Aloe vera and wound healing: a brief review

Aloe vera possesses a great therapeutic importance in traditional medicine. It has attracted the attention of modern medical fields due to its wide pharmacological applications. The bioactive substances in Aloe vera proved to have antioxidant, anti-inflammatory, antibacterial, and antiviral properties. Taken into our consideration the long history of clinical applications of Aloe vera in traditional medicine, especially for promoting the healing of cutaneous wounds with rare adverse effects, it provides a cheap alternative to many expensive synthetic drugs. Recent techniques in tissue engineering created novel scaffolds based on Aloe gel extracts for wound healing applications. Nonetheless, further guided researche is required to foster the development of Aloe vera based scaffolds for the benefit of worldwide populations. Here, I systemically summarize the main events following wounding and the mechanism of action of Aloe vera in promoting the healing process. I hope to provide a solid piece of information that might be helpful for designing new research studies into this topic.


INTRODUCTION
Mammalian skin serves as a protective physical barrier against mechanical and chemical injuries, as well as microbial invasion (Plotczyk, Higgins, 2019).The loss of skin integrity requires rapid and efficient amendments of the ruptured tissue to maintain body homeostasis, in a process known as wound healing (Rittié, 2016;Sorg et al., 2017).The healing of a skin wound is a complicated and dynamic process necessitating integrative reactions of multiple structures, mediators, and cell lines (Rodrigues et al., 2019).Wounds may result from several conditions including skin injuries, burns, accidents, surgery, arterial disease and trauma.They can be broadly categorized into acute and chronic wounds (Hughes et al., 2017).
All wounds could be considered acute at the advent of injury, regardless of cause (Whitney, 2005).Wound closure taking place in a predictable and acceptable amount of time characterizes acute wounds, and it restores the structural and functional integrity of the skin at a definite time.In contrary, chronic wounds occur when the healing trajectory is disrupted and doesn't follow an expected time course, hence the entire process is delayed (Galea, 2018).The main objective of wound treatment is to accelerate the closure rate of a wound as much as possible with minimal pain, anxiety and scarring.Thus, continuously exploring new innovative interventions will pave the way for a better quality of life for patients who suffer wounds.Moreover, it will lower the total cost of wound -related health maintenance (Teplicki et al., 2018).

The inflammatory phase
The inflammatory phase immediately follows the wounding incidence, and it takes approximately four days (Coger et al., 2019).It mainly fulfills two main goals.The first is to maintain tissue hemostasis, which this could be achieved by contraction of the smooth muscle cells, closure of the ruptured large blood vessels, and accumulation of platelets to thrombose the smaller damaged vessels (Nurden, 2018).The second goal is to rid the wound of contaminants, bacteria and other unfavorable debris (Landén, Li, Ståhle, 2016).Instantly after wound incidence polymorphonuclear leukocytes (neutrophils) migrate from the adjoining microvasculature and act to accomplish this mission.Neutrophils seem to be short-lived cells and undergo apoptosis after a few hours at the site of injuries.Nevertheless, some scientist assumed that neutrophil behavior is more sophisticated and that they may migrate back into the nearby vasculature (de Oliveira, Rosowski, Huttenlocher, 2016).Another type of cell called (macrophages), appears at the wounding site approximately two days postinjury (Hesketh et al., 2017).These type of cells acts to remove necrotic tissue and phagocytizing bacteria and foreign debris (Goldberg, Diegelmann, 2017).Moreover, macrophages initiates two crucial events in the healing process; namely angiogenesis and fibroplasia (Gonzalez et al., 2016).These events are mediated by cytokines released by the activated macrophages (Minutti et al., 2017).Angiogenesis begins three days post-injury and is a prerequisite to provide the metabolic requirements of the healing process, while collagen synthesis and fibroplasia occur by the third to the fifth-day post-wounding (Hanna, Giacopelli, 1997).

