Archives of Dermatological Research (2023) 315:943–955

https://doi.org/10.1007/s00403-022-02455-8

ORIGINAL PAPER

Use of propolis for skin wound healing: systematic review

and meta‑analysis
Julia Carnelós Machado Velho1 · Thais Amaral França1 · Maria José Malagutti‑Ferreira1 ·
Edilson Rodrigues Albuquerque2 · Francislaine Aparecida dos Reis Lívero2 · Murilo Racy Soares3 ·
Ademilson Espencer Egea Soares4 · João Tadeu Ribeiro‑Paes1

Received: 5 September 2022 / Revised: 19 October 2022 / Accepted: 31 October 2022 / Published online: 23 November 2022
© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2022

Abstract
Propolis is a natural resin that is produced by bees. It has anti-inflammatory and antibiotic properties, promotes reepitheliza-
tion, and stimulates skin regeneration. Propolis has great potential for the development of new therapeutic approaches to treat
skin ulcers. The present study performed a systematic review and meta-analysis of published studies of the use of propolis
for the regeneration of cutaneous wounds and its efficacy as a therapeutic agent. Data were collected from articles in the
PubMed, SCOPUS, and Web of Science databases that were published since 1900 by searching the terms “propolis” AND
“wound healing.” This search yielded 633 articles, of which 43 were included in this systematic review and meta-analysis.
The results showed that interest in the therapeutic efficacy of propolis has increased over the years. The studies reported
that the propolis was effective for the treatment of skin ulcers by promoting a higher percentage of healing than classically
employed interventions. The mode of propolis application has also evolved. An increasing number of studies combined
it with other substances and materials to achieve additive or synergistic effects on the skin regeneration process. Propolis
appears to be an effective therapeutic alternative for the treatment of skin ulcers.

Keywords Dressings · Natural products · Alternative therapy · Skin wounds · Wound regeneration

Introduction remodeling. It acts to stop bleeding, prevent infection by

The skin acts as a physical and chemical barrier that pro-
tects internal organs and the body as a whole against patho-
gens and dehydration [1, 2]. The skin is most often exposed
to injury and trauma, which represents a potential risk to
the body’s integrity. Skin regeneration is characterized by
four stages: hemostasis, inflammation, proliferation, and
* João Tadeu Ribeiro‑Paes
ribeiro.paes@unesp.br
1
Department of Biotechnology, São Paulo State University
(UNESP), Assis, São Paulo, Brazil
2
Preclinical Research Laboratory of Natural Products,
Universidade Paranaense (UNIPAR), Umuarama, Paraná,
Brazil
3
Department of Obstetrics and Gynecology, Ribeirão Preto
Medical School, University of São Paulo, Ribeirão Preto,
São Paulo, Brazil
4
Department of Genetics, Ribeirão Preto Medical School,
University of São Paulo, Ribeirão Preto, São Paulo, Brazil
removing debris and microorganisms from the wound bed,
proliferate epithelial cells and fibroblasts, stimulate angio-
genesis, granulation tissue formation, collagen deposition,
epithelialization, and wound retraction, and remodel new
tissue [3].
Skin lesions are a serious public health problem on a
global scale and “are a health quality indicator that generates
substantial morbidity and considerable health care costs”
[4]. An estimated 2% of hospitalized patients worldwide
are affected by chronic skin ulcers [4]. In 2017/2018, the
United Kingdom’s National Health Service estimated that
3.8 million people were affected by some type of wounds, at
a cost of ~ £8.3 billion [5]. In the United States, skin injuries
affected the quality of life of 2.5% of the population and
affected ~ 8.2 million healthcare beneficiaries in 2014, with
estimated expenditures between USD$28.1 and USD$96.8
billion for all types of wounds [6].
Sparse data on the occurrence and expenditures of skin
wounds have been reported in Brazil. Brito, de Vascon-
celos Generoso, and Correia [7] assessed the prevalence

