Phytomedicine 38 (2018) 57–65

Contents lists available at ScienceDirect

Phytomedicine
journal homepage: www.elsevier.com/locate/phymed

Review

Could essential oils enhance biopolymers performance for wound healing? A T

systematic review
Mercedes Pérez-Recaldea,b,*, Ignacio E. Ruiz Ariasa, Élida B. Hermidaa,b
a
Lab3Bio (Laboratorio de Biomateriales, Biomecánica y Bioinstrumentación), Escuela de Ciencia y Tecnología, Universidad Nacional de San Martín, 25 de Mayo 1143,
B1650HMK General San Martín, Provincia de Buenos Aires, Argentina
b
Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Godoy Cruz 2290, C1425FQB CABA, Argentina

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

Keywords: Background: Millions of people in the world suffer from chronic wounds of different etiologies such as diabetic
Essential oils foot and leg ulcers, without solutions nowadays. Molecules obtained from plants offer an alternative to aid
Wound healing wound healing. Strong evidence about essential oils (EO) anti-inflammatory and antimicrobial properties is
Monoterpenoids thoroughly described in literature and their chemical compositions are well characterized. More recently, EO
Biopolymers
effects in experimental wounds have begun to be analyzed.
Skin regeneration
Aim: We aim to summarize the evidence of EO in experimental wounds, and the possibility of combining them
Active dressings
with biopolymers commonly used in skin regeneration.
Methods: Electronic databases such as ScienceDirect, PubMed and Scopus were used to search scientific con-
tributions until March 2017, using relevant keywords. In a first step, literature focusing on EO and/or mono- or
sesqui-terpenoids effects in rodent wounds was identified and summarized. In all cases, chemical structures and
EO composition were detailed, as well as references to in vitro activities previously determined, e.g. antibacterial,
antioxidant or anti-inflammatory. In a second step, scientific literature devoted to combine EO and biopolymers
with the focus set on wound healing innovations, was collected and analyzed.
Results: Treatments with EO from species of genders Lavandula, Croton, Blumea, Eucalyptus, Pinus, Cymbopogon,
Eucalyptus, Cedrus, Abies, Rosmarinus, Origanum, Salvia and Plectranthus, have shown positive results in rodent
wounds. All of these EO were mainly composed by monoterpenoids—thymol, 1,8-cineole, linalool—or mono-
terpenes, as limonene or pinenes. Experimental wounds in rodents have shown faster closure rate, better col-
lagen deposition and/or enhanced fibroblasts proliferation. In blends with biopolymers, several EO combined
with chitosan, alginate, gelatin or collagen, were processed to give active films or nanofibers, with antioxidant,
anti-inflammatory or antimicrobial activities. Curiously, all of these works were carried out since 2010.
Conclusions: There is significant evidence about the effectivity of EO as wound healers. The incorporation of EO
into a polymer matrix that contributes to wound healing is still incipient. However, scientific based evidence of
the EO incorporation in resorbable polymeric scaffolds was found and analyzed herein. In summary, EO-bio-
polymer dressings or scaffolds have become promising artifacts regarding wound treatments, especially in
chronic wounds, where treating infection and inflammation are still important issues.

Introduction
Challenges in wound healing
Wound healing, triggered by a skin damage, consists of a cascade of
biochemical processes carried out to restore the structure and function
of the injured or diseased tissue. Four overlapped phases must be ac-
complished for the restitution of normal skin: blood clotting,
inflammation, new tissue formation and tissue remodeling. The last two
phases comprise complex mechanisms like cellular proliferation, col-
lagen synthesis and granulation tissue formation as well as matrix de-
gradation and new collagen deposition, concurrently with wound
contraction and scar formation (Sanon et al., 2016).
When an extensive dermo-epidermal skin loss—such as a deep
burn—occurs, dressings are quite suitable to enhance the first phases of
the healing process but not enough to achieve the last two. The

