Medicinal Plants from Latin America with Wound Healing Activity: Ethnomedicine, Phytochemistry, Preclinical and Clinical Studies—A Review

Latin America is a multicultural region with ancient traditional medicine. There is extensive knowledge of the use of medicinal plants for wound healing in this region. Nevertheless, many of these medicinal plants lack pharmacological, toxicological, and chemical studies. This review focuses on the ethnomedicinal, phytochemical, and pharmacological (preclinical and clinical) studies of medicinal plants with wound healing activity, from Latin America. An electronic database search was conducted by consulting scientific articles and books. A total of 305 plant species with wound healing activity were recorded, based on traditional medicine. Most medicinal plants used in wound healing in Latin America are topically administered; their methods of preparation are mainly by water infusion from aerial parts. Only thirty-five percent of medicinal plants used in traditional medicine for wound healing have been experimentally validated for their pharmacological effects, and the wound healing activity of five medicinal plants has been studied in clinical trials. In all, 25 compounds (mostly terpenes and flavonoids) have been isolated from medicinal plants with wound healing activity; therefore, extensive work is necessary for a multidisciplinary approach to evaluate the wound healing effects of medicinal plants in Latin America. The mechanism of action of medicinal plants, their toxicological actions on the skin, and their bioactive compounds, have yet to be investigated. This review on the ethnomedicinal, phytochemical, and pharmacological studies, of medicinal plants from Latin America with wound healing activity, offers promising data for further studies, as well as providing new insights into their possible role in wound care.


Introduction
Skin is the primary barrier that confers protection to the body against physical, biological, and chemical agents. Wounds are breaks, or openings, in the epithelium and can cause physical disability. Untreated wounds might result in hematomas and lacerations. Wound healing could be acute or chronic and focuses on decreasing tissue damage, increasing tissue perfusion and oxygenation, restoring the affected tissue, inducing migration and proliferation of keratinocytes, and promoting angiogenesis. Wound healing is a natural process for repairing and regenerating tissue damage and consists of hemostasis (coagulation), inflammation, proliferation (angiogenesis, granulation, re-epithelialization), and tissue remodeling phases [1,2]. In the hemostasis stage of wound healing, injured blood vessels rapidly constrict and platelet aggregation takes place to clot formation, providing a scaffold for incoming inflammatory cells. Inflammation, the second stage in the wound healing processes, occurs 5-7 h after skin disruption and involves the participation of several pro-inflammatory cytokines, including interleukins (IL)-6 and IL-1β, tumor necrosis factor (TNF)-α, and growth factors such as transforming growth factor-β (TGF-β), that promote

Ethnomedicinal Information
A total of 305 plant species were recorded with wound healing activity, based on traditional medicine ( Table 1). Most of the ethnomedicinal information was gathered from bibliographic sources dated from the last 20 years. Piper genus recorded the highest number (10) of plant species, followed by Croton (six members), and Solanum (five members) genera. The Asteraceae family recorded the highest (42 members) number of plants with wound healing properties, followed by the Fabaceae family (39 members). Only 18% of medicinal plants are orally administered. The main method of preparation is by infusion (36%), followed by decoction (24%), pulverized plant parts (12%), cataplasm (9%), maceration (7%), decoction (6%), and others. The main plant part used are leaves (38%), followed by bark (15%), whole plant (13%), aerial parts (11%), latex (8%), roots (7%), and others. This information shows that medicinal plants used for wound healing in Latin America are topically administered, and the extraction is mainly carried out by infusion with water of aerial parts. The main phytochemical components of the Piper genus are alkaloids, Latex, topical [ Engl. Tubercle, topical [33] Araliaceae Oreopanax andreanus Marchal Decoction of leaves, topical [23] Arecaceae Attalea speciosa Mart. Seed oil, topical [29] Socratea exorrhiza (Mart.) H. Wendl.

