Journal of Ethnopharmacology 298 (2022) 115663

Contents lists available at ScienceDirect

Journal of Ethnopharmacology
journal homepage: www.elsevier.com/locate/jethpharm

Investigation on wound healing effect of Mediterranean medicinal plants

and some related phenolic compounds: A review
Ibrahim Mssillou a, *, Meryem Bakour a, Meryem Slighoua b, Hassan Laaroussi a,
Hamza Saghrouchni c, Fatima Ez-Zahra Amrati b, Badiaa Lyoussi a, Elhoussine Derwich a, d
a
Laboratory of Natural Substances, Pharmacology, Environment, Modeling, Health & Quality of Life (SNAMOPEQ), Faculty of Sciences Dhar El Mahraz, Sidi Mohamed
Ben Abdellah University, Fez 30000, Morocco
b
Laboratory of Biotechnology, Health, Agrofood and Environment (LBEAS), Faculty of Sciences Dhar El Mahraz, Sidi Mohamed Ben Abdellah University, Fez, 30000,
Morocco
c
Department of Biotechnology, Institute of Natural and Applied Sciences, Çukurova University, 01330 Balcalı/Sarıçam, Adana, Turkey
d
Unity of GC/MS and GC, City of Innovation, Sidi Mohamed Ben Abdellah University, Fez, 30000, Morocco

A R T I C L E I N F O A B S T R A C T

Keywords: Ethnopharmacological relevance: The human skin constitutes a biological barrier against external stress and
Mediterranean medicinal plants wounds can reduce the role of its physiological structure. In medical sciences, wounds are considered a major
Wound healing problem that requires urgent intervention. For centuries, medicinal plants have been used in the Mediterranean
Skin anatomy
countries for many purposes and against wounds.
Polyphenolic compounds
Therapies
Aim of this review: Provides an outlook on the Mediterranean medicinal plants used in wound healing.
Furthermore, the wound healing effect of polyphenolic compounds and their chemical structures are also
summarized. Moreover, we discussed the wound healing process, the structure of the skin, and the current
therapies in wound healing.
Materials and methods: The search was performed in several databases such as ScienceDirect, PubMed, Google
Scholar, Scopus, and Web of Science. The following Keywords were used individually and/or in combination: the
Mediterranean, wound healing, medicinal plants, phenolic compounds, composition, flavonoid, tannin.
Results: The wound healing process is distinguished by four phases, which are respectively, hemostasis,
inflammation, proliferation, and remodeling. The Mediterranean medicinal plants are widely used in the treat­
ment of wounds. The finding showed that eighty-nine species belonging to forty families were evaluated for their
wound-healing effect in this area. The Asteraceae family was the most reported family with 12 species followed
by Lamiaceae (11 species). Tunisia, Egypt, Morocco, and Algeria were the countries where these plants are
frequently used in wound healing. In addition to medicinal plants, results showed that nineteen phenolic com­
pounds from different classes are used in wound treatment. Tyrosol, hydroxytyrosol, curcumin, luteolin, chrysin,
rutin, kaempferol, quercetin, icariin, morin, epigallocatechin gallate, taxifolin, silymarin, hesperidin, naringin,
isoliquiritin, puerarin, genistein, and daidzein were the main compounds that showed wound-healing effect.
Conclusion: In conclusion, medicinal plants and polyphenolic compounds provide therapeutic evidence in wound
healing and for the development of new drugs in this field.

Abbreviations: AC, aqueous control group; C, control group; CD31, cluster of differentiation 31; CTRL, control; ECM, extracellular matrix; EGCG, epigallocatechin
gallate; EGF, epidermal growth factor; EOs, essential oils; EtFr, ethyl acetate fraction; EtOH, ethanol extract; FGF, fibroblast growth factor; GAME, methanolic extract
of Globularia alypum; HCE, Aesculus hippocastanum; HaCaT, cultured human keratinocyte (cells); HxFr, n-hexane fraction; IGF, insulin-like growth factors; IGF-1,
insulin-like growth factor 1; IL, interleukin; MMPs, matrix metalloproteinases; MZL, methanol extract of Zizyphus lotus; NF-κB, nuclear factor kappa-light-chain-
enhancer of activated B cells; Nrf2, nuclear factor-erythroid factor 2-related factor 2; OEO, essential oil of Origanum vulgare; OFI, Opuntia ficus-indica; P53, gene;
PDGF, platelet-derived growth factor; PDL, Distilled leaves by-product; SAP, Saponifiable oily fraction; SDA, standard drug; STZ, streptozotocin; TGF, transforming
growth factor; TGF-β, transforming growth factor-β; TIMPS, tissue inhibitor of metalloproteinase; TME, Forsskaolea tenacissima L. methanolic extract; TNF-α, tumor
necrosis factor alpha; TS, tensile strength; UNSAP, Unsaponifiable oily fraction; VEGF, vascular endothelial growth factor.
* Corresponding author.
E-mail address: mssillouibrahim@gmail.com (I. Mssillou).