Abbreviations:EO, Essential oil/s

⁎
Corresponding author at: Lab3Bio (Laboratorio de Biomateriales, Biomecánica y Bioinstrumentación), Escuela de Ciencia y Tecnología, Universidad Nacional de San Martín, 25 de
Mayo 1143, B1650HMK San Martín, Provincia de Buenos Aires, Argentina.
E-mail address: mrecalde@unsam.edu.ar (M. Pérez-Recalde).

https://doi.org/10.1016/j.phymed.2017.09.024
Received 29 May 2017; Received in revised form 7 August 2017; Accepted 24 September 2017
0944-7113/ © 2017 Elsevier GmbH. All rights reserved.
M. Pérez-Recalde et al.
challenge to build up an artifact that allows wound healing in both
chronic and acute wounds has promoted research and development of
dressings and scaffolds during the last decades (Vyas and
Vasconez, 2014). It is worthwhile to notice that chronic wounds are
considered a major burden worldwide, by the number of affected
people and by the different stages and complexities involved under the
label “chronic wound”. In fact, several million people in the world that
suffer from chronic wounds, remain stalled typically in the in-
flammatory phase (Frykberg and Banks, 2015), affecting their normal
activities and diminishing their quality of life. These lesions proceed
from different etiologies like diabetic, venous or pressure ulcers and, in
particular, chronic lower extremity ulcers: all of them with enormous
social and economic implications. For example, the annual cost of
caring for chronic wounds in the United States approaches US $25
billion.
According to their different stages, identification of the optimal
dressings for each particular chronic wound type is one important issue
nowadays. Besides, new therapeutic agents intended for diabetic
wounds management are required (Abu-al-basal, 2010). Having this
goal in mind, current research is focused on the one hand, on nano-
technological sensors to monitor the biochemical state of wound and,
on the other hand, on the incorporation of biological material such as
stem cells or vegetable extracts to solutions, gels or solid products used
as dressings (Dabiri et al., 2016). Indeed, therapeutic dressings with
plant extracts constitute an increasing tendency in chronic wound
healing, due to the well-known antioxidant and anti-inflammatory
properties (Boateng and Catanzano, 2015). Although essential oils were
thoroughly analyzed with regard to the properties mentioned before,
not as much as work was devoted to their use for wound healing.
Meanwhile, active dressings made of polymers such hydrogels or
hydrocolloids and plant extracts are being explored as promising de-
vices for controlled delivery of analgesics, growth factors, antimicrobial
and anti-inflammatory agents (Aoyagi et al., 2007). These polymeric
matrices exhibit emergent properties in comparison with topical agents
in the form of solutions, creams or ointments, which may be absorbed
faster than required by the healing process.
Since a profuse revision of the research and development of re-
sorbable biopolymers used to make dressings and scaffolds can be found
in the literature (Michler, 2016; Pachence et al., 2007; Park et al.,
2017), this review focuses on the current knowledge of EO effects in
wounds, and on the analysis of dressings where EO and resorbable
polymers synergically combine to promote wound healing.
Then, Results presents a summary of the experimental evidence of
EO remarkable healing effects determined by in vitro and in vivo tests;
Table 1 emerges as a corollary of the revision of work developed
worldwide in the last years. After that, synergic effects due to the
combination of EO and resorbable polymers for wound dressings are
the key issue of the contributions discussed in "Biopolymers and EO for
wound healing".
Plant molecules effects on skin regeneration
A large amount of surveys and experimental evidence sustain plant
beneficial properties on wound healing as well as on a wide range of
skin diseases (Agyare et al., 2016; Kumar et al., 2007; Sabale et al,
2012; Sharma et al., 2013). The effectiveness of those active principles
used for wound treatments has been demonstrated rather recently by
