Chemistry Biodiversity - 2023 - Antonio Pereira

doi.org/10.1002/cbdv.
202201021 REVIEW
Traditional Plants Used in Southern Brazil as a Source to Wound

Healing Therapies
Isabela Antonio Pereira,a Benhur Judah Cury,b Ruan Kaio Silva Nunes,b and Luisa Mota da Silva*b
a
Nursing Course. University of Vale do Itajaí - UNIVALI, Itajaí, Brazil
b
Postgraduate Program in Pharmaceutical Sciences, University of Vale do Itajaí-UNIVALI, Itajaí, Brazil,
e-mail: [email protected]; [email protected]
In southern Brazil, the biodiversity is great and the traditional use of medicinal plants for wound healing has
been documented in ethnobotanical studies and pharmacological studies have assessed their wound properties
and phytochemistry. Therefore, this study evaluated ethnobotanical surveys regarding medicinal plants used in
southern Brazil for wound healing and studies about the healing properties of these plants published between
2000 and 2022. To retrieve articles related to the study, Web of Science, PubMed (NLM), Open Access Journals,
Scielo, Lilacs, and Google Scholar, with keywords including medicinal plants, wound healing, and South of Brazil,
have been used. As a result, 73 medicinal plants belonging to 39 families were found in ethnobotanical surveys
as a traditional resource used for wound healing in southern Brazil, 15 of which were cited more than once.
Besides, 14 of these 15 plants were also used as healing agents worldwide. The most cited plant with healing
actions in southern Brazil was Symphytum officinale L. (comfrey). From 2000 to date, 44 articles scientifically
demonstrated the wound-healing effects of the southern Brazilian plants found in ethnobotanical surveys
reviewed. The folk medicine of southern Brazil presents a variety of medicinal plants for wound-healing
purposes, and scientific data were found for some of those plants. However, the wound-healing properties of
many plants have yet to be investigated, and the current literature still needs more phytochemical information
about the plants studied. Aside from this, the future focus should be on the standardization of herbal extracts,
and further research is required to investigate the pharmacological mechanisms. Clinical research in this area
remains in its infancy and warrants more robust further clinical studies.
Keywords: medicinal plants, healing, wounds, Southern Brazil, folk medicine, comfrey.
Ethnobotanical surveys are essential to register

1. Introduction
with scientific criteria the use of medicinal plants in
The therapeutic use of medicinal plants in human each region. Later ethnopharmacological studies are
health is a millenary practice historically built on the carried out to collaborate with experimental evidence
character of common sense that mentions culture and to validate the traditional knowledge.
health since these aspects do not happen in isolation Many issues need to be known about the tradi-
but are introduced in a determined historical tional use of a species to direct experimental studies
context.[1] People’s interaction with the local biodiver- correctly. It is essential to know the place of the
sity has accumulated essential knowledge. Considering harvest, seasonality issues, the part used, and the
that Brazil is one of the countries with the most method of preparation employed by the population to
incredible biodiversity in the world and that there is enjoy the therapeutic benefits of the plant in question,
also a rich ethnic and cultural diversity, because of the which is usually done in the form of teas and infusions.
miscegenation from the colonization of the country, Increasingly, the authors have been concerned with
the wealth of medicinal plants in biodiversity from guiding themselves by these items in the experimental
Brazilian biomes is vast. design construction of their studies.
Chem. Biodiversity 2023, 20, e202201021 © 2023 Wiley-VHCA AG, Zurich, Switzerland
16121880, 2023, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/cbdv.202201021 by UFRA - Universidade Federal Rural da Amazonia, Wiley Online Library on [04/09/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Chem. Biodiversity 2023, 20, e202201021
Southern Brazil (Figure 1) is a biome with a after the injury occurs, a cascade of physiological
remarkable biodiversity of plant species, many of events is triggered to obtain tissue reconstruction as a
which are used by local communities as a source of result, such a process is common in all wounds,
treatment for different diseases, including wounds. regardless of the etiological agent.[2] Thus, wound
Therefore, this study revisits the traditional use of healing is expressed by a dynamic and systemic
medicinal plants from southern Brazil in healing process that contains stages of inflammation, angio-
wounds and the pharmacological characteristics of the genesis, formation of granulation tissue, and finally,
reported plant species and critically analyses the the remodeling of fibroblast connective tissue,[3]
pharmacological investigations and phytochemical during this process occurs the release of chemokines,
data (when available) that substantiate the actions proliferation of fibroblasts, formation of connective
that are reported. tissue and migration of leukocytes.[4] Therefore, several
Wounds occur due to different etiological factors medicinal plants are important to assist in these
that can cause damage to skin integrity. In this case, phases, ensuring speed and efficiency in the process
Isabela Antonio Pereira, a nursing Luisa Mota da Silva, pharmacist

student at the University of Vale (2004, Catholic University of San-
do Itajaí. Nursing intern at the tos), Specialist (2007), Master
Department of Epidemiological (2010), and Ph.D. (2014) in Phar-
Surveillance of Navegantes (Santa macology from the Federal Uni-
Catarina, Brazil). versity of Paraná (UFPR). She was
a postdoctoral fellow (PNPD/
CAPES) in the Graduate Program
in Pharmaceutical Sciences
(PPGCF) at the University of Vale
do Itajaí (UNIVALI) between 2014
Benhur Judah Cury, a pharmacist and 2016. She guides research in
from the University of Vale do the pathophysiology and pharmacology of the gastro-
Itajaí (UNIVALI, Brazil, 2019). Mas- intestinal tract, developing research to evaluate targets
ter in Pharmaceutical Sciences by and therapeutic alternatives for diseases such as gastric
the Graduate Program in Pharma- ulcer, gastritis, and inflammatory bowel diseases. In
ceutical Sciences at UNIVALI (Bra- addition, she also develops research that investigates the
zil, 2022). He was a scientific role of the brain-gut axis in neuropsychiatric comorbidities
initiation fellow collaborating with of inflammatory bowel diseases and the importance of this
research in the pharmacology of axis in autism spectrum disorder. She also collaborates on
natural products. He has experi- projects involving central nervous system pharmacology
ence around Pharmacology, with and cardiorenal pharmacology. She is a reviewer for
an emphasis on the Pharmacology different international journals and an ad hoc consultant
of the Gastrointestinal Tract. He also has experience as a for the CNPQ and FAPESC agencies. She is the Leader of
physical-chemical quality control analyst for natural prod- the Research Group at CNPq for the Biological Evaluation
ucts and analytical instrumentation. of Natural and Synthetic Products and Research Productiv-
ity Scholarship (CNPq) since 2019. She is a member of the
Ruan Kaio Silva Nunes, nutritionist Brazilian Society of Pharmacology and Experimental Ther-
graduated from the University of apeutics (SBFTE) since 2008 and a Member of the Board of
Vale do Itajaí (UNIVALI, 2021). SBFTE Inspector (triennium 2021 to 2023) and Univali’s
During graduation, he was a sci- Animal Experimentation Ethics Committee since 2018.
entific initiation scholarship and is
currently a master’s student in the
graduate program in pharmaceut-
ical sciences at UNIVALI with a
scholarship from the Coordination
for the Improvement of Higher
Education Personnel (CAPES, Bra-
zil) in the line of research in the
pharmacology of natural products.
www.cb.wiley.com (2 of 27) e202201021 © 2023 Wiley-VHCA AG, Zurich, Switzerland

Figure 1. A Map of South America (white) highlighting the geopolitical division of Brazil (gray) and South region (soft gray); B South
region highlighting Paraná, Santa Catarina, and Rio Grande do Sul States.
so that it is used properly and with the support of a

health professional.[5] process has been mentioned since prehistory[6] and is
In Brazil, the national phytotherapeutic policy aims widely used in southern Brazil.[7] However, many plants
to expand the therapeutic alternatives offered to users still need scientific research to prove their action and
of the Unified Health System (SUS), through access to safety, and it is necessary to educate the population
medicinal and herbal plants, with safety, efficacy, and and the health professional on the correct use of
proven quality, aiming to improve the health care for plants as a therapeutic resource.[8,9]
the population and social inclusion. The use of In this scenario and given the importance of the
medicinal plants to accelerate the wound healing search for information that contains evidence about

the safety and efficacy of medicinal plants to treat plant used, preparation form, the study methods, the
wounds, this critical review has the main objective to activity potential, and the main active chemical
highlight the most used medicinal plants in the components reported.
southern region of Brazil and revisit critically, following
popular use, studies published in the last 22 years
reporting their pharmacological activity to assist the
3. Results and Discussion
wound healing process to present their relevance in
the source for new therapies to wound healing. In a preliminary review to gather articles describing
Southern Brazilian plants used to treat wounds, 261
articles were selected for both electronic and manual
searches. After removing duplicates and triaging
2. Materials and Methods
relevant titles and abstracts, a total of 12 articles with
The present work reflects an analysis of data through a ethnobotanical surveys met the inclusion criteria. Of
narrative and critical review of the literature, which these articles, 4 were from the state of Paraná, 4 were
aimed to answer the following questions: 1: “Following from the state of Santa Catarina, and 4 were from the
published ethnopharmacology surveys, what are the state of Rio Grande do Sul.
main medicinal plants used in wound healing in the In this step, 73 plant species are described as used
southern region of Brazil?”, and 2: “Are the scientific by southern communities and different populations
ethnopharmacological reports selected from the last also use 14 in Brazil as wound-healing agents.
22 years about the efficacy of these plants in agree- In the twelve articles that carried out ethnobotan-
ment with the popular use?” ical surveys, the predominance of women in partic-
First, we reviewed articles describing the use of ipation in the research was identified in 9 of the
medicinal plants in communities in southern Brazil to analyzed articles. The predominance of women dem-
treat wounds. The descriptors previously consulted onstrates the importance of women in the trans-
from the DeCs (Health Sciences Descriptors) were mission of information between generations and the
used: “Medicinal plants” AND “Wound healing”, their responsibility for care and attention to collective
Portuguese correspondents, “Medicinal plants” and health, using medicinal plants for such execution.[10]
“Healing of wounds and the keyword” and “South of The plants mentioned to treat wounds in the southern
Brazil” with the Boolean operator AND in the following region of Brazil cited in the ethnobotanical surveys
portals: PubMed, Virtual Health Library, Scielo, and evaluated are shown in Table 1.
LILACS. Next, the name of each species in the list of Analyzing the data emerging in the present review
medicinal plants used in southern Brazil to accelerate from the ethnobotanical surveys, it was possible to
wound healing obtained in the first step was con- identify 73 medicinal plants that are used to wound
sulted by Web of Science, PubMed (NLM), Open Access healing in southern Brazil, 15 (20.5 %) of them cited
Journals, Scielo, Lilacs, and Google Scholar to search more than once, considered as the main ones. In
for original articles that had studied those plant addition, 39 families were found, and 19 (48 %) were
species to heal wounds, whether preclinical or clinical. described more than once. The Asteraceae family was
The criteria for inclusion of the articles were: 1) the most popular, being addressed in 16 medicinal
publications in English, Portuguese, or Spanish be- plants. Furthermore, the most cited plant with healing
tween 2000 and 2022; and 2) studies carried out with action in the southern region of Brazil was Symphytum
Southern Brazilian plants in which results of the officinale L. (comfrey), described in 6 of the 12
investigations show plants that have improved preclin- analyzed ethnobotanical surveys.
ical or clinical wound healing. Studies without an assay After analyzing the 12 ethnobotanical surveys,
in wound healing were excluded, as well as reviews, another 44 studies were reviewed here due to their
and ethnobotanical studies with the citation of the scientific relevance in describing the effects in wound
genus only and without specification of its popular healing of the Southern Brazilian plants found in those
use. reviewed ethnobotanical surveys, totaling 56 articles
The documented list of Southern Brazilian plants reviewed in this research. The ethnopharmacological
used to treat wounds obtained was composed of the studies about the healing wound properties of South-
plant used, popular name, family, preparation form, ern Brazilian plants are shown in Table 2.
and indication. The revised ethnopharmacological Next, we list medicinal plants used to treat wounds
studies were critically evaluated about the part of the in southern Brazil and reviewed research about their