Preclinical Wound Healing Research
A total of 108 species (35%) belonging to 50 families had pharmacological evidence of wound healing activity in preclinical and/or clinical studies. Members of the Asteraceae and Fabaceae families had the highest number of reports on wound healing activity. It is a common trend that, in Latin America, these two botanical families contain a high number of members with medicinal effects [5,[8][9][10][11].
Of the 108 plant species with pharmacological activity tested, 66 (61%) had ethnomedicinal information of wound healing activity (Table 1). This finding indicates that 39% of plants (i.e., Pereskia aculeata Mill. and Plinia peruviana (Poir.) Govaerts) with pharmacological studies on wound healing activity did not consider folk medicinal knowledge. Traditional knowledge is a tool for finding new drugs. For instance, valepotriates (e.g., valtrate, acevaltrate, and didro-valtrate) with sedative actions were isolated from Valeriana officinalis L., a medicinal plant used for the folk treatment of anxiety and other mental disorders. On the contrary, drugs such as paclitaxel were not isolated following ethnomedicinal information, due to Taxus brevifolia Nutt. was used as a diuretic and bronchodilator agent in traditional medicine [6].
In our literature search, 123 preclinical studies on the wound healing activity of medicinal plants were identified and categorized in extracts with in vitro and in vivo wound healing activity (Tables 2 and 3), and in vivo wound healing activity of plant extracts with different pharmaceutical formulations (Table 4). A total of 39 plant species were investigated for in vitro wound healing activity; four of these plant species lacked wound healing effects ( Table 2). The most frequently used plant parts investigated were leaves, with 24 species, followed by aerial parts (16 species), bark (three species), and fruit (two species), among others. Although aqueous extracts are frequently used in folk medicine, ethanol was the most reported solvent for performing wound healing assays (74%), followed by hexane (33%), methanol (10%), and others. Although infusions are frequently used in folk medicine, ethanolic extracts are used the most for performing wound healing assays. Thus, it would be interesting to validate the activity and safety of the most traditional preparations and identify their bioactive compounds. Compounds such as 3α-hydroxymasticadienoic acid (1), 3β, 6β, 16β-trihydroxylup-20(29)-ene (11), 1,2 tetradecanediol, 1-hydrogen sulfate, sodium (17), and others mentioned in this review (Table 5), are easier to isolate using nonpolar solvents. In this case, the use of solvents (water or ethanol), commonly used in traditional medicine, could not be useful to obtain these kinds of compounds. Some of the studies employed two or more solvents, such as hydroalcoholic solutions. The combination of different solvents could increase the obtention of compounds such as terpenes.
The in vitro scratch assay was the method of choice for studying the wound healing activity of these plants, and Swiss 3T3 was the most frequently used cell line, followed by HaCaT and L929. Typically, the scratch assay has been extensively used as a tool for studying cell migration under different experimental conditions ( Figure 1). Moreover, this model is effective for the screening and identification of new drugs or active compounds through bioactivity-guided fractionation, and to determine the effective concentration 50 (EC 50 ) [64]. Many studies did not report EC 50 values; this value is important to evaluate the potency of new drugs for wound healing. The calculation of the EC 50 value is useful for selecting compounds or plant extracts with wound healing activity. Fibroblast proliferation and collagen synthesis are also two processes to study wound healing under in vitro conditions. Fibroblasts are one the most abundant cells in skin tissue and play an essential role in initiating the proliferative phase and subsequent tissue remodeling during wound recovery. During their proliferation, fibroblasts produce extracellular matrix proteins (fibronectin, hyaluronan, and proteoglycans) and collagen. Thus, decreased fibroblast proliferation could lead to delayed or chronic non-healing wounds [2]. Some plants, such as Arrabidaea chica (Bonpl.) B. Verl. (accepted name: Fridericia chica (Bonpl.) L.G. Lohmann) and Mimosa tenuiflora (Willd.) Poir (Table 2) stimulate fibroblast proliferation, which could be a useful strategy for wound healing.   