in vitro*, as well as showed antimutagenic effects in animals [87].

The tea tree (*Melaleuca alternifolia*) oil is an essential oil derived from the leaves of the tea tree that are used as a complementary therapy in Australia. The latter is mostly related to its known antiseptic, antibacterial, antifungal and anti-inflammatory activities [82]. Several studies report about its potential use in wound healing applications. Halcon and Milkus, for example, tested the tea tree oil as an antimicrobial agent in the case of *Staphylococcus aureus* infections [88]. Although this study was based only on a small clinical trial combined with case studies, the authors nevertheless showed the potential of the tea tree oil treatment of osteomyelitis and in chronic wound healing [88]. Another study was performed by Hammer et al., who investigated the effect of tea tree oil on transient and commensal skin flora *in vitro* [89]. They compared the effectiveness of different concentrations to induce bactericidal action and found the tea tree oil to be effective against *Staphylococcus aureus* and most Gram-negative bacteria (reduction to 0.25%), but was less effective against coagulase-negative staphylococci and micrococci (8%) [89]. Two groups of researchers tested also commercially available products based on tea tree extracts (including the essential oil). Sherry et al. claimed that the antimicrobial preparation from extracts of tea tree oil and eucalyptus showed an activity against methicillin-resistant *Staphylococcus aureus* (MRSA) [90]. Faoagali et al. evaluated the activity

just covered by the gauze [85].

*4.1.2.2. Chamomile oil*

*4.1.2.3. Tea tree oil*

#### *4.1.1.2. Non-flavonoid polyphenols*

Non-flavonoid metabolites also comprise several subgroups (**Figure 3**) [74]. Many of these compounds occur mainly as complicated biopolymers. In this, they are different from their flavonoid counterparts by lacking a defined primary carbon base, which results in unique chemical structures for respective polyphenols [75]. An important subgroup of non-flavonoid compounds from plants are phenolic acids, which can be further divided into hydroxycinnamic acids (e.g. caffeic acid, chlorogenic acid, o-, m- and p-coumaric acids, ferulic acids, and sinapic acids), and hydroxybenzoic acids (e.g. gallic acid, p-hydroxybenzoic acid, protocatechuic acid, vanillic and syringic acids) [55]. Both classes often occur in plants in the glycoside form. In plant tissues, phenolic acids can be bound to various compounds, e.g., flavonoids, fatty acids, sterols and cell wall polymers [76]. Another widely distributed group of phenolic compounds in plants are tannins, which may occur as hydrolysable tannins (formed in the pathway of the phenolic acids with sugar polymerization) and condensed tannins (a combination of flavonoids) [77]. Lignans are phenylpropanoid dimers, whereas the most commonly known ones include secoisolariciresinol, lariciresinol, pinoresinol and matairesinol [55]. The most known and researched stilbene is resveratrol, which is present in many edible plant species (e.g. grapes, peanuts, and berries) [78]. Resveratrol plays an important part in the plant defence against mechanical injury, pathogen infection, and UV radiation [78].

#### *4.1.2. Essential oils*

By definition, essential oils are concentrated hydrophobic liquids that contain volatile aroma compounds derived from plants [79]. The term essential has not an analogous meaning as in the case of essential amino acids or essential fatty acids. In the latter cases, essential corresponds to a lack of mechanism for their respective synthesis in a specific organism, which also means that these have to be acquired by other means (e.g. diet) [80]. In general, essential oils are extracted by distillation (e.g. by steam). Other processes include expression, solvent extraction, absolute oil extraction, resin tapping and cold pressing [81]. Due to their (often) pleasant fragrance, they are commonly used as components in perfumes, cosmetics, soaps and other products, for flavouring food and drink, and for other similar applications [80]. There are several essential oils derived from plants with high potential to be used in wound treatment [82]. Some of the most important essential oils with proven beneficial effect on wound healing (either in traditional medicine or based on research studies), are described in more detail below.