Table 1. Medicinal plants that are cited in ethnobotanical surveys to treat wounds in southern Brazil.
Family Specie/Scientific name Popular name Part used Refs.
Adoxaceae Sambucus australis cham. E Sabugueiro/acapora/ Flowers, fruits [69]
Schltgl sabugo-negro and barks
Alliaceae Allium sativum Alho Bulb [11,68]
Amaranthaceae Alternanthera dentata Penicillina Leaves [68]
(Moench) Stuchlik
Chenopodium ambrosioides Erva-de-santa-maria Leaves [68,73]
L.
Anacardiaceae Schinus therebin sativum Aroeira Leaves [73]
Apiaceae Apium sellowianum Wolff Aipo Leaves [46]
Petiveria alliacea L. Guiné Whole plant [12,46]
Petroselinum crispum (Mill.) Salsão Roots and aerial [46]
A. W. Hill parts
Araceae Monstera deliciosa Liebm. Banana-de-macaco Leaves [12]
Araliaceae Hydrocotyle bonariensis Chapéu-de-cobra/ Whole plant [68]
Comm. ex Lam. erva-capitão
Asteraceae Acanthospermum australe Carrapicho Leaves [68]
(Loefl.) O. Kuntze
Achillea millefolium Linn. Mil-folhada/Pronto- Leaves and [46,73]
Alívio branches
Achyrocline satureioides Marcela/macela Leaves and [69,11,73]
(Lam.) DC Flowers
Ageratum conyzoides L. Picão-roxo Leaves [69]
Arctium lappa L. Baldrana/Baldana Gel [11,46,68]
Artemisia absinthium L. Losna Leaves [46,73]
Bidens alba L. DC. Picão-preto Leaves [68]
Bidens pilosa L. Picão-preto Roots and flower [68]
Calendula officinalis L. Calêndula Whole plant [7,11,46,69]
Chamomilla recutita L. Camomila or Maçanil- Dried flower; [7,69]
ha leaves
Heterothalamus Less. Erva-formigueiro Leaves [68]
Porophyllum ruderale (Jacq.) Picão-branco Whole plant [12]
Cass.
Senecio brasiliensis Maria-mole Whole plant [11]
(Spreng.) Less.
Solidago chilensis Meyen Arnica/arnica-brasi- Stem and leaves [68,69]
leira
Tanacetum vulgare L. Catinga-de-mulata/ Flowers and [68]
palma leaves
Xanthium cavanillesii Carrapicho Leaf or Whole [68]
Schouw plant
Asphodelaceae Aloe saponária Haw Aloe-sabão Leaves [68]
Boraginaceae Symphytum officinale L. Comfrei Leaves [7,11,12,31,46,68]
Cactaceae Opuntia ficus-indica (L.) Cactus Terminal clado- [68]
des
Pereskia aculeata Miller. Ora-pro-nóbis Leaves [75]
Caesalpinaceae Copaifera trapezifolia Pau-de-óleo Resin [74]
Hayne.
Celastraceae Maytenus ilicifolia Mart. ex Espinheira-Santa/can- Leaves [7,11,46,75]
Reissek corosa
Clusiaceae Rhedia gardneriana planch Bacupari/saputá Fruits and leaves [73]
Crassulaceae Bryophyllum pinnatum Folha-da-fortuna Leaves [11]
Sedum dendroideum Moc. & Balsamo/bálsamo-ale- Leaves [12,68]
Sessé ex DC. meão
Sedum madagascariense Balsamo Leaves [47]
Euphorbiaceae Jatropha multifida Linn. Mertiolate/flor-de- Leaves and [12,47]
sangue stems

Table 1. (cont.)
Family Specie/Scientific name Popular name Part used Refs.
Equisetaceae Equisetum hyemale L. Cavalinha Branches or [7]
whole plant
Fabaceae Myroxylon peruiferum L. f. Bálsamo/cabreúva Fruits, leaves [69]
and resin
Senna occidentalis L. Link Sene Leaves [69]
Geraniaceae Pelargonium odoratissimum Malva-de-cheiro Leaves [68]
(L.) L’Hér.
Lamiaceae Leonurus sibiricus L. Rubim/erva-macaé Leaves [12]
Mentha × piperita L. hortelã-pimenta or Branches and [7]
hortelã-preta leaves
Ocimum basilicum Linn. Alfavaca/Manjericão Branches with [73]
fresh leaves
Rosmarinus officinalis L. Alecrim/alecrim-do- Leaves [46,47]
jardim
Lauraceae Persea americana Mill. Abacateiro Leaves [68]
Lythraceae Heimia salicifolia (H.B.K.) Sarandi Leaves [46]
Link
Malvaceae Malva parviflora L. Malva cheirosa or mal- Leaves and [7,68]
va stems
Malvaceae Malva sylvestris L. Malva Leaves [11,46,68,69]
Meliaceae Melia azedarach Cinamomo Trunk bark [11]
Myrtaceae Eucalyptus glubulus Labill. Eucalipto-cheiroso/eu- Leaves and [75]
calipto stems
Myristicaceae Virola surinamensis (Rol. Ex Noz-Moscada/Ucuuba Fruit peels [69]
Rottb) Warb.
Passifloraceae Passiflora alata, P. edulis, P. Maracujá Fruit peels [73]
incarnata
Piperaceae Piper umbellatum L. Pariparova Leaves [11]
Plantaginaceae Plantago australis Lam. Tanchagem Leaves and [7,46,68]
seeds
Plantago major L. Transagem Whole plant [7,11,69]
Polygonaceae Muehlenbeckia sagittifolia Salsaparrilha Leaves [46]
(Ort.) Meisn
Polygonum hydropiperoides Erva-de-bicho Whole plant [11,69]
Michaux
Rosaceae Fragaria vesca L. Morango Fruit and leaves [68,69]
Rosa × alba L. Rosa-Branca Flower core [12,73]
Ruscaceae Sanseviera trifasciata Espada de são Jorge Leaves [73]
Rutaceae Citrus sinensis Laranja Leaves [11,68]
Ruta graveolens Linn. Arruda Leaves [74]
Salicaceae Salix humboldtiana Willd. Salgueiro Barks [68]
Sapotaceae Mimusops elengi Linn. Cereja-Espanhola Fruits [74]
Solanaceae Solanum americanum Mill. Erva-moura/maria- Leaves [11]
pretinha
Verbenaceae Stachytarpheta cayennensis Gervão Leaves, stems [11]
(Rich.) Vahl and roots
Xanthorrhoeaceae Aloe arborescens Mill. Babosa doce or Babo- Leaves, stems [7,12,68,73,74,76,77]
sa
Aloe vera (L.) Burm.f. Babosa or aloe vera Leaves [7,11,12,69,75]
popular use and effectiveness published between the 3.1. Symphytum officinale L.
years 2000, and 2022. Finally, we present comments
on those studies and future perspectives for research The results showed that the medicinal plant most
in this field. cited with healing activity was Symphytum officinale L.,
popularly known as Comfrey. The leaves of this plant

Table 2. Experimental studies about the healing wound effects of plants used to wound healing in southern Brazil.
Scientific Used Type of extract Type of study/ Main results Refs.
name part Experimental model
Allium Bulb Thiosulfinate- In vitro study with human Topical applications of the [59]
sativum L. enriched Allium keratinocyte cells and in - extract accelerate wound
sativum extract vivo experiments to verify healing in vivo and in vitro
(TASE). wound healing in a mur- tests. Moreover, topical
ine model. applications of TASE upre-
gulated the expression
levels of epidermal mRNA
for elongation of very long
chain fatty acids-4, β-
Hydroxy β-methylglutaryl-
CoA, serine palmitoyltrans-
ferase, filaggrin, loricrin,
and involucrin on day 3
after wounding.
Allium Bulb Garlic oil with An experimental study The mixture of honey and [60]
sativum L. honey. evaluating antioxidant, A. sativum has an en-
synergistic antimicrobial, hanced wound-healing ef-
and burn wound healing fect when compared to
in rats. the usual treatment. Be-
sides, the synergistic anti-
microbial effect against all
tested strains was verified.
Allium Bulb Aged garlic An experimental study us- The topical application of [61]
sativum L. water-ethanol ing chicken dorsum skin 15 % AGS had a significant
extract (AGS) excisional wound assay. improvement in wound
healing, increased prolifer-
ative phase, and complete
re-epithelization. Further-
more, the AGS application
increased neovasculariza-
tion in the wound site.
Allium Bulb Ethanolic aged An experimental study us- The aged garlic extract [62]
sativum L. garlic extract ing skin burn with a hot accelerates the inflamma-
stamp after toxicity in- tory and proliferative
duced by malathion and/ phase of burn-healing.
or carbaryl in male rats.
Aloe arbores- Leaves Whole plant An experimental study us- Topical application of the [17]
cens Mill. juice ing two types of injury extract improves the injury
models in rabbits, linear- healing process, and selec-
incision, and punch-inci- tively inhibits microbial
sion. growth.
Aloe arbores- Leaves Boiled water, An in vitro study evaluat- Ethanol extracts were able [18]
cens Mill. ethyl acetate ing antibacterial and anti- to inhibit the growth of all
and ethanol ex- fungal activity. tested Gram-positive and
tracts Gram-negative bacterial
strains and showed anti-
fungal activity against all
tested strains.
Aloe arbores- Leaves Crude leaf ex- An in vitro study assessing The study supports the [19]
cens Mill. tract Aloe arbor- antiproliferative effect, topical application of Aloe
escens prodifferentiative activity, arborescens Miller in the
and antibacterial action. treatment of hyperprolifer-
ative skin disease or squ-
amous cell carcinoma.