many biochemical, molecular and pharmacological studies (Arun et al.,
2013; Parsaeimehr et al., 2014; Sharma et al., 2013).
On one hand, organic, aqueous or hydro-alcoholic extractions are
found among the main methods to obtain active molecules from plants.
For instance, flavonoids, phenolic acids, cumarins and polysaccharides
from the Achyrocline satureioides ethanolic extract, promote keratino-
cytes and fibroblasts proliferation and exhibit antimicrobial and anti-
inflammatory effects (Alerico et al., 2015). In addition, the polyphenols
rich fraction obtained by organic extraction from Dicranopteris linearis,
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Phytomedicine 38 (2018) 57–65
has shown beneficial effects on fibroblasts proliferation and migration
in the wound bed (Ponnusamy et al., 2015). By last, the efficacy of
Pongamia pinnata methanolic extract with alkaloids, saponins, flavo-
noids, terpenes and steroids has been demonstrated in wounds, in-
flammations, ulcers and skin infections due to antimicrobial and anti-
oxidant effects (Dwedi et al., 2017).
On the other hand, EO is the largest group of secondary metabolites
produced by plants. Chemically, EO consist of a complex mix of
monoterpenes—10 carbons—and sesquiterpenes—15 carbons—in
minor proportion; they can be extracted by water or steam distillation,
or by cold pressing in the case of citric fruits. Due to their uses in
cosmetics, fragrances and food the chemical composition and effects on
skin of EO have been thoroughly studied since decades. In addition,
strong evidence of EO anti-inflammatory, antioxidant and antimicrobial
effects—three crucial issues in chronic wounds treatment—has been
reported (Guilhon et al., 2011; Jayasena and Cho, 2013; Raut and
Karuppayil, 2014; Semeniuc et al., 2017; Zuzarte et al., 2013). In fact,
face an infection, the normal healing is disrupted by the inflammatory
phase, the wound becomes chronic and promotes a delay in the pro-
liferation phase (Yates et al., 2009). Regarding diabetic wounds, Can-
dida is the most common yeast that infects them and leads to the delay
in wound healing process (Mlinaric-Missoni et al., 2005).
However, despite this background, EO and their main components
are scarcely used for wound healing. Therefore, the research work on
their effects in experimental wounds is meaning enough to deserve a
summary according to their main properties, as stated in Table 1. Be-
fore this summary, considerations of the current knowledge of EO cy-
totoxicity are exposed.
Methods
Search strategy
Using electronic databases, such as PubMed, Scopus and
ScienceDirect, the search was carried out with “essential oils”, “wound
healing” “terpenoids” and “terpenes” as the main keywords. From this
search, only papers including an animal model were considered. In a
second step, “polymers”, “biopolymers” and “dressing” were added to
the same previous keywords: works devoted to combine EO and bio-
polymers aimed to wound healing were selected, with or without an-
imal model.
Study selection
From the search described above 12 works demonstrating EO effects
in experimental wounds, and 7 works having combined biopolymers
with EO were found. For all of them, the EO composition as well as the
chemical structures of the terpenoids could be determined (in some
cases in the same paper, in other in previous references). This feature
enhanced the analysis of the data, detailed in the following section.
Data extraction
Data were collected and examined using standard procedures.
Chemical structures of the EO, details of the animal model, doses and
time of administration, histological assessment and biochemical me-
chanisms highlighted from the chosen articles were analyzed and
summarized. Similarly, data about chemical blends between polymers
and EO were compiled.
Methodological quality and assessment
Correct positive and negative controls were assessed to guarantee
the experiment quality. Linear incision and circular full-thickness ex-
cision were the typical wound models; wound contraction rate and
complete histological analysis were the experimental methods usually
M. Pérez-Recalde et al. Phytomedicine 38 (2018) 57–65

