ABSTRACT

Aloe Vera has different therapeutic effects, including wound healing. The objective of this review is to determine the potential efficacy of the topical use of Aloe Vera in the healing of skin wounds. A bibliographic search of preclinical and clinical studies was carried out from 1999 to 2020, which included the therapeutic use of Aloe vera in the healing of: burns, surgical wounds, lactation disorders, anal fissure and anal fistula; in the databases of the VHL regional portal, PubMed and Google Scholar. It was obtained that the topical administration of Aloe vera was effective in the healing of the mentioned wounds by mainly increasing epithelization and collagen content. In conclusion, the evidence suggests that the properties and pharmacological presentation, chemical components and the effectiveness of Aloe vera to reduce the healing time of wounds make this plant a great therapeutic alternative; however, more studies are required regarding its antimicrobial property.

Keywords: Aloe vera, wound healing, burns, surgical wounds, fissure in anus. (source: MeSH NLM)

RESUMEN

El Aloe Vera tiene distintos efectos terapéuticos, entre ellos, la cicatrización de heridas. El objetivo de esta revisión es determinar la potencial eficacia del uso tópico del Aloe Vera en la cicatrización de heridas cutáneas. Se realizó una búsqueda bibliográfica de estudios preclínicos y clínicos desde 1999 hasta el 2020, que incluyeran el uso terapéutico del Aloe vera en la cicatrización de: quemaduras, heridas quirúrgicas, trastornos de la lactancia, fisura anal y fístula anal; en las bases de datos del Portal regional de la BVS, PubMed y Google Scholar. Se obtuvo que la administración tópica del Aloe vera fue eficaz en la cicatrización de las heridas mencionadas al aumentar principalmente la epitelización y el contenido de colágeno. En conclusión, la evidencia sugiere que las propiedades y presentación farmacológica, componentes químicos y la eficacia del Aloe vera para disminuir el tiempo de la cicatrización de las heridas hacen de esta planta una gran alternativa terapéutica; sin embargo se requieren más estudios respecto su propiedad antimicrobiana.

Palabras Clave: Aloe vera, cicatrización de heridas, quemaduras, heridas quirúrgicas, fisura anal. (fuente: DeCS BIREME).

INTRODUCTION

Aloe vera is a medicinal plant belonging to the genus Aloe and the lilaceae family, used for millennia by different cultures ^(1,2,3,4)It is commonly known as Aloe barbadensis Miller^(3,4,5). Its geographic origin is believed to be northwestern Africa^(1,2), , specifically Sudan, and it was later introduced in the Mediterranean region and most of the warm areas of the world.⁽³⁾ Regarding the impact of the use of medicinal plants in Peru, trends indicate that 76% of EsSalud policyholders would have no problem being treated with medicinal plants. In contrast, almost 90,000 policyholders use complementary medicine services in the 83 Peruvian complementary medicine care centers. It is also important to highlight that the highest consumption of medicinal plants is to treat diseases of the digestive, genitourinary, and respiratory systems⁽⁶⁾.

The therapeutic effects of Aloe vera have been attributed over the years⁽³⁾, among them, we can highlight the acceleration of wound healing, anti-inflammatory, moisturizing, anti-allergic, disinfectant, antimicrobial, antiseptic, anthelmintic, among others^(1,2). Currently, many investigations, both clinical and preclinical, have shown that Aloe vera is a biomaterial with great potential for wound healing, such as burns, surgical and postoperative wounds, anal and mammary fissures, and anal fistulas; through its topical administration by means of ointments, creams or gels. This places Aloe vera as a possible therapeutic alternative or complementary treatment for the aforementioned wounds.

However, it has been observed that worldwide research regarding this topic has ceased to be updated over time, thus demonstrating a shortage of information on this important property of Aloe vera, being this reflected especially at the national level, having Latin America in 2018, about North America and Asia, only with approximately 6.05% of publications on complementary medicine⁽⁶⁾. The therapeutic use of Aloe vera in wound healing represents one more treatment option, so it is appropriate to know its effects evaluated through preclinical and clinical studies, which represent a higher level of evidence. Therefore, it is important to review the potential efficacy of using Aloe Vera in wound healing.