Table 2. (cont.)
Aloe vera (L.) Leaves Aloe vera inner An experimental study us- Both methods of applica- [33]
Burm.f. gel ing surgically induced tion showed accelerating
wounds in rats. tissue regeneration. Micro-
current associated with
Aloe vera gel increased the
healing area, number of
cells and new vessels at
day 10.
Aloe vera (L.) Leaves Aloe vera inner An experimental study us- The results suggest A. vera [34]
Burm.f. gel ing in vitro analyses of cell accelerates wound healing
proliferation and migra- by promoting the prolifer-
tion on human primary ation, and migration of
skin fibroblasts. fibroblasts and keratino-
cytes.
Aloe vera (L.) Leaves Aloe vera freez- An experimental study A high dose of topical [35]
Burm.f. er-dried poder wound defect on the dor- application of A. vera sig-
sum back of rats. nificantly increased the
percentage of wound
healing area after 20 days
of injury. In addition, the
treated animals increased
the number of fibrocytes,
and macrophages and in-
creased the diameter of
the blood vessels.
Aloe vera (L.) Leaves Aloe vera inner A double-blind, random- Topical Aloe vera gel sig- [36]
Burm.f. gel ized, human-controlled nificantly demonstrated
clinical trial and system- accelerated skin graft heal-
atic review of patients ing but showed no signifi-
who underwent split- cant pain relief.
thickness skin graft.
Aloe vera (L.) Leaves Freeze dried A study evaluating the The combination of amni- [37]
Burm.f. powder from second-degree burn-in- otic membrane and Aloe
Aloe vera gel duced in rats, and in vitro vera extract promotes Ha-
wound healing scratch as- CaT and HFF1 cell attach-
says, cytotoxicity, biocom- ment and proliferation.
patibility, cell attachment Scratch assay demon-
and proliferation. strated significantly accel-
erated wound closure. An-
imals treated with the
same association showed
accelerated wound closure
through re-epithelializa-
tion and wound contrac-
tion, besides, the animals
present increased epitheli-
alization and angiogene-
sis.
Aloe vera (L.) Flowers Ethanol extract In vitro study using hu- The A. vera flower and [40]
Burm.f. of flowers and man dermal fibroblast Aloe gel mixture synergis-
Aloe vera gel (NHDF) cells. tically induced the prolif-
eration, migration, and es-
pecially extracellular
matrix formation of nor-
mal human dermal fibro-
blasts cells by enhancing

Table 2. (cont.)
the expression of micro-
fibril-associated glycopro-
tein 4.
Aloe vera (L.) Leaves Aloe vera gel A preclinical study using Macroscopic observations [38]
Burm.f. excisional wounds created of the aloe gel and/or
on the back skin of strep- olive oil-treated group ex-
tozotocin-induced dia- hibited almost complete
betic rats. healing at day 14, while
other groups were still in
progress. Immunohisto-
chemical analysis showed
a mild expression pattern
of nuclear factor-кB. While
the cell proliferation and
angiogenesis markers
were upregulated.
Arctium Root Aqueous extract In vitro analyses with Ca- The data suggested that [65]
lappa L. nine immortalized dermal the burdock has implica-
fibroblast-hTERT. Cell via- tions for cell adhesion and
bility and adhesion assay, gene expression with the
RNA sequencing, and qRT- modulation of catenin
PCR. Wnt/β signaling and chon-
droitin sulfate biosynthe-
sis, which are particularly
important for the wound
healing process.
Arctium Leaves Full-sized leaf A prospective, commun- The use of this herbal [66]
lappa L. ity-based participatory remedy seems to be an
clinical research. acceptable alternative to
conventional care for
burns, the patients relate
quickly, or entire pain
ameliorate after B&W/bur-
dock dressing application.
Arctium Leaves Aqueous extract An in vitro study that eval- The dressing with the [67]
lappa L. uated the antimicrobial plant showed no antimi-
and cytotoxic activities of crobial activity and inhib-
Amish burn ointment and ited skin cells in vitro at
leaves of burdock. higher concentrations.
These results suggest cau-
tion in the use of dress-
ings if there is more than
a minimal risk of complica-
tions of burn injury.
Calendula Flowers Calendula etha- A case study of the treat- The study presented an [24]
officinalis L. nolic extract ment of a lacerating advantage in the inflam-
wound in the pectoral matory phase of the heal-
region of unknown trau- ing process, favored epi-
matic origin in equine. thelialization, and
demonstrated the bacter-
icidal action of the lacerat-
ing wound.
Calendula Leaves Hydroalcoholic A human randomized The use of calendula oint- [26]
officinalis L. extract controlled clinical trial, ment considerably in-
evaluate of calendula oint- creases the healing speed
of the cesarean wound at

Table 2. (cont.)
ment on cesarean wound days 3, 6, and 9 after
healing. surgery, without any side
effects.
Calendula Whole Plant oil A randomized, controlled, Low-level laser therapy [27]
officinalis L. plant and prospective and inter- performed alone or associ-
ventionist clinical case ated with Calendula offici-
study. nalis oil was effective in
relieving pain and acceler-
ating the process of tissue
repair of diabetic foot.
Calendula Flowers Hydroethanolic An experimental study us- The extract stimulates the [28]
officinalis L. extract ing in vivo wound healing proliferation and migra-
assay in mice, and in vitro tion of human dermal fi-
scratch assay. broblast cells. Treated
mice with C. officinalis
showed faster wound
healing and increased ex-
pression of CTGF and α-
SMA.
Calendula Flowers Hydroglycolic A human clinical trial, pro- Findings indicate that Cal- [29]
officinalis L. extract spective non-randomized endula officinalis extract is
controlled study. Evaluate 40 % more effective in epi-
the healing rates of ve- thelization than the con-
nous leg ulcers. trol group. Patients
treated had a 4-fold in-
crease in percentage heal-
ing velocity per week.
Citrus sinensis Fruits Dry extract An experimental study The bioavailable fraction [54]
(L.) Osbeck that evaluated in vitro and presented higher anti-in-
ex vivo, using the murine flammatory and antioxi-
macrophage Cell lines dant potential in about
J774 A.1 and primary peri- the initial extract, thus
toneal macrophages. highlighting its potential
nutraceutical value.
Citrus sinensis Fruits Oil from the Cit- An in vitro and in vivo re- Results suggest a benefi- [55]
(L.) Osbeck rus sinensis search in the treatment of cial influence of antioxi-
plant chronic wounds. dants on the wound re-
pairing process.
Fragaria Fruits Crude extract An in vitro study that eval- The results presented by [70]
vesca L. uated cell viability and the authors show that the
inflammatory markers, polyphenolic extracts of
skin fibroblast migration, strawberries were more
and proliferation assay. active against the expres-
sion of the IL-1β and IL-6
genes and the strawberry
has an action on the mi-
gration of fibroblasts,
which directly assists in
the healing process.
Malva parvi- Leaves Methanol ex- A study employing acetic Results demonstrated that [71]
flora L. tract and aque- acid-induced vascular per- Methanol extract inhibited
ous extract meability in mice, and the croton oil-induced ear
croton oil-induced ear edema, and methanol,
edema in mice. and aqueous extract sig-
nificantly inhibited the

Table 2. (cont.)
acetic acid-induced vascu-
lar permeability.
Malva Flowers Aqueous extract An experimental study us- Reduction of the inflam- [41]
sylvestris L. ing skin cut wound in matory cells at days 4 and
BALB/c mice. 7, keratinization of the
wound edge. On day 10
the wound shows better
healing, less fibrosis, and
scar formation.
Malva Flowers Hydroalcoholic An experimental study The healing rate in treated [42]
sylvestris L. extract with diabetic rat wound animals presented 63 %
healing. more effective than usual
treatment, besides lower-
ing acute and chronic in-
flammation. Moreover, col-
lagen deposit and
neovascularization are
higher in the treated
group.
Malva Stems Ethanolic An experimental study us- The study shows a signifi- [43]
sylvestris L. and extract ing oral wounds induced cant reduction in the
leaves in rats. wounds over a period.
Malva Flowers Diethyl ether A study to evaluate The findings demonstrate [44]
sylvestris L. extract wound healing in alloxan- that the extract of M. syl-
induced diabetic rats. vestris effectively stimu-
lates wound contraction,
besides increased collagen
bands organization, in-
creased fibroblasts, and
reduce inflammatory cells
at the wound site.
Malva Flowers Hydroalcoholic An experimental study us- On the 15th day after in- [45]
sylvestris L. extract ing burn wound induced jury induction, the treated
with hot metal plate in group showed a 35 % of
rats. reduction in the wound
area. The histological anal-
ysis presented ell-formed
horizontally oriented colla-
gen fibers.
Maytenus ili- Leaves Tincture An in vitro study evaluat- Maytenus ilicifolia extract [51]
cifolia Mart. from ing the antimicrobial ac- showed slightly higher in-
ex Reissek aerial tivity of medicinal herbal hibition halos to other
parts extracts products
Petiveria Dry N-hexanic and An in vitro study using Hydrophilic extract of P. [50]
alliacea L. leaves, ethanolic ex- scratch assay and evaluat- alliaccea completely inhib-
aerial tracts ing inflammatory markers. its NF-кB DNA binding
parts, and inhibits 67 % of p38α
and MAPK activity.
flowers
Plantago Leaves Hydroalcoholic An in vitro study using A mixture of Plantago ma- [20]
major L. extract full-thickness skin wounds jor and Aloe vera can im-
model in Sprague-Dawley prove wound healing by
rats. increasing fibroblast prolif-
eration, collagen beam
synthesis, and revasculari-
zation in skin lesions.