https://doi.org/10.1016/j.jep.2022.115663
Received 30 May 2022; Received in revised form 7 August 2022; Accepted 19 August 2022
Available online 28 August 2022
0378-8741/© 2022 Elsevier B.V. All rights reserved.
I. Mssillou et al.
1. Introduction
The skin is the largest organ in the body and plays a crucial protec­
tive role against external stress. Injuries, burns, and illness can lead to
grave disabilities in this barrier (Tottoli et al., 2020). Wounds are
defined as an injury in the tissue like cut, burns, and blow where the skin
is usually cut. Usually, these injuries are the result of several chronic
diseases such as trauma, diabetes, and cancer, which are among the
challenging clinical problems (Shrivastav et al., 2018; Valente et al.,
2019). Around the world, six million people are suffering from
non-healing wounds and specifically aged persons (85%), with enor­
mous financial health care reaching 3 billion dollars per year (Paladini
and Pollini, 2019). For healthy people, the wound can be recovered in a
few days depending on its severity and far from infections which can
cause the prolongation of the healing process (Yadav et al., 2021). Acute
wounds are normally repaired during the healing process, while, this
process is interrupted in chronic wounds. This failure involves chronic
inflammation due to excessive neutrophil infiltration and leads to a long
time of healing (Sabale et al., 2012). The treatment of chronic inflam­
mation is a difficult medical problem that requires considerable health
care resources (Zhao et al., 2016). In addition, it was revealed that the
chronic oral consumption of anti-inflammatory drugs such as Ibuprofen
and aspirin was associated with an increased risk of breast cancer and
estrogen receptor/progesterone receptor -negative breast cancer
respectively (Marshall et al., 2005).
The physiology of wound healing is a complex biological and mo­
lecular process of recovering the normal structure and functions of
injured tissues. This process includes several phases, such as inflam­
mation which consists of hemostasis and inflammation of the tissue,
then the proliferation, where the angiogenesis and the construction of an
extracellular matrix are the main steps with the intervention of several
cellular mediators. Finally, the wound closed, and the healthy tissue
recovered during the remodeling phase (Belachew et al., 2020).
Recently, several studies have been carried out on the healing effect
of medicinal plants and their herbal formulations. It has been proven
that certain plants increase the rate of renewal of damaged tissues in vivo
(Naeimi et al., 2020; Ponnanikajamideen et al., 2019; Sallehuddin et al.,
2020) and in vitro studies (Bolla et al., 2019; Low et al., 2021) and
excisional and incisional experimental models (Nagoba and Davane,
2019). Many studies described healing agents from medicinal plants in
the ethnobotanical literature. These natural products have a protective
role against wound infection and stimulate tissue regeneration by sup­
porting the immune system. Furthermore, 1/3 of herbal remedies are
devoted to skin disorders and wounds (Budovsky et al., 2015; Kumar
et al., 2007). Currently, the use of orthodox medicine and the side effects
of chemical drugs has led scientists to search for new safer, and more
effective natural alternatives from the plant kingdom. Confirmation of
traditional approaches and the use of medicinal plants in health care is
mainly the objective of numerous research (Almoshari, 2022).
In the Mediterranean region, there are more than 10,000 medicinal
and aromatic plants that require deep investigation. The Mediterranean
basin extends from latitude 30-40◦ N and longitude 10◦ W to 40◦ E (Car­
rubba and Scalenghe, 2012). This specific location offers hot, dry sum­
mers and cool, rainy winters (Carrubba and Scalenghe, 2012).This
region represents a true hotspot of global diversity and a valuable
phylogenetic resource (Fares et al., 2011; N. Myers et al., 2000). The
Mediterranean region contains approximately 10% of the world’s higher
plants (Médail et al., 1999). Some of these plants have been used for
centuries in folk medicine for medication and cosmetic purposes using
traditional methods for preparations such as cooking and maceration
(Gouthamchandra et al., 2010). Although this area represents only 1.6%
of the Earth’s surface, it contains more than 10% of the world’s vascular
plants. Furthermore, the region is characterized by the presence of 25,
000 native species, with a high rate of endemism (Grigoriadou et al.,
2020a).
Nowadays, the search for natural compounds with healing properties
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Journal of Ethnopharmacology 298 (2022) 115663
is a leading tendency of green chemistry. In this sense, natural com­
pounds from medicinal plants can ameliorate the innate immune
response by stimulating cell proliferation, differentiation of keratino­
cytes and dermal fibroblasts, and can play an essential role in collagen
synthesis which leads to the acceleration of the wound healing process
(Agyare et al., 2011; Okuda, 2005). Therefore, plant-derived poly­
phenols are considered as the most discussed compounds which could
act as an anti-inflammatory, antioxidant, and antimicrobial agents in the
wound healing process (Korkina et al., 2012). These compounds are
known to promote epithelization (Farzaei et al., 2015), increase vascu­
logenesis and angiogenesis (Caban and Lewandowska, 2021), and
modulate the inflammatory cytokines (Hu et al., 2011), and enhance
wound contraction rates (Yin et al., 2015). Therefore, it is necessary to
illustrate the role of some of these compounds in wound healing to better
understand their role in this process. Polyphenols are a large family of
organic chemicals characterized by the presence of hydroxyl groups
attached to aromatic rings (Balasundram et al., 2006). These secondary
metabolites are mainly divided into flavonoid and non-flavonoid com­
pounds. The category of flavonoids contains flavanones, flavonols, fla­
vones, flavan-3-ols, isoflavones, and anthocyanidins. On another hand,
phenolic acids, lignans, stilbenes, tannins, and lignins are the main
non-flavonoid compounds (Arct and Pytkowska, 2008; Okuda, 2005).
Moreover, several studies reported the pharmacological properties of
polyphenolic compounds from plants such as anticancer (Pampaloni
et al., 2014) estrogenic (Slighoua et al., 2022), and inhibition of
acetylcholinesterase (Wu et al., 2022) and in wound care (Guimarães
et al., 2021). In addition to the pharmaceutical interest, these com­
pounds have particularly important wound healing properties (Działo
et al., 2016). Furthermore, the topical application of polyphenols ac­
celerates skin wound healing, thanks to their anti-inflammatory effect
(Korkina et al., 2012).
Since the treatment and conventional management of wound healing
required a substantial economic cost for health care systems worldwide.
Certainly, the scientific valorization of medicinal plants with wound
healing properties from Mediterranean areas will have a substantial
positive impact on the environment, quality of life, and the basic circular
economy in both developed and developing countries. This review aims
to clarify the importance of medicinal plants used for wound healing in
the Mediterranean region and review the studies that have been pub­
lished in this sense. Through this research, we try to collect some data on
polyphenolic compounds used in wound healing and discuss their
mechanism of action. In addition to this, this review aims to provide an
overview of the healing process and the anatomy of the skin, as well as
some information on the current therapies used in wound healing.
2. Methodology
This review was conducted on published articles and research about
wound healing effects of medicinal plants in Mediterranean countries.
The wound healing properties of polyphenolic compounds are also
discussed in this review. First, the skin anatomy and some general in­
formation about wounds are provided. Next, the wound healing process
and its different phases are summarized and the current and advanced
therapies in wound healing are also presented. Finally, we have pro­
vided a background on the Mediterranean region and its medicinal
plants. The search was performed in several databases such as Scien­
ceDirect, PubMed, Google Scholar, Scopus, and Web of Science. The
following Keywords were used individually and/or in combination: the
Mediterranean, wound healing, medicinal plants, phenolic compounds,
composition, flavonoid, and tannin. Chemical structures of phenolic
compounds were drawn using ACD/ChemSketch®.
3. Skin anatomy and wounds
The skin consists of three-layer which are successively the epidermis,
dermis, and hypodermis with the presence of some sublayers (Fig. 1)
I. Mssillou et al.
(Yazarlu et al., 2021).
The epidermis constitutes a biological and physical barrier, this layer
comprises keratinocytes (95%) and other cells which are principally
derived from Keratinocytes (Gantwerker and Hom, 2011; Mohamed and
Hargest, 2022). Furthermore, some immunological cells in this layer
such as Langerhans cells and dendritic cells are specifically involved in
wound healing (Kabashima et al., 2019).
The dermis is the layer below the epidermis that gives skin its
durability, strength, and flexibility (Ita, 2020; Mohamed and Hargest,
2022). This layer is composed of collagen (about 70% of the dry weight
of skin) (Boiten et al., 2019), and is divided into the papillary dermis and
reticular dermis (Mohamed and Hargest, 2022).
The hypodermis is located below the dermis and above the under­
lying muscle as the third and deepest layer. This layer is consist of ad­
ipocytes which are very essential in vitamin D production (Agarwal and
Krishnamurthy, 2022; Khavkin and Ellis, 2011).
Wounds are defined as any disordering in the anatomically out and
functional integrity of the living tissue. This disruption affects nega­
tively the epithelial physiology and can lead to the loss of underlying
connective tissue (Singh et al., 2017). Wounds can be produced due to
physical, chemical, thermal, immunological insult, or microbial in­
fections. Wounds are categorized as open when the skin is torn, cut, or
punctured, while in closed wounds the skin is intact and this type of
wound can be generated due to force trauma where damage reaches the
underlying tissues, muscles, and internal organs (Agyare et al., 2016).
Principally, the physiology of wound healing process reveals the wound
type as acute or chronic (Yazarlu et al., 2021). Acute wounds are
repaired during the physiological process, on the other hand, chronic
wounds take a long time to repair and are interrupted during the healing
process due to infection or underlying serious illness (Razdan et al.,
2022).
Fig. 1. Skin anatomy and wound healing process.
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Journal of Ethnopharmacology 298 (2022) 115663
4. Wound healing process
Actual knowledge of the wound healing process occurs in five
chronological phases which are strongly dependent on each other; (i)
hemostasis and coagulation phase; (ii) inflammation; (iii) proliferation,
and (v) remodeling (Fig. 1) (Loo et al., 2022).
4.1. Hemostasis
Immediately after an injury, reflex restriction of the microvascula­
ture system nearby to the damage site; degranulation, and aggregation
of thrombocytes occur to then form a platelet plug in the early phase.
The blood clot formed by the platelets is composed of fibronectin, fibrin,
vitronectin, and thrombospondin (Velnar et al., 2009). The principal
aim of these mechanisms is to limit blood loss, a way to protect the vital
organs despite skin damage (Gurtner et al., 2008). In addition to the
platelet-derived growth factor (PDGF), transforming growth factor-β
(TGF-β), epidermal growth factor, and insulin-like growth factors (IGF)
which destroy collagen and also invite fibroblasts to the site, histamine,
serotonin, and other mediators are released from thrombocytes to in­
crease the vascular and cellular permeability (Hazrati et al., 2022;
Lawrence, 1998). Then, to seal any temporarily potential skin opening,
thrombosis via coagulation reaction takes place (Rodrigues et al., 2018).
The second aim of this phase is a long-term one, which is to prepare a
provisional matrix for white cell migration that is needed in the in­
flammatory phase (Velnar et al., 2009).
4.2. Inflammation
Subsequently, the inflammation phase kicks in, this phase includes
the infiltration of neutrophils, lymphocytes, and infiltration of
I. Mssillou et al.
monocytes and their differentiation into macrophages that attract
various chemo attractive agents, to establish an immune barrier against
invading micro-organisms and engulf any debris present at the wound
site (Schäffer and Barbul, 1998). This phase is divided into two separate
phases, an early inflammatory phase, and a late inflammatory phase.
During the early inflammation phase, the neutrophils start with the
critical task of phagocytosis. Then, the cell remnants and apoptotic
bodies are then phagocytosed by macrophages (Hart, 2013). The
pro-inflammatory M1 macrophage phenotype releases cytokines such as
interleukin (IL)-6 and IL-1β, as well as proteases known as matrix met­
alloproteinases (MMPs) (Krzyszczyk et al., 2018). The late inflammation
phase involves the anti-inflammatory M2 macrophages which release
complement components and several growth factors such as vascular
endothelial growth factor (VEGF), insulin-like growth factor 1 (IGF-1),
fibroblast growth factor (FGF), epidermal growth factor (EGF) and
transforming growth factor (TGF)-β along with anti-inflammatory cy­
tokines such as IL-10 (Rodrigues et al., 2018; Velnar et al., 2009). The
last cells to arrive at the wound site are lymphocytes, which play a main
role in the regulation of collagenase, which is essential for collagen
remodeling, the production of extracellular matrix (ECM), and their
breakdown (Hart, 2013). The first two phases appear to be the chemo­
taxis phase in which immune cells and platelets contribute to the in­
flammatory reaction by releasing mediators and cytokines.
4.3. Proliferation
The next chronological phase is proliferation, which involves gran­
ulation, re-epithelialization, and angiogenesis (Sorg et al., 2017). This
phase is characterized by fibroblasts migration which proliferates pro­
fusely and begins to synthesize new ECM components such as fibrin,
collagen I, III, fibronectin, glycosaminoglycans, proteoglycans, and the
matrix proteins hyaluronan (Heather et al., 2018). The role of ECM is
crucial in the physical maintenance and homeostasis of tissues. In
addition, ECM is implicated in various biological phenomena such as
cell proliferation, differentiation, and migration (Kular et al., 2014).
During this time, fibroblasts change to their myofibroblast phenotype.
Newly differentiated myofibroblasts contain thick cytoplasmic actin and
actively extend pseudopodia, attaching to fibronectin and collagen in
the ECM; due to this property, these cells generate contractile forces to
physically bring the edges of the wound together to facilitate wound
contraction (Goldberg et al., 2007). Meanwhile, mesenchymal stem cells
start differentiating into keratinocytes. In fact, a fresh epidermal layer
begins to form on the surface from the wound edges through the pro­
liferation and migration of epithelial cells during the process of
re-epithelialization (Pastar et al., 2014). During the process of angio­
genesis, previously damaged or lost blood vessels are also slowly
replaced (Sorg et al., 2017). The formation of new blood vessels takes
place simultaneously during all phases of wound healing. In addition,
many angiogenic factors secreted during the hemostasis phase promote
angiogenesis. Resident endothelial cells can respond either with acti­
vating angiogenic factors, such as FGF, VEGF, PDGF, angiogenin, TGF-α,
and TGF-β or with inhibiting factors, such as angiostatin and steroids, to
maintain a delicate balance (Arndt et al., 2018).
4.4. Remodeling
As the last phase of wound healing, the remodeling phase is
responsible for the establishment of new epithelium and finally, scar
tissue formation (Velnar et al., 2009). In this way, the wound is stabi­
lized, and complete healing is characterized by a sealed opening. This is
followed by the remodeling process, which can last for several months or
years after the wound has fully closed and involves the maturation of
vascular functions and ECM remodeling, which leads to the maturation
of underlying skin tissue along with the manifestation of scar tissue
(Hess, 2008). Synthesis of the ECM is initiated contemporarily with
granulation tissue formation (Ramasastry, 2005). Changes that
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Journal of Ethnopharmacology 298 (2022) 115663
gradually occur during this phase include the replacement of type III
collagen with type I collagen and an increase in diameter, hyaluronic
acid, and fibronectin are subject to degradation, along with the degra­
dation of unnecessary ECM components by MMPs (Baum and Arpey,
2005). This phase is strictly controlled by regulatory mechanisms before
maintaining a delicate balance between degradation and synthesis. As
the wound heals, the concentration of fibroblasts and macrophages is
further reduced by apoptosis (Greenhalgh, 1998). Over time, capillary
growth stops, and blood flow and metabolic activity decrease at the
wound site (O’Kane, 2002).
5. Current and advanced therapies in wound healing
Wound care is a challenging issue, nevertheless, there are several
well-documented procedures with high efficiency. Currently, several
types of wound dressing have been reported as functional therapy for
wound management (Liang et al., 2021; Peng et al., 2022). The micro­
bial infections delay the wound healing process, leading to non-healing
wounds which require prolonged hospitalization and high financial
expenditures. Usually, typical approaches are used, such as debridement
and vascular surgery. Antimicrobial peptides provide substantial stim­
ulation to the innate immunity (de Souza et al., 2022). Consequently,
this approach represents a favorable therapy for the management of
chronic wounds, due to the multifunctionality of antimicrobial peptides
on microorganisms and inflammation (de Souza et al., 2022).
Vacuum-assisted closure procedure is a promising therapy for wound
healing through the application of negative pressure by controlled suc­
tion to the wound surface (Howe, 2015; Vidalis et al., 2022).
Currently, there is numerous advancement in wound care technol­
ogies, including hyperbaric oxygen (Nasiry et al., 2022; Oley et al.,
2022), antioxidative nanomaterials (He et al., 2022), application of
bacteriophages for the treatment of wound infections (Chang et al.,
2020), photobiomodulation and regenerative medicine techniques
(Buote, 2022), immuno-modulatory biomaterials for anti-inflammatory
response (Lynch and Lavelle, 2022) and promoting angiogenesis (Guo
et al., 2022). Mesenchymal stromal cells in wound healing applications
provide promising effects for wound care (Riedl et al., 2021). Drug
carriers such as polyesters, hydrogels, and liposomes are the most widely
used materials in wound healing applications (Lu et al., 2022).
Platelet-derived growth factors, skin substitutes, cell therapies,
epidermal growth factors, and fibroblast growth factors are
well-established therapy systems in wound healing (Bhatnagar et al.,
2022; Sharma et al., 2021; Xiumei Zhang et al., 2021). Furthermore,
modern tissue engineering, low-level laser therapy, and artificial skin
are used in wound treatment (Kordestani, 2019; Mudigonda et al.,
2022).
However, it is established that current treatments are often expen­
sive, time-consuming and limited in their effectiveness (Pang et al.,
2017). Although the presence of these various treatments, they do not
guarantee an efficient, cheap, and rapid reparative process. Hence, the
need for natural therapeutic alternatives such as medicinal plants and
plants-derived compounds to the current available treatments appears
necessary.
6. An overview of Mediterranean medicinal plants
The Mediterranean region covers an area of seven million square
kilometers and hosts about 150 million people. The Mediterranean basin
has a specific location which is extending from latitude 30–40◦ N and
longitude 10◦ W to 40◦ E (Carrubba and Scalenghe, 2012). According to
Carrubba and Scalenghe (2012), this area is characterized by warm dry
summers and cool rainy winters with the presence of several
sub-climates. This geographical location offers an average temperature
that varies between 9 and 20 ◦ C and rainfall varies from 200 to 2000 mm
(Carrubba and Scalenghe, 2012).
One of the richest hotspots of the world is the Mediterranean floristic
I. Mssillou et al.
region. Thus, it should be maintained as a conservation sanctuary
(Norman Myers et al., 2000; Vargas, 2020). Although this region oc­
cupies only 1.6% of the earth’s surface, it contains approximately 10%
of the world’s higher plants (Médail et al., 1999). This region houses
around 25,000 species of flouring plants (20% of the world’s total
floristic richness with 10.8 species/1000 km2), and a very high rate of
endemism, however, it is difficult to provide precise data because no
overall floristic assessment of the region has been performed (Heywood,
1999; Medail and Quezel, 1997). There are 10 hotspots were defined in
this basin: The Canary Islands and Madeira, the High and Middle Atlas
Mountains, the Baetic-Rifan complex, the Maritime and Ligurian Alps,
the Tyrrhe-nian Islands, southern and central Greece, Crete, S. Anatolia,
and Cyprus, the Syria-Lebanon-Palestine area, and the Cyrenaic Medi­
terranean (Médail et al., 1999). Within the Mediterranean region, most
of the plant species richness is concentrated in the Iberian Peninsula
(Andalousia) and Morocco (Atlas and Rif Mountains), as well as in the
Balkan and Anatolian Peninsulas (some parts of Turkey and Greece)
(Rafael et al., 2013).
Generally, the diversity of Mediterranean flora and ecosystems is
quite important and no longer needs to be demonstrated. Native me­
dicinal plants have been used in the Mediterranean since antiquity for
nutritional purposes and the treatment of various diseases and disorders
(Fakchich and Elachouri, 2021). Some medicinal plants have
well-established use and significant health claims associated with a
sufficient number of studies demonstrating their properties (Bouyahya
et al., 2021; Grigoriadou et al., 2020b). Several ethnobotanical studies
show that traditional plant knowledge still exists in many parts of the
Mediterranean region (Fakir et al., 2009). A comparison of traditional
medicinal plant use in different Mediterranean countries reveals that the
knowledge of medicinal plants is still well sustained. In research, eth­
nopharmacology draws from traditional practices as new sources of
inspiration for the development of possible new phytomedicines or the
synthesis of active principles (Naghibi et al., 2014). According to Car­
rubba and Scalenghe (2012), 73 species belonging to 24 families have
been used traditionally in the Mediterranean countries as cosmetic,
medicinal, condiments, liqueurs, infusions, colorants, foods, food addi­
tives, sweeteners, antioxidants, or bioactive products. Some species are
widely used in this area such as Anethum graveolens, Petroselinum
crispum, Pimpinella anisum, Brassica spp., Rosa spp., Calendula officinalis,
and numerous plant from Lamiaceae which is the most used family in
this region (Nieto, 2017).
7. Wound healing properties of Mediterranean medicinal plants
The Mediterranean area is rich in medicinal plants that have been
used in traditional medicine to treat wounds and skin disorders. Several
plants are reported to treat wounds in Mediterranean countries. Eighty-
nine species belonging to forty families are reported in the literature as
an effective factor in wound healing (Table 1). According to the findings,
Tunisia, Egypt, Morocco, and Algeria are the countries where these
plants are often used to treat skin diseases and wounds. The results
showed that leaves and aerial parts were the most organs used in the
preparation of extracts/ointments during the pharmacological evalua­
tion of medicinal plants in wound healing. It has been confirmed
through other studies that leaves are the most suitable part for phar­
macological studies due to their richness with bioactive compounds and
their simple harvesting (Alnomasy et al., 2021; Altemimi et al., 2017;
Bhat et al., 2013).
Unfortunately, no research or report has been performed on the
wound healing activity of medicinal plants in several Mediterranean
countries such as Greece, Albania, Montenegro, Bosnia, Syria, Croatia,
Libya, Lebanon, Cyprus, Monaco, and Malta. Several models in vitro and
in vivo are reported in the evaluation of wound healing such as excision
wounds, burn wounds, full-thickness, linear Incision, fractional laser
burn, scratch wound healing assay, and cells line. In vivo assay would be
more suitable for testing wound healing activity of plants and would be
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Journal of Ethnopharmacology 298 (2022) 115663
more specific than in vitro models; however in vivo essays have some
disadvantages such as higher cost, long time of evaluation, and large
variation in animals’ responses (Woo et al., 2012). The results demon­
strate that the evaluation period reported in the studies of ranged from
7h to 55 days depending on the model used and the ability of extracts to
accelerate wound healing.
In this review, the Asteraceae family was the most representative
family with 12 species followed by Lamiaceae (11 species).
7.1. Asteraceae
Plants from the Asteraceae family are commonly used for wound
healing remedies in Mediterranean countries especially Morocco,
Algeria, Turkey, Italy, and Tunisia (Table 1). Ethnopharmacological
studies performed in different countries have shown the use of several
plants from the Asteraceae family as wound-healing agents (Carvalho
et al., 2018). In this review, many species belonging to this family have
been known for their extensive use in wound healing such as:
Achillea biebersteinii Afan. is locally named Sarıçiçek in Turkish
(Akkol et al., 2011), and is widely used as a folk remedy to treat
abdominal pain, wounds and stomachache as well (Sezik et al., 2001).
Hormozi and Baharvand (2019) have proposed that A. biebersteinii may
inhibit scar formation by the regulation of transforming growth factor β1
and the expression of basic fibroblasts growth factor on gene and protein
levels in murine embryonic fibroblasts. This plant possesses high rates of
phenolic acids and flavonoids (Gaweł-Bęben et al., 2020).
Some other Achillea species have been reported to possess wound
healing activities in turkey such as Achillea coarctata Poir., Achillea
kotschyi Boiss., and Achillea lycaonica Boiss. et Heldr. (Agar et al., 2015).
Several biological activities have been reported on various Achillea
species, including antibacterial, antioxidant, anti-inflammatory, and
antispasmodic activities (Candan et al., 2003; Karamenderes and
Apaydin, 2003).
Anacyclus pyrethrum L. is commonly known as African pyrethrum,
Akarkarha, Tigendesste, and Igendess, which is indigenous to Morocco,
Algeria, and Spain (Jawhari et al., 2020). The roots of this plant are used
in traditional medicine for treating toothache, salivary secretion,
angina, digestive problems, lethargy, and female infertility (Jawhari
et al., 2020). A. pyrethrum has been reported in some scientific reports as
antimicrobial (Amine et al., 2017), antioxidant (Pahuja et al., 2013),
anti-inflammatory (Manouze et al., 2017), antidiabetic and hep­
atoprotective (Usmani et al., 2016). The wound healing effect of
A. pyrethrum was proved in the study of Mohammadi et al. (2017) using
Scratch wound-healing assay. A. pyrethrum has been reported with high
contents of polyphenols and flavonoids (Jawhari et al., 2020).
Two Artemisia species (Artemisia absinthium L. and Artemisia cam­
pestris L.) were reported to possess wound healing activity respectively
in Morocco and Algeria. A. absinthium is commonly called wormwood
and usually used in traditional medicine as antidiabetic, antihyperten­
sive, anti-inflammatory and as a wound healing agent (Bouasla and
Bouasla, 2017; Boudjelal et al., 2013, 2020). The essential oil of
A. absinthium shows a high wound healing rate in the study of Benkhaled
et al. (2020). A. campestris is a perennial aromatic herb; it is widespread
in Northern Africa and other similar Mediterranean agro-ecological
zones and is commonly used as herbal medicine (Ghlissi et al.,
2016b). It has been reported to possess many traditional uses with
pharmacological evidence like anti-diabetic, antioxidant (Sefi et al.,
2010), anti-inflammatory (Dib and El Alaoui-Faris, 2019), and anti­
hyperlipidemic (Sefi et al., 2011). These species are rich in phenolic
compounds (Moalla et al., 2021).
Centaurea Africana L., is an endemic plant of North Africa, hence the
name Africana (Zaouani et al., 2016). Generally, the genus Centaurea has
been reported with a wide range of bioactive secondary metabolites in
particular flavonoids (Shoeb et al., 2006). C. Africana has been
confirmed to possess good anti-inflammatory and wound healing ac­
tivities (Zaouani et al., 2016).
I. Mssillou et al. Journal of Ethnopharmacology 298 (2022) 115663