Table 1
Studies of essential oils applied in wounds animal models.

(continued on next page)

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Table 1 (continued)

(continued on next page)

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Table 1 (continued)

61
M. Pérez-Recalde et al.
considered for the wound assessment. For the histological analysis,
hydroxyproline content and Masson trichrome stain were preferred to
evaluate collagen content and maturation within the dermis at different
times.
Results: terpenes and terpenoids from essential oils in wound
healing
Cytotoxicity
The concentration and the particular blend of each EO are im-
portant for the cytotoxicity and thus for the application of the EO in
medicine. In an extreme, EO at high concentrations may be cytotoxic
and thus useful for treating cancerous cells (Bhardwaj et al., 2013).
Regarding the chemical structure of EO components, when terpenes
presents functional groups such as alcohol, ketone or aldehyde, they
receive the name of terpenoids; menthol, carvone, neral are just a few
examples. Terpenoids bearing-OH groups in their structure have been
pointed out as the cause of more membrane disruptions than those
lacking polar groups, like limonene, or those which accept hydrogen
bonds, like 1,8-cineole.
A revision of the in vitro toxicological studies of terpenoids suitable
for wound healing specially focused on the IC50—the half maximal
inhibitory concentration—is considered here. For example, lemon
myrtle oil (from Backhousia citriodora) and its main component, citral,
exhibit high toxicity against primary cell cultures of dermal and a cell
line fibroblasts, with IC50 ranging from 0.008% to 0.014% (w/v)
(Hayes and Markovic, 2002). Lavender oil becomes cytotoxic for en-
dothelial cells and fibroblasts at 0.25% (v/v) and clove oil has been
shown to be highly toxic at a concentration of 0.03% (Prashar et al.,
2004). Tea tree essential oil (from Melaleuca alternifolia) and its main
component, terpinen-4-ol, showed high antimicrobial activity in low
concentrations against Staphylococcus and, meanwhile, were not toxic
for murine fibroblasts until 1% v/v (Loughlin et al., 2008).
Mendanha and coworkers thoroughly analyzed the membrane
fluidity enhancement and fibroblast cytotoxicity of several terpenes and
terpenoids (Mendanha et al., 2012). In particular, fibroblast toxicity of
nerolidol, α-terpineol, L-(-)-carvone, (+)-limonene, L-menthone, D/L-
menthol, pulegone and 1,8-cineole were determined. In these in vitro
conditions, toxicity was ranging from 0.6 mM—for nerolidol: 15 car-
bons, hydroxyl group—up to 4 mM—for 1,8-cineole: 10 carbons, ether
group. Viability reduction was correlated to an increase in membrane
fluidity and, in all cases, 6.3 × 1010 terpenes/cell were enough to affect
fluidity and thus, cellular viability.
From general considerations, even in wound healing where there is
no epidermal barrier, it is accepted that therapeutic concentrations that
impart no apparent irritation or toxicity are one or two orders higher
than in vitro cytotoxic concentrations, typically 4–12% v/v (Tisserand
and Young, 2014). The concentration range presented in Table 1 ex-
tends from 1 to 20%.
Experimental enhancement of healing process in animal models
In Table 1, the information concerning research on EO and their
effects in experimental wounds is summarized by the year of publica-
tion. From left to right, the first column of Table 1 contains the EO
source—whole plant and part of it—and the chemical structures of the
main terpenes or terpenoids that composes it. Furthermore, when in
presence of an EO extremely rich in only one compound, it is appointed
with its percentage. In these cases (Khorshid et al., 2010; Malveira
Cavalcanti et al., 2012; Pang et al., 2014), experiments were performed
in parallel with the pure main terpene/terpenoid, to give consistent
results than with the oil blend.
Two EO are presented in 4th and 5th rows (Süntar et al., 2012;
Tumen et al., 2011), with similar results, but separately applied. De-
picted main components are in common because they belong to the
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Phytomedicine 38 (2018) 57–65
same gender or family. Interestingly, in both works other EO from the
same group was tested with negative results, indicating the importance
of each particular blend.
Only in one case (Süntar et al., 2011) two essential oils—from Or-
iganum and Salvia—were blended in one tested formulation.
Two works were performed on diabetic mice (Abu-al-basal, 2010;
Kandimalla et al., 2016) and one of them in Candida infected wounds