#### *4.1.2.1. Lavender oil*

Lavender (*Lavandula*) oil, derived from lavender flowers, is one of the most commonly used essential oils in various therapies. Due to its antibacterial and antifungal properties, it has been used to treat bites [82]. There are also reports describing its anti-depressant activity, as well as its effect on smooth muscles (acting as a muscle relaxant) [83]. Several researchers have performed many different studies in relation to the potential beneficial effect of lavender oil in various wound care applications [83]. One of these studies, conducted by Kane et al., reports about the significantly reduced pain intensity after aromatherapy using lavender oil during dressing changes in treatment of vascular wounds when compared with control therapies [84]. Another study showing a potential use of lavender oil in wound care is the study by Hartman and Coetzee [85]. They studied the effect of lavender and chamomile essential oils on wound healing in five patients with chronic wounds in a timespan of months. The wounds were graded using the US National Pressure Ulcer Advisory Panel (NPUAP) guidelines based on depth and visual characteristics [85]. The treatment protocol used in this study includes a treatment with a 6 wt.% solution of two drops of lavender oil and one drop of German chamomile, which were applied directly onto the wound, and subsequently covered with a gauze. Their result was that the wounds treated with the oils healed more quickly compared to the control wounds without the additional treatment using the essential oils, which were just covered by the gauze [85].

#### *4.1.2.2. Chamomile oil*

as glycosides [70]. The main sources of flavonoids in the diet are fruits and vegetables. They occur also in certain grains, seeds, and spices, as well as in wine, tea, coffee, cocoa, and herbal essences [71]. All flavonoid compounds contain phenol-groups, which in general induces an antioxidant activity [72]. Other actions are diverse-several structures reduce inflammation or

Non-flavonoid metabolites also comprise several subgroups (**Figure 3**) [74]. Many of these compounds occur mainly as complicated biopolymers. In this, they are different from their flavonoid counterparts by lacking a defined primary carbon base, which results in unique chemical structures for respective polyphenols [75]. An important subgroup of non-flavonoid compounds from plants are phenolic acids, which can be further divided into hydroxycinnamic acids (e.g. caffeic acid, chlorogenic acid, o-, m- and p-coumaric acids, ferulic acids, and sinapic acids), and hydroxybenzoic acids (e.g. gallic acid, p-hydroxybenzoic acid, protocatechuic acid, vanillic and syringic acids) [55]. Both classes often occur in plants in the glycoside form. In plant tissues, phenolic acids can be bound to various compounds, e.g., flavonoids, fatty acids, sterols and cell wall polymers [76]. Another widely distributed group of phenolic compounds in plants are tannins, which may occur as hydrolysable tannins (formed in the pathway of the phenolic acids with sugar polymerization) and condensed tannins (a combination of flavonoids) [77]. Lignans are phenylpropanoid dimers, whereas the most commonly known ones include secoisolariciresinol, lariciresinol, pinoresinol and matairesinol [55]. The most known and researched stilbene is resveratrol, which is present in many edible plant species (e.g. grapes, peanuts, and berries) [78]. Resveratrol plays an important part in the plant

defence against mechanical injury, pathogen infection, and UV radiation [78].

medicine or based on research studies), are described in more detail below.

By definition, essential oils are concentrated hydrophobic liquids that contain volatile aroma compounds derived from plants [79]. The term essential has not an analogous meaning as in the case of essential amino acids or essential fatty acids. In the latter cases, essential corresponds to a lack of mechanism for their respective synthesis in a specific organism, which also means that these have to be acquired by other means (e.g. diet) [80]. In general, essential oils are extracted by distillation (e.g. by steam). Other processes include expression, solvent extraction, absolute oil extraction, resin tapping and cold pressing [81]. Due to their (often) pleasant fragrance, they are commonly used as components in perfumes, cosmetics, soaps and other products, for flavouring food and drink, and for other similar applications [80]. There are several essential oils derived from plants with high potential to be used in wound treatment [82]. Some of the most important essential oils with proven beneficial effect on wound healing (either in traditional

Lavender (*Lavandula*) oil, derived from lavender flowers, is one of the most commonly used essential oils in various therapies. Due to its antibacterial and antifungal properties, it has

carcinogenicity [73].