In all, 39 studies were identified for in vivo wound healing activity of medicinal plants ( Table 3). Five of the investigated plants (Mentzelia cordifolia, Muehlenbeckia tamnifolia, Mutisia acuminata, Spondias mombin, and Amphipterygium adstringens) showed no wound healing activity [88,89]. The leaves (49%), followed by fruit (15%), flowers (15%), and bark (10%), were the most investigated plant parts screened for in vivo wound healing activity. Ethanol was also the most reported solvent for performing wound healing assays (64%), followed by water (62%), methanol (20%), and others. Some of the studies employed two or more solvents for extraction. Since ethanol is the most widely used solvent for the extraction of bioactive compounds such as polyphenols [90], which have generated great interest in wound treatment, the frequent use of this solvent in these assays is not surprising [91]. Consequently, scientists often choose polar solvents, based on the nature of these types of bioactive compounds. The extraction of compounds with wound healing activity, such as terpenes, could be increased with the use of solvents such as dichloromethane. Seven studies have investigated the oral administration of medicinal plants (Pyrostegia venusta (Ker Gawl.) Miers, Plantago australis Lam., Persea americana Mill., Anacardium occidentale L., Coronopus didymus (L.) Sm., Chamaesyce hirta (L.) Millsp, and Cecropia peltata L.). Interestingly, neither species is related to oral use, based on ethnobotanical claims related to wounds.    In all, 45 studies were identified for in vivo wound healing activity of medicinal plant extracts, using different pharmaceutical formulations ( Table 4). The leaves (50%) were also the most investigated plant parts, followed by fruit (9%), bark (7%), aerial parts (7%), roots (4%), and others. Petroleum jelly and gels were the main ingredients for preparing various formulations, and ethanol extracts, followed by methanol, were the most reported for performing wound healing assays. An important aspect to consider in pharmaceutical formulations is the assessment of their stability, manufacturing processes, and their biological effect in long-term studies. Many plant extracts can suffer degradation of their active compounds through time, and lose or decrease their pharmacological activity.
Excision and incision assays are employed to assess in vivo wound healing (Tables 3  and 4). Some of these studies reported results using both methods. In four cases, wounds were infected with Staphylococcus aureus to assess the effectiveness of antimicrobial activity and faster wound healing rate. Ten studies investigated the efficacy of wound healingpromoting activity in diabetic conditions by simulating the stages of the chronic healing process. Streptozotocin is used for inducing experimental diabetes in rodents. In addition, some medicinal plants, listed in Tables 3 and 4, were screened for wound healing activity in combination with other in vitro activities, such as anti-inflammatory, antibacterial, and antioxidant effects. Duration of wound healing shows a high variation among studies, ranging from a minimum of 7 to a maximum of 21 days for the excision model and 2 to 30 days for the incision model. The wound repair process occurs in the following order: hemostasis, inflammation, proliferation, and tissue remodeling [2]. The effectiveness of wound healing can be highly dependent on the time and the treatment. The inflammatory phase is crucial in the wound healing process [3]; therefore, a prolonged inflammatory phase could contribute to chronic wound healing. Several in vivo and in vitro studies have demonstrated that medicinal plants and isolated compounds can induce an early inflammation process, which accelerates wound healing [118]. Most of the studies reported wound contraction activity higher than 90% in the first days. For example, topical administration of F. chica leaves extract reduces the ulcer area after the 2nd day and healed wounds after 10 days (96%) of treatment in rats [71]; the aqueous extract from Bowdichia virgilioides Kunth stem barks induces wound contraction from day 6 and appears to heal wounds in 9 days (91%) in mice [108]. It is possible that these plant extracts induce an early peak of inflammation on day 1, or even earlier. Bardaa et al. [103] demonstrated that extracted oil from Cucurbita pepo L. seeds seems to accelerate the hemostasis phase in rats, and contraction was observed from day 3 to day 11 (91.6%) of the experiment. The polysaccharide-rich extract of Caesalpinia ferrea Mart. ex Tul. accelerates wound healing by changing the stage of inflammation via modulation of inflammatory mediators [109]. This is an important result, since the main goal in wound management is healing as soon as possible to prevent chronic wound healing. Therefore, in vivo experiments performed up to 11 days would be more relevant to assess the efficacy of wound healing, since wounds in rodents commonly heal between 7-14 days [119]. Particularly in rats, active contraction ceases after 12 days [120].