(Kandimalla et al., 2016), in which the authors claim that the EO ex-
hibited anti-candidiasis mediated wound-healing.
Apart from in vivo experiments focused on Table 1, works exposed in
vitro test for other EO bioactivities: antimicrobial (Matos Ximenes et al.,
2013; Sugumar et al., 2014; Süntar et al., 2011); anti-inflammatory
(Süntar et al., 2012; Tumen et al., 2011); antinociceptive
(Matos Ximenes et al., 2013) or antioxidant (Ben Djeema et al., 2016).
Only in the case of Plectranthus tenuiflorus (Khorshid et al., 2010), in
vitro proliferative effect on human fibroblasts was analyzed, and for this
reason included in row 1st, column 3 in Table 1.
Regarding the antimicrobial activity, Matos Ximenes and coworkers
evaluated Croton adamantinus EO against bacteria isolated from wound
infected areas in patients, and found positive results for Staphylococcus
but neither for Pseudomonas nor for Enterobacter (Gram-). Sugumar and
coworkers also evaluated 1,8-cineole against the clinical pathogen
Staphylococcus aureus, demonstrating significant antibacterial activity;
in the case of the blend of sage and origanum, meanwhile, anti-
microbial activity against S. aureus, Pseudomonas aeruginosa and also
Candida albicans was exhibited (Süntar et al., 2011).
EO effects on the inflammatory phase of wound healing were ex-
amined using the method of Whittle—based on the inhibition of acetic
acid induced capillary permeability (Tumen et al., 2011). A dose-de-
pendent inhibitory activity was observed for both Abies cilicica and
Cedrus libani EO, at the dose of 200 mg/kg with a 30% as the highest
inhibitory value. The same technic was used by Süntar and coworkers
(2012) with EO from Pinus species, administering each test sample or-
ally 0.2 ml/20 g body weight. Antinociceptive effects already known for
1,8-cineole and for methyl-eugenol, were confirmed by Matos Ximenes
and coworkers both by the formalin test and by the abdominal con-
tortion essay.
Regarding methods used to evaluate EO on rodent experimental
wounds, circular excision to wound size assessment and histological
evaluation, including determination of collagen fibers by Masson, are
the most common techniques, followed by linear incision to evaluate
treated skin mechanical strength. Results allow to demonstrate an ac-
celeration of wound closure and a faster and/or better reepithelializa-
tion, as it is detailed in column 3 in Table 1. Histological observations
regarding these results are, for example: more abundant and better
organized collagen fibers and higher vascularization (Abu-al-
basal, 2010), full-thickness epidermal regeneration Tumen et al., 2011),
a decrease in the swelling and exudates of the cutaneous wounds and an
enhancement of the fibroblast density (Malveira Cavalcanti et al.,
2012), a reduction in leucocytes or inflammatory cells number
(Pang et al., 2014), a faster replacement of type III collagen by type I,
and an increased TGF-β levels and myofibroblasts in the early phase of
healing (Mori et al., 2016). It is noteworthy the additional and complete
anti-candidiasis effect showed by Cymbopogon nardus EO in diabetic
wounds (Kandimalla et al., 2016).
According to the antimicrobial activity exhibited by several EO, tea
tree oil (from M. alternifolia) is, as far as we know, the only oil that was
already essayed in chronic human wounds (Edmondson et al., 2011; Lee
et al., 2014) infected by S. aureus methicillin-resistant (MRSA), a per-
sistent problem in elderly patients. In particular, Lee and coworkers
essayed 10% v/v of topical preparation in a randomized controlled
trial, in a nursing home residents. Infections in 14/16 patients of the EO
group were completely eradicated after the 4 weeks treatment, and 16/
16 achieved to close the wounds: both outcomes were significantly
different from the control group.
The first report about monoterpenoids in wound healing (Barreto
M. Pérez-Recalde et al.
et al., 2014) presented five works in animal models using purified
borneol, α-terpineol and thymol as well as genipin and aucubin, two
iridoid-derivatives monoterpenes. Similar cases were listed by Vyas and
Vasconez (2014), who incorporated a study conducted with pure li-
monene in a comprehensive review that included the last developments
on biological molecules—interestingly, all small terpenes/terpe-
noids—and, moreover, advances on skin substitutes, biomembranes
and scaffolds. This work claims that anti-inflammatory properties of
monoterpenes are highly correlated with wound healing. In the same
way, Barreto and coworkers comprise in their work also antimicrobial,