Table 1
Mediterranean medicinal plants with wound healing properties.
Family Species Part Country Extract/formulation/ Model Evaluation Effects References
ointment period

Amaranthaceae Hammada Leaves Tunisia Polysaccharide Excision wound 16 days On the 16th day, a Eleroui et al.
scoparia Pomel. composite films complete closure of the (2021)
wounds was observed
in the groups treated
with biodegradable
film P1 and standard
drug Cytol Centella®
Amaryllidaceae Allium sativum Bulbs Algeria Extract with Euphorbia Burn wounds 36 days Total wound healing Ait
L. honey on the 24th day Abderrahim
achieved in the mixture et al. (2019)
and silver
sulfadiazine® groups
Spain – Full-thickness 8 days 40% of wound Santiago et al.
(5 mm reduction on the 4th (2020)
diameter) day and only 22%
occurred in the vehicle-
treated group
Egypt Aqueous Excision wound 12 days Significant reduction Sarhan et al.
of 9 mm with all the tested (2016)
dressings as well as the
Aquacel®Ag compared
to the negative control
on days 5 and 7.
Anacardiaceae Pistacia lentiscus Fruit Algeria Oil, SAP and UNSAP Excision wound 26 days The percentage wound Boulebda
L. contraction at day 26 et al. (2009)
was 99.8 ± 0.2%, 97.2
± 0.2%, 99.8 ± 0.2%
and 96.0 ± 4.1%
respectively for the oil,
SAP, UNSAP and the
negative control
Bark Algeria 10% and 30% of hydro- Excision wound 28 days 100% of healing in Hemida et al.
ethanolic extract both concentrations on (2021)
day 24, and only 91%
for Cicatryl-bio®
Fruits Algeria Hexane extract Excision wound 15 days On day 15, the healing Boukeloua
process reached 95.29 et al. (2016)
± 1.39% and 92.68 ±
1.46% in the control
Fruits Algeria Virgin fatty oil Burn wounds 28 days Burn wound closure of Djerrou et al.
96.93 ± 4.95% was (2010)
achieved on day 28,
and 83.40 ± 12.85%
for the control.
Leaves Tunisia Distilled leaves by- 1.5 × 1 cm oval 14 days The contraction Elloumi et al.
product (PDL) incision reached 88.83 ± (2022)
1.85% using PDL
Arecaceae Phoenix – Tunisia The sap Excision wound 12 days On day 12, we noticed Abdennabi
dactylifera L. (1.5 cm × 1 cm) a complete healing in et al. (2016)
the group treated with
P. dactylifera
Asteraceae Achillea Aerial parts Turkey n-hexane, chloroform, Incision/ 9 days The n-hexane extract Akkol et al.
biebersteinii ethyl acetate, and Excision showed 84.2% and (2011)
Afan. methanol extracts (1%) 40.1% of contraction,
while Madecassol
showed 100% in
excision model.
Achillea Aerial parts Turkey Methanolic extract/ NIH-3T3 mouse – Total cell numbers Agar et al.
coarctata Poir. extracts were dissolved fibroblast cells increased only with (2015a)
in DMSO were used in A. kotschyi at
vitro. concentrations from
2.5 to 20 μg/mL.