128 Herbal Medicine

*4.1.2. Essential oils*

*4.1.2.1. Lavender oil*

*4.1.1.2. Non-flavonoid polyphenols*

The wound healing aiding properties of chamomile (*Matricaria chamomilla* L.) oil, derived from chamomile flowers, were investigated also by Glowania et al. [86]. This double-blind study included 14 patients in which chamomile oil, when added to standard dressings, significantly improved the weeping and drying associated with dermabrasion wounds [86]. Another study that reports evaluation of potential positive effects on wound healing is a review of the bioactivity of chamomile, conducted by McKay et al. [87]. They found a moderate antimicrobial and a significant antiplatelet activity *in vitro*, as well as showed antimutagenic effects in animals [87].

#### *4.1.2.3. Tea tree oil*

The tea tree (*Melaleuca alternifolia*) oil is an essential oil derived from the leaves of the tea tree that are used as a complementary therapy in Australia. The latter is mostly related to its known antiseptic, antibacterial, antifungal and anti-inflammatory activities [82]. Several studies report about its potential use in wound healing applications. Halcon and Milkus, for example, tested the tea tree oil as an antimicrobial agent in the case of *Staphylococcus aureus* infections [88]. Although this study was based only on a small clinical trial combined with case studies, the authors nevertheless showed the potential of the tea tree oil treatment of osteomyelitis and in chronic wound healing [88]. Another study was performed by Hammer et al., who investigated the effect of tea tree oil on transient and commensal skin flora *in vitro* [89]. They compared the effectiveness of different concentrations to induce bactericidal action and found the tea tree oil to be effective against *Staphylococcus aureus* and most Gram-negative bacteria (reduction to 0.25%), but was less effective against coagulase-negative staphylococci and micrococci (8%) [89]. Two groups of researchers tested also commercially available products based on tea tree extracts (including the essential oil). Sherry et al. claimed that the antimicrobial preparation from extracts of tea tree oil and eucalyptus showed an activity against methicillin-resistant *Staphylococcus aureus* (MRSA) [90]. Faoagali et al. evaluated the activity of another commercially available tea tree oil-based cream against different bacteria and confirmed its effectiveness against *Staphylococcus aureus* and *Escherichia coli* [91].

An overview of the main chemical components of the above described essential oils is depicted

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Research on plant-derived compounds with potential use in wound healing drugs is a developing area in modern biomedical sciences. Scientists who are trying to develop newer drugs from natural resources are looking towards different regions, where there is a strong evidence of plant in traditional medicine (India, Africa, etc.) [105]. Most of these herbal medicines are not isolated compounds, but rather extracts composed of several constituents, which synergistically aid the wound healing process [106]. Not many have been screened scientifically for the evaluation of their wound healing activity in different pharmacological models and patients, but the potential of most remains unexplored [107]. The most important groups of compounds were described above, whereas we briefly review some of the less commonly

in **Figure 4**.

*4.1.3. Other compounds with wound healing properties*

**Figure 4.** An overview of chemical structures of the above mentioned essential oils.

used compounds and groups.

#### *4.1.2.4. Thyme oil*

Thyme (*Thymus vulgaris*) is an aromatic plant, commonly used in preparation of several dishes, whereas its essential oil has been widely reported to contribute to the healing of burns [82]. Thyme essential oil is derived from the steam distillation of the leaves, stems and flowers of the plant. One of such is the study by Dursun et al., who investigated the impact of thyme oil on the formation of nitric oxide, which is an important inflammatory mediator [92]. They studied the effect of thyme oil on burn wound in rats and showed that it not only decreased the amount of nitric oxide produced in response to the burn, but also facilitated wound healing [92]. Several other studies were conducted in regard of the potential antimicrobial activity of the thyme oil. For example, Bozin et al. showed an effective antibacterial and antifungal activity *in vitro* [93]. Their results are in agreement with another study that was performed by Shin and Kim, who determined a significant inhibitory action of thyme oil against both antibiotic-susceptible and resistant strains of *Streptococci, Staphylococcus aureus* and *Salmonella typhimurium* [94]. With the aim to evaluate the thyme oil's potential antifungal action, Giordani et al. combined it with amphotericin B and showed that it significantly potentiated the effectiveness of the latter [95]. Finally, Komarcevic discussed the available evidence showing that topically applied thyme oil increased collagen deposition, angiogenesis and keratinocyte migration, all together significantly contributing to the efficiency of wound healing [96].