The proliferative phase
The proliferative phase may last as long as three weeks post-injury.The activated macrophages mediate the release of fibroblast stimulating factors and angiogenesis factors (AGF) (Delavary et al., 2011;Landén, Li, Ståhle, 2016).Fibroblast stimulating factors promote the proliferation of fibroblasts, which plays an essential role in the proliferative phase.In turn, the fibroblasts produce collagen and proteoglycans (Tracy, Minasian, Caterson, 2016).AGF promote the growth of the new blood vessels and capillary buds (Oike et al., 2004).The neovasculature together with the collagen and proteoglycans constitute the granulation tissue which, fills the wounded defects (Teller, White, 2011).The synthesis of collagen increases wound tensile strength (Panchatcharam et al., 2006;Darby et al., 2014).The borders of the wound come closer to each other due to the contraction of the wound, decreasing the wounded area.This process is mediated by a distinct type of fibroblast that have a contractile nature known as myofibroblasts (Li, Wang, 2011).The proliferative phase also includes the re-epithelization process, in which the surrounding epithelial cells actively divide and migrate over the granulation tissue to link both edges of the wound (Rousselle, Braye, Dayan, 2019).The re-epithelization process is critical in wound closure as the newly generated epithelial tissue acts as a physical barrier blocking contaminant and microbial invasions from the external environment and precluding body fluid leaks.The wound closure rate is directly affected by wound size as larger defects require more time to close because migrating epithelial cells have to travel longer distances to link both edges (Taniguchi, Matsumoto-Oda, 2018).Moreover, the moist wound surface facilitates epithelial cell migration, while, dry surface inhibits epithelial cell migration (Hamman, 2008).Hence, the primary goal of new wound dressing compounds is to provide a humid microenvironment for the wound to facilitate re-epithelization (Chiaula et al., 2019;Weller, Team, 2019).

The remodeling phase
The remodeling or maturation phase is the final step in the healing process.It begins approximately three weeks post-wounding and may last for more than one year (Gonzalez et al., 2016).In this phase, the production of collagen by fibroblasts is continued.Collagenases are a group of enzymes secreted during this phase, which act to re-organize collagen bundles in a parallel arrangement, and lysis the collagen bundles produced during the proliferative phase (Qing, 2017).The closure of the wounded area and a gradual increase in tensile strength still progress in this phase.The ultimate strength of a healed wound depends on the quantity of collagen biosynthesis and the extent of crosslinking between neighboring collagen bundles.At the end of the maturation phase, the wound reaches maximal tensile strength, which is typically 80% of the strength of the original uninjured cutaneous tissue (Bowden et al., 2016).
Generally, wounds heal in a timeframe of four to six weeks.However, chronic wounds fail to heal within this period.Several factors can impair the healing process including; diabetes, hypoxia, ischemia, bacterial infection, collagen synthesis defects, malnutrition, smoking, and dehydration (Wallace, Basehore, Zito, 2020).

Aloe vera history and its clinical relevance
Aloe vera is a perennial succulent plant that belongs to the family Liliaceae.More than 400 species have been identified in this family (Sánchez-Machado et al., 2017).This xerophytic herbaceous plant developed an ability to store water in the tissue of leaves, hence it is indigenous to arid subtropical and tropical regions.It has characteristic short stem, and fleshy leaves with lance shaped apex, tapered end, and serrate margin (Steenkamp, Stewart, 2007).Two main products are produced from these plants; the aloe gel and yellow latex (aloe juice).Aloe gel, is extracted from the core leaf pulp present in the innermost part and is composed of parenchymal cells which act to store water and other nutrients.The Aloe juice is a yellow and better latex, produced from the marginal cells of the leaves (Gupta, Diaa Massoud, , Hanan H. Abd-Elhafeez Malhotra, 2012).Historically, several cultural traditions have considered Aloe vera a potent medicinal plant with therapeutic and cosmetic applications.The clinical applications of Aloe vera are wide and include: antinflammation, immunomodulatory, cardiovascular, and antibacterial (Maan et al., 2018;Gao et al., 2019;Kumar et al., 2019).Furthermore, the healing properties of Aloe vera have been proposed for curing wounds since ancient times.The Pharaohs first used Aloe vera for wound remedy (Yohannes, 2018;Akbar, 2020).Other cultures worldwide followed them, such as Chinese, Greek, Spanish, Indian, and Iranian.Aloe vera is well-known for its magnificent healing properties, being called the silent healer or the healing plant (Singh et al., 2018;Ibrahim et al., 2019)"id":"ITEM-1","issue":"2","issued":{"date-parts":[["2019"]]},"ti tle":"Clinical Uses and Toxicity of Aloe vera: An Evidence-Based Comprehensive Retrospective Review (2007-2017.Many studies demonstrated that the benefits of Aloe vera are always associated with high polysaccharide content (Minjares-Fuentes, Femenia, 2017; Chen et al., 2019;Soares et al., 2019).Recent studies showed that Aloe vera extract triggers the proliferation of several cell lines and accelerates the wound closure in both standard and diabetic rats (Atiba, Ueno, Uzuka, 2011;Galehdari et al., 2016;Mohi-Eldin, Allaam, 2017;Gao et al. 2019;Abdel-Mohsen et al., 2020).

