Aloe vera—Mechanisms of Action, Uses, and Potential Uses in Plastic Surgery and Wound Healing

Aloe vera has been used for centuries for medicinal purposes. Clinical and experimental evidence indicates usefulness for skin moisturization, promoting wound healing, thermal skin injury, frostbite, and ischemic skin insults. Aloe vera has anti-inflammatory, vasodilatory, antimicrobial, and proliferative actions, which have been investigated in various experimental models and in various in vitro studies. This extensive literature review of the properties and actions of Aloe vera finds substantial evidence for the reported and also likely clinical usefulness for Aloe vera in Plastic Surgery and in wound care and wound healing. Though further clinical investigation is warranted, Aloe vera use may likely be indicated in situations where its effects could positively influence outcomes, such as wound healing, flap vascularity, and inflammatory skin pathologies.


Introduction
Aloe vera is a succulent tropical plant native to the Arabian Peninsula. Early documented usage of the plant dates back to ancient Greece and Egypt, where it was used to alleviate sunburns and as skin beauty care [1]. Aloe vera was utilized regularly to aid in wound healing during times of war and exploration, from and injury may be the result of many pathophysiologies. In those which result in local tissue ischemia and cell death, the microcirculation in dermal tissue is affected. In injuries due to heat, cold, chemicals, electricity, crush, friction, radiation, or other wound etiologies, ischemic microvascular changes occur in nonreversible damage zones of dermal tissue, resulting in cell death. However, reversible and relatively ischemic areas are potentially salvageable [3] [4] [5]. Thus, an agent that would inhibit ischemia, microbes, and inflammation would be of positive value to support and augment wound healing.
The mucilaginous tissue in the Aloe vera leaf contains phytochemicals, and its anti-oxidative, anti-inflammatory, anti-microbial, and proliferative properties have been shown to promote wound healing in both animal and human models [6] [7] [8] [9]. Enhancing these properties can help augment blood supply and tip the scale of relative ischemia to adequate perfusion, thereby salvaging reversible ischemic skin injury.
This review describes and identifies the effects and mechanisms that Aloe vera has on skin care and wound healing. We then propose uses and the potential utility of Aloe vera in the field of plastic surgery as it pertains to wound healing.

Review
The myriad of compounds that make up the composition of Aloe vera gel has been shown to have positive therapeutic properties in skin wound healing as well as other acute and chronic disease processes [10]. Table 1 lists the constituents that have been isolated from Aloe vera. We discuss Aloe vera's anti-inflammatory and vasodilatory, anti-microbial, anti-oxidant, and proliferative effects on skin healing. We also propose clinical uses based on the available data of its mechanisms of action.

Anti-Inflammatory and Vasodilatory Effects
Prostaglandins and thromboxanes are eicosanoid compounds formed from arachidonic acid. They serve as signaling molecules that are present in most tissues and organs, and they are necessary to orchestrate complex inflammatory reactions [11] [12] [13]. Eicosanoids are synthesized using two isoforms of cyclooxygenases. Knockout of cyclooxygenase (COX) genes in mice has been shown to impair inflammatory responses [14]. Clinically, nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids are used to reduce the inflammatory response by targeting the arachidonic pathway that produces these molecules.   There is a balance between the vasodilatory actions of certain prostaglandins and the vasoconstricting actions of thromboxanes. Found at the endothelial border, prostaglandin E 1 (PGE 1 ) and prostaglandin I 2 (PGI 2 ) are vasodilators that counteract the vasoconstricting effects of thromboxane B 2 (T x B 2 ) and prostaglandin F 2α (PGF 2α ) [15] [16]. Robson et al. demonstrated histologic imbalances of the two forces in burned tissues [4]. As perfusion is paramount for the viability of the burn wound zone of stasis, reducing vasoconstricting prostaglandins and increasing vasodilatory endogenous prostaglandin mediators reduce areas of dermal ischemia. Exogenous prostaglandins (specifically PGI 2 ) delivered intravenously to an experimental axial skin flap model showed significantly greater flap survival compared to controls [17]. Inhibition of thromboxane (specifically T x B 2 ) has been shown to support perfusion of the dermal and subdermal plexuses [3] [18]. When used in combination, synergistic effects of inhibiting thromboxane and injecting prostaglandin I 2 resulted in an even higher percentage of skin flap survival by promoting increased perfusion to ischemic flap tissue compared to control [19]. Subsequently, use of selective thromboxane inhibitors such as thromboxane synthetase inhibitors and cyclooxygenase inhibitors have been shown to increase wound perfusion [18].  [20]. Aloe vera cream (Dermaide Aloe  ) and aspirin have been shown to prevent progression of frostbite injuries following rapid rewarming [21]. DelBeccaro et al. and Heggers et al. both attributed increased tissue survivability in frostbite, electrical, intra-arterial drug, and thermal injuries to the vasodilatory effects of Aloe vera and other anti-thromboxane agents such as methimazole and imidazole [18] [22]. Use of Aloe vera alone and when combined with another specific anti-thromboxane agent (methimazole) were shown to have the greatest effects of tissue survival, wound healing, and decreased morbidity in dermal injury with associated ischemia [22].
Extracts of the phytochemical constituents present in Aloe vera, have demonstrated anti-inflammatory and vasodilatory activity through COX inhibition [23]. Salicylic acid, a known COX inhibitor, is present in large quantity in fresh Aloe vera [24]. Anthraquinones are aromatic organic compounds found in numerous plants. Emodin and emolin, anthraquinone derivatives found in Aloe, act as competitive inhibitors of thromboxane synthetase and have significant anti-inflammatory properties [25].
Other Aloe vera compounds have been shown to modulate the inflammatory response. Aloesin appears to affect migration of both fibroblasts and leukocytes [26]. In early phases of wound healing, Aloesin promotes leukocyte extravasation and cytokine and growth factor release. Aloesin is thought to act on leukocyte migration via phosphorylation of Cdc42 and Rac1, signaling proteins that coordinate and regulate actin dynamics and cell polarization [27]. The inflammatory markers TNF-α, IL-1β, IL-6, and TGF-β1 mediate leukocyte signaling, migration, and phagocytosis, and are significantly increased in the presence of aloesin. Another Aloe pro-inflammatory compound is acemannan. Acemannan activates macrophages and enhances bactericidal activity [28] [29]. Additionally, Aloe extracts have been shown to decrease inflammatory markers and affect DNA repair capacity [30] [31]. Wahedi et al. demonstrated significant decreases in macrophage and neutrophil activity in later phases of inflammation with Aloesin administration [26]. Use of Aloe on experimental burn wounds demonstrated a significant decrease in TNF-α and IL-6 levels and reduction in leukocyte adhesion on postcapillary venules [31]. NAE-8  , an Aloe vera-based extract, has been shown to decrease levels of TNF-α and IL-1β [30].