Achillea Slight increases were

kotschyi Boiss. observed with
A. coarctata.

Achillea A. lycaonica did not

lycaonica Boiss. increase the total
et Heldr. number of cells in NIH-
3T3 cultures
Anacyclus Morocco Circular full- 18 days On day 18, all the Jawhari et al.
pyrethrum L. thickness groups that received (2020)
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6
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Table 1 (continued )
Family Species Part Country Extract/formulation/ Model Evaluation Effects References
ointment period

Roots, seeds, Cream (5% and 10%) the creams (roots,

leaves, and from the hydro-ethanolic seeds, leaves, and
capitula extract capitula) showed 100%
of regression of the
wounds
Artemisia Aerial parts Algeria Methanol extract (5% Excision wound 18 days on day 18, the Boudjelal
absinthium L. and 10%) in petroleum concentration 5% and et al. (2020)
jelly 10% showed
respectively a
contraction of 76.73 ±
2.97% and 81.49 ±
2.83%
Essential oil (5 and 10%) 21 days A wound contraction of Benkhaled
in petroleum jelly 91.81 ± 2.01% and et al. (2020)
97.23 ± 3.25% was
respectively observed
in the group treated
with 5 and 10% of the
ointment
Artemisia Leaves Tunisia Aqueous extract Excision wound 12 days After 12 days, the Ghlissi et al.
campestris L. (2 cm) wound area of the (2016b)
A. campestris treated
group was completely
healed.
Centaurea Roots Algeria 5 and 10% of methanolic Excision and 16 days A wound contraction of Zaouani et al.
Africana L. extract incision wound 80.11 ± 4.74% and (2016)
97.99 ± 5.43% was
achieved on the last
day respectively for 5
and 10%
concentrations
Asteraceae Cynara humilis roots Morocco Ointment 30% in Thermal Burn 18 days On day 18, C. humilis Salhi et al.
L. petroleum jelly model revealed a significant (2021)
reduction (6.93 ± 0.25
cm2) compared to the
SDA group (8.30 ±
0.37 cm2), and
petrolatum group
(10.05 ± 0.28 cm2)
Dittrichia Leaves Tunisia 2.5% and 5% of Circular full- 12 days After 12 days, mice Rhimi et al.
viscosa L. ethanolic extract in black thickness treated with ointments (2019)
sesame oil containing D. viscosa at
2.5% and 5% were
totally healed while the
vehicle showed a 57%
healing rate
Dittrichia Leaves Morocco Hydro-ethanolic extract Burn wounds 21 days A contraction of 99.28 Mssillou et al.
viscosa L. ± 0.44% has been (2022b)
recorded on the last
day of the treatment.
Echinacea Root Italy Ethanolic Excision wound 72 h E. pallida enhanced Speroni et al.
purpurea L. of 1.5 cm wound healing (2002)
markedly after 48 and
72 h, for the control
group and E. purpurea.
Echinacea
pallida Nutt.
Apiaceae Pimpinella Seeds Tunisia Polysaccharide’s Fractional CO2 7 days The wound area of Ghlissi et al.
anisum L. hydrogel laser burn hydrogel treated mice (2020)
was significantly
decreased as compared
to that of untreated
group at 3 (P < 0.01)
and 7 (P < 0.001) days
Boraginaceae Arnebia Roots Turkey Hexane, chloroform, Incision wound 9 days Significant wound Akkol et al.
densiflora ethyl acetate and model/Excision healing activity was (2009)
Nordm. methanol (1%) in glycol wound model observed using hexane
stearate, 1,2-propylene extract at 1%
glycol, liquid paraffin
(3:6:1)..
Boraginaceae Echium Aerial parts Turkey Fractionated chloroform linear incision 12 days Echium species Eruygur et al.
angustifolium and root extract (10 mg/mL). (1 cm) demonstrated a (2016)
Miller. significant
improvement in wound
tensile strength as
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7
I. Mssillou et al. Journal of Ethnopharmacology 298 (2022) 115663

Table 1 (continued )
Family Species Part Country Extract/formulation/ Model Evaluation Effects References
ointment period

compared to other
groups.
Echium italicum
L.
Echium
parviflorum
Moench.
Echium vulgare
L.
Cactaceae Opuntia ficus- Seeds Tunisia Fixed oil Burn wounds 7 days On day 7, the wounds Bardaa et al.
indica L. were completely closed (2016b)
Flowers Mucilage and A full thickness 13 days By day 13 of the Ammar et al.
methanolic extracts wound area (1.5 treatment, almost (2015)
cm × 1 cm) wounds treated with
Opuntia flower extracts
showed complete
wound closure (more
than 98% of wound
contraction was
achieved),
Seeds Oil Excision wound 15 days OFI oil has sped up skin Khémiri et al.
closure compared to (2019)
controls and the
reference group
Cladodes Italy Polysaccharide Excision wound 7 days The fractions showed Trombetta
good wound healing et al. (2006)
activity. The control
shows no evidence of
epithelial
reorganization
Calophyllaceae Calophyllum Nuts France Oil Scratch wound 24h The gap was closed Ansel et al.
inophyllum L. healing assay after 14 h, even faster (2016)
than in vitamin C-
treated cells (15 h). In
cells treated with free
oil, the wound closed
only after 16 h.
Campanulaceae Michauxia Root and herb Turkey methanolic extracts (1%) Linear incision 9 days M. nuda and Güvenç et al.
campanuloides in glycol stearate, 1,2- wound model. M. tchihatchewii (2012)
L’Hérit propylene glycol, liquid Circular excision demonstrated the best
paraffin (3:6:1). wound model. wound healing. On the
other hand, the rest of
the species did not
show any remarkable
wound healing
activity.
Michauxia
laevigata
L’Hérit
Michauxia nuda
L’Hérit
Michauxia
thyrsoidea
L’Hérit
Michauxia
tchihatchewii
L’Hérit
Cannabaceae Celtis australis Seeds Morocco 1g of ethyl acetate wound (15 mm 12 days At the sixth day, the Abbouyi et al.
L. extract length and 5 mm group treated with the (2015)
depth). plant extract showed
94% of reduction of the
wound
Caryophyllaceae Telephium Whole plant Morocco 5% of Hydro-ethanolic Burn wound 55 days On day 55, the Nejjari et al.
imperati L. extract in Vaseline creation percentages of (2019)
reduction of the burned
area for the test,
reference and control
groups were
respectively 95.5%,
97.5% and 75.75%.
Crassulaceae Sedum acre L. Aerial parts Italy Hydro-methanolic Scratch wound 24h S. acre significantly Chiocchio
healing assay increased the et al. (2019)
percentage of wound
healing at each of the
tested concentration
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8
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Table 1 (continued )
Family Species Part Country Extract/formulation/ Model Evaluation Effects References
ointment period

and time laps,

compared to control.
Crassulaceae Sedum album L. Aerial parts Italy Hydro-methanolic Scratch wound 24h S. album ability to Chiocchio
healing assay increase the percentage et al. (2019)
of wound healing was
confirmed at each time
laps only for the lowest
concentration tested,
Sedum S. hispanicum strongly
hispanicum L. increased the
percentage of wound
healing after 6 and 12
h, with the effect after
6 h being higher than
the one observed after
12 h.
Sedum rupestre S. rupestre wound
L. healing activity on
HaCaT was observed at
each of the tested
concentration after 12
and 24 h. After 6 h,
instead, only the lowest
concentration gave
statistically significant
results.
Sedum S. sexangulare caused
sexangulare L. cytotoxic effects after
24 h of treatment.
However, after 6 and
12 h, an increase in
wound healing
percentage was
observed.
Cucurbitaceae Cucurbita pepo Seeds Tunisia Fixed oil Burn wounds 7 days On day 7, the wound Bardaa et al.
L. area was 0.18 ± 0.18 (2016b)
cm2
Excision wound 11 days A contraction of 91.6 Bardaa et al.
± 0.7% was observed (2016a)
on the last day of the
experiment in the
group treated with the
oil
Cupressaceae Juniperus Berries Turkey Essential oils/ointment Linear Incision 9 days The study revealed Tumen et al.
oxycedrus L. base consisting of glycol Wound Model that J. oxycedrus(1.69 (2011)
stearate, 1, 2 propylene and Circular ± 0.60) and
glycol, and liquid excision wound J. phoenicea (1.76 ±
paraffin (3: 6: 1) in 1% model 0.61) display
concentration. remarkable wound
healing compared to
the control (3.14 ±
1.49).
Juniperus
phoenicea L.
Ephedraceae Ephedra alata whole plant Palestine Aqueous extract The wound 15 days E. alata ointment Kittana et al.
Decne. healing of burn significantly improved (2017)
ulcers the healing of the
wound ulcers, whereas
it showed no advantage
on the quality of the
healing of burn ulcers.
Elatinaceae Bergia Aerial parts Egypt EtOH: ethanol extract A circular 10 days The ointments Ezzat et al.
ammannioides HxFr: n-hexane fraction wound of 1.5 formulated from EtOH, (2016)
Henye ex Roth. EtFr: ethyl acetate cm2 area was HxFr, and EtFr at both
fraction produced in the 5% and 10%
dorsal inter- concentration showed
scapular region significant activities at
p < 0.01 relative to the
control.
Fabaceae Cytisus triflorus Aerial parts Algeria 5% from acetone extract Excision wound 14 days On day 14, the results Yahiaoui
L’Her in glycol stearate: showed a percentage of et al. (2018)
propylene glycol: liquid contraction equal to
paraffin (3:6:1) 94.52%, compared to
Madecassol® group
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Table 1 (continued )
Family Species Part Country Extract/formulation/ Model Evaluation Effects References
ointment period

with 96.55% of
contraction
Ononis Aerial parts Turkey Aqueous and methanolic Linear incision – O. macrosperma display Süntar et al.
basiadnata Hub. extracts in glycol and circular remarkable wound (2011)
& Mor. stearate, 1,2 propylene excision healing and anti-
Ononis glycol, liquid paraffin experimental inflammatory
macrosperma (3:6:1) in 1% models activities.
Hub. & Mor. concentration.
Ononis
sessilifolia
Bornm.
Fabaceae Trigonella Seeds Tunisia Polysaccharide’s Excision wound 14 days A wound contraction of Ktari et al.
foenum-graecum hydrogel (1.5 cm × 1 cm) 100% was observed on (2017)
L. day 14
Sophora gibbosa Aerial parts Egypt Ethyl acetate Full-thickness 14 days In vivo evaluation Shalaby et al.
DC. skin wound revealed that the (2021)
(diameter 1 cm) dressing displayed
superior wound repair
compared to the
control in terms of
histological
examination
Ginkgoaceae Ginkgo biloba L. Leaves – Cream based on Ginkgo Excision wound 13 days On day 13 postinjury, Bardaa et al.
biloba the closure of the (2021)
diabetic wounds
treated with G. biloba
(100%) was
significantly faster
than those of the
control
Globulariaceae Globularia Leaves Tunisia Methanolic extract Burn wounds 16 days On day 16, increased Ghlissi et al.
alypum L. (GAME) wound coverage was (2016a)
observed in GAME-
treated animals
Graminaceae Triticum vulgare – Italy Aqueous extract (TVE) Scratch wound 48 h After 10 h, the D’Agostino
L. healing assay difference became et al. (2020)
significant, especially
in the samples treated
with 10% and 5% v/v
TVE, which proved
superior to control
Seeds Aqueous Scratch wound 7h Accelerated the wound Tito et al.
healing assay repair capacity of the (2020)
cells, respectively, by
14% and 28%.
Seeds Aqueous extract (TVE) Scratch wound 30 h/7 days Fractions from TVE Sanguigno
healing assay/ showed a pro- et al. (2015)
excision model proliferative effect in
NIH-3T3 fibroblasts
also in in vivo models of
skin lesion with a
comparable effect to
Fitostimoline®
Lamiaceae Origanum – Morocco Essential oil + T. vulgaris Circular full- 2 weeks At the end of the Mekkaoui
vulgare L. honey thickness skin experiment the wound et al. (2021)
wound contraction was equal
to 77.36 ± 1.12% for
O. vulgare, 89.65 ±
1.03% for R. officinalis,
82.14 ± 0.41% for
T. vulgaris and 57.12 ±
0.86 for the control
Rosmarinus Essential oil + T. vulgaris
officinalis L. honey
Thymus vulgaris Essential oil + T. vulgaris
L. honey
Teucrium Aerial parts Morocco T. polium extract (TBF) Excision wound 8 days At 4 days, the TBF- (Kharroubi
polium L. treated wounds almost et al., 2021)
healed (98%), while
64%, 44% and, 33% of
were achieved for the
ointment, elastic
adhesive dressing and
untreated wounds
Leaves Morocco Burn wounds 18 days
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Table 1 (continued )
Family Species Part Country Extract/formulation/ Model Evaluation Effects References
ointment period