SEARCH STRATEGIES

The bibliographic databases used were the VHL regional portal and PubMed. The search was carried out in June 2021. A secondary search was also performed by reviewing the bibliographic references of the papers that were finally included. The words used for the search and subsequent selection of articles were in the case of the VHL Regional Portal: (aloe vera) AND (wound healing), and in the case of PubMed: ("aloe vera"[All Fields]) AND ("wound healing"[All Fields]). Within the inclusion criteria, articles that included any of the following keywords supported by DeCS, "burns, surgical wounds, anal fissure and fistula, and breast fissures" were considered as part of the project. Also included were articles that will feature the word "skin scarring." Regarding the years, only articles that met the criteria mentioned above and were also in the range of 10 years old (1999-2020) were included in the research. However, most of the original articles used had a recent age range; an article from the year 1999 was used because its information is still current as it is cited to date by different authors. According to the type of study, preclinical and clinical studies were included. In the exclusion criteria, review articles and those dealing mainly with non-cutaneous avulsions or wound prevention were not considered as part of the review of the efficacy of using Aloe vera.

PHYTOCHEMISTRY

Aloe vera 'aloe vera' is a xerophytic and succulent species native to Africa; 75 active principles have been found in the plant, and it presents phenolic compounds, mainly chromones and anthraquinones, located in the inner layer of the epidermal cells; the gelatinous and colorless parenchyma is mainly constituted by water, mucilages, acids and organic salts, enzymes, saponins, tannins, traces of alkaloids and vitamins.⁷

Having a high water content is one of the main characteristics of the aloe plant; likewise, the gel is 99% water. In addition, A. vera has many compounds that possess biological activity. It was found that the main compounds of the plant were invariable with aloeresin A, aloesin and aloin (both epimers A and B) occupying between 70% and 97% of the dry weight of the plant, with an approximate ratio of 4: 3: 2. On the other hand, the minor compounds were less evenly distributed.⁸

MECHANISM OF ACTION

Wound healing is a dynamic process that occurs in 3 phases. The first phase is inflammation, hyperemia and leukocyte infiltration. The second phase consists of the elimination of dead tissue. The third phase is proliferation consisting of epithelial regeneration and fibrous tissue formation⁽¹⁾.

Aloe vera has been used for many years to treat wounds, burns and various skin conditions. On the other hand, it forms part of cosmetic products due to its moisturizing and anti-aging properties on the skin^(9,10).

Its healing effect is because aloe vera has a marked effect in the treatment of scar tissue and the prevention of scar formation after injury to the skin. This is because Aloe vera stimulates cell production through the activity of amino acids, which are the basis for new cell formation. Due to the ability of its enzymes, promotes regeneration in the deeper layers of the skin⁽¹¹⁾.

It has been demonstrated that Aloe vera has a healing property thanks to the different active molecules that it presents; these act on fibroblasts, macrophages, and the activity of the cells of the epidermis; in addition, they stimulate the formation of the epidermis, the synthesis, the remodeling process of collagen and improve the tensile stress⁽¹²⁾. This property of Aloe vera is due to mannose-6-phosphate^(1,13,14), which binds to fibroblast growth factor and enhances their activity⁽²⁾. En adición, mediante la administración tópica u oral⁽¹⁾ In addition, by topical or oral administration1 of Aloe gel on a wound, glucomannans, which are important polysaccharides of this plant, and gibberellin interact with fibroblast growth factor receptors, stimulating their activity and cell proliferation in situ^(15,16). They also promote collagen production above and across the wound, accelerating healing^(16,17).