Table 2. (cont.)
Plantago Leaves Ethanol and A study using experiments Both types of extracts [21]
Major L. water-based on the porcine wound- stimulated wound healing
extracts healing model. by dose-response pattern
on swine skin, but
ethanol-based extract had
a slightly stronger effect.
Plantago Leaves Gel containing A clinical trial on patients Plantago extract gel re- [22]
Major L. a hydroalco- with diabetic foot ulcer or duced the wound size
holic extract pressure ulcer. compared to the control
at the end of the first and
second weeks. Further-
more, the number of pa-
tients with complete
wound healing in the
group treated with Planta-
go extract gel was signifi-
cantly more than in the
control group.
Rosmarinus Aerial Aqueous extract A study using full-thick- The essential oil of Ros- [48]
officinalis L. parts of and essential oil ness excision cutaneous marinus officinalis and
the wound induction in dia- aqueous extract presented
plant betic mice. Reduced inflammation
and enhanced wound
contraction, re-epitheliali-
zation, regeneration of
granulation tissue, angio-
genesis, and collagen dep-
osition in the wound heal-
ing process.
Sedum den- Leaves n-Hexanic and A in vitro study using Moderate influence in the [50]
droideum ethanolic fibroblasts. fibroblast’s migration to
Moc. & Sessé extracts and proliferation into the
ex DC. wounded monolayer
scratch assay.
Sedum den- Leaves Polysaccharides A in vitro study using The polysaccharide from [58]
droideum from infusion of THP-1 cells (macro- aqueous infusion stimu-
Moc. & Sessé Sedum dendroi- phages). lates the secretion of tu-
ex DC. deum leaves moral necrose factor
(TNF), interleukin (IL)-1β,
and IL-10 cytokines in
THP-1 macrophages, act-
ing as immunostimulatory
agents and showing their
anti-inflammatory effect.
In contrast, they reduce
TNF and IL1-β secretion
induced by lipopolysac-
charide, showing anti-in-
flammatory effects.
Sedum den- Leaves Hexane extract A study using burn inju- The electrospinning Poly [57]
droideum ries model in rats. (Latic Acid) membrane iso-
Moc. & Sessé lated or associated with S.
ex DC. dendrodeum extract,
stimulated the healing of
burn lesions, and in-
creased fibroblasts, colla-

Table 2. (cont.)
gen fibers, and blood ves-
sels. The extract of S. den-
droideum promoted the
increase of collagen fibers.
Symphytum Aerial Ethanolic A human clinical trial, Reduced the size of fresh [13]
officinale L. parts extract randomized, controlled abrasions of patients, re-
double-blind study evalu- gression time was faster
ating the wound healing and there were no adverse
effects of a topically ap- effects.
plied preparation.
Symphytum Aerial Ethanolic A human clinical trial, A cure rate of 50 % has [14]
officinale L. parts extract randomized, controlled achieved 0.9 days earlier
double-blind study evalu- with the highest than with
ating the wound healing the lower concentration
effects of a topically ap- cream, with no adverse
plied preparation. effects.
Symphytum Leaves Aqueous An experimental study us- The treatment with the [15]
officinale L. glycolic extract ing open wound model in extract induced greater re-
rats. pair in damaged tissue
and better efficacy to con-
trol the inflammatory
process and induce colla-
gen deposition at 8 % con-
centration.
Symphytum Aerial Ethanolic A human clinical trial, The extract reduced the [16]
officinale L. parts extract open, prospective using total area of the ulcers, as
Symphytum herb extract well as their depth.
cream in the treatment of
pressure ulcers.
are used for wound healing, study, lifting, lifting pain, of the children rated the benefit of the cream in the
and washing[7] due to its lantoin content, which 10 % concentration of active ingredient as significantly
possesses healing action,[11] in addition to being used better when compared to the control preparation, and
for whitening skin blemishes and general pain.[12] the cure rates were rated after 2 –3 days as “good” at
Some studies address the effectiveness of this plant 46 % and “very good” in 44 % of cases. In addition, on
with action on wound healing. In a double-blind the 7–9 days after the treatment, it was reported that
clinical study, 278 patients with recent abrasions were patients who received the cream with the plant active
separated into two groups, and one group was applied at a concentration of 10 %, had a rating of ‘good’ or
a topical cream based on S. officinale extract (10 %), ‘very good’ in 93 % of cases, while the control
while the other group received a cream with a formulation showed 74 %. It was also reported that no
concentration of 1 % of the active ingredient (refer- adverse effects or problems with tolerability were
ence product). The positive experience concerning the found.[14]
benefits in wound healing by using the plant was According to the study by Araújo et al.,[15] the
highlighted because after 2 to 3 days of application of in vivo topical healing activity of S. officinale leaf
the formulation, it was found that the reduction in extracts was analyzed in three pharmaceutical formu-
wound size was on average 49 % for the test cream lations, carbomer gel, glycerol-alcoholic solution, and
and 29 % for the reference product.[13] Oil/Water emulsion (soft lotion), comparing qualitative
Another double-blind, randomized study on 108 and quantitative histological analysis. The results
children (aged 3 to 12 years) analyzed the healing showed that on the 28th day of the treatment, the
effects of a cream extract from the S. officinale. The emulsion in the concentration of 8 % comfrey extract
children had recent abrasions. The doctors and parents showed 240 % collagen deposition and reduced by

46 % the cellular infiltrate in the inflamed tissue when bacterial strains and showed antifungal activity against
compared to the positive control group (lantoin). all tested strains.[18]
Therefore, those authors concluded that this formula- A chemical, biochemical, and cellular approach
tion promoted the most advanced repair of damaged were carried out to explore the antiproliferative and
tissue.[15] pro-differentiating activity of the Aloe arborescens leaf
In a clinical trial designed as a prospective, extract by Luccia et al.[19] Gas chromatography per-
randomized, reference-controlled, double-blind clinical formed on the extract showed that the plant is rich in
multicenter, parallel-group, patients with acute lateral aloe-emodin, and this molecule has antioxidant and
ankle distortions were used to test the effectiveness anti-tumor properties, according to the literature. The
and safety of a cream containing S. officinale extract in research also showed that the Aloe extract has
the treatment of pressure ulcers was analyzed. The antiproliferative effects, and it reduced cell prolifer-
study was carried out with 161 patients, who had a ation by up to 40 % within 54 h after exposure of the
total of 198 decubitus ulcers in stages II and III. The cells to the extract. Furthermore, it was observed that
patients were treated with S. officinale herb extract squamous carcinoma cells treated with Aloe extract
cream topically. The results presented by the authors showed a dramatic reduction in levels of the oncogene
showed that the cream was able to heal the bedsores ΔNp63α, found in high levels in squamous carcinoma
of 86 % of patients between days 25 and 30 of cells that are especially important for the initial
treatment, in addition, the area and depth of the survival of these tumor cells.[19]
lesion were reduced by 89 % and 88 %, respectively.[16] After analyzing the experimental Aloe arborescens’s
In southern Brazil, S. officinale plant leaf is abun- effects on the wound healing process studies, it is
dantly used for wound healing treatment. Besides, it is possible to identify that the results were obtained
worth mentioning that the comfrey leaves are crushed using the leaf. However, in the Southern region of
in warm water and applied to the wound twice a day. Brazil, in addition to the use of leaves, their stems are
However, the studies reviewed here tested a cream or also used, but it is observed that no experimental
a gel preparation containing aerial parts or the studies tested this plant part. Therefore, before clinical
pressure juice of S. officinale in humans. studies, other experimental studies must be conducted
Although this plant is widely used to treat internal with the stems of this plant to prove its efficacy and
and external wounds, such as gastric ulcers, studies safety in the wound healing process.
that explore how components of S. officinale leaves
would exert such effects are still awaited. In addition,
3.3. Plantago major L.
studies verifying the cutaneous toxicity of comfrey
preparations are also needed. The wound-healing effect of Plantago major leaves has
been shown in a few animal studies. An experimental
study with the P. major and Aloe vera also addresses
3.2. Aloe arborescens Mill
the importance and effectiveness of the synergy
In a preliminary assessment carried out by Jia and between both medicinal plants in treating wounds.
collaborators[17] with the leaves of the Aloe arborescens Using rats (Sprague-Dawley), separated into a control
Mill, positive results regarding its wound healing were group (without treatment), a vehicle group, and a
described.[17] The authors showed that the group group treated with a gel containing 5 % of P. major
treated with a preparation of whole-leaf juice signifi- extract and 5 % of Aloe vera extract (once a day for
cantly reduced the severity of the wound on the third 15 days), Ashkani-Esfahani et al.,[20] described that the
day compared to the control group. In addition, treatment with the gel was able to reduce injury by
selective microbial growth inhibition activity for 8 % per day, while the control group and vehicle group
Cryptococcus neoformans has been described, and no reduced by 6 % and 5 % per day, respectively. In
side effects on the skin during observations have been addition, the gel administration increased the numer-
reported.[17] ical density of fibroblasts and the density of the
Still, a comparative South African study of three collagen bundles and vessels.[20]
species of Aloe demonstrated the therapeutic activity In another study, the activity of the aqueous and
of these plants to their capacity for microbial inhibition ethanolic extracts of P. major’s frozen and dried leaves
against agents that may interfere with the healing of P. major was evaluated in a swine ex-vivo wound
process. Ethanol extracts of Aloe sp. inhibited the healing model.[21] According to the results presented
growth of all tested Gram-positive and Gram-negative by the authors, both the ethanolic extract and the