Salvia Hexane, ethyl acetate, n- On day 9, the observed Guaouguaou

verbenaca L. butanol extracts healed areas were et al. (2018)
29.17% (base), 44.34%
(hexane), 47.55%
(ethyl acetate), 49.16%
(n-butanol) and
41.09% silver
sulfadiazine
Rosmarinus Aerial parts Algeria Essential oils Burn wounds 25 days At the 25 days, a Hamza et al.
officinalis L. percentage of wound (2020)
healing equal to 36.48
± 1.12% was achieved
and 6.65 ± 0.16% in
the intreated group.
Marrubium Aerial parts Algeria 5% in glycol stearate: Excision wound 14 days On day 14, the results Yahiaoui
vulgare L. propylene glycol: liquid showed a percentage of et al. (2018)
paraffin (3:6:1) contraction equal to
93.79% and 96.55% in
Madecassol® group
Teucrium Aerial parts Algeria 10% gel prepared using Excision wound 14 days On day 14, the Meguellati
polium L. and callus the powder/callus in application of T. polium et al. (2019)
Vaseline leads in 100% of
wound contraction,
and 50.4% in the
negative control
Lavandula leaves, stems Algeria Essential oils (EOs) Excision wound 16 days On days 4, 11, and 16, Boukhatem
stoechas L. and cream (0.5%) wound contractions et al. (2021)
inflorescences were 26.4%, 78%, and
96.3% for the group
treated with EOs,
which was more
efficient than
Madecassol® group
Lamiaceae Lavandula Aerial parts Algeria Methanolic extract (5 Excision wound 18 days On day 18, the wound Baali et al.
stoechas L. and 10%) in petroleum contraction recorded (2021)
jelly was 93.1 ± 2.88%,
97.19 ± 1.06% for
L. stoechas and 69.22
± 5.30%, 81.89 ±
5.99% for M. pulegium
and 40.95 ± 2.65 in
the untreated group
Mentha
pulegium L.
Mentha piperita Aerial parts Algeria 0.5% essential oil a Excision wound 15 days Decrease in wound Kehili et al.
L. topical cream area rate between the (2020)
6th (1.67 ± 0.14 mm2)
and the 9th (0.49 ±
0.22 mm2) compared
to Madecassol® (2.23
± 0.35 mm2)
Teucrium Aerial parts Algeria Methanolic extract (5%, Excision wound 16 days A wound contraction of Chabane et al.
polium L. 10%) in petroleum jelly 92.00 ± 0.14% was (2021)
recorded on day 16 for
10%.
Lavandula aspic Inflorescence Morocco Essential (4%) in vehicle Excision wound 14 days a marked wound- Ben Djemaa
ointment healing potential was et al. (2016)
exerted by the essential
oil dealing with
comparable effects of
the reference drug (p =
0.75).
Marrubium Leaves Tunisia Methanolic extract Human Dermal 48h After 24 h cells are sub- Amri et al.
vulgare L. Fibroblasts confluent and after 48 (2017)
h the complete
confluence is reached
Morocco Hydro-ethanolic extract Burn wounds 21 days A contraction of 97.78 Mssillou et al.
± 4.95% has been (2022b)
recorded in the last day
of the treatment.
Salvia haenkei Aerial part Italy Hydroalcoholic 1)Scratch 48 h 1)S. haenkei did not Scrima et al.
Benth. wound healing 18 days induce a statistically (2020)
assay significant increase in
2)Excision the fibroblasts
wound of 3 mm migration rate.
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Table 1 (continued )
Family Species Part Country Extract/formulation/ Model Evaluation Effects References
ointment period

2) A wound-healing
rate higher than that of
the negative control,
and very similar to that
of positive control
(60%) at day four.
Origanum Aerial parts Italy Essential oil Scratch wound 72 h Improvement of the Avola et al.
vulgare L. healing assay artificial lesion was (2020)
observed with OEO
treatment (25 μg/mL)
0–72 h after injury.
Lamiaceae Thymus vulgaris Leaves Egypt Ethanolic Surgical wound 16 days Significant reduction Shaban et al.
L. of (1 cm × 1 cm) (P < 0.05) in wound (2015)
size starting from eight
day onwards in
comparison with non-
treated group
Rosmarinus – Egypt Essential oils Full thickness 14 days A significant increase Labib et al.
officinalis L. in the wound (2019)
contraction percent by
1.63 compared to the
negative control group,
on day 14
Linaceae Linum Seeds Algeria Crude oil Burn wounds 28 days Burn wound closure of Beroual et al.
usitatissimum L. 98.07 ± 9.8% was (2017)
achieved on day 28,
and 89.03 ± 9.6% in
the untreated group
linum Seeds Tunisia Fixed oil Burn wounds 7 days On day 7, the wound Bardaa et al.
usitatissimum L. area was 0.15 ± 0.15 (2016b)
cm2
Lythraceae Lawsonia Leaves Algeria 50% of powder in Excision wound 24 days A contraction from Yassine et al.
inermis L. petroleum jelly 89.23% to 99.85% (2020)
between the 12th to
15th days compared to
75.79–96.37% in the
control group
Lawsonia Leaves Tunisia Aqueous extract Excision wound 12 days After 12 days, the Jridi et al.
inermis L. incorporated with (150 mm2) control group attended (2017)
cuttlefish skin gelatin only 80.88 ± 1.67% of
contraction, while all
treated groups showed
a significant reduction
in wound area (p <
0.05).
Lawsonia – Tunisia Oil Excision wound 11 days On day 11 a Rekik et al.
inermis L. contraction of 100% (2019)
was observed in the
group treated with oil
Malvaceae Hibiscus Leaves Italy Hydro-ethanolic Scratch wound 24h Accelerating the di Martino
syriacus L. healing assay wound healing process et al. (2017)
and stimulating the
expression of
biomarkers
Ophioglossaceae Ophioglossum Aerial parts Italy Galactoglycerolipids Scratch wound 24 h A significant increase Clericuzio
vulgatum L. healing assay in wound closure rate et al. (2014)
with respect to the
control
Plantaginaceae Plantago Leaves Slovenia Aqueous Wound tensile 21 days A significant increase Kováč et al.
lanceolata L. strength in wound TS when (2015)
compared with the
untreated control
Poaceae Zea mays L. Corn silk Egypt Aqueous Scratch wound 48 h At 48 h, the Makvandi
healing assay formulations decreased et al. (2019)
the wound area from
70 μm2 to 20 μm2 while
for the control the area
decreases only to 40
μm2
Primulaceae Anagallis Aerial parts Spain Methanolic COX-1 and COX- – Strong Inhibition of López et al.
arvensis L. 2 inhibitory COX-1 and -2 (2011)
Anagallis activity
foemina Mill.
Ranunculaceae Clematis Aerial part Tunisia Essential oils (Anemonin Excision wound 13 days The closure was almost Saidi et al.
flammula L. 0.012%) completed in the group (2018)
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Table 1 (continued )
Family Species Part Country Extract/formulation/ Model Evaluation Effects References
ointment period

treated with anemonin

on day 13
Rhamnaceae Zizyphus lotus L. Leaves Algeria 10% of methanol extract Excision wound 16 days In treated group, there Saiah et al.
prepared in petroleum was an increase from (2018)
jelly 8.91 ± 1.36% to 84.23
± 2.18% and 4.84 ± 6
1.43% in the control.
Rosaceae Prunus Spinosa Ripe fruits Italy Hydro-ethanolic Scratch wound 24h Concentrations of 40 Coppari et al.
L. healing assay and 80 μg/mL (2021)
determined a
significant increase in
the percentage of
wound healing
compared to CTRL and
ETOH groups
Rutaceae Citrus reticulata Fruits peels Morocco 0.5% and 10% of Burn wounds 22 days On the 16th day, the Dahmani
Blanco. phenolic extract of percentages of burned et al. (2020)
C. reticulata prepared in area reduction for both
tween 80 and Vaseline concentrations were
100%. 100% was
reached in the positive
control on day 22 and
the negative control
showed only 98.32%.
Salicaceae Populus alba L. Aerial parts Algeria Essential oils Burn wounds 25 days On day 25, the results a Hamza et al.
percentage of wound (2020)
healing equal to 29.99
± 0.8, compared to
untreated group with a
percentage of 4.99 ±
2.3
Sapindaceae Aesculus Nuts Slovenia Aqueous Wound Tensile 21 days At day 21 skin wound Kováč et al.
hippocastanum Strength treatment significantly (2020)
L. Measurement increased tensile
strength (TS) in
comparison with
control group (41.4 ±
8.4 g/mm2) control
group (AC = 44.7 ±
17.4 g/mm2)
Sapotaceae Argania spinosa Fruits Algeria Skeels Seed Oil Excision wound 12 days A high surface Dakiche et al.
L. reduction on the 6th (2017)
and 12th days with
rates of 63.6% and
90.6%, respectively
and better than the
untreated group.
Argania spinosa Fruit Morocco Argan oil Burn wounds 14 days A great contraction Avsar et al.
L. levels (31% on day 7, (2016)
76% on day 14) than
the silver sulfadiazine
group (22% on day 7,
69% on day 14), (P <
0.05)
Solanaceae Atropa Nuts Slovenia Aqueous Wound tensile 5 days Higher wound TS Gál et al.
belladonna L. strength results were found in (2009)
rats treated for 2 days
in the B5-T2 group
(10.3 ± 2.0 g/mm2),
while the highest
wound stiffness was
measured in animals
from the B5-T5 group
treated for 5 days (10.7
± 2.5 g/mm2).
Withania Foliar parts Morocco hydro-ethanolic extract Thermal burn 20 days After 15 days, the EL Moussaoui
frutescens L. (5% and 10%) prepared method. treated wounds healed et al. (2020)
in petroleum jelly completely, while the
control batch still had
average surfaces of
0.68 ± 0.04 cm2
Theaceae Camellia Leaves Egypt Methanol Excision wounds 14 days A significant increase Shahein
sinensis L. in the wound healing (2017)
activity was observed
in the animals treated
(continued on next page)

13
I. Mssillou et al. Journal of Ethnopharmacology 298 (2022) 115663

Table 1 (continued )
Family Species Part Country Extract/formulation/ Model Evaluation Effects References
ointment period

with (0.6 and 6%)

green tea extract,
compared to the
control group
Urticaceae Urtica dioica L. Leaves Tunisia 10% of hydro-ethanolic Excision wound 11 days A wound contraction of Zouari
extract in glycerol 92.39 ± 1.13% was Bouassida
observed on the last et al. (2017)
day of the treatment
compared to the
negative control (60.91
± 1.16%)
Forsskaolea Ariel parts Egypt Methanolic Excision wound 15 days The TME group showed Assaf et al.
tenacissima of 2 mm a marked increase in (2019)
L. wound healing activity
(97.9%, P < 0.001)
compared with
standard group
(96.8%, P < 0.001) and
negative control group
(68.0%, P < 0.001)
Xanthorrhoeaceae Aloe vera L. Leaves Egypt Methanolic Excision wound 10 days A. eru showed the El Sayed et al.
of 2 mm × 5 mm highest effect in (2016)
reducing the wounds
area which reached
86.2% by day 10,
compared to the
untreated group (4.6%)
Aloe arborescens
Mill.
Aloe eru
Schweinf.
Aloe
grandidentata
Salm-Dyck
Aloe perfoliate
L.
Aloe brevifolia
Mill.
Aloe Saponaria
All.
Aloe ferox Mill.