The bioactive polysaccharides abundantly present in Aloe vera (AVP), favor fibroblast proliferation and generation of hyaluronic acid and hydroxyproline in fibroblasts; therefore, they possibly play an important role in the remodeling of the extracellular matrix (ECM) during wound healing^(13,14,18). In relation to this, in a preclinical study they treated open skin wounds on the back of 45 rats with AVP, at 25mg or 50mg for 30 days topically, and it was evidenced that, at the transcriptional level, they regulate the gene expression of Matrix Metalloproteinase (MMP-3) and Tissue Inhibitor of Metalloproteinase-2 (TIMP-2) during skin repair and this directly helps to regulate the healing activity of Aloe vera gel. Also, they may influence granulation tissue formation and wound closure by increasing the production of ECM components, including glycosaminoglycans and collagen⁽¹⁹⁾.

Acemannan, a β-(1,4)-soluble acetylated polymannose⁽¹⁸⁾ and considered to be the main functional component of Aloe vera, promotes tissue repair1 . Its potential molecular mechanisms and role in healing are not very clear. However, in a preclinical in vitro study using a mouse skin wound model and primary skin fibroblasts; they found that this polysaccharide is able to significantly accelerate cutaneous skin wound closure and cell proliferation by promoting cyclin D1 expression in cultured fibroblasts via the AKT/mTOR signaling pathway, which increased eukaryotic translation initiation factor-4F (eIF4F) activity and cyclin D1 translation, thereby promoting healing⁽²⁰⁾.

Finally, the presence of vitamin C in Aloe vera gel can stimulate the production of collagen, aiding in healing. In the case of vitamin E, glutathione peroxidase and superoxide dismutase, neutralize the inflammatory effects of free radicals produced during wound recovery^(16,21).

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THERAPEUTIC EFFICACY

Burns

Burns are lesions in the skin or other organs caused by physical and/or chemical trauma that produce the denaturation of tissue proteins and lead to an alteration of the superficial integument until the total destruction of the tissues involved. They are classified by degrees, considering three levels: first degree, second degree and third degree⁽²²⁾ .

Burn care is often expensive so every effort should be made to provide hospital care in the shortest possible time⁽²³⁾ . Herbal products appear to possess efficacy without toxicity and at less cost than synthetics. The goal of current burn treatments is to accelerate healing and prevent wound infection, as poor healing may be a consequence of pathological conditions.⁽²⁴⁾

Aloe vera is one of the effective herbs for healing, as it has organic compounds such as amino acids, polysaccharides in its extracts, which are effective as antimicrobial barriers, rapid healing, maintenance of environmental moisture and pain relief.⁽²⁵⁾

Two preclinical studies and two clinical studies were found that evaluated the effects of Aloe vera on burns, where all of them suggested its capacity as a better healing agent in less time, compared to other compounds. A greater capacity of Aloe vera to decrease pain and inflammation, as well as to increase epithelization and decrease the size of the lesion is also mentioned. However, regarding its competence to prevent wound colonization or infections, the results were not significant (Table 1).

With regard to preclinical studies, Hosseinimehr et al.⁽²³⁾ treated thermal burns with Aloe vera gel and found a significant increase in re-epithelialization compared to standard treatment with silver sulfadiazine. Similar results were reported in the study by Akhoondinasab et al.⁽²⁴⁾ , who evaluated the healing effect on second and third degree burns, and also observed less inflammation compared to silver sulfadiazine.

Regarding clinical studies, Shahzad et al.⁽²⁵⁾ and Muangman et al.⁽²⁶⁾ evaluated the effect of Aloe vera on second degree burns. In the former, they applied an aloe vera gel that favored epithelialization and pain relief; while in the latter, they applied dressings with an herbal extract containing aloe vera, presenting a greater decrease in healing time, hospital stay and pain, but reaching up to 64% of patients with bacterial colonization in the wound. Therefore, the results regarding the antimicrobial properties of Aloe are somewhat mixed and further studies on this aspect are recommended.