aqueous extract at a concentration of 1.0 mg/mL officinalis. As in the study by Martins et al.,[25] where C.
showed an increase of approximately 50 % in the officinalis was used topically in horses, it was found
progress of wound healing, compared to the control that its ability to favor epithelialization in addition to
group. The authors also mention that this effect may having bactericidal action.
be associated with the diversity of compounds that A Calendula ointment prepared with 2 % hydro-
the plant has, which have anti-inflammatory, antiox- alcoholic extract was used every 12 h in a randomized
idant, and antimicrobial action. clinical trial with 72 patients. The healing power of
Recently, a clinical study was performed to assess wounds resulting from cesarean sections for 10 days
the wound properties of P. major evaluating patients was evaluated, compared to the control group that
with diabetic foot ulcers and pressure ulcers. In this received routine hospital treatment. Through a REEDA
study, Ghanadian et al.[22] demonstrated the clinical (Redness, Odema, Ecchymosis, Discharge, Approxima-
efficacy of a gel containing 10 % of P. major hydro- tion) scale evaluation form, the authors showed that
alcoholic extract on diabetic foot ulcers and pressure the group treated with marigold ointment could
ulcers healing, showing that the topical application of completely heal the wounds in 6 days.[26]
this gel accelerates the healing of the ulcers, reducing A randomized experimental clinical study, with a
the wound’s erythema, decreasing the wound size. doppler ultrasound using the ankle-brachial index, was
According to the experimental studies mentioned carried out to analyze the effects of low-level laser
above, the Plantago major plant is effective in therapy alone or associated with 5 mL of the oil from
accelerating the wound healing process when used in C. officinalis to treat diabetic foot ulcers. Approxi-
gel format containing its extracts, and this effect is mately 46 % of the patients treated with marigold oil
probably mediated by bioactive compounds found in associated with laser therapy presented pain reduction
its leaves. In comparison with the southern region of after treatment, whereas the control group did not
Brazil, where the entire plant is used, it is important to present any reduction in pain. In addition, the group
highlight the need for studies that investigate the treated with laser or marigold, or a combination of
healing effect of other parts of the plant. Therefore, both, showed a significant reduction around the lesion
the potential of leaves of P. major application in the as described by Carvalho et al.[27]
wound healing process has been validated scientifi- Still, in in vitro and in vivo studies of the aqueous
cally, but more studies are awaited. fraction (FA) and the hydroethanolic extract (EH) of C.
It’s important to mention that Cardoso et al.[23] officinalis carried out by Dinda and collaborators[28]
recently reviewed four studies about the wound revealed that after the 24-treatment period, both FA
healing effects of P. major and described that more and EH increased cell proliferation of dermal fibro-
rigorous preclinical studies with adequate sample sizes blasts. In addition, the EH incubation increased the
are required to identify the best concentrations and expression of connective tissue growth factor (CTGF)
formulations as well as increase understanding about by 100 %. It promoted an increase in smooth muscle
the mechanisms of action of P. major in wound alpha-actin (α-SMA), a marker of fibroblast differ-
healing. Indeed, we agree with Cardoso et al.,[23] and entiation responsible for wound contraction, by 60 %.
we emphasize that experimental studies with phyto- The incubation with FA showed an increase of 70 % for
chemical data on the components responsible for the CTGF and 50 % for α-SMA. The in vivo evaluation of
observed effects are necessary in addition to under- the induction of a 5 mm diameter wound showed that
standing the mechanisms of action by which the both the EH-treated group and the FA-treated group
constituents of this plant promote their effects.[23] could completely heal the wound within 13 days of
treatment, while the placebo group had approximately
30 % lesions in the wound. The authors of the work
3.4. Calendula officinalis L.
relate this activity to the presence of triterpene
A study by Boscarato and collaborators[24] evaluated compounds and flavonoids in C. officinalis.
the activity of a non-ionic cream containing 2.0 % Another study with an extract of C. officinalis in
lyophilized extract of Calendula officinalis in the wound healing was carried out to analyze the
lacerating wound of equine, applied twice a day for therapeutic efficacy of the plant in venous leg ulcers.
40 days. During treatment, the authors reported the The study had participants patients treated with an
absence of infection in the wound, in addition to the extract of C. officinalis in the form of spray and control
visible filling of the base with granulation tissue, such patients who received the hospital’s standard proce-
activities are already associated with the use of C. dure. The results described that patients who achieved

complete epithelialization in 30 weeks were 74 % and 3.5. Aloe vera (L.) Burm.f.
32 %, in the C. officinalis extract and control groups,
respectively. In addition, the authors also show data Aloe vera is a well-known traditional medicinal plant
on wound healing speed per week, where the group that has been used to treat skin disorders, including
treated with the extract showed a healing rate 4 times wounds. Several in vitro and in vivo studies have also
higher than the control, 7.4 % and 1.7 % per week, confirmed its wound-healing activities in the consis-
respectively. In addition, it was observed that no tency of its historical and traditional uses.
adverse events were experienced during treatment In the study performed by Mendonça et al.,[33]
with the plant extract. Therefore, the research con- lesions were surgically induced in Wistar rats, and the
cluded that the extract of C. officinalis is effective and pharmacological activity of a topical gel containing
safe for the treatment of venous leg ulcers.[29] the Aloe vera plant was measured, combined or not
In addition to the healing potential in external with microcurrent treatment for 10 days with the
wounds, some preclinical studies have described the application of treatments once a day. On the last day
potential of C. officinalis extracts to treat gastric and of treatment, it was observed that only the groups
intestinal ulcers. Tanideh et al.[30] showed that oral and that received microcurrent (10 μA/2 min) or associa-
enema forms of hydroalcoholic extract of C. officinalis tion with A. vera gel showed an increase in cell
can be offered as potential therapeutic agents to treat proliferation and angiogenesis. Moreover, the group
ulcerative colitis because verified a significant increase treated with A. vera and the group treated with
in the body weight of rats treated with C. officinalis microcurrent, and the group treated with the associa-
extract at 3000 mg/kg orally, or 20 % intracolonic gel tions presented effectiveness in wound healing, being
form of marigold extract. Acute inflammation and approximately 18 %, 35 %, and 47 %, respectively,
granular atrophy after ulcerative colitis were resolved greater than the control group.[33] However, despite
entirely with 20 % intracolonic gel and 3000 mg/kg their positive results, those authors did not investigate
orally. Nevertheless, despite the positive results the mechanism of action or compounds present in the
reached by Tanideh et al.,[30] it is evident that the oral leaves of A. vera involved in the effects achieved.
dose used is high, making it challenging to translate In another study, Teplicki and contributors[34]
the data into a clinical context. Furthermore, Da Silva evaluated the effects of an Aloe vera commercial gel at
et al.[31] also described the anti-ulcer potential of an concentrations of 1 %, 2 %, and 3 % in wound healing
extract from C. officinalis flowers. However, the com- by employing in vitro models.[34] The effect of the
pounds that mediate the healing effects in ulcerated preparation containing A. vera was tested on the
gastrointestinal mucosa remain unknown. proliferation and migration of fibroblasts, which
Given the evidence presented, C. officinalis has showed 4 times more concentration of cells for the
wound-healing potential, mainly in its leaves and group treated with 2 % and 5 times more for the group
flowers. In addition, in the Brazilian South region, the treated with 3 % of the extract on the fifth day of
use of whole plants is cited to treat wounds. Indeed, treatment, compared with the control. Besides, the
Givol et al.[32] reviewed articles published between extract in the concentration of 3 % increased the
1992 and 2016 about wound healing and repair cellular migration of fibroblasts by 64 %, compared to
properties of C. officinalis, confirming the beneficial the control group. Although the extract of A. vera was
effects of the use of ointments containing calendula able to increase the proliferation of keratinocytes in
extract during wound healing. Furthermore, Givol the three concentrations tested, the group treated
et al.[32] point to the limited number of clinical trials with extract in the concentration of 1 % showed a
and their methodological differences, which remain dramatic increase in the concentrations of keratino-
evident in the articles published between the years cytes, about 30 × 103 cells/mL compared to < 1.5 ×
2000 and 2022 reviewed here. So, large clinical 103 cells/mL of the control. The authors also show that
prospective, well-designed, randomized control trials the A. vera extract at 1 % stimulated up to 74 % of the
with validated and consistent outcome measures to migration of keratinocytes, compared to the control
establish the efficacy of calendula extract on wound group.[34] However, the composition of bioactive
healing are still awaited, as well as the identification of compounds in the commercial gel employed was not
isolated compounds mediating the wound effects. investigated and did not present a biomarker respon-
sible for cell proliferation.
In addition, another experimental study, but in rats,
with a rectangular 2 × 2 cm cutaneous wound evaluat-

ing the topical application of A. vera (25 and 50 mg/ not cause any change in cell viability; in addition, it
mL solubilized in 0.9 % saline) was published by Oryan was found that the formulation with the combination
and collaborators.[35] The authors showed in their of treatments was able to increase the cell prolifer-
results that the topical application of A. vera had a ation of keratinocytes by 2 times.[37]
dose-dependent effect, where the concentration of Recently, Massoud et al.[38] described the efficacy of
50 mg/mL was more effective in the results of the the topical application of Aloe gel and olive oil in
biochemical, morphological, and biomechanical char- enhancing diabetic wounds using histological and
acteristics of the healing of skin wounds in rats, after immunohistochemical analysis. Those authors created
the 30-day treatment period. Among the histological excisional wounds on the back skin of streptozotocin-
and histomorphometric results of the extract at induced diabetic rats. The macroscopic observations of
50 mg/mL, it was seen that there was a reduction in the Aloe gel and/or olive oil-treated group exhibited
total cellularity by up to 40 %, due to the trans- almost complete healing at day 14, while other groups
formation of fibroblasts into fibrocytes that showed an were still in progress. Moreover, the application of
increase in their concentrations up to 3 times more Aloe gel and/or olive oil reduced the expression of
than the control group. In addition, on the thirtieth nuclear factor kappa-light-chain-enhancer of activated
day of treatment, the group treated with A. vera B cells (NF-кB) and increased the cell proliferation and
presented larger caliber vessels.[35] angiogenesis markers in the healing wound. Agreeing,
A double-blind, randomized study with 24 patients that the beneficial effects of A. vera in streptozotocin-
who underwent skin graft removal from the thigh was induced diabetic rats were recently reviewed by
performed by Burusapat et al.,[36] to analyze the use of Haghani et al.[39]
topical Aloe vera gel in wound healing in partial- To date, most studies about its wound-healing
thickness skin graft donor areas. The study divided the effects are based on the A. vera gel and latex.
patients into two groups, one group treated with the Innovatively, Razia and collaborators[40] showed for the
gel containing Aloe vera and another group treated first time the synergistic effect of the A. vera flower
with a placebo; the group receiving gel based on Aloe and Aloe gel on cutaneous wound healing, revealing
vera was able to achieve total epithelialization in its molecular mechanism targeting microfibril-associ-
approximately 11 days after treatment, while the ated glycoprotein 4 (MFAP4) and its associated signal-
placebo group took up to 14 days to achieve complete ing pathway. Despite the limitation of the study,
epithelialization. because it was performed in vitro using cell culture,
Another study using the burn healing gel prepared the authors show that due to its results, MFAP4 was
from human amniotic membrane and A. vera extract recognized as a new potential biomarker of wound
was carried out to identify the effectiveness of the healing promoted by A. vera, which can be confirmed
extract in healing wounds and burns, in vivo and through further in vivo studies.
in vitro models. The research was carried out with a According to the above studies, the popular use of
formulation containing 2 % human amniotic mem- the A. vera plant is proven to aid the wound healing
brane and 2 % A. vera. In the in vivo trial, burns were process, and it is justified by its ability to accelerate
induced in rats, and the animals were treated with A. cell proliferation. Interestingly, we found in vitro, and
vera or human amniotic membrane or a combination in vivo non-clinical and clinical studies published
of both, compared to the control group that did not between 2000 and 2022 to evaluate the healing
receive treatment. After twelve days of treatment, it wound of A. vera; however, these studies did not
was found that the control group had the lowest cure achieve the phytochemical composition of their prep-
rate, while the group that received only A. vera had arations or extracts, and the clinical trial publication
the best cure rate among all groups. Moreover, from was performed only with 24 patients. So, as pointed
the tenth to the eighth day, the same group showed a out above to other species, further large clinical trials
cure rate of up to 77 %, while the group treated with with validated and consistent outcome measures are
the association showed 73 %, and the group treated needed to establish the efficacy and safety of A. vera
only with human amniotic membrane showed a cure extract on wound healing.
rate of 67 %. Through a histological analysis, the
authors showed that on the 24th day of treatment, all
3.6. Malva sylvestris Linn.
groups that received treatment showed an increase in
angiogenesis, compared to the control group. In vitro The flowers of Malva sylvestris are an important
studies, it was found that the dose of 500 μg/mL did medicinal plant in Brazilian traditional medicine that