Chemical composition of Aloe vera
Aloe vera is a succulent plant that can store a huge amount of water in its inner tissue, hence water contributes approximately 99 to 99.5% of its chemical constituents (Kumar et al., 2019).The remaining part consists of a wide range of fat and water-soluble components including minerals, amino acids, enzymes, vitamins, polysaccharides, phenols, sterols and additional organic compounds (Boudreau, Beland, 2006;Hashemi, Madani, Abediankenari, 2015).Aloe gel is comprised of about 55% polysaccharides, 17% sugars, 16% minerals, 7% amino acids, 4% fatty acids, and 1% phenolic compounds.The major components of the yellow bitter latex are anthraquinones and glycosides (Rahman, Carter, Bhattarai, 2017).The chemical constituents of the Aloe vera plant vary according to the species, climatic conditions, and the growth environment (Klein, Penneys, 1988).It has been postulated that the heterogeneous composition of Aloe vera gel perhaps contributes to its therapeutic and pharmacological properties (Talmadge et al., 2004;Hamman, 2008).More than 240 bioactive substances with medicinal and nutritional properties were identified in the Aloe vera leaves (Singh et al. 2019).The main chemical constituents and their recognized biological activities are listed in (Figure 2).

Aloe vera and wound healing
In traditional medicine, Aloe vera had been considered a healing plant acting to accelerate the closure rate of a wound.The usage of Aloe vera as skin curative acts also to reduces the severity of mucocutaneous problems including gingivitis (Al-Maweri et al., 2020)"type":"article-journal","volume":"18"},"uris":[" http://www.mendeley.com/documents/?uuid=2bb55554-8178-46c3-8824-5d81bd6d7402"]}],"mendeley":{"forma ttedCitation":" (Al-Maweri et al. 2020, oral submucosa fibrosis (Al-Maweri et al., 2019), vaginal atrophy in menopausal women (Palacios, Mejía, Neyro, 2015), and mucosa damage induced by chemotherapy and radiotherapy (Sahebnasagh et al., 2017;Alkhouli, Laflouf, Alhaddad, 2021).The mechanism of action of Aloe vera on promote the wound healing has been extensively studied on experimental animals (Bunyapraphatsara et al., 1996;Choi et al., 2001;Choi, Chung, 2003;Mendonça et al., 2009;Oryan et al., 2016).Several hypotheses have been postulated for this crucial role in reducing pain, fighting inflammation, moisturizing the wound, quantitative and qualitative improvement in the collagen composition, and increasing the migration of the wound's neighbouring epithelial cells (Gupta, FIGURE 2 -Aloe vera bioactive ingredients and its biological activities.Diaa Massoud, , Hanan H. Abd-Elhafeez Malhotra, 2012), (Figure3).The key regulator of the action of Aloe vera in prompting healing is the existence of a mannose-rich polysaccharide; called glucomannan which acts together with gibberellin and growth hormone stimulating fibroblasts to actively proliferate.Upon triggering fibroblast activation and proliferation, the collagen biogenesis significantly increases both quantitatively and qualitatively (Surjushe, Vasani, 2008).The amount of collagen in the wounded area not only increases, but the transversal connections between bands also increase and other subtypes of collagen are created.Consequently, the wounded area decreases and the healing process accelerates significantly ( Surjushe, Vasani, Saple, 2008;Hashemi, Madani, Abediankenari, 2015).Interestingly, (Teplicki et al., 2018) reported that Aloe vera accelerates wound healing not only through promoting the active proliferation of fibroblasts and keratinocytes but also because it showed protective action for keratinocytes against preservative-induced death.Moreover, the biogenesis of hyaluronic acid and dermatan sulfate significantly increased in the granulation tissue after oral and topical therapy with Aloe vera (Mahor, Ali, 2016).The topical application of Aloe vera gel may also stimulate angiogenesis and increases the blood supply to the wound, thus better fulfilling its metabolic requirements (Sargowo, Handaya, Tjokroprawiro, 2012;Hamid, Soliman, 2015).The humectant action of mucopolysaccharides contained in Aloe vera gel contributes to the moisturizing of the skin (Dal'Belo, Gaspar, Maia Campos, 2006).
The anti-inf lammatory and anesthetic action of Aloe vera may be attained by the inhibition of the cyclooxygenase pathway by decreasing prostaglandin E2.C-glycosyl chromone, a novel anti-inflammatory agent was isolated from the gel extract (Hutter et al., 1996).
Moreover, hydrolyzing enzymes such as carboxypeptidase and bradykinase were isolated from Alo; both enzymes act as potent anti-inflammatory substances, by breaking down bradykinin which induces pain (Takzare et al., 2009;Anuradha, Patil, Asha, 2017;Maan et al., 2018).Recent studies in mice, showed that the anti-inflammatory properties of Aloe vera are related to its strong ability to inhibit cytokines, ROS production and blocking the signaling of JAK1-STAT1/3 (Sánchez et al. 2020).Additionally, rhein (0.3 μM), rhein sulfates/glucuronides (1.0 μM), and aloe-emodin sulfates/glucuronides (0.5 μM) suppressed nitric oxide production, iNOS expression, pro-inflammatory cytokines, and phosphorylation of MAPKs (Li et al., 2017).Acemannan is an additional polysaccharide extracted from Aloe vera that act as a potent anti-inflammatory agent on the upregulation of white blood cell activity during the healing process (Tamura et al., 2009;Liu et al., 2019).(Thunyakitpisal et al., 2017) demonstrated that acemannan improved IL-6 and IL-8 expression and NF-κB/DNA binding in human gingival fibroblast through a toll-like receptor signaling pathway.Aloin also modulates oral inflammatory diseases through the inhibition of salivary IL-1β-prompted IL-8 production by reducing p38 and extracellular signalregulated kinase pathways (Na et al., 2016).AVH200 ® , is a standardized Aloe vera extract which contains mainly aloin and acemannan, and acts to reduce cytokine production and activation of T cells in healthy human individuals aged 18 -60 years (Ahluwalia et al., 2016).
Additionally, anthraquinone is another organic compound with natural pigments which is responsible for the characteristic color of Aloe vera leaves, and has been postulated to play an important role in minimizing bacterial infection and viral invasion (Kuzuya et al., 2001;Tamura et al., 2009).