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and characteristics of pressure ulcers in hospitals in differ-
ent regions of Brazil from March 2009 to February 2011.
These authors found that 16.9% of patients had pressure
ulcers. Becker et al. [8] evaluated the incidence and risk
factors of pressure ulcers in adult patients who were admit-
ted to intensive care units and reported an incidence of
13.6% of patients with pressure ulcers.
Self-regeneration of the skin is generally a consider-
ably fast and efficient process. However, extensive injuries,
deep burns, and such diseases as diabetes and peripheral
neuropathy can compromise the normal process of skin
healing and regeneration, often resulting in chronic ulcers
[9]. Classic procedures that are routinely used therapeu-
tically for skin ulcers have employed such materials as
gauze and cotton. However, these dressings have low
permeability and allow the leakage of exudates, which
can facilitate bacterial infection and cause bleeding and
damage to newly formed tissue when these dressings are
removed [10].
Researchers have sought to develop new therapeutic alter-
natives for cutaneous ulcers, such as dressings that interact
with the wound through the release of bioactive molecules
and the development of materials that are able to maintain
appropriate conditions for optimal skin regeneration [2,
11–15].
Besides that, therapeutic alternatives that are based on
natural components, such as Aloe vera (vegetable based), sil-
ver (mineral based), and honey and propolis (animal based),
have been proposed, based on practices and knowledge from
different countries and cultures. Egyptians and Persians,
for example, have used propolis and honey to treat wounds
since the beginning of human civilization [16]. In recent
decades, researchers have revealed more information about
the mechanisms of action and biological activities of these
compounds by characterizing their active constituents and
evaluating their anti-inflammatory, antibiotic, antifungal,
and antioxidant effects [9, 17–19].
Propolis is an animal product that is produced by bees.
Together with honey, propolis is one of the best known
antibacterial and anti-inflammatory agents that has been
used by humans since ancient times [20]. In recent years,
experimental research has shown that honey and propolis
can accelerate and improve the percentage of wound repair
than classically used procedures [21–26].
Propolis is a strongly adhesive natural resin that consists
of plant exudates, wax, and salivary secretions from bees.
It is known as a bee hive protector. Propolis is largely com-
posed of flavonoids, phenolic acids, fatty acids, vitamins,
ketones, and sugars, whose composition varies according to
the locality where it is produced [27, 28]. In Brazilian terri-
tory, 13 different types of propolis have been identified based
on the locality and plant species by which it is produced,
including brown, green, and red propolis [29].
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In addition to having documented anti-inflammatory and
antibiotic effects [30, 31], propolis has been shown to have
antitumor [32, 33] and antioxidant [20, 31] effects. With
regard to skin wound regeneration, propolis can lead to an
increase in reepithelialization, fibroblast growth factor-2
expression, and collagen deposition and stimulate the cel-
lular proliferation of keratinocytes and fibroblasts, thereby
contributing to faster and more effective skin regeneration
[34–36].
Considering the epidemiological impact of skin lesions
and potential of propolis as a new therapeutic alternative
for skin ulcers, we conducted a systematic review and meta-
analysis of the administration of propolis for the regenera-
tion of skin ulcers. We evaluated its efficacy in the treatment
of these wounds.
Materials and methods
Data search
The present systematic review and meta-analysis followed
the criteria of Preferred Reporting Items for Systematic
Reviews and Meta-Analyses (PRISMA) [37]. Data were
obtained from the SCOPUS, Web of Science, and PubMed
databases by searching the terms “propolis” AND “wound
healing” in the title, abstract, and keywords or as “Topics”
in Web of Science for all years. The databases were last