On the other hand, many studies using the incision wound model found that plant extracts improved wound healing activity by increased wound tensile strength, or breaking strength, suggesting an increase in collagen synthesis and the formation of stable molecular crosslinks to form fibers. In particular, the latex of Jatropha neopauciflora Pax and the oleoresin of Copaifera langsdorffii Desf. are two promising exudates that increase wound tensile strength by 100% and 99%, respectively. Plants produce different types of exudates, including latexes and oleoresin with a protective capacity against herbivores and phytopathogens [121]. Latex and oleoresin were also two forms of application. This confirmed the potential as a new bioactive chemical resource, not only for wound healing, but also for antimicrobial activity in infected wounds.
Of the 84 reports investigating wound healing activity in vivo, (Tables 1 and 2), there were a total of 8 irritation studies reported (9.5%). The remaining 76 studies did not report irritation in their results. The studies that reported 90% of wound contraction activity lacked an irritation assessment test as part of the toxicity test. Considering the potential hyper sensibility reaction associated with some plants [122], it is noteworthy to include irritability assays when screening for wound healing properties of medicinal plants and their derivatives. For example, the essential oil from Lippia sidoides Cham. (accepted name: Lippia origanoides Kunth), commonly found in the Northeast of Brazil, is traditionally used for treating wounds and superficial infections. However, de Oliveira et al. [123] revealed an irritant response to the skin when applied topically in high concentrations, without wound healing activity. Thus, even when no healing wound activity is found during preclinical studies of plants used in traditional medicine, the use of an irritability test can corroborate their safety. A topical application can reduce adverse reactions (e.g., systemic bleeding, duodenal ulcers, electrolyte imbalance, etc.) shown by oral administration. Topical application could reduce pharmacokinetic interactions with other drugs.   Wistar rats for 10 days, at 1% (excision wound) no effect [148]  Wistar rats for 21 days, after 7 and 10 days 72% and 79% at 5%, respectively, (excision wound) [153] Lythraceae Lafoensia pacari A.St.-Hil.
In many cases, phytochemical studies were carried out to identify the main components of the extracts using analytical techniques such as HPLC, HPLC-ESI-MS/MS, NMR, and GC-MS, which are currently used for chemical standardization of plant extracts. These techniques require specific knowledge of analytical methods and special training. Among the identified compounds, phenolic compounds such as chlorogenic acid, catechin, and quercetin derivatives, are the most reported. Five of these investigations have pursued the standardization of crude plant extracts. Considering that natural ingredients, including plant extracts, are becoming more popular in modern skin care formulations [165], appropriate standardization could improve efficiency and ensure their safety and quality control. It is known that, in some cases, chemical-standardized plant extracts displayed better activities than isolated compounds. This can be attributed to the synergistic effects among compounds, rather than one compound responsible for biological activity.
In all, 15 studies reported the isolation of bioactive compounds (Table 5). A total of 25 compounds, mostly belonging to the terpenoid and flavonoid classes, were isolated from 16 plants and investigated for wound healing activity, using various preclinical models (Table 5, Figure 2). Although it is sometimes difficult to investigate the effect of isolated compounds, due to the small quantities obtained, many of the isolated compounds reported here have been tested in rodent models. To perform and improve these experiments, the authors reported the use of the commercial form of some compounds, such as oleanolic acid (10) [44], trans-anethole (16) [140], and (+)-epi-α-bisabolol (21) [166]. The isolation of new compounds requires more time to elucidate the chemical structure; this is a challenge that faces many scientific groups. The molecular mechanisms of action underlying the wound healing effect of most of the isolated compounds listed in this review are yet to be clarified. However, some representative compounds generally displayed their wound healing activity by modulation of inflammatory mediators, migration and/or proliferation of fibroblasts, antioxidant effect, enhanced angiogenesis, and/or increased collagen deposition (Figure 1).