Side effects
Due to its wonderful healing properties Aloe vera is widely considered as an efficient herbal medicine with therapeutic uses for both diabetic and normal wounds.
Aloe vera is considered much more reliable and costeffective in terms of the consistency and speed of wound healing when compared to the alternative therapies currently available.
No serious adverse reactions were demonstrated following topical application of Aloe vera.Nonethless, recent studies reported that Aloe vera extracts may contain toxic components and may cause some adverse impacts.The topical application of Aloe vera on cutaneous wounds may cause minimal transient pain, a stinging sensation, burning, redness and rare cases of dermatitis in sensitive persons.The allergic reactions mainly originate from anthraquinones.Hence, it would be advisable to smear it on a small area first to test the potential allergic reaction ( Surjushe, Vasani, Saple, 2008;Mahor, Ali, 2016).On the other hand, oral ingestion of Aloe preparations may be asscociated with some problems such as hypokalemia, diarrhea, pseudomelanosis coli, nephrotoxicity, and hepatotoxicity, in addition to phototoxicity and  (Guo, Mei, 2016).Moreover, whole leaf extract of Aloe vera induce carcinogenicity in rats, hence it was classified as a possible carcinogen for human by the international agency for research on cancer (Grosse et al., 2013;Cancer, 2015).

CONCLUSION AND FUTURE PROSPECTIVES
In conclusion, Aloe vera derivatives have a long history of pharmaceutical applications.Moreover, the usage of Aloe vera as a skin curative is still growing.Recent techniques in tissue engineering created novel scaffolds based on Aloe vera gel extracts for wound healing applications (Gil-Cifuentes, Jiménez, Fontanilla, 2019;Rubio-Elizalde et al., 2019).Incorporation of Aloe vera within natural and synthetic polymers built to mimic the original architecture of the human body may reduce their adverse effects (Tran, Hamid, Cheong, 2018;Ezhilarasu et al., 2019;Ghorbani, Nezhad-Mokhtari, Ramazani, 2020).Hence, further guided studies are required to foster the development of Aloe vera based products for the benefits of worldwide populations.

FIGURE 1 -
FIGURE 1 -Normal wound Phases and main events included.

FIGURE 3 -
FIGURE 3 -Action mechanism of Aloe vera in promoting wound healing.