has been used as a remedy against edema, bum, and described that the pharmacological and biological
wound and for its antimicrobial and anti-inflammatory activity of M. sylvestris can be related to the existence
activities. An assessment of the healing activity of skin of naphthoquinones, anthocyanins, flavonoids, or
wounds in mice using dried flowers of Malva sylvestris mucilaginous polysaccharides and revealed that the
employing an aqueous extract of 1 % was performed total flavonoid and anthocyanin contents for M.
by Afshar and collaborators.[41] The effects of this sylvestris extract were 20.477 mg/g and 0.781 mg/g,
extract were compared to the positive and negative respectively.
control. According to the authors, on the tenth day of In contrast, research carried out to identify the
treatment, the mice treated with M. sylvestris showed a healing effect of an orobase containing M. sylvestris
reduction in the number of inflammatory cells (poly- ethanolic extract was performed by Kovalik et al.[43]
morphonuclear and mononuclear) by up to 8 times, Those authors evaluated its effect on a wound in the
presenting less edema and more remarkable collagen palate mucosa of rats. The results demonstrated that
synthesis, when compared to the negative control. the extract of M. sylvestris had no difference in the
Furthermore, the group treated with the formulation healing wounds of the palatine mucosa of rats when
containing M. sylvestris showed an 85 % reduction in compared to the control group.[43]
fibroblast activity compared to the negative control It is worth mentioning yet another research explor-
group, indicating the approach to the end of the ing the healing activity of flowers from M. sylvestris
healing process. However, despite their interesting and Punica granatum in wounds of diabetic rats
results from an in vivo model and the extractive induced by alloxan using a diethyl ether extract. The
method like the popular use, Afshar et al.[41] did not results showed that, between days 3 and 15 of the
describe phytochemical assays to determine the treatment, diabetic animals that received a simple
composition of the tested extract. base ointment containing an extract of M. sylvestris
Another study was carried out with the use of demonstrated a significant reduction in the wound
polyurethane-based nanofiber dressings containing area, compared to the reduction for the wound found
extract of dried flowers from M. sylvestris in different in the group treated with simple base ointment and
concentrations, its activity was evaluated in the the group treated with nitrofurazone ointment. On the
healing process of diabetic wounds. The nanofiber eighteenth day of treatment, the group treated with
dressings containing the highest concentrations (15 M. sylvestris was able to completely heal the lesion,
and 20 %) of the extract showed better treatment due to the increase in the collagen concentration, the
effectiveness. Regarding its antimicrobial activity, it proliferation of fibroblasts, and angiogenesis. In addi-
was reported that dressings that had 15 % and 20 % tion, the study’s authors state that Malva Sylvestris
extract of M. sylvestris showed 70 % activity against effectively stimulates the contraction of the wound
Staphylococcus aureus. In addition, they also showed and accelerates the healing process when compared
71 % activity against Escherichia coli. The evaluation of to the control group.[44] However, the authors did not
the healing power of the dressing with plant extract in assess the phytochemical composition of the extract
an in vivo model showed that after 14 days of treat- used. In addition, the solvent used to prepare the
ment, the animals that received dressings containing extract does not reflect the popular extractive form.
15 and 20 % of the extract showed 95 % wound Another study was carried out to analyze the
healing for both groups, while the control group effectiveness of the cream containing M. sylvestris in
showed only 32 % of the cure. Furthermore, was concentrations of 5 and 10 % in burns and wounds in
reported through histomorphometric analysis that an in vivo model. The research was carried out in five
these same groups on the fourteenth day showed a groups, and the induction of the burn was carried out
reduction in inflammatory cells by 65 % and 67 %, with hot metal plates. On the fifteenth day, the
respectively, in addition to a higher epithelialization animals treated with the cream of M. sylvestris at a
score and an increase in angiogenesis, when com- concentration of 5 % and 10 % showed a reduction in
pared to the control.[42] the wound area by 64 % and 61 %, respectively, while
Interestingly, the study performed by Almasian the group that received only the base cream showed a
et al.[42] also showed that M. sylvestris flowers hydro- 40 % reduction in the lesion area. Another group
alcoholic extract enhanced the mechanical and ther- treated with silver sulfadiazine, the positive control of
mal properties of nanofibers in a polymer matrix the study, presented a reduction of 21 % in the wound.
resulting in an increase in the release of the bioactive The authors show that the groups treated with M.
compounds time up to 85 h. Those authors also sylvestris could contract the wounds by more than

90 % on the twentieth day. In addition, the extension It is important to highlight that in southern Brazil,
of granulation tissue, reepithelization, and new dermis the R. officinalis is used in the wound-healing process
was assessed by histology, and the treatment with through its leaves. However, in the experimental study
cream of M. sylvestris at a concentration of 10 % cited in this review, the use of the plant was effective
showed better healing effects when compared to the through the aerial parts of the plant (stem, leaf, flower,
other groups.[45] However, like other studies reviewed and fruits) that are used to make the essential oil of
here, the results described by Nasiri et al.[45] do not the study. Therefore, it is worth mentioning that the
present the phytochemical composition of the extract plant can be used in the wound healing process, not
of M. sylvestris flowers incorporated in the cream. only with its leaves but also with other forms of use.
Given the studies addressed, it is important to
highlight that M. sylvestris is a great option for wound
3.8. Petiveria alliacea L. e Maytenus ilicifolia Mart. ex
treatment, mainly on the skin. Various parts of the
Reissek
plant, such as its leaves and flowers, can be used.
Besides, a topical form and a promissory form as The plant Petiveria alliacea L is popularly used for
polyurethane-based nanofiber dressing with plant healing and improving fever. In addition, it is used to
extract have been tested. In Southern Brazil, only the improve inflammation, toothache, and headache.[46,12]
leaf is used, but most studies evaluated the flower of The leaves of Maytenus ilicifolia Mart. ex Reissek has
this medicinal species. Thus, this review allows other been used to treat gastric lesions by inhibiting the
forms of knowledge about the use of the M. sylvestris secretion of juice, promoting the healing of stomach
plant for wound healing. Nevertheless, is important to ulcers, and being a source of antioxidant agents.[49]
emphasize those studies about the effects of aqueous An important contribution to the effects of P.
or hydroalcoholic extract from leaves of M. sylvestris in alliacea was the study performed by Schmidt et al.[50]
wound healing remain a need, as well as studies which proved the effectiveness of this medicinal plant
assessing its effects by oral route, to contribute to the in the wound-healing process. The research investi-
validation of its popular use in Southern Brazil. gated hexane and ethanolic extracts from twelve
plants as wound-healing agents in biological assays. It
is known that NF-kB is involved in the transcription of
3.7. Rosmarinus officinalis L.
several genes associated with the inflammatory re-
Folk medicine uses different parts of this plant, for sponse; however, Schmidt et al.[50] presented that the
example, the dried leaves to heal wounds, tea to wash ethanolic extract of P. alliacea was able to completely
wounds, heart palpitations, digestion, liver problems, inhibit its binding to DNA at the concentration of
and as a tonic.[46] In addition, it is also used for 100 μg/mL. In addition, the hydrophilic extract was
tranquilizing purposes Fuck et al.[47] also able to inhibit the phosphorylation of p38α by up
In a successful study, the aqueous extract, and the to 68 %, such protein is linked to the production of
essential oil of Rosmarinus officinalis, both obtained pro-inflammatory cytokines. On the other hand, the
from the aerial parts of the plant were applied extract did not present a significant result related to
intraperitoneally in alloxan-induced diabetes in mice the proliferation and migration of fibroblasts, as well
to evaluate their healing effects of induced wounds in as the release of elastase. However, the authors claim
these animals, for a period of up to 15 days. The that the ethanolic extract of P. alliacea has shown
authors reported in their results that R. officinalis promising results for future studies.
essential oil was the most active in the healing of In the Southern region of Brazil, the part of the
diabetic wounds, the wound contraction in this group plant used is not mentioned in any of the twelve
was 93 %, while the control group showed 64 % of articles reviewed. However, in the above experimental
wound contraction. In addition, it was observed that study, in which soluble components of P. alliacea were
on the fifteenth day of treatment, the group that used, the author’s prominence of the plant in the
received the essential oil presented 70 % more gran- wound healing process is notorious. For this reason, it
ulation tissue than the control group. In addition, the is recommended that the use of the plant in the
same treatment was able to reduce serum glucose treatment of wounds be carried out in proven ways
concentrations and restore the animal’s initial body through scientific studies so that its use is done
weight. Although the essential oil performed better, effectively and more safely.
the extract of R. officinalis also showed promising About the Maytenus ilicifolia, a medicinal plant
results in the healing process.[48] used in the Brazilian Unified Health System (SUS), an