Clinical Wound Healing Research
Despite some promising preclinical results, clinical research aiming to study the wound healing activity of Latin American plants is still limited, and only seven clinical trials were found in the search (Table 6), mostly double-blind randomized controlled trials. Only one study [171] was carried out in a long-term period (1 year). Clinical assays should also consider chronic wounds, which affect the patient's quality of life. The treatment of chronic wounds is expensive, and ineffective in some cases, and some drugs can induce side effects that may lead to many patients abandoning their treatment [172]. All studies are phase 1 and include a low number of participants (<100). Clinical studies are expensive, but it is necessary to continue the evaluation of plant extracts cited in the table in phase 2 and 3 assays.
We noted that three studies employed extracts for chronic venous leg ulcers, and involved less than 50 subjects. Among these, Mimosa tenuiflora (Willd.) Poir. reduces ulcer size by 93% after the 8th treatment week [173]. Individuals living with venous leg ulcers suffer from symptoms such as pain, odor, exudate, and swelling, combined with restricted mobility, resulting from compression therapy that negatively affects their quality of life [174]. Medicinal plants are promising options for treating venous ulcers [175]. Thus, this is a potential field to evaluate the effect of those plants with important wound healing activity. It is crucial to note that all the plant species used in the clinical trials listed in Table 6 have reported traditional use related to wound healing. These features emphasize the importance of how ethnomedical information provides significant advantages for identifying which plants are most likely to be useful in clinical trials.

Mechanism of Action
The molecular mechanisms underlying the beneficial effects of some of the plants listed here are associated with different stages of the wound healing process. The common wound healing mechanism of action involves the modulation of inflammatory mediators (i.e., TNFα, IL-1, and IL-6), either by inducing the production of pro-inflammatory cytokines in the early wound healing process, or by reducing the expression of pro-inflammatory cytokines after 48 h. Simultaneously, the accumulation of anti-inflammatory cytokines and growth factors (i.e., IL-10 and TGF-β) contribute to successful wound closure.
TNF-α, IL-6, and IL-1β, are closely involved in the early wound healing process [181,182], with a gradual decline thereafter. A subtle balance of these pro-inflammatory cytokines is crucial for coordinating cellular processes during wound healing, since overexpression, or a very low reduction, can generate an unfavorable environment and alter the outcome of wound repair. For example, a persistently high level of TNF-α is associated with impaired healing leading to a decrease in collagen production, while regulated production of IL-6 can induce collagen deposition in wound sites [182].
The oral administration of 100 mg/kg methanolic extract of Pyrostegia venusta flowers increased the levels of IL-10, with the subsequent decrease in the serum levels of TNF-α and IL-6 after 48 h of treatment in Wistar rats, with excision wound, without affecting collagen formation and hydroxyproline production [98]. IL-10 can limit tissue damage caused by inflammation by decreasing the levels of pro-inflammatory mediators and providing protection against further tissue damage, which helps wound closure, with less scar formation [1,3].
In alloxan-diabetic mice, the topical treatment with 200 mg/kg oleoresin from Copaifera paupera decreased the TNF-α levels and increased the levels of IL-10 after 7 days of treatment, whereas the levels of MCP-1 (monocyte chemoattractant protein-1) were decreased after 10 days of treatment [111]. A study indicated that low expression of MCP-1 in db/db mice liver could explain the constant infections under diabetic conditions, and the same study suggested that using MCP-1 in the early stages could promote the healing of diabetic wounds [183].