consulted on August 24, 2021. In addition to the articles sur-
veyed, the reference lists in these articles were also searched.
We sought to identify the largest possible number of studies
that are related to the theme of this systematic review.
Inclusion criteria
We included studies that (i) evaluated the application of
propolis as a therapeutic agent for the repair of skin ulcers
and (ii) were available as full text in English or Portuguese.
Exclusion criteria
We excluded studies that (i) evaluated only one case report,
(ii) did not address in vivo testing of wounds in animals
or humans, (iii) did not assess wound healing percentage/
rate or wound area/size, (iv) did not report their results as
means and standard deviations (which makes it impossible
to perform a meta-analysis), and (v) after performing the
analyses had results that differed considerably from the rest
(i.e., outliers), possibly leading to statistically incoherent
final results in this meta-analysis.
Archives of Dermatological Research (2023) 315:943–955
Data extraction
Information on wound area and the percentage of healing
was extracted from the articles. Results that were presented
by the articles as units of measurement area (­ cm2 or m
­ m2) or
length/diameter (cm or mm) were transformed into percent-
ages of remaining area, according Eq. (1). Numerical data
that were not presented in the text of the studies or in tables
and that were presented only in graphs were extracted as
proportions according to Eq. (2).
Percentage of remaining area = (Final area)∕(Initial area) × 100
(1)
Lx
x= .y (2)
Ly
where Lx is the measurement of the result in the graph, Ly
is the measurement of the y-axis for a given value, y is the
determined value of y, and x is the result of the experiment,
leading to an approximate result.
Meta‑analysis
To perform the meta-analysis, a period of approximately
2 weeks of treatment was standardized for all studies to
avoid potentially biased results. The parameters that were
used to perform the meta-analysis were the percentage of
healing and percentage of remaining area by comparing the
most complete propolis-containing treatment with the posi-
tive control or reference treatment. A third analysis was also
conducted to evaluate the effect of propolis that was com-
bined with biomaterials or other compounds or biomolecules
Fig. 1  Flowchart of the article
identification process of stud-
ies of propolis for skin ulcer
regeneration. Modified from
PRISMA flow
945
compared with the effect of propolis alone on the percentage
of healing.
The meta-analysis was performed using a random effect
model for all parameters because of the high heterogene-
ity of the data (I2 = 89.5 for percentage of wound healing,
I2 = 88.75 for percentage of remaining area, and I2 = 93.15
for propolis combination treatments, p < 0.0001). The meta-
for package [38] of R software was used, using as inputs the
sample sizes of the control and treatment groups and the
means and standard deviations for each of the groups.
Results
A total of 633 articles were found in all databases, of which
43 were included in the present systematic review and meta-
analysis after excluding duplicates (n = 260) and selecting
studies according to the inclusion and exclusion criteria
(Fig. 1).
The first published study among the articles included was
from 2008 [39] and was the only one from this year (Table 1,
Fig. 2). A gradual increase in the number of studies on the
topic was evident over the years. Notably, although 2013
stood out as one of the years with the highest number of
publications of the 43 total articles included, only 12 were
published in 2008 to 2014 (Fig. 2A).
More than two-thirds of the articles were published in
the last 7 years (Fig. 2A). For the distribution of articles
according to the country of publication, Brazil stood out
with 33% of the published articles, followed by Iran (18%),
Egypt (16%), and Iraq (9%). Other countries like India,
Poland, Australia, the United States, and Nigeria were
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Table 1  Studies included in the systematic review of propolis administration for skin ulcer regeneration
Author Year Country Administration Recipient Type of wound Parameters Treatment