Cynara humilis L. is a tiny plant from the Mediterranean region,
which has been confirmed for its biological activities such as antioxi­
dant, and antimicrobial (El Khomsi et al., 2022; Salhi et al., 2021). The
roots of this plant are traditionally used to treat wounds and burns in
Morocco (Salhi et al., 2019). However, there is no report on the wound
healing effect of C. humilis outside Morocco. El Khomsi et al. (2022) have
proved the richness of this plant with polyphenols.
Dittrichia viscosa L. a perennial plant abundant in the Mediterranean
areas (Mrid et al., 2022). Its wound healing effect has been reported in
Morocco and Tunisia (Mssillou et al., 2022b; Rhimi et al., 2019). It was
reported in the study of Mssillou et al. (2022b) that burn healing was
accelerated by the combination of D. viscosa ointment and Marrubium
vulgare L., (another Mediterranean plant). D. viscosa is known for its
richness with secondary metabolites such as polyphenols and sesqui­
terpene, and its antioxidant, antimicrobial, and insecticidal activities
have been reported in many studies (Mssillou et al., 2021, 2022a; Rhimi
et al., 2017, 2019). The wound healing properties of D. viscosa have been
reported outside the Mediterranean region in the study of Khalil et al.
(2007). This plant contains a wide range of polyphenols (Grauso et al.,
2020).
Two Echinacea species (Echinacea purpurea L. and Echinacea pallida
Nutt.) were reported in Italy for their wound healing ability (Speroni
et al., 2002). A review has been conducted on the chemistry, pharma­
cology and clinical properties E. purpurea and E. pallida by Barnes et al.
(2010). E. purpurea has been reported in another study as a wound
healing agent (Bialik-Wąs et al., 2021) and was recognized with high
phytochemical contents especially polyphenols (Banica et al., 2020;
Oniszczuk et al., 2019).
7.2. Lamiaceae
Plants belonging to the Lamiaceae family are also commonly used for
wound healing in the Mediterranean area (Table 1). Several plants
belonging to this family are reported in this review as an effective agent
for wound healing such as:
Origanum vulgare L., is a perennial herb distributed in Europe, North
Africa, America, and Asia (Zhang et al., 2014). This plant is commonly
used in the treatment of several ailments such as cold, cough, and
digestive disorders (Yin et al., 2012). It has been known for its strong
antioxidant and antimicrobial activities (Lemhadri et al., 2004). The
phenolic compounds including flavonoids and phenolic acids are very
abundant in O. vulgare (Chou et al., 2010; Zhang et al., 2014). In this
review, the essential oils of O. vulgare are reported in Morocco and Italy
as a useful agent in wound treatments (Avola et al., 2020; Mekkaoui
et al., 2021). Sankar et al. (2014) reported a significant wound healing
activity of O. vulgare using an excision wound model in Albino rats.
Another study conducted by Han and Parker (2017), proved the
anti-inflammatory, tissue remodeling, immunomodulatory, and anti­
cancer activities O. vulgare essential oil in a human skin disease model.
In addition, this species exhibits high antioxidant and antimicrobial
activities and known to treat many diseases (Şahin et al., 2004).
Rosmarinus officinalis L., commonly known as rosemary. This plant
has antifungal, antiviral, antibacterial, anti-inflammatory, antitumor,
antithrombotic, antinociceptive, antidepressant, antiulcerogenic, and