Surgical wounds

Surgical wounds are incisions made during a surgical procedure and can have 4 types: class I are non-infected surgical wounds where no inflammation is found and no entry into the respiratory, digestive, genital or urinary tract, class II are operative wounds where the respiratory, alimentary, genital or urinary tract is entered under controlled conditions and without unusual contamination, Class III are surgical wounds with major interruptions in sterile technique or gastrointestinal tract effusions and incisions in which there is acute nonpurulent inflammation, and Class IV are surgical wounds where viscera are perforated or there is acute inflammation with pus during the operation, and there is a late presentation of traumatic wounds with existing contamination and devitalized tissue.^(27,28)

Five preclinical studies and three clinical studies were found that evaluated the effect of Aloe vera on surgical wounds including incisions and excisions in animals, and procedures in humans such as hemorrhoidectomy, episiotomy and cesarean section, using Aloe vera in various formulations as treatment: gel, cream and ointment (Table 2).

Regarding preclinical studies, research by Khan et al.⁽²⁹⁾ , Oryan et al.⁽³⁰⁾ , Brandão et al.⁽³¹⁾ and Kusmardi et al.⁽³²⁾ used Aloe vera in gel form and observed improved healing parameters at the macroscopic (wound healing and contraction) and microscopic (epithelialization, alignment, tissue organization, fibroblastic proliferation) levels in rats. On the other hand, Ashkani-Esfahani et al.⁽³³⁾ studied the use of Aloe vera in combination with Plantago major and observed similar results highlighting a faster wound closure rate.

Regarding clinical studies, it was found that Aloe vera increased and helped in the healing process after its application for 5 to 28 days, depending on the wound evaluated. In the study by Eshghi et al.⁽³⁴⁾ an Aloe vera cream was applied to surgical wounds from hemorrhoidectomy 3 times a day until 28 days postoperatively, finding significantly greater healing only after 2 weeks of treatment. On the other hand, Eghdampour et al.⁽³⁵⁾ conducted a study where Aloe vera ointment was applied on episiorrhaphy every 8 hours for 5 days, finding an increase in the speed of wound healing. Finally, in the study by Molazem et al.⁽³⁶⁾ bandages with Aloe vera gel were applied on the cesarean surgical wound up to 8 days post-operatively, showing significant improvements in healing and no side effects.

Breast fissures

Nipple fissures are excoriation or ulcer-like lesions that develop on the mother's nipples and generate great pain during breastfeeding37 . Two clinical studies were found that evaluated the effect of Aloe vera on breast fissures, both investigations showed that Aloe vera is effective in reducing the intensity of pain and damage to the nipple, improving the condition of breast fissures (Table 3).

In the studies reviewed, it was observed that breast fissures can be effectively treated by topically applying 0.5ml of Aloe vera gel alone⁽³⁸⁾ or by adding 3 to 4 drops of one's own breast milk⁽³⁹⁾ , 3 times a day after each feeding, on the nipples and around the areola^(38,39) . With the above treatment, Alamolhoda et al.⁽³⁸⁾ and Eshgizade et al.⁽³⁹⁾ concurred in their findings, finding a significant improvement in the intensity of pain and breast fissure.

Anal fissures

Anal fissures are lesions presenting as short lacerations or ulcerations which may extend from the pectineal line to the anal margin. Most of these occur in the posterior raphe and usually reduce the patient's quality of life.

Anal fissures can be acute, if the lesion does not extend for more than 6-8 weeks and heals spontaneously (adhering to conservative measures such as hygienic-dietary treatment); or chronic, if they exceed this period and have a high resistance to healing⁽⁴⁰⁾.

Two clinical studies were found that evaluated the effect of Aloe vera on anal fissures, using rectal ointment preparations based on Aloe vera, which, together with other methods, achieved wound healing in almost all cases (Table 4).

In both studies, topical application of preparations containing Aloe vera gel (preparations with 0.5% Aloe vera powder and others with Aloe aqueous extract, respectively) 3 times a day, preceded by sitz baths and associated with a dietary regimen rich in fiber and the consumption of laxatives by medical indication was performed. A significant decrease in bleeding and healing times was observed in the first weeks of treatment. In the first study, Rahmani et al.⁽⁴¹⁾ obtained that 29 people out of 30 showed improvement in wound healing at the end of their study. On the other hand, Sarabia et al.⁽⁴²⁾ compared the efficacy of Aloe vera gel with other commercial products such as proctocaine and poladicanol 1%, achieving wound healing in all patients who received treatment with Aloe vera, although in a later period compared to poladicanol 1%.