McLennan et al. 2008 Australia Topical Sprague–Dawley Acute (diabetics) Area Propolis
rats
Eroksuz and 2009 Turkey Topical Rabbit Acute Area Propolis cream
Canpolat
Sehn et al. 2009 Brazil Topical Wistar rats Acute Area Propolis ointment
Khorasgani et al. 2010 Iran Topical Rats Acute Wound healingPropolis cream
Iyyam Pillai et al. 2010 India Topical Wistar rats Acute Wound healingPropolis ointment
Ahmed et al. 2011 Egypt Topical Wistar rats Burn (diabetics) Area Propolis-reference
mixture creams
Barud et al. 2013 Brazil Dressing Holtzman rats Acute Time for complete Biocelullose mem-
healing brane + propolis
Abu-Ahmed et al. 2013 Egypt Topical Equines (horses Chronic and acute Area Propolis (powder)
and donkeys)
Abdel-Wahed 2013 Egypt Topical Dogs Acute Area and wound Propolis (powder)
et al. healing
Kucharzewski 2013 Poland Topical Clinical trial Chronic Area Propolis ointment
et al.
Sulaiman et al. 2014 Pakistan Topical Albino rats Burn Area and wound Microemulsion
healing containing
Nigella sativa
honey and
concentrated
ethanolic extract
of propolis
Henshaw et al. 2014 Australia Topical Clinical trial Foot ulcer Area and wound Propolis
healing
Patil et al. 2015 India Topical Wistar rats Burn Wound healing Propolis-loaded
silver nanopar-
ticles
Abu-Seida 2015 Egypt Topical Mongrel dogs Acute Area Macrogol ointment
with propolis
Takzaree et al. 2015 Iran Topical Wistar rats Acute Area and wound Honey + propolis
healing
Hozzein et al. 2015 Saudi Arabia Topical BALB/c mice Acute (diabetics) Wound healing Propolis ethanolic
solution
Khorasani et al. 2016 Iran Topical Wistar rats Acute Wound healing Honey + propolis
(powder)
Silva et al. 2016 Brazil Topical Wistar rats Acute Area Base cream + geo-
propolis
Sarhan and 2017 Egypt Dressing Mice Acute Area Honey, polyvinyl
Azzazy alcohol, chitosan
nanofibrous with
propolis extract
Corrêa et al. 2017 Brazil Oral Swiss mice Acute Wound healing Red propolis etha-
nolic extract
Rosseto et al. 2017 Brazil Topical SKH-1 mice Acute Wound healing Solid lipid nanopar-
ticles + Propolis
extract
Nani et al. 2018 Brazil Topical Wistar rats Acute Area Ointment (Alpa-
Wash) containing
Brazilian micro-
nized propolis
and Peucedanum
ostruthium leaf
extract