antioxidant, low-toxicity features and fibroblast growth effects, parti-
cularly for thymol.
Biopolymers and EO for wound healing
Collagen and silk fibroin—proteins—as well as chitosan and algi-
nate—polysaccharides—are biopolymers used for scaffolds and dres-
sings. All of them are extracted from natural sources and proved to have
excellent to good biocompatibility and efficacy in wound healing.
Scientific literature shows many examples where these biomaterials are
functionalized with organic molecules to achieve new solutions for the
different healing processes. Particularly, recently Das and coworkers
(Das et al, 2016) presented a review regarding the progress of medicinal
plant extract-conjugated polymeric constructs. However, just since
2010 the possible enhancement of these biomaterials combined with
EO has been explored. Thus, in this section, we present experiences
where polymers and EO were combined aiming to wound healing.
Even though, it is worthy to point out the experimental evidence
about combining EO and polymers is more abundant in other fields of
application, as food packaging. EO antioxidant and antimicrobial
properties determine the success of these blends, where chitosan has
been largely exploited (Elsabee and Abdou, 2013; Atarés and
Chiralt, 2016; Elsabee et al., 2015). Also for food packaging or air
freshener applications, lemongrass, rosemary pepper and basil EO have
been successfully incorporated to cellulose ester films
(Rocha Bastos et al., 2016).
Works devoted to combine a certain biopolymer with different EO
intended to wound healing are presented in paragraphs 4.1 to 4.3, ac-
cording to the biopolymer used. Chemical aspects and, when available,
results in experimental wounds are presented. Resorbable polyesters
are very used in medicine and are suitable for wound dressings, their
blends with EO have been oriented only for packaging so far. Despite of
this the principal contributions regarding polyesters and EO are sum-
marized in paragraph 4.4 as preliminary results for future wound
healing developments.
Collagen and gelatin
Anti-inflammatory and antinociceptive activities of Lippia gracilis EO
have been experimentally demonstrated (Guilhon et al., 2011). Given
that thymol is its main component, anti-inflammatory and wound-
healing activity of the purified terpenoid in mice was tested, using
active collagen dressings (Riella et al., 2012). Thus, pure thymol was
mixed 10% in collagen (1% in 0.5 M acetic acid with 20% w/w of
plasticizer); the dispersion was casted and allowed to dry in order to
obtain films. As result of the use of the collagen-thymol dressings in
wounds, a reduction of the wound area, and a better and denser col-
lagen deposition were observed. After these exciting results, Kavoosi
and coworkers prepared gelatin film forming solutions (10% in water)
with thymol at different concentrations (1, 2, 4, and 8% w/w), glycerol
(25% w/w) as plasticizer and glutaraldehyde (2% w/w) as crosslinker.
Gelatin-thymol films have exhibited so excellent antioxidant and anti-
bacterial properties in vitro, that the authors proposed their potential
use as nanowound dressings, highlighting thymol as a safe and effective
source of natural antioxidant and antimicrobial agents (Kavoosi et al.,
2013).
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Phytomedicine 38 (2018) 57–65
Chitosan
Pure sesquiterpene nerolidol -abundant for example in neroli, jas-
mine, tea tree or ginger essential oil—was incorporated into a chitosan
hydrogel (Gonalves Ferreira et al., 2016). 1 or 2 ml of pure nerolidol
was added to 50 ml of chitosan 2% v/v dissolved in acetic acid, under
magnetic stirring for 10 min, giving 2% and 4% of nerolidol respec-
tively; pH was adjusted to 4. The assessment of the antimicrobial ac-
tivity in vitro showed a synergistic effect between the two materials.
Besides, healing was tested in mice, with circular excision wounds.
Animals were treated daily and both macroscopic and histological
wound evaluations were followed at 7, 14 and 21 days. Wounds treated
with chitosan-nerolidol 2%, have presented less size since day 7, cor-
responding with higher fibroblast proliferation and better collagen re-
organization, both confirmed by histological methods. According to the
authors, it was the first time that these two natural and low-cost ma-
terials were combined. Interestingly, the inflammatory process in
wounds treated with chitosan +4% nerolidol was enhanced, eviden-
cing the relevance of the compound concentration.
Another EO-chitosan combination for wound dressings comes from