in vitro study evaluated the biological activity of bioavailable C. sinensis also inhibited the production of
tinctures or essential oils of this medicinal plant reactive oxygen species. The extracts of C. sinensis
against pathogenic microorganisms of wound oral decreased the translocation of NF-kB in macrophages
interest. The results demonstrated that the tincture of stimulated with LPS, and the authors point out that
the M. ilicifolia plant showed the largest halos of such activity may be associated with polymeth-
inhibition, 19, 13, and 12 mm of halo for Streptococcus oxyflavones present in C. sinensis.[54]
mutans, Streptococcus oralis, and Streptococcus salivar- A Polish study emphasizes that orange oil from the
ius, respectively, compared to other plants.[51] peels C. sinensis plant is today a direction for much
Although the tincture of M. ilicifolia did not show the in vitro and in vivo research in treating chronic
best minimum inhibitory concentration, this plant still wounds. The authors related this activity to the
shows promising activity in wound healing, mainly in compounds present in the oil, such as linalool,
oral mucosa, since it has antimicrobial, antioxidant, decanal, and geraniol, among others, which have
and healing activities.[52] antibacterial activity against Staphylococcus aureus,
It is denoted that the leaf from M. ilicifolia is used including the resistant methicillin strain, in addition,
in the Southern region of Brazil and accelerates the the oil is safe because it did not present cytotoxicity in
wound healing process. Indeed, recently De Moura HEK 001 cells (human keratinocytes). Furthermore, the
and collaborators[53] described that the M. ilicifolia authors indicate that the antioxidant capacity of
extract accelerated the closure of wounds at a orange oil would be related to its healing potential,
concentration of 4 %, presenting anti-inflammatory since the reduction in oxygenated radicals would
effects and hemoglobin increased, along with in- facilitate the arrival of oxygen in the affected tissues,
creased soluble, total, and type III collagens in the which allows processes such as angiogenesis, stimula-
wound. In addition, the authors also described that tion of fibroblasts, and proliferation of keratinocytes
the extract application increased the pro-metallopro- occur correctly.[55]
teinase (MMP)-9 and MMP9 activity after day 7th of The C. sinensis has been used in southern Brazil
treatment. The authors also concluded that this plant’s through its leaves used as a poultice applied in
phenolic compounds and tannins could be associated wounds. However, in the reviewed experimental
with the anti-inflammatory and healing activities studies, other parts of this plant were tested, such as
evidenced. However, the use of leaves as an infusion its barks and fruits, demonstrating positive effects in
has not been found in the literature; for this reason, treating wounds. Therefore, future studies assessing
further studies about the use of M. ilicifolia infusions or the efficacy of leaf preparations on wounds and
tinctures for wound healing are suggested. Its applica- identifying parallelly their bioactive compounds were
tion is recommended with scientifically proven forms recommended. It was not possible to include any
for greater safety. clinical studies about the effects of C. sinensis in
wounds, which are necessary for future investigations.
3.9. Citrus sinensis (L.) Osbeck
3.10. Sedum dendroideum D.C.
The citrus plants contain large amounts of flavonoids
that benefit human health. Given this, a study The S. dendroideum D.C. has been used in traditional
evaluated the antioxidant and anti-inflammatory ac- South Brazilian medicine as a wound healing agent. In
tion of Citrus sinensis extract from fruits and its agreeing to ethnobotanical surveys, Schmidt, and
bioavailable in vitro and ex vivo, using the murine collaborators[50] also presented S. dendroideum as a
macrophage cell lines J774 A.1 and primary peritoneal medicinal plant used in traditional South Brazilian
macrophages. The results showed that the extract of medicine as a wound healing agent.
Citrus sinensis and Citrus sinensis bioavailable prepara- Thereon, Oliveira et al.[56] evaluated the chemical
tion in the same concentrations (250–25 μg/mL) was structure, and anti-inflammatory effect of polysacchar-
able to inhibit the inducible nitric oxide synthase ides from an infusion of Sedum dendroideum D.C.
(iNOS) and cyclooxygenase (COX)-2, in a dose-depend- leaves. In this research, a soluble fraction of the
ent manner. In addition, a reduction in the concen- infusion was separated by dialysis, where it was
trations of tumor necroses factor (TNF) and interleukin obtained 2 fractions, retained fraction (FR), and eluted
(IL)-6 by more than 55 and 60 % have been reported fraction (FE). The retained fraction was tested in vitro
for the bioavailable C. sinensis group at a concen- in the release of pro-inflammatory and anti-inflamma-
tration of 250 μg/mL. In addition, the incubation with tory cytokines by macrophages. According to the

results, FR is not able to stimulate the release of IL-10, used for treating various health problems. Indeed, in
but it was evidenced that macrophages, when the Brazilian south, macerated garlic bulbs have been
incubated with the retained polysaccharides (50 μg/ applied to wounds, and here were reviewed articles
mL), and lipopolysaccharides (LPS), decrease the from 2000 to date about garlic efficacy in wound
secretion of TNF and IL 1β by these macrophages in therapy.
up to 26 % and 59 %, respectively, compared to the Santiago and collaborators[59] carried out a study
group that was incubated with LPS only. This data with a preparation from Allium sativum L. enriched
indicates that the polysaccharides obtained from the with thiosulfinate (TASE) using in vivo and in vitro
extractive process have an important role in the anti- models. Unlike most of the studies reviewed, the
inflammatory effect of S. dendroideum in wounds. In authors were careful about the stability assessment
addition, the results presented by the authors show and the standardization in terms of allicilin in the
that the tested polysaccharides do not have a in vitro test solution and the in vivo tested extract,
cytotoxic effect.[56] which is 2 and 0.5 μg/mL of allicin, respectively.[59] In
Another research involving the S. dendroideum the results obtained, the addition of TASE at 176 μg/
aimed to evaluate the healing process using biopol- mL in HaCaT cells, which are keratinocytes, increased
ymer (poly-lactic acid) membranes associated with S. the cell viability and reduced the lesion area (scratch-
dendroideum extract in concentrations of 10 and 25 % ing) by 90 %, while the control group showed a
in induced burns in rats. The results showed that on reduction of 65 %. In addition, the in vivo trial using
the fourteenth day of the treatment, the membrane mice submitted a circular wound at 5 mm diameter on
associated with the extract at a concentration of 10 % each flank (2 wounds per animal) also showed a
increased collagen fibers by 27 %. Furthermore, this significant difference in the lesion, with the group
group showed an increase in the number of fibroblasts treated with TASE showing a reduction of 40 % in the
by 50 % and new vessels compared to the untreated wound area, while the control group reduced by 22 %.
group. The effect of the extract applied in isolation The authors also show that TASE influences epidermal
was also evaluated, which showed an increase in permeability on the eighth day of treatment, as it
collagen fibers at 28 % and in the number of reduced the loss of transepidermal water by 26 %,
fibroblasts at 10 %, however, in this group, there was compared to the control group. The extract was also
no significant angiogenesis, compared to the control able to stimulate the expression of proteins related to
group. On the other hand, it was observed that the cell differentiation of the epidermis (philagrin, involu-
groups treated with the biopolymer, alone or in crine, and loricrine) and enzymes that synthesize some
association, showed an intense inflammatory response lipids since the differentiation of keratinocytes and the
concerning the control group, of which the authors production of epidermal lipids are essential in the
correlate this effect to the biopolymer membrane formation of the epidermal permeability barrier.
itself[57] because it is already mentioned in the In addition, another study on biological activity and
literature.[58] wound recovery with the use of A. sativum and honey,
Given the studies reviewed, it is notorious that the in an isolated or associated way, was carried out by
S. dendroideum, popularly named balsam, can be great Abderrahim and collaborators.[60] The association of
potential to treat wounds. Unlike other plants, poly- honey at a concentration of 5 % with garlic at 0.1 %
saccharides from leaf infusions have been identified as showed a minimum inhibitory concentration (MIC)
bioactive compounds, at least in vitro. However, the 10 times lower for S. aureus, compared to the MIC of A.
balm is macerated until it becomes a paste and sativum alone, and 17 times lower for activity against
applied to the affected area in folk medicine in the P. aeruginosa at the concentration of 0.24 % of garlic.
south of Brazil. None of the studies reviewed evaluated The authors performed a 2,2-diphenyl-1-picrylhydrazyl
this form of administration in vivo for wound healing. (DPPH) test to assess the antioxidant activity, where A.
Moreover, no clinical studies for the wound-healing sativum was 29 % more efficient than honey, this
effect of this plant were found during the review activity is directly associated with higher concentra-
process. tions of phenolic compounds and flavonoids in A.
sativum, 52 %, and 84 %, respectively, compared to
honey. In addition, the authors evaluated the healing
3.11. Allium sativum L.
power by employing an in vivo model, where it was
Allium sativum L. (garlic) is one of the best-researched, found that the association of A. sativum with honey
best-selling herbal remedies and is also commonly was able to generate shorter epithelialization and