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Table 1  (continued)
Author Year Country Administration Recipient Type of wound Parameters Treatment

Al-Waili 2018 Iraq/United States Topical New Zealand Acute Area and wound Two types of
rabbits healing propolis combina-
tion
Eyarefe et al. 2018 Nigeria Topical Albino rats Acute Area and wound Propolis extract
healing
Voss et al. 2018 Brazil Dressing Swiss mice Acute (diabetics) Wound healing Cellulose film
with polyvinyl
alcohol + vitamin
C + propolis
Balata et al. 2018 Egypt Dressing Wistar rats Acute Area and wound Propolis emulgel
healing
Ibraheim and 2018 Iraq Topical Dogs Acute Area Propolis ointment
Hayder
Kim 2018 South Korea Dressing Sprague–Dawley Acute Wound healing Carbopol hydro-
rats gel containing
propolis
Picolotto et al. 2019 Brazil Dressing Swiss mice Acute Area Bacterial cellulose
membrane associ-
ated with red
propolis
Kalil et al. 2019 Brazil Topical Sheep Acute Wound healing Green propolis
ointment
Eskandarinia et al. 2019 Iran Dressing Wistar rats Acute Area Film dressings
of cornstarch/
hyaluronic acid/
ethanolic extract
of propolis
Marquele-Oliveira 2019 Brazil Dressing Wistar rats Acute Area Biocellulose
et al. membrane with
microemulsified
propolis
Alberti et al. 2019 Brazil Topical Swiss mice Acute (diabetics) Wound healing Nanoparticles of
propolis
Al-Irayfawee1 2019 Iraq Topical Clinical trial Foot ulcer Area Propolis extract
et al.
Khodabakhshia 2019 Iran Dressing Wistar rats Acute Area and wound Propolis-coated
et al. healing polyurethane
Krupp et al 2019 Brazil Dressing Wistar rats Burn Wound healing Natural rubber-
propolis mem-
branes
Eskandarinia et al. 2020 Iran Dressing Wistar rats Acute Area and wound Dense polyure-
healing thane/propolis
membrane + bio-
degradable
polycaprolactone/
gelatin nanofi-
brous scaffold
Eskandarinia et al. 2020 Iran Dressing Wistar rats Acute Area Polyurethane/
hyaluronic
acid nanofibers
enriched with
propolis
Bayrami et al. 2020 Iran Dressing Wistar rats Acute Wound healing Gauze coated with
ZnO/CuO/Ag
nanocomposites
and propolis
extract

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Table 1  (continued)
Author Year Country Administration Recipient Type of wound Parameters Treatment

Alberti et al. 2020 Brazil Topical Swiss mice Acute (diabetics) Wound healing Nanofibrous scaf-
folds of polyvinyl
alcohol with
propolis nanopar-
ticles
Maciel et al. 2020 Brazil Topical Wistar rats Area and wound Low-level laser
healing therapy in the
presence of honey
and hydroalco-
holic propolis
solution
Sahib et al. 2020 Iraq Topical Albino rats Acute Wound healing Propolis ointment
Eyarefe 2021 Nigeria Topical Albino rats Acute (infected) Wound healing Propolis ethanolic
extract