14
I. Mssillou et al.
antioxidant activities (de Macedo et al., 2020; Ribeiro-Santos et al.,
2015). R. officinalis is known to possess numerous pharmacological
properties and is also used in food industries and for cosmetic purposes
(de Macedo et al., 2020). Polyphenols and flavonoids have been re­
ported in the leaves of R. officinalis by many authors (Borrás-Linares
et al., 2014; de Macedo et al., 2020). The results indicate that the
essential oils of this plant are used in some Mediterranean countries such
as Morocco (Mekkaoui et al., 2021), Algeria (Hamza et al., 2020) and
Egypt (Labib et al., 2019) for wounds treatment. R. officinalis was re­
ported in the study of Abu-Al-Basal (2010) as an effective agent for
wound healing on full-thickness excision cutaneous wounds in
alloxan-induced-diabetic. Another study was conducted on the wound
healing activity of essential oils from R. officinalis in streptozotocin
induced diabetic rats (Umasankar et al., 2012). A study was performed
on R. officinalis (2% and 4%) using 63 Wistar. Wounds were infected
with a solution containing Candida albicans. The results of this study
showed that the 4% R. officinalis cream group has the highest wound
healing than the other groups (Nejati et al., 2015). Furthermore, a
hydrogel wound dressings loaded with R. officinalis has proved its
effectiveness on wounds (Gavan et al., 2022).
It was revealed that the incorporation of Melaleuca alternifolia
Maiden & Betche., and R. officinalis essential oil in chitosan-based
preparations ameliorates different stages of wound healing and
decreased the oxidative stress (Labib et al., 2019).
Thymus vulgaris L., or thyme, known as “garden thyme” is an aro­
matic and perennial flowering plant (Hosseinzadeh et al., 2015). This
plant is known to possess extensive pharmacological properties, and is
mainly used for the treatment of wounds (Basch et al., 2004; Kuete,
2017). T. vulgaris is used in Morocco (Mekkaoui et al., 2021), and Egypt
(Shaban et al., 2015) for wound healing. T. vulgaris was also extensively
used against plague in the late 1340s (Basch et al., 2004).
Teucrium polium L., is a medicinal plant used for over 2000 years in
traditional medicine due to its diuretic, diaphoretic, tonic, antipyretic,
antispasmodic, and properties (Ljubuncic et al., 2006). In addition, the
plant possesses hypoglycemic, insulinotropic, and anti-inflammatory
(Ljubuncic et al., 2006). The results showed that this plant is used in
Morocco (Kharroubi et al., 2021) and Algeria (Chabane et al., 2021;
Meguellati et al., 2019) for wound healing. The main compounds of this
plant are flavonoids and terpenoids (Bahramikia and Yazdanparast,
2012). The wound healing effect of T. polium was reported in another
study of Fallah Huseini et al. (2020).
Salvia verbenaca L., is called “Zargtoun” in Arabic and is used tradi­
tionally by Algerians for wound healing (González et al., 2010; Righi
et al., 2021). This plant is endemic to the Mediterranean region (Mrabti
et al., 2022). Its antioxidant and antibacterial activities are
well-documented (Djeridane et al., 2006; Russo et al., 2015). One study
was conducted on its wound healing effect in Morocco (Guaouguaou
et al., 2018). In traditional medicine, the leaves of S. verbenaca are used
for the treatment of wounds, burns, and abscesses (Salhi et al., 2019).
Moreover, it was reported in the Moroccan traditional medicine as a
useful plant for wound healing (Guaouguaou et al., 2019).
Marrubium vulgare L., known as “horehound” is originated in the
region between the Mediterranean Sea and Central Asia (Aćimović et al.,
2020). This plant is a natural source of phenolic compounds such as
phenolic acids and flavonoids (Aćimović et al., 2020). M. vulgare is
known for its numerous biological properties and its pharmacological
activities (Abadi and Hassani, 2013; Aćimović et al., 2020; Amri et al.,
2017). Its wound healing activity was reported in Morocco, Tunisia and
Algeria (Amri et al., 2017; Mssillou et al., 2022b; Yahiaoui et al., 2018).
Lavandula stoechas L., is a common plant in the Mediterranean area
and known by its cosmetic, food, perfumery, and pharmaceutical pur­
poses (Baali et al., 2021). It is used traditionally for burn wound infec­
tion control and healing (Celep et al., 2018). Our results demonstrate
that this plant is used in Algeria for wound healing with scientific evi­
dence (Baali et al., 2021; Boukhatem et al., 2021). Indeed, the flower of
this L. stoechas is traditionally used in Turkish phytotherapy as a wound
15
Journal of Ethnopharmacology 298 (2022) 115663
healing agent (Ez zoubi et al., 2020; Gürdal and Kültür, 2013). Many
studies have been performed to evaluate the antimicrobial, antifungal,
analgesic, antitumor, antiviral, antidepressant, and topical
anti-inflammatory effects (Algieri et al., 2016; Angioni et al., 2006;
Mahmoudi et al., 2020).
The results showed that the aerial parts of Mentha pulegium L., and
Mentha piperita L., are used for wound healing in Algeria (Baali et al.,
2021; Kehili et al., 2020). M. pulegium essential oil has been reported for
its antibacterial and wound healing efficacy (Khezri et al., 2020).
Another study conducted on M. pulegium showed its relevant potency to
treat burn wounds (Vaghardoost et al., 2019). Concerning M. piperita it
has proven that this plant enhance wound healing in rats with diabetes
Type I (Mojally et al., 2022), and its topical application on cutaneous
wound healing was evaluated in the study of (Amirzade-Iranaq et al.,
2022).
Lavandula aspic L. also known as Lavandula latifolia Medik., is a
strongly aromatic shrub plant traditionally used in herbal medicine for
the treatment of several skin disorders, including wounds, burns, and
ulcers (Ben Djemaa et al., 2016). The only study found on its wound
healing effect, was performed in Algeria by Ben Djemaa et al. (2016).
Salvia haenkei Benth., is effective in ameliorating the wound
contraction rate on keratinocyte cell cultures; whereas the positive
control, showed only a 67% reduction in the wound size (Scrima et al.,
2020). Recently, a new medical use was attributed to S. haenkei, which
demonstrated an antisenescence activity of this plant, suggesting the
potential use of S. haenkei based products for antiaging skin treatments
(Matic et al., 2016). The extract of this plant can decrease the level of
senescent cells by affecting the IL1α release and reducing reactive oxy­
gen species generation (Cocetta et al., 2021).
Medicinal plants reported for their wound healing activity, act
through angiogenesis, activation of NF-κB, favouring pro-inflammatory
cytokines, upregulation of iNOS and alpha-1 type-1 collagen, and
fibroblast proliferation (Chaachouay et al., 2019; Firdous and Sautya,
2018). During wound healing, the regulation of inflammation and
oxidation is a crucial step. High concentrations release of free radicals
can delay the wound healing process by causing proteins damages
(Sharifi et al., 2013). Süntar et al. (2012) demonstrate that the antiox­
idant activity in medicinal plants co-exists with their wound healing
potential. Induction of COX-2 in the repair process is considered one of
the first responses to inflammatory stimuli (Futagami et al., 2002).
Persistent inflammation in chronic wounds is due to the Upregulation of
COX-2. However, the high COX-2 expression causes a delay in the
healing process (Wilgus et al., 2003). Since inflammation and free rad­
icals would delay the healing process, therefore, the mechanism of ac­
tion of these plants as anti-inflammatory and antioxidant agents would
be scientific evidence of their wound healing effect (George et al., 2015;
Righi et al., 2021; Sathyanarayanan et al., 2017).
It is well known that the microbial infection in wounds can cause the
retardation of the healing process by the production of proinflammatory
cytokines (Guo and DiPietro, 2010). Several plants included in this re­
view possess antimicrobial activity and this characteristic would accel­
erate the wound healing process by protecting wounds from microbial
infections.
7.3. Species with clinical evidence
Although the high rate of medicinal plants used in traditional med­
icine for wound healing in Mediterranean countries, there is a lack of
clinical trials on these plants. However, only five species in this review
were evaluated clinically for their wound healing potential in other
studies.
7.3.1. Triticum vulgare L
This plant is known for its curative effects in traditional medicine,
especially as an effective agent for accelerating tissue repair (Sanguigno
et al., 2015). In particular, scientific research has well-documented the
I. Mssillou et al.
traditional use of T. vulgare in Iranian phytotherapy for cosmetic pur­
poses related to skin beauty, and repairing face minute pores (Mikaili
et al., 2012). In the study conducted by Funel et al. (2020), it has been
confirmed that T. vulgare has an effect on inflammatory pathways linked
to the molecular mechanism of wound healing. Moreover, it has been
demonstrated that T. vulgare extract accelerates the healing processes
and tissue regeneration (Martini et al., 2011). T. vulgare extract is
commonly used for treatment related to skin disorders and
re-epithelialization or tissue regeneration such as decubitus ulcers,
burns, venous leg ulcers, dystrophic diseases, and scarring delays
(Martini et al., 2011; Serafini et al., 2012). Furthermore, the Fitosti­
moline® is a wound healing medicine developed from the aqueous
extract of T. vulgare, and it is used in all conditions requiring epithelial
restoring (Martini et al., 2011).
A clinical trial was carried out by Romanelli et al. (2015) with the
purpose to evaluate the effect of the topical application of T. vulgare
(aqueous extract) using different vehicles for the treatment of venous
lower leg ulcers. The vehicles used by Romanelli et al. (2015) were
cream, impregnated gauzes, foam, hydrogel, and dressing gel. In this
context, fifty patients were randomized to receive one of the vehicles
and the patients received the treatment for 29 days or before that if the
healing is achieved. The wound size reduction was measured using a
non-invasive laser scanner instrument. Romanelli et al. (2015) observed
that the cream showed the greatest reduction in wound size. It was noted
that one ulcer was healed in the patients treated with dressing gel at the
last visit, while the cream group showed two healed ulcers and three in
the gauze group. Moreover, in these groups and the hydrogel group the
reduction size of wounds was 40%–50%. In this clinical trial, it has been
observed that the patients treated with the gauzes presented greater
efficacy in terms of signs/symptoms. It has been concluded that the
extract of T. vulgare may be useful in the treatment of chronic venous
ulcers (Romanelli et al., 2015).
7.3.2. Lavandula stoechas L
Vakilian et al. (2011), have evaluated the clinical efficacy of
L. stoechas in wound healing. 120 primiparous women with a singleton
pregnancy were randomized for this clinical trial. Patients considered as
the case group received L. stoechas oil and patients treated with
Povidone-iodine were considered as the control group. The evaluation of
incision sites was performed on the 10th day postpartum. 25 patients in
the case group showed no pain (p = 0.06), and 17 in the control group.
Both groups showed no difference in surgical site complications. Vaki­
lian et al. (2011) observed that L. stoechas oil reduce redness in incision
site compared to the control group (p < 0.001), and suggest the use of
this oil for episiotomy wound care.
7.3.3. Teucrium polium L
The clinical efficiency of T. polium ointment on diabetic foot ulcers
was evaluated by Fallah Huseini et al. (2021). The study was conducted
on 70 diabetic patients suffering from foot ulcers, which were divided
into groups (treated group and control group). The group treated with
T. polium ointment showed a significant decrease in ulcer surface
compared to the placebo group (p < 0.0001) at end of the study. Fallah
Huseini et al. (2021) found that T. polium ointment improves the healing
time of diabetic non-infected foot ulcers.
7.3.4. Lawsonia inermis L
L. inermis is a plant belonging to Lythraceae and its wound healing
effect has been proved in several studies and using several models
(Daemi et al., 2019; Jridi et al., 2017; Metwally et al., 2022; Nayak et al.,
2007).
The study of Rafiei et al. (2019) was designed to evaluate the wound
healing activity of L. inermis using a clinical trial on pressure ulcers. Two
groups were used; a group designed as control and the other one received L.
inermis ointment. The results obtained in this study revealed that L. inermis
decrease the area of pressure ulcer.
16
Journal of Ethnopharmacology 298 (2022) 115663
7.3.5. Aloe vera L
A. vera is known for its therapeutic effects and for many centuries it
has been used in traditional medicine against many diseases and disor­
ders (Prasad and Srivastava, 2021). The gel of this plant possesses a high
therapeutic potential and it has been described for burn wound healing
since the Roman era (Maenthaisong et al., 2007a). The wound healing
potential of this plant was proved in many studies (Choi et al., 2001;
Khan et al., 2013; Muller et al., 2003; Takzare et al., 2009).
In the clinical trial performed by Shahzad and Ahmed (2013) on
patients with second-degree burns, it has been demonstrated that A. vera
promotes cell proliferation and acts as an anti-inflammatory agent, and
stimulates wound epithelialization compared to silver sulfadiazine. In
another clinical study, A. vera gel showed faster-wound healing activity
in patients with split-thickness skin graft donor-sites (Burusapat et al.,
2018).
Other clinical trials were performed with the purpose to evaluate the
wound healing potential of A. vera. The study performed by Maenthaisong
et al. (2007b) showed that this plant presents an important curative
effect in first- and second-degree burn wounds and accelerates the
process of healing to 9 days. Furthermore, some other studies have been
reported on the clinical evidence of using A. vera in skin ulcers, and
postoperative wounds (Molazem et al., 2015; Eshghi et al., 2010).
7.4. Future needs
Based on the data presented in Table 1, we suggest future research
and studies in purpose to understand and boost the effect of these me­
dicinal plants in healing acute and chronic wounds. Future research
should be focusing on the:
Identification and characterization of new compounds in medicinal
plants which contain an array of wound healing agents. To improve the
efficacy of these plants and their isolated compounds, additional in vitro
and in vivo studies need to be conducted. It is important to note that
there are few approved products for wound treatment, while there is
great potential for the discovery and development of new drugs based on
the properties of these plants in wound healing.
Furthermore, herbal compounds can be incorporated into bio­
polymers that can enhance the activity, thereby boosting their wound
healing effect. Medicinal plant-based polymers can be made by poly­
merization techniques from various polymers to integrate new dressing
materials. The design, development, and application of these bio­
polymers in dressings is an interesting area of research because they can
improve the wound healing process.
Assessment of chronic toxicity and allergy triggering potential of
these plants: it is recommended to consider the long-term toxicity of
these plants and their compounds on human cells in order to identify the
adequate period of topical application and dressing.
Execution of clinical studies: rigorous clinical trials need to be un­
dertaken to evaluate the wound healing effect of these plants. Moreover,
it is necessary to evaluate the resistance of these plants to micro-
organisms: in addition to the healing effect of these plants, it is also of
immense importance to study the resistance of their extracts toward
microbes to avoid microbial infections in the wound site.
8. Polyphenols in wound healing and mechanism of action
Many plants in Table 1 were reported to contain a high level of
polyphenols. These compounds are known to possess a wide range of
pharmacological and biological properties, including their ability to
accelerate the wound healing process (Guimarães et al., 2021). Unfor­
tunately, there are no specific reports or research on their mechanism of
action in this process. In this context, we try in this part to involve some
research already published on the individual effect of some phenolic
compounds in wound healing and discuss their mechanism of action.
Over the recent few years, researchers have focused not only on total
biological matrix extracts but also on their bio-valuable antioxidant
I. Mssillou et al.
phytochemicals such as flavonoids and non-flavonoids molecules (Ber­
telli et al., 2021). Polyphenols are a family of complex molecules that
plants produce naturally to defend themselves against various ecological
and physiological attacks such as UV radiation, insect attack, and
wounding (Khoddami et al., 2013). These molecules exhibit a large
spectrum of pharmacological benefits, they act as antioxidants, and
anti-inflammatories, prevent heart disease, and are effective in healing
wounds (Cianciosi et al., 2018). An aromatic ring bearing one or more
hydroxyl groups is the basic structural feature of phenolic compounds.
These compounds are classified into simple phenols or polyphenols
including phenolic acids and flavonoids (Balasundram et al., 2006).
There is growing evidence that topical application of nutraceuticals
such as plant polyphenols was potentially effective in wound healing
and to alleviating skin disorders (Korkina et al., 2012). The
anti-inflammatory and wound healing effects of phenolic compounds
documented in the literature are summarized in Table 2. It was revealed
that tyrosol and hydroxytyrosol have a promising wound healing effect
similar to non-steroidal anti-inflammatory drugs (Aspirin, Ibuprofen,
and Naproxen) and a COX-2 selective drug (Celecoxib). In addition, it
was shown that hydroxytyrosol exhibits a good anti-inflammatory ef­
fect, improves endothelial function, and lowered oxidative stress (Yadav
et al., 2020).
Curcumin is a flavonoid polyphenol that showed antioxidant and
antibacterial properties and it accelerates the healing process by
improving the rate of wound contraction (Abbas et al., 2019).
Bioactive compounds such as luteolin, chrysin, rutin, kaempferol,
quercetin, hesperetin, and naringenin are widely found in Achillea spe­
cies (Achillea coarctata Poir., Achillea kotschyi Boiss., Achillea lycaonica
Boiss. et Heldr.), and in Lamiaceae species such as R. officinalis,
O. vulgare, and T. vulgaris (Table 1) (Ammar et al., 2015b; Hossain et al.,
2010). These compounds are known for their anti-inflammatory anti­
oxidant and wound healing effect.
As a part of its wound healing process, luteolin, a flavonoid mostly
found in the plant kingdom, has been reported to down-regulate cyto­
kines and inflammatory mediators mainly interferon-β (IFN-β), tumor
necrosis factor-α (TNF-α), interleukins (IL− 1β, IL-2, IL-6, IL-8, IL-12, and
IL-17); and upregulates mRNA expression of anti-inflammatory cyto­
kines namely IL-10. Moreover, in vivo investigation indicates that
luteolin accelerates re-epithelization of skin wounds and improves
impaired healing in diabetic animals. Authors suggest that exerts its
wound healing properties by targeting several cellular and molecular
pathways. Accordingly, in addition to its anti-oxidative and anti-
inflammatory efficacies, luteolin enhances the expression of ubiquitin
carboxy-terminal hydrolase (UCH)-L1and inhibits the expression of
vascular endothelial growth factor (VEGF), therefor accelerating the
healing process (Chen et al., 2021). Chen et al. (2021) have demon­
strated that the topical administration of luteolin in STZ-induced Dia­
betic rats improves wound healing, accelerates wound re-epithelization,
and attenuates NF-κB-induced inflammatory response and
Nrf2-mediated oxidative response. In addition, Mohammadi and co­
workers revealed that chrysin has positive effects on wound healing and
inflammation by increasing the expression of the genes responsible for
the healing effect (P53, TIMPS, MMPS, and IL-6) (Z. Mohammadi et al.,
2017). In two studies conducted by Almeida et al. (2012), and Pivec
et al. (2019), the results revealed that rutin ameliorates wound healing
and reduces oxidative damage.
The wound treatment with flavonol compounds showed good results.
For instance, in a study conducted by Özay et al. (2019), the treatment of
diabetic rats with kaempferol ointments was effective in wound healing,
it strengthened the tensile, increased the hydroxyproline and collagen in
the wound, and accelerated the re-epithelialization and facilitated
wound closure. Similar good results were obtained by other flavonols
such as quercetin, icariin, and morin. The signaling pathways involved
in the wound healing effect of these natural compounds are the
up-regulation of IL-10, M2 macrophage, CD31, and VEGF-α and
down-regulation of NF-κB, matrix metalloproteinase’s (MMP-2 and
17
Journal of Ethnopharmacology 298 (2022) 115663
MMP-9), and TNF-α (Fu et al., 2020; Ponrasu et al., 2018; Singh et al.,
2019).
Epigallocatechin Gallate (EGCG) is a main flavanol constituent in
green tea (Camellia sinensis L.) (Table 1) (Dorchies et al., 2006). It was
shown that EGCG accelerated wound healing, enhanced the vasculari­
zation of the wound, and modulated growth factors and inflammatory
cytokines (Kar et al., 2019). In a study conducted by Chen et al. (2020),
it was proved that the encapsulation of green tea polyphenol nano­
spheres in PVA/alginate hydrogel could ameliorate wound healing of
diabetic rats through the regulation of the phosphatidylinositol 3-hy­
droxy kinase/protein kinase B/mammalian target of rapamycin
(PI3K/AKT) signaling pathway. Interestingly, a randomized,
double-blind, placebo-controlled clinical trial conducted by Shahrah­
mani et al. (2018) investigated the effect of green tea ointment and
EGCG, its major active component, on wound healing and episiotomy
pain in 99 primiparous women. Results of this study showed that EGCG
especially green polyphenol-rich tea ointment improves wound healing
and releases episiotomy pain as compared to the placebo group. Even
though there are many studies investigating the wound healing prop­
erties of EGCG, its involved mechanism remains unclear. EGCG has been
shown to exhibit wound healing properties through a negative effect on
the transforming growth factor-1/Smad TGF-1/Smad signal trans­
duction, as an accelerated skin and tissues regeneration pathway (Li
et al., 2019).
The application of liposomes containing taxifolin (a flavanonol
compound) increased the regeneration and the epithelialization of the
burned skin (Shubina and Shatalin, 2012). Silymarin (flavonolignan)
reduced the number of lymphocytes, increased the number of fibrocytes,
and improved the alignment of the healing tissue (Oryan et al., 2012).
Isoliquiritin (Isoflavonoid) enhanced wound healing and promoted
angiogenesis and the inflammatory response (Liu et al., 2020).
Hesperidin and naringin are two flavanone compounds that accel­
erated wound healing, collagen synthesis, vasculogenesis, and angio­
genesis (Li et al., 2018; Salehi et al., 2018). It was shown that isoflavone
such as puerarin, genistein, and daidzein reduced oxidative stress,
modulated proinflammatory cytokine expression during the early stage
of wound healing, accelerated the process of regeneration, and pro­
moted the re-epithelialization (Park et al., 2011; Yamaguchi et al., 2012;
Zhang et al., 2019).
In sum, wound healing processes can be delayed by free radicals or
microbial infection. Once the damaged tissue loses its primary function
as a protective barrier, it becomes susceptible to invasion by microor­
ganisms. Several studies have shown that wound infections delay the
healing process (Hoque et al., 2017; Muthuswamy et al., 2019; Y. Zhang
et al., 2021). The phenolic compounds found in healing plants play a
primordial role in wound healing thanks to their antioxidant,
anti-inflammatory, and antimicrobial properties. They can increase cell
proliferation and accelerate the process of re-epithelialization (Azad­
pour et al., 2014; Melguizo-Rodríguez et al., 2021).
9. Conclusion
Although clinical advancement and conventional medicine in the
treatment of wounds, it persists as an urgent issue that requires the
intervention of multifield and the development of new safe, and efficient
drugs. In this review, we have focused on medicinal plants used in
Mediterranean countries and some related polyphenolic compounds as
natural alternatives in the treatments of wounds. The geographical
location of this region allows the presence of high diversity of plants that
are commonly used in folk medicine for many purposes including wound
healing. For the first time, this review provides an outlook on eighty-
nine species used in wound healing in this area. Also, some clinical
trials were performed on certain species such as Triticum vulgare L.,
Lavandula stoechas L., Teucrium polium L., Lawsonia inermis L. and, Aloe
vera L. During this review, it has been observed that certain limitations
are related to wound healing studies, specifically, the lack of
I. Mssillou et al. Journal of Ethnopharmacology 298 (2022) 115663