On the other hand, topical application of formulations containing 10% oleoresin and 10% hydroalcoholic extract of leaves from C. langsdorffii reduced the levels of TNF-α, IL-1β, and IL-6 levels, and increased the IL-10 levels after 3 days in skin biopsies [144]. In addition to IL-10, C. langsdorffii increased the FGF-2 and TGF-β (growth factors) gene expression, which are closely involved in granulation tissue formation, re-epithelialization, matrix formation, and remodeling. The wound healing effect of Strychnos pseudoquina A. St.-Hil. is also associated with the increase of IL-10 and TGF-β levels, as well as cellularity stimulation, collagen, elastic fibers deposition, and attenuation of oxidative damage in scar tissue [151,152].
Another important mechanism proposed for the wound healing activity of C. langsdorffii is the regulation of MMP-2, and MMP-9 expression: two matrix metalloproteinases that contribute to the advancement of the proliferative stage, including migration of fibroblasts and keratinocytes, angiogenesis, and re-epithelialization. These observations suggest the influence of C. langsdorffii creams stimulating the wound re-epithelialization mechanism [144]. Similarly, de Moura et al. [137] demonstrated that topical treatment with the hydroalcoholic extract of Maytenus ilicifolia Mart. ex Reissek leaves contributes to the advancement of the proliferative stage, probably by increasing the activity of MMP-9.
Nitric oxide (NO) also plays a central role in the regulation of homeostasis, inflammation, and antimicrobial action, in the wound healing process. NO is produced at higher levels by iNOS (inducible nitric oxide synthase) during the inflammatory phase, and modulation of this production has been seen as an attractive solution to impaired wound healing [184]. The wound healing effect of the three plants listed here is associated with NO regulation.
The reduction of TNF-α and IL-1β levels, and MPO (myeloperoxidase activity) accompanying the up-regulation of TGF-β, iNOS, and NO production, was observed in the first days after wound induction in rat topical treatment with polysaccharide-rich extract of Caesalpinia ferrea stem barks [109]. The authors suggested that the reduced polymorphonuclear influx and expression/levels of cytokines (TNF-α, IL-1β), paralleled with the increased levels of antinociceptive mediators (iNOS, NO) in the first days after the wound induction, make the polysaccharide-rich extract of C. ferrea stem barks an ideal candidate for the treatment of inflammatory and painful cutaneous wounds.
Topical application of a gel containing 10% N-Methyl-(2S,4R)-trans-4-Hydroxy-L-Proline (23), an L-proline derivative isolated from Sideroxylon obtusifolium (Humb. ex Roem. and Schult.) T.D. Penn. leaves, improves the wound healing process by upregulating iNOS and COX-2 (cyclooxygenase-2) activities in the second day after wound induction [169]. Interestingly, other proline derivatives are present in plant extracts with anti-inflammatory and antinociceptive effects [185,186]. Due to the close relationship in the L-proline derivatives structures, (23) could be effective in pain management and wound care.
Although NO is produced at higher levels by iNOS during the inflammatory phase [184], the role of this molecule in wound healing could be controversial, according to other studies. For example, topical administration of 5% Struthanthus vulgaris (Vell.) Mart. ointment reduces NO production in the early stages of healing, as well as altering the release of TNF-α, IL-1α, IL-10, and TGF-β [153]. Looking forward, future research on the wound healing effect of medicinal plants should also focus on NO production, and its related biochemical mechanisms, since the exact mechanisms of action are poorly understood.
Another component of cell signaling involved in wound healing is the activation of the mitogen-activated protein kinase (MAPK) signaling pathway, particularly extracellular signal-regulated kinase (ERK) 1/2 and p38 MAPK. Both ERK1/2 and p38 are activated by tissue wounding facilitating wound closure. ERK 1/2 pathway activation is associated with the mediation of proliferation, differentiation, and migration, of various cell types [187]. The hydroethanolic leaf extract of Lafoensia pacari A.St.-Hil. increases the p-ERK1/2 expression in L929 fibroblasts. The specific mechanism of the hydroethanolic leaf extract of L. pacari bioactivity is not completely characterized, but the experimental model used in this work allowed the authors to suggest that this plant might exert cell proliferation during wound healing [80].