contraction time when compared to animals that ology applied was limited, non-randomized, and
received betadine solution or isolated honey. unblinded.
Interestingly, a study analyzed the action of aged According to the revised studies, it is noticed that
garlic extract in concentrations of 1, 5, 10, and 15 % in the A. sativum (garlic) is an important ally in the
the healing of wounds induced in chickens. The treatment of wounds applied topically. Historically,
authors’ results showed that, on the fourth day of garlic-containing compounds have been used on
treatment, the three highest concentrations of aged wounds to improve healing and ward off infection,
garlic preparation promoted wound contraction of and in southern Brazil, garlic bulb is applied directly to
more than 50 % in a dose-dependent manner, while the wounds. The studies have described garlic’s
the control group had a contraction of less than 30 %. efficacy, mainly under ointment, which contains differ-
In addition, the group that received the garlic ent concentrations of garlic extracts, mostly non-
preparation at a concentration of 15 %, on the sixth standardized in terms of alicillin. Therefore, studies
day of treatment presented contraction of the injury employing standardized extracts and concentrations
by more than 90 % and obtained complete re- would facilitate interpreting the data obtained. Never-
epithelization, histological findings revealed the pres- theless, given that there is a direct application of
ence of stratified neoepithelium and increased angio- macerated garlic in the southern region of Brazil in
genesis in contrast, the control group had incomplete wounds, studies on the adverse effect of this type of
reepithelialization, presence of immature epithelial use are still necessary.
cells and less formation of new vessels.[61]
Gamal Ramadan and contributors[62] presented in
3.12. Arctium lappa L.
their study the protective action of aged garlic extract
(EAV) on pesticide-induced rat poisoning (Malathion Arctium lappa L., popularly named bardana in Portu-
and Carbaril) during a 28-day oral treatment period, in guese and burdock in English is a Japanese plant that
addition to this, on day 29 of the experiment, three grows spontaneously in fields, woods, and rural areas
animals were separated from their groups and a hot in Brazil.[64] Regarding experimental evidence regard-
wound was induced to evaluate healing parameters.[62] ing A. lappa, a study analyzed the mechanisms
The authors state that on the twenty-sixth day of involved in its actions on canine immortalized dermal
treatment of the injury caused by the burn, the control hTERT fibroblasts.[65] These cells were or were not
and EAV groups were able to completely heal the incubated with hydrogen peroxide (H2O2, 200 μM) and
tissue damage caused, in addition, two days after this then incubated with the extract of burdock in different
period, the animals intoxicated by Melation or Carbaril concentrations (1, 10, 50, 100, 200, and 500 μg/mL), in
treated with EAV they were also able to heal the addition to a control group that received only vehicle.
wound thoroughly, while animals that were intoxi- The results on cell viability indicate that cells that
cated with both pesticides and were not treated with received H2O2 and were treated with burdock at
EAV, had a healing time greater than 34 days. In concentrations of 1 and 10 μg/mL showed 79 and
addition, the authors still mention that EAV can 66 % of viability, respectively, compared to the control.
modulate and practically revert to basal levels of the Furthermore, using PCR assay, the authors described
immunosuppression and the hematotoxicity caused that the extract of burdock when administered alone,
by Malathion and Carbaril. promotes up-regulation in the expression of the Dish-
Alhashim and Lombardo[63] determined the efficacy evelled Segment Polarity Protein 3 (DVL3) gene, which
of a 30 % garlic ointment topical on surgical wounds causes a decrease in the expression of Glycogen
of seventeen, compared with vaseline by analysis of Synthase Kinase 3 Beta (GSK3β). In contrast, the
visual analog scales and digital photograph analysis.[63] treatment with H2O2 isolated or associated with the
The researchers described those patients treated with extract of burdock presented up-regulation for GSK3β;
garlic healed the wounds better at 2 and 4 weeks, in addition, the burdock extract was also able to
showing less erythema at the garlic sites. However, the stimulate the expression of mRNA for superoxide
study of Alhashim and Lombardo[63] was a prelude to dismutase 2 (SOD2). Furthermore, the authors state
additional studies to determine whether topical that Arctium Lappa L. has an action on cell adhesion in
application of garlic can prevent wound infection or if gene expression with Wnt/β catenin signaling modu-
it can be used to treat clinically infected wounds due lation and chondroitin sulfate biosynthesis, which are
to the lower number of patients because the method- important factors for the healing process.[65]

Still, another study observed that the action of show that the polyphenolic extracts of strawberry
Burdock leaves was associated with an ointment for were more active against the expression of the IL-1β,
burns and wounds in an Amish community in the USA and IL-6 genes compared to blackberry, with up to
that had first- and second-degree burns. The studied 75 % of suppression for the extract fraction rich in
patients claimed to decrease or even extinguish the proanthocyanidins. In addition, the strawberry affects
pain after the application of the formulation; in the migration of fibroblasts, which directly assists in
addition, the patients’ burns did not show an infec- the healing process. The research stood out as the
tious process and obtained a total cure in a maximum anti-inflammatory properties of the two wild fruits’
of 14 days.[66] polyphenolics, as this action is mainly associated with
In addition, the study by Mary Rieman and proanthocyanidins.[70]
contributors,[67] aimed at evaluating in vitro some The part of the F. vesca plant used is the fruit.
components of the Amish burn ointment and dress- However, in the Southern region of Brazil, the form of
ings containing burdock leaf extract. According to the use of the plant is not mentioned. Thus, it is necessary
authors, whether due to the use of the aqueous to emphasize that it is recommended to use proven
fraction of the extract or the variety of components of plant forms to treat wounds. Therefore, its use is
the ointment for burn, both did not show antimicro- indicated through fruits. Furthermore, more studies
bial action, in addition to presenting a reduction in are awaited with the F. vesca.
cell viability in the highest concentrations tested, the About M. parviflora, a study was found that aimed
study also points out that the use methods should be to evaluate the anti-inflammatory and antioxidant
done with caution and with expert monitoring.[67] activities of the methanolic and aqueous extract of the
In the Southern region of Brazil, the plant A. lappa leaves of M. parviflora. The investigation showed that
has been used as a gel. However, the use of plants for the methanolic extract inhibited ear edema induced
the treatment of wounds must be carried out safely. by croton oil by 57 %, being even more efficient than
For this reason, studies that verify the skin toxicity of animals treated with indomethacin (positive control);
burdock preparations need to be carried out, as well however, the aqueous extract did not manifest any
as research that identifies the secondary metabolites action. It was also reported that the methanolic extract
present in this plant and that in fact, have a crucial and the aqueous extract at concentrations of 500 and
role in wound healing. Furthermore, after advances in 360 mg/Kg significantly inhibited the vascular perme-
non-clinical studies, well-structured clinical studies ability stimulated by acetic acid by 36 and 40 %,
also need to be conducted to understand better the respectively. In addition, the authors evaluated the
effect of roots or leaves from A. lappa on wound antioxidant action of the extracts, which showed dose-
healing. dependent activity and similar action potential for
both extracts, compared with a standard antioxidant,
BHT.[71] This antioxidant and anti-inflammatory activity
3.13. Fragaria vesca L. and Malva parviflora L.
were directly associated with the presence of
Fragaria vesca L. is a plant used as a plant to treat flavonoids.[72]
depurative, vermifuge, and diuretic problems, inflam- After analyzing the studies, it is noted that M.
mation in the kidneys and bladder, urine retention, parviflora can be used to accelerate the wound healing
heartburn, dysentery, arthritis, gout, rheumatism, in- process. However, its use must be carried out correctly
flammation in the throat and mouth, allergies, and appropriately. In South Brazil, the part plant
wounds, cleansing of the skin, anemia, cholesterol, applied is its leaves and stem, and no findings were
and uric acid. In addition, it is used for wound found about the efficacy of their stems. For this
healing.[68,69] Malva parviflora L. is popularly used to reason, it is recommended that researchers evaluate
treat aphtha, acts as an anti-inflammatory, bladder the efficacy of the stems from M. parviflora for wound
problems, healing, toothache, sore throat, wounds, healing. In addition, there is a notable lack of studies
wounds in the uterus, infection, kidney problems, and that analyze the use of F. vesca to assist in the
thrush, in addition to healing wounds.[7,68] improvement of wound healing.
About the F. vesca, a study analyzed the anti-
inflammatory and healing properties of the polyphe-
nolic extracts of strawberry and blackberry fruits. The
researchers observed polyphenolic profiles present in
the crude extracts of strawberry and blackberry and

4. Conclusions
REEDA Redness, Odema, Ecchymosis, Discharge, Ap-
Medicinal plants represent relevant alternatives for the proximation
wound-healing process, which begin to be part of SOD2 Superoxide Dismutase 2
primary health care in Brazil when their use is proven SUS Brazilian Unified Health System
by studies that affirm their healing effect. However, TASE Allium sativum Enriched with Thiosulfinate
most often, the use of medicinal plants in treating TNF Tumor Necroses Factor
wounds is merely based on folklore without any α-SMA Smooth Muscle Alpha-Actin
scientific evidence of efficacy, and the effective
compounds are unknown. Therefore, this research
review scientific data on some medicinal plants cited
Acknowledgement
in the ethnobotanical surveys as healing agents in the
Brazilian south. The wound-healing properties of many The research project was funded by the “Coordenação
cited plants have yet to be investigated, and research- de Aperfeiçoamento de Pessoal de Nível Superior
ers need to fill that gap. Besides, the actual literature (CAPES)” as a master’s scholarship to Benhur Judah
available needs isolation and characterization of the Cury and Ruan Kaio Silva Nunes. Also, we thank for the
bioactive compounds of the studied plants, and support in the form of a scholarship (PQ 2) from
studies should be planned to evaluate preparations “Conselho Nacional de Desenvolvimento Científico e
that resemble widespread use. Aside from this, the Tecnológico – CNPq”.
future focus of ethnopharmacological studies about
the reviewed plants to treat wounds should be on the
standardization of herbal extracts and to investigate
Conflict of Interest
their pharmacological mechanisms. In addition, clinical
research in this area is in its infancy and warrants The authors declare no conflict of interest.
further clinical studies.
Data Availability Statement

Abbreviations
The data that support the findings of this study are
BHT Butylhydroxytoluene available from the corresponding author upon reason-
COX-2 Cyclooxygenase 2 able request.
CTGF Connective Tissue Growth Factor
DNA Deoxyribonucleic acid
DPPH 2,2-diphenyl-1-picrylhydrazyl
Author Contribution Statement
EAV Aged Garlic Extract
EH Hydroethanolic Extract All authors contributed to the study. Isabela Antonio
FA Aqueous Fraction Pereira: Conceptualization, Resources, Data acquiring,
FE Eluted Fraction Writing-Original draft preparation. Benhur Judah Cury:
FR Retained Fraction Resources, Data acquiring, Methodology, Writing-Orig-
GSK3β Glycogen Synthase Kinase 3 Beta inal draft preparation. Ruan Kaio Silva Nunes: Review,
hTERT Telomerase Reverse Transcriptase Editing, Writing-Original draft preparation. Luisa Mota
IL-1β Interleukin 1β da Silva: Conceptualization, Methodology, Formal
IL-6 Interleukin 6 analysis, Resources, Writing, Review, Submitting, Proj-
iNOS Inducible Nitric Oxide Synthase ect administration, and Funding acquiring.
LPS Lipopolissacarides
MFAP4 Microfibril-Associated Glycoprotein 4
MIC Minimum Inhibitory Concentration
MMP-9 Metalloproteinase 9 References
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of plant species for medicinal purposes by two commun- Accepted January 10, 2023

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doi.org/10.1002/cbdv.

Traditional Plants Used in Southern Brazil as a Source to Wound

Ethnobotanical surveys are essential to register

Isabela Antonio Pereira, a nursing Luisa Mota da Silva, pharmacist

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