the antimicrobial properties of thyme essential oil (from Thymus vul-
garis) (Altiok et al., 2010). Chitosan solution was prepared by dissolving
0.5 g low molecular weight chitosan in 25 ml of 2% acetic acid; etha-
nolic solution of 10% v/v of EO was added dropwisely into the chitosan
solution to obtain several final concentrations ranging from 0.2 to 1.2%
v/v. Solutions were casted onto polystyrene Petri dishes, vacuum dried
at room temperature for 24 h and then further dried at 40 °C for 5 h.
Concentration 1.2% v/v showed the highest antimicrobial and anti-
oxidant activities, as well as the mix polymer-EO showed a slight in-
crease in water vapor and oxygen transmission rates, positive features
for wound healing materials.
Even though genipin is not a component of an essential oil—it is a
monoterpenoid of the iridoid compounds group, extracted from some
fruits, in particular from the genus Genipa and Gardenia—it is well-
known by acting as natural crosslinker into polymers with amino
groups, like chitosan (Muzzarelli, 2009). Polymeric blends of silk fi-
broin-chitosan using genipin as crosslinker were prepared by electro-
spinning in order to assess nanofibrous scaffolds with potential use for
wound dressings and tissue engineering, (Zhang et al., 2010). Not only
water-resistant ability and mechanical properties of fibers were im-
proved after cross-linking, but also the tested scaffolds in rectangular
wounds in rats, allowed more densely fibroblast proliferation, arranged
in better order than in the control group.
Alginate
Regarding both the 1,8-cineole anti-inflammatory and antiseptic
properties of 1,8-cineole and alginate fibers ability for caring moderate
to highly exuding chronic and acute wounds, Eucalyptus globulus EO and
alginate were combined to produce nanofibers by wet spinning matrix
(Khajavi et al., 2014). The antibacterial activity of loaded samples and
its increase by the EO content was confirmed. Thus, 1,8-ci-
neole + alginate nanofibers were proposed as a suitable combination
for occlusive or semiocclusive wound dressings.
In a recent experimental work, alginate films were separately mixed
with ten different EO in order to assess antibacterial and antifungal
properties of the films (Liakos et al., 2014). Sodium alginate was dis-
solved in hot water (3% w/v) and, after cooling, glycerol was added
(1% v/v) as plasticizer. EO from Helicrysum italicum (immortelle),
chamomile blue, cinnamon, lavender, tea tree, peppermint, eucalyptus,
lemongrass or lemon were separately added. Each EO was slowly
blended to alginate/glycerol solutions and Igepal 1% was added as
surfactant; final solutions were casted and left to dry under ambient
conditions. 16%, 50% and 66% of the film dry weight were the used
concentrations. Films proved to be stable under different humidity
environments and inhibited bacterial and fungal growth, according to
M. Pérez-Recalde et al.
the EO type and concentration. The authors suggest that these results
might be useful to design novel antimicrobial wound dressings, as well
as biodegradable coatings for other medical applications.
Forthcoming polyesters
Biodegradable polyesters have generated an enormous interest be-
cause of their applicability in the biomedical field (Mogoşanu and
Grumezescu, 2014). In particular, this class of polymers is suitable for
wound dressings since they offer a good barrier with accurate me-
chanical properties. Another attractive property of the biopolyesters is
their capacity of hydrolytic degradation in vivo by physiologically oc-
curring enzymes. In addition, due to the backbone ester linkages, the
macromolecular structure can be tuned according to specific applica-
tions.
These biopolymers have already been blended with EO to enhance
physical properties of the polymeric products. For instance, the 40-
carbons terpene β-carotene was successfully mixed with three different
biodegradable polyesters: polylactic acid (PLA), Poly-ε-caprolactone
(PCL) and poly(hydroxybutyrate-co-hydroxyvalerate) (PHBV), looking
for spreading the capabilities of these bioplastics (López-Rubio and
Lagaron, 2010). PLA is a bioactive thermoplastic aliphatic polyester
derived from renewable resources, such as corn starch, tapioca roots or
sugarcane. PCL is a well-known synthetic biopolymer that has attractive
properties not only in medical but also industrial applications. Its low
glass transition temperature (-60 °C), low melting temperature (56-
60 °C) and high thermal stability range make PCL suitable for a large
range of application, from medical and pharmaceutical uses to packa-