Fig. 2  Number of articles on the

administration of propolis for
skin ulcer regeneration by (A)
year and (B) country from 2008
to 2021

responsible for the publication of one or two articles among
those that were analyzed herein, comprising 24% as “Oth-
ers” in Fig. 2B.
The results also showed that of the 43 articles, 10 admin-
istered propolis as an extract or powder, 11 administered
propolis as an ointment or cream, and 22 administered
propolis with some biomaterial, compound, or other therapy.
Among the combinations tested were latex membranes [40],
biocellulose [41–43], polyurethane [44], silver, honey, and
laser therapy [45–47].
Effect of propolis administration on cutaneous
wound healing
The effect of propolis administration on skin ulcers was eval-
uated as the percentage of wound healing (wound closure)
and percentage of remaining wound area. The effect size of
propolis on the percentage of remaining area was significant
(random effect model = −2.9474, 95% confidence interval
[CI]: −3.6970 to −2.1978, p < 0.0001; Fig. 3).
Similarly, for the effect of propolis on the percent-
age of wound healing, the effect size was also significant
(random effect model = 2.0995, 95% CI: 1.0972–3.1017,
p < 0.0001; Fig. 4).
The effect size of propolis combined with biomateri-
als, substances, or other treatments on the percentage of
wound healing was also evaluated using a random effect
model (I2 = 93.15, p < 0.0001), which was also significant
(random effect model = 5.1886, 95% CI: 2.8759–7.5013,
p < 0.0001; Fig. 5).
Bias analysis
Publication bias was assessed using a funnel plot of the
relation between standard deviation and the difference of
standardized means and using Egger’s regression test. The
funnel plot distribution was asymmetric for percent area
remaining (Egger’s regression: z = −9.0549, p < 0.0001),
percent healing (Egger’s regression: z = 4.2981,
p < 0.0001), and wound healing of propolis combinations
(Egger’s regression: z = 7.2747, p < 0.0001; Fig. 6A–C).

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Fig. 3  Forest plot of the effect
size of propolis on the percent-
age of remaining area
Fig. 4  Forest plot of the effect
size of propolis on the percent-
age of wound healing
Discussion
Considering that treatment approaches that are classically
employed for cutaneous ulcers have presented unsatisfac-
tory results in different clinical situations, new therapeu-
tic alternatives have been proposed, including the use of
compounds that have been used since antiquity to treat
various types of diseases. The number of studies of the
949
use of propolis for the treatment and regeneration of cuta-
neous ulcers has increased significantly, especially in the
last decade.
The results of this meta-analysis showed that propolis was
significantly more effective than controls in reducing the
wound area and consequently achieving a higher percentage
of regeneration. These findings justify research interest and
the increase in the number of publications on applications
of propolis for the treatment of cutaneous ulcers.
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Fig. 5  Forest plot of the effect
size of propolis combination
treatments on the percentage of
wound healing
According to the data that were collected in the present
systematic review, Brazil, Iran, Egypt, and Iraq stand out
as leaders in research on the subject. There may be a direct
relationship between this finding and the fact that propolis
preparations are popularly known in these countries, espe-
cially green and red propolis in Brazil and Iranian propolis.
Al-Waili [48] compared the efficacy of two samples of
propolis that were collected in different regions of Iraq at
different times of the year. Consequently, these samples
were produced from different flora because vegetation in
this geographic area varies according to climate and time
of the year. The results showed higher efficacy of one of the
samples. When these two types of propolis were mixed, a
higher rate of wound regeneration was observed compared
with either of the two samples alone, thus revealing their
synergistic action.
Propolis composition includes several types of mol-
ecules with potential regenerative and differentiation
effects, such as flavonoids, phenolic acids, fatty acids, vita-
mins, ketones, and sugars. Being produced from plant sap,
the composition of propolis varies according to several
aspects, such as, the botanical composition, geographical
origin, time of collection and environmental conditions
[49]. This variation in composition, and therefore in the
presence and concentration of secondary metabolites, may
result in different results for treatments developed with
different types of propolis. Besides, the mechanisms of
action in the regenerative process promoted by propolis
are not well defined. This can be a very complex issue
with natural products, whose activity is not due to a single
chemical entity, but to a mixture of constituents, some of
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which are not yet identified. Some natural products contain
many active compounds that act through different mecha-
nisms and unique interactions collectively have very high
efficacy [50].
Propolis appears to be effective in regenerating skin
ulcers overall, however, this efficacy does not appear to be
related solely to only one type of propolis that is tested. The
analysis of results from studies that used propolis of differ-
ent origins suggested that other aspects influence efficacy
with regard to regeneration more than the type of propolis
per se. Studies that used Iranian [28, 51–54], Egyptian [46],
Brazilian red [43], or Iraqi [48] propolis all reported similar
results, achieving more than 90% regeneration of wounds
after 14 days of treatment.
Interestingly, studies of propolis of the same origin [46,
55] reported quite different results. Sarhan and Azzazy [46]
achieved 100% wound regeneration on day 12 of treatment,
whereas Ahmed et al. [55] reported regeneration of only
30% after 14 days of treatment. The reason for this discrep-
ancy may have more than one explanation.
One aspect to be considered is individual variations of
wounds in each experimental design. Sarhan and Azzazy
[46] evaluated the effect of Egyptian propolis on an acute
“punch” wound, whereas Ahmed et al. [55] applied propolis
to treat burns in animals with induced diabetes, a pathologi-
cal condition that makes the skin regeneration process more
complex. Additionally, Sarhan and Azzazy [46] applied
propolis combined with nanofibers that were made of honey,
polyvinyl acid, and chitosan, whereas Ahmed et al. [55]
applied propolis combined with a commercial ointment with
healing properties (1% silver sulfadiazine, Dermazine®).
Archives of Dermatological Research (2023) 315:943–955 951