Anal fistula

The anal fistula is the chronic phase of an anal abscess. This is a duct with fibrous walls that communicate the anal crypt where the abscess originated with the perianal skin or with the rectum, so that there will be a primary orifice (the crypt) and a secondary orifice (cutaneous or mucosal). There are different types of anal fistulas and pain is the main symptom, which is intense and disabling⁽⁴³⁾.

Two preclinical studies were found that evaluated the effect of Aloe vera on anal fistulas (), both were performed on male Wistar albino rats subjected to anal fistulas and treated for 30 days. Cavassana et al.⁽⁴⁴⁾ worked by injecting daily 0.3 ml of a solution composed of carbapolol plus Aloe vera extract into the fistulous tracts; Comparin et al.⁽⁴⁵⁾ performed their study by applying a seton soaked in glycerin and Aloe vera extract into the fistulous tract. Although both studies do not agree that Aloe vera can cause closure of the fistulous tract, they do agree that it significantly reduces the diameter of the fistulous tract, as well as signs of inflammation.

Among the limitations presented during the development of this review were, in the first place, those related to language. Most of the articles used in this study were found in languages other than Spanish, such as English and Persian. In the latter, the articles only had the abstract available in English, so it was not possible to obtain more data from the article. On the other hand, some difficulty was encountered when searching for more up-to-date studies on the article's subject, since the vast majority of studies were more than 20 years old. Finally, in the case of preclinical studies in mice, some samples were not as significant as in human studies.

ADVERSE REACTIONS AND CONTRAINDICATIONS

Although aloe vera gel has several beneficial properties that help wound healing and reduce inflammation, there are not many references for its adverse effects. In its topical application, the freshly obtained gel is normally used (100%) or in preparations with 10-70% of fresh gel, this could be contraindicated in people with allergies to plants of the liliaceae family, which could occasionally cause dermatitis, photodermatitis, allergic reactions, delay wound healing or in case of aloemodin, which is one of the components of aloe vera, it is capable of inducing skin alterations produced by ultraviolet radiation⁽⁴⁶⁾.

Aloe vera juice is a product that contains a minimum concentration of 50% Aloe vera gel⁽⁸⁾ . About this, there are clinical cases that show adverse reactions resulting from its topical administration. There is a report of a clinical case in which a 6 year old patient presented urticaria due to direct contact with aloe vera juice placed on his back, developing within a few minutes confluent and intensely pruritic haematous lesions all over the surface⁽⁴⁷⁾ . A case was also reported of a 72-year-old female patient who presented a 3-month history of pruritic erythema on her legs and eyelids, which appeared shortly after applying Aloe vera leaf juice to her legs. Subsequently, she underwent a two-day patch test and tested positive for reactions to Aloe vera gel⁽⁴⁸⁾.

CONCLUSION

It was concluded that Aloe vera possesses different bioactive components, such as the polysaccharides Acemannan and Glucomannan, which contain mannose-6-phosphate; also, phytohormones such as gibberellin; vitamin C; among others. It was determined that these act synergistically in the 3 phases of the healing process, thus giving Aloe vera its therapeutic property in healing. After the analysis of the studies, the pharmacological efficacy of Aloe vera in wound healing was evidenced. In the case of burns and surgical wounds, it was observed that this medicinal plant generally increased epithelization and collagen content and decreased healing time. Similarly, with respect to mammary fissures and anal fissures, and fistulas, it was shown that Aloe vera could be a potential treatment to improve these lesions. Thanks to its low cost and great accessibility by the population, it can be considered an alternative and effective treatment for the different types of wounds mentioned; however, more studies are required regarding its antimicrobial property.

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