ging. PHBV, by last, is a resorbable biopolymer from natural source,
belonging to the polyhydroxyalkanoates (PHAs) group, fully biode-
gradable and biocompatible polyesters, very promising for biomedical
applications, including wound healing (Williams and Martin, 2005; Ke
et al., 2017).
Recently, PLA-EO films were prepared, including bergamot, lem-
ongrass, rosemary, and clove EO. Resulting films showed superior
mechanical and antimicrobial properties than PLA. These promising
results encouraged the authors to investigate its application in food
preservation (Qin et al., 2017). Regarding PCL, it has been used for
controlled drug release and absorbable surgical suture; electrospinning
and 3D melting printing may be used to easily produce scaffolds for
tissue engineering (Cama et al., 2017). A work showed by spectroscopic
methods that PHAs and catechin—a natural antioxidant flavonoid ob-
tained from tea leaves—interact by H-bonding (Jianchun et al., 2003).
The only evidence in the literature regarding the combination of PHAs
and EO is for an active food packaging bilayer film (Marqués Laliga,
Magister Thesis, 2015) added clove and origanum essential oil, and
separately eugenol, thymol and carvacrol, by pulverization onto PHBV
films. As a result of this work, films exhibited different mechanical
properties from control film, and good antimicrobial activity like ter-
penes alone.
Thus, up to the present, no blends of these biopolyesters with EO
were developed for wound healing, but there are experiences in other
fields that encourage progress in this regard. Aliphatic polyesters, such
as poly(glycolic acid) (PGA) and poly(lactic acid) (PLA), has been used
for nearly 40 year as wound healing and suture material, they are
generally regarded as safe and approved by US Food and Drug
Administration (FDA). Therefore, in this sense, the combination of
biopolyesters with EO could be a promising next upgrade in wound
healing applications.
Discussion
EO are chemically characterized in detail and have been safely used
since decades in perfumery, food and sanitation products. In addition,
anti-inflammatory and anti-microbial properties point out the cap-
ability of EO upon healing. The most remarkable research, developed in
64
Phytomedicine 38 (2018) 57–65
the last ten years, has been presented and summarized along the paper.
In fact, Table 1 focused on the proper EO concentration for therapeutic
use and main results of the experimental models in rodents with the
morphological and histological assessment of the healed wound. Much
more EO and purified terpenoids remain still to be studied; however,
evidences are meaning enough, indicating that particular blend as well
as the presence of determined molecules, with different functional
groups—such thymol, limonene—seem to be important.
Given that bioresorbable polymers have provided solutions to skin
regeneration, the possibility of combining them with active biomole-
cules derived from EO becomes a good challenge to advance in pending
solutions. According to what has been collected herein, EO combined
with different natural polymers such alginate, collagen or chitosan were
successfully processed to give nanofibers or films, keeping the terpenes
healing properties. Furthermore, the EO release rate, their traces in the
wound bed, and synergic effects of terpenes/terpenoids remain to be
studied. Considering the state of wound healing treatments, it would be
worth more exploring this field: in fact, most of the EO summarized in
Table 1, have not been studied yet blended with biopolymeric struc-
tures. In the same way, polymers of current increasing interest in bio-
medical applications, like resorbable polyesters, could be taken ad-
vantage of EO properties for wound healing. EO could be specially
considered not only for chronic infected wounds, but also for enhancing
healing process with polymer scaffolds or dressings.
Acknowledgments
This work has been partially supported by the grant EMPRETECNO
0037/2012 of the National Agency for the Promotion of Science and
Technology of Argentina.
E.B.H. is full professor at the National University of San Martin
(Argentina) and Principal Researcher of the Argentine Council of
Scientific and Technological Research (CONICET). M.P.R. is
Postdoctoral fellow of CONICET at the School of Science and
Technology of the National University of San Martin.
I.E.R.A. is Postdoctoral fellow of School of Science and Technology
of the National University of San Martin.
Conflict of interest
None
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