Fig. 6  Funnel plot of the rela-

tion between standard deviation
and the difference of standard-
ized means for percentage of
remaining wound area (A),
wound healing (B), and wound
healing of propolis combina-
tions (C)

Bayrami et al. [56] tested Iranian propolis combined with and negative outcomes with these combinations. Thus,
zinc oxide (ZnO), copper oxide (CuO), and silver (Ag) in although the same type of propolis was used in these stud-
several different combinations. They found both positive ies, the propolis/ZnO and propolis/Ag/ZnO combinations

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were more effective in promoting wound regeneration than
the other combinations.
The great majority of the studies that were evaluated in
this systematic review applied the therapeutic compounds
topically or in the form of dressings [47, 57–59]. Only
Corrêa et al. [30] administered an ethanolic extract of red
propolis orally to animals. Until 2014, most of the published
studies administered propolis in the form of an alcoholic or
aqueous extract [39, 60] or as a cream or powder [34, 61,
62]. Exceptions were Barud et al. [41], who evaluated the
healing potential of a biocellulose membrane that was asso-
ciated with propolis, and Sulaiman et al. [63], who combined
an ethanolic extract of propolis with honey.
Since 2015, nearly half of the published articles used a
biomaterial, compound, or other therapy that was associated
with propolis. Among these, the most used combinations
were cellulose/bacterial cellulose [41–43, 64], honey [23,
51], polyvinyl alcohol [24, 46], and polyurethane [28, 44,
53]. Other studies combined more than one biomaterial or
composite [46, 53].
The results of this meta-analysis show that these combi-
nations are successful treatments, in which the administra-
tion of propolis together with another compound or material
was significantly more effective in the healing process than
propolis alone. These other compounds or material may gen-
erally have properties that are favorable to the regeneration
of epithelial tissue, resulting in possible additive or syner-
gistic effects. Takzaree et al. [23] showed that the admin-
istration of a combination of honey and propolis was more
effective than either of them applied alone.
These therapeutic components were evaluated in different
types of wounds, including acute wounds [65–68] burns [40,
45], and chronic wounds [69]. Eyarefe [25] administered
an ethanolic extract of propolis on acute wounds that were
infected with bacteria. Four studies evaluated wound regen-
eration in animals with induced diabetes [24, 56, 70, 71]. An
acute wound in a healthy animal will likely undergo a much
more efficient and faster healing process than a wound in a
diabetic animal or a lesion that is exposed to microorgan-
isms, such as bacteria. Therefore, comparisons of the results
of these studies that were obtained within the same treatment
time without considering these other circumstances may not
reflect clinical reality and thus may represent an analytical
bias of the results.
However, these circumstances emphasize the treatment
effect, as was presented by Voss et al. [42]. In this study, the
effect of cellulosic films that were combined with vitamin
C and propolis was compared between diabetic and non-
diabetic rats. No significant difference in effects on ulcer
regeneration was found between the treatment and control.
However, when the process of wound repair was evaluated
in diabetic animals, the results showed that the treatment
had a significantly greater effect than the control, reaching
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a regeneration rate that was very close to wounds in non-
diabetic animals. A similar result was reported by Mclennan
et al. [39].
The procedures currently used to treat skin ulcers use
dressings that have low permeability and allow the leakage
of exudates, facilitating bacterial infection, besides caus-
ing damage to the newly formed tissue when removed. This
process can hinder skin regeneration, especially when the
wound is difficult to heal, such as infected wounds or chronic
wounds. In contrast, the antibiotic effect of propolis enables
the elimination and prevention of bacteria in the wound. In
addition, its anti-inflammatory and antioxidant effect may
be responsible for stimulating the regeneration process of
chronic ulcers, such as diabetic ulcers. Thus, propolis could
promote a faster and more effective regenerative process,
even for wounds that are difficult to heal.
Another notable aspect that varied among studies was the
different species that were used to evaluate ulcer repair. Most
of the articles evaluated the efficacy of treatments in rats or
mice, but some studies used dogs [72–74], rabbits [48, 75],
horses [76], and sheep [77]. We also identified three clinical
studies, in which the therapeutic compound was applied to
patients with chronic wounds [60, 62, 69].
This variety of species may partially explain the hetero-
geneity of results of the present meta-analysis. Nonetheless,
the findings strongly suggest the high potential of propolis
for veterinary use to resolve wounds that are otherwise diffi-
cult to manage clinically, especially in species that are more
susceptible to injuries, such as horses and sheep, because of
their specific physiological and behavioral characteristics
[78].
In summary, the present systematic review and meta-
analysis found strong evidence that propolis has therapeutic
promise for the treatment of skin ulcers, including difficult-
to-heal ulcers that are found in patients with diabetes and in
bedridden patients with pressure ulcers. The findings justify
the growing interest in propolis in regenerative medicine,
especially over the last few years. New studies are seeking
to optimize the therapeutic effects of propolis by combining
it with other substances and biomaterials to achieve additive
or synergistic effects to improve the regeneration process of
cutaneous ulcers of different etiologies.
Limitations
Although the present systematic review attempted to include
all published articles that meet the inclusion criteria, the bias
analysis indicated that there may be publication bias for all
parameters evaluated. Another limitation was the presence
of different controls in each study. We initially sought to
compare propolis with a positive control or reference treat-
ment. However, some studies used only negative controls
(e.g., gauze or saline solution application) and compared
Archives of Dermatological Research (2023) 315:943–955
propolis to no intervention. This difference in controls may
have considerably affected the final results of the meta-
analysis because propolis likely has much more pronounced
effects statistically compared with a negative control relative
to a positive control or reference treatment. The efficacy of
propolis that is equal to, or slightly better than, a reference
treatment would be a much more clinically relevant finding.
Another limitation was the analysis of only one aspect
of wounds (i.e., wound area), which may limit a more thor-
ough understanding of the effects of propolis on all aspects
of tissue regeneration. Future studies should include data
on histological analyses of tissues, in addition to evaluating
the presence or absence of indicators of the healing process,
such as reepithelialization or granulation. Besides that, it
would be of great importance to produce studies that try
to determine more precisely which are the mechanisms of
action involved in the efficacy of propolis in regenerating
skin ulcers.
Acknowledgements We thank Dr. Luiz Felipe Machado Velho for sug-
gestions during project development and Dr. Jéssica Andrade Vilas
Boas for suggestions on protocols and scripts for the analyses and meta-
analysis. This research was developed with the support of Universidade
Estadual Paulista (UNESP).
Author contributions The study conception and design were performed
for JCMV and JTRP Literature review and data collection for meta-
analysis were performed by JCMV, TAF, ERA and MMF. The data
analysis were performed by JCMV, TAF, AEES and JTRP. The first
draft of the manuscript was written by JCMV and JTRP and the criti-
cal review of the manuscript were performed by JCMV, JTRP, FARL,
MRS and AEES. All authors commented on previous versions of the
manuscript. All authors read and approved the final manuscript.
Declarations
Conflict of interest The authors declare that they have no conflict of
interest and no competing interests.
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