Future Considerations
Limited irritability studies are currently available, suggesting that detailed toxicity assays are still required for different medicinal plant extracts, especially for those with significant wound healing activity. Several compounds (i.e., 2-(3,4-dihydroxy-phenyl)-5,7-dihydroxy-chromen-4-one, 1,2 tetradecanediol, Kaempferol 3-O-α-D-glucoside, and others) showed wound healing activity that could be considered for candidates in clinical trials. Special attention should be given to plant extracts such as Croton lechleri, Ageratina pichinchensis, and others, which showed wound healing activity without adverse reactions in clinical trials. All plants reported with clinical wound healing activity have an ethnomedicinal use related to healing wounds. Thus, traditional knowledge is a useful tool to obtain plants as candidates for clinical evaluation.
Latin American countries face economic and health problems due to the high prevalence of diabetes, and the elderly population is expected to increase in the next two decades [188]. The wound healing activity of plant extracts and compounds should also be evaluated in diabetes-induced in vivo models, where a risk of infection can occur. Access to primary healthcare systems is difficult in this region; therefore, people living in rural areas still depend on traditional medicine. Plants with wound healing activity evaluated in clinical trials could be incorporated into national health systems, as an alternative therapy, in case of lacking allopathic medicine in rural areas.

Materials and Methods
An electronic database search was conducted using ScienceDirect, PubMed, SciFinder, SciELO, and Google Scholar from January to June 2022. The search included the following keywords: "American", "Latin American", "medicinal plants", "wound healing", "ethnopharmacological", "ethnomedicinal", and "ethnobotanical". Ethnobotanical information from books was also considered for this review. Only scientific articles published in English, Spanish, or Portuguese, were contemplated. In ethnobotanical studies, only information presenting complete data on the way of preparation, route of administration, plant part used, and the scientific name of the plant species was considered. Only preclinical and clinical studies regarding the single use of a medicinal plant were considered. The study design, dose, duration, patient type, the main outcome, and adverse effects of the herbal treatment, were collected from clinical trials. Scientific works without information on the percentage of wound contraction, tensile strength, or breaking strength, were excluded. In some cases, percentages of wound healing activity were calculated from the information presented in the scientific article. No pharmaceutical formulations based on nanotechnology were contemplated. For each species, the accepted botanical names were validated and updated, if necessary, by consulting the Missouri Botanical Garden (http://tropicos.org/, accessed on 12 May 2022). The chemical structures were drawn using the ChemDraw Ultra 12.0 software.

Conclusions
In Latin America, there is extensive folk knowledge of medicinal plants for wound healing. This practice is important for primary health care, especially in rural areas. Medicinal plants from Latin America are a source of compounds with wound healing activity. A few plant species (22%) have been scientifically validated to support ethnomedical use, and demonstrate their efficacy. Since 65% of medicinal plants with empirical wound healing activity are yet to be studied, extensive work is necessary for a multidisciplinary approach to evaluate the wound healing effects of medicinal plants in Latin America.
Only two formulations containing plant extracts were evaluated for wound healing activity in clinical trials. The pharmaceutical formulation requires the evaluation of their manufacture and stability, for assessing their efficacy in clinical trials.
Several reports have described the wound healing potential of plant extracts, or their isolated compounds, but their mechanism of action are yet to be explained. The mechanism of action could help to prepare combinations of compounds with different mechanisms of action for inducing synergistic actions. It is necessary to carry out phase 2 and 3 clinical trials in long-term studies, to evaluate the wound healing activity of plant extracts (e.g., Croton lechleri and Ageratina pichinchensis).