Table 2
Wound healing effect of phenolic compounds dominantly present in medicinal plants.
Type of Phenolic compound Chemical structure Key results Reference
compound

Phenolic Tyrosol - Possesses a good binding affinity as compared to other non- Yadav et al.
Derivatives steroidal anti-inflammatory drugs (Aspirin, Ibuprofen, and (2020)
Naproxen) and a COX-2 selective drug (Celecoxib).
Hydroxytyrosol - Reduces the production of mitochondrial superoxide Calabriso et al.
induced by phorbol myristate acetate. (2018)
- Improves the inflamed endothelial mitochondrial function
and prevents mitochondrial oxidative dysfunction.
- Improves endothelial function in inflammatory conditions
by promoting mitochondrial biogenesis
Flavonoid Curcumin - Accelerates the healing process by improving the rate of Abbas et al.
polyphenol wound contraction (2019)
- Has an antioxidant effect and it is effective against Gram-
positive and Gram-negative bacteria

Flavone Luteolin - The administration of Luteolin in STZ-induced diabetic rats Chen et al.
improves wound healing, accelerates wound re- (2021)
epithelization, and attenuates NF-κB induced inflammatory
response and Nrf2-mediated oxidative response.

Chrysin - Has positive effects on the expression of the genes (Z. Mohammadi
responsible for the healing effect (P53, TIMPS, MMPS, and et al., 2017)
IL-6)

Rutin - Ameliorates wound healing Almeida et al.

- Reduces the oxidative damage (2012)

- Has a positive therapeutic effect on healing Pivec et al.

- Has good antioxidant activity (2019)
Flavonol Kaempferol - The treatment with kaempferol ointments was effective in Özay et al.
wound healing of diabetic rats. (2019)
- The tensile strength with kaempferol ointments was
significantly higher than that in the nondiabetic control
and vehicle groups.
- The hydroxyproline and collagen in the wound were
increased by kaempferol.
- The wound resistance was improved by kaempferol.
- Kaempferol accelerated re-epithelialization and facilitated
wound closure.
Quercetin - The treatment of diabetic rats with quercetin inhibited the Fu et al. (2020)
inflammation and accelerated wound healing.

Flavonol Icariin - Accelerates the wound healing in rats Singh et al.

. (2019)

Flavonol Morin Ponrasu et al.

(2018)

18 (continued on next page)

I. Mssillou et al. Journal of Ethnopharmacology 298 (2022) 115663

Table 2 (continued )
Type of Phenolic compound Chemical structure Key results Reference
compound

- The treatment with Morin reduced significantly the time of

re-epithelialization and enhanced the rate of wound
contraction by increasing collagen synthesis

Flavanol Epigallocatechin - Treatment of wounds in Wistar rats by EGCG accelerated Kar et al. (2019)
Gallate (EGCG) healing properties.
- Is characterized by better wound contraction.
- Enhanced the vascularization of the wound.
- Modulated growth factors and inflammatory cytokines.

Flavanonol Taxifolin - The application of liposomes containing taxifolin increased Shubina and
the regeneration and the epithelialization of the burned Shatalin (2012)
skin.
- taxifolin exhibit anti-inflammatory activity

Flavonolignans Silymarin - Reduces the number of lymphocytes, increased the number Oryan et al.
of fibrocytes, and improved the alignment of the healing (2012)
tissue
- Enhanced the collaged fibers and fibroblasts and increased
the ultimate tensile strength

Flavanone Hesperidin - Accelerated the wound healing, vasculogenesis, and Li et al. (2018)
angiogenesis

Naringin - Accelerated the collagen synthesis Salehi et al.

- Improved the rate of wound contraction (2018)

Isoflavonoid Isoliquiritin - Enhanced the wound healing Liu et al. (2020)

- Promoted the angiogenesis and the inflammatory response

(continued on next page)

19
I. Mssillou et al.
Table 2 (continued )
Type of Phenolic compound Chemical structure
compound
Isoflavone Daidzein
Genistein
Isoflavone Puerarin
information in clinical trials whether on phenolic compounds or the
medicinal plants reported in this review, and the molecular evidences
that can illustrate the main mechanism of action. However, we conclude
that Mediterranean medicinal plants and their related phenolic com­
pounds are extremely promising potential tools for wound healing.
Furthermore, we hope that the current review constitutes a strong sci­
entific basis for future research on new drugs destinated to wound
healing and skin disorder.
CRediT authorship contribution statement
Ibrahim Mssillou: Conceptualization, Writing – review & editing,
Formal analysis, Writing – original draft, contributed to the conception
and design of the systematic review and meta-analysis. contributed to
the initial electronic literature search, study eligibility assessment, data
extraction and quality and risk of bias assessment, and analysis and
interpretation. drafted the manuscript. critically revised the manuscript.
All authors approved the final version of the manuscript. Meryem
Bakour: Conceptualization, Writing – review & editing, Formal anal­
ysis, Writing – original draft, contributed to the conception and design of
the systematic review and meta-analysis. contributed to the initial
electronic literature search, study eligibility assessment, data extraction
and quality and risk of bias assessment, and analysis and interpretation.
drafted the manuscript. critically revised the manuscript. All authors
approved the final version of the manuscript. Meryem Slighoua:
Writing – review & editing, Formal analysis, contributed to the
conception and design of the systematic review and meta-analysis.
contributed to the initial electronic literature search, study eligibility
assessment, data extraction and quality and risk of bias assessment, and
analysis and interpretation. All authors approved the final version of the
manuscript. Hassan Laaroussi: Conceptualization, Writing – review &
editing, Formal analysis, contributed to the conception and design of the
systematic review and meta-analysis. All authors approved the final
version of the manuscript. Hamza Saghrouchni: Writing – original
draft, drafted the manuscript. All authors approved the final version of
the manuscript. Fatima Ez-Zahra Amrati: Formal analysis, contributed
to the initial electronic literature search, study eligibility assessment,
data extraction and quality and risk of bias assessment, and analysis and
interpretation. All authors approved the final version of the manuscript.
Badiaa Lyoussi: critically revised the manuscript. All authors approved
the final version of the manuscript. Elhoussine Derwich: critically
20
Journal of Ethnopharmacology 298 (2022) 115663
Key results Reference
- Promoted the re-epithelialization Yamaguchi et al.
- Reduced the enlargement of the wound area during the (2012)
inflammatory phase
- Reduced the oxidative stress Park et al. (2011)
- Modulated proinflammatory cytokine expression during
the early stage of wound healing
- Has good antioxidant activity Zhang et al.
- Accelerates the process of the regeneration of the full- (2019)
thickness skin-defect-regeneration process
revised the manuscript. All authors approved the final version of the
manuscript..
Declaration of competing interest
We wish to confirm that there are no known conflicts of interest
associated with this publication and there has been no significant
financial support for this work that could have influenced its outcome.
Data availability
The datasets generated in the current study are available in the
Tables attached to this paper.
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