Anti-Microbial Effects
Because injury site is prone to infection, topical treatment with antimicrobial agents is frequently utilized in burn wound treatment. Silvadene  cream contains 1% micronized silver sulfadiazine. It is an antimicrobial agent commonly used for partial and full thickness burns. However, silver sulfadiazine can negatively affect wound healing time [32]. Heggers et al. demonstrated that the wound retardant effect of silver sulfadiazine could be reversed with the addition of Aloe gel [33]. This is likely due to anthraquinone derivatives emodin, Aloe-emodin, aloin, and chrysophanic acid, which have both antimicrobial and anti-inflammatory activity [20] (Table 2).
Anthraquinones have been shown to exhibit antimicrobial properties by altering solute transport through membranes, cell walls, and fatty acid elongation [10] [34]. Reports vary, but some studies demonstrate up to 18 species of microorganisms inhibited by Aloe preparations [6]. Aloe vera was able to inhibit

Anti-Oxidant Effects
Reactive oxygen species (ROS) are naturally formed as a byproduct of cellular oxidative phosphorylation in cytochrome oxidation, phagocytosis, and the inflammatory process. Normally, the body maintains a balance of anti-oxidant enzymes, mainly superoxide dismutase and glutathione synthetase. In the presence of increased oxidants (tissue injury), the balance is shifted, which may cause local or systemic healing and homeostatic dysfunction [36].
Formation of reactive oxygen species in the presence of significant traumatic or metabolic injury is of concern due to the potential for sepsis and organ failure

Proliferative Wound Healing Effects
Aloe vera extract influences initial short-term inflammation promoting neutrophil infiltration and cytokine release. Activated leukocytes, macrophages, and fibroblasts release cytokines and growth factors to initiate angiogenesis and wound healing. While tissue inflammation is eventually reduced in the presence of Aloe extracts, the presence of growth factors is sustained. Transforming growth factor-Beta 1 (TGF-β1) is a major growth factor in wound healing [40]. ing SMAD and MAPK signaling pathways, which are critical for collagen development and angiogenesis [43]. By upregulating these signaling pathways, Aloe vera can stimulate increased rates of re-epithelialization and angiogenesis by increasing TGF-β activity [44].
Other growth factors affected by Aloe extracts include vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). Moon et al. attributed increased expression of VEGF with β-sitosterol, a compound found in Aloe vera [45]. β-sitosterol is known to enhance expression of other angiogenic proteins, such as van Willebrand Factor (vWF), VEGF receptor (Flk-1), and matrix laminin [46]. With dichloromethane extraction of Aloe vera gel, Lee et al. Heggers et al. found that lectins from Aloe vera increased collagen activity, which increased wound contraction and breaking strength [22]. Collagen synthesis by fibroblasts also depends on the presence of oxygen, which is further augmented by Aloe vera due to its vasodilatory effects [7] [51]. Aloe vera decreases wound healing time in skin wound and injuries due likely to the interplay of the above processes. An efficacy study on wound healing times indicated a summary weighted mean difference in healing time that was 8.79 days shorter in the Aloe vera group [52]. Results were most improved in first and second degree burns, where perfusion is salvageable. Additional experimental models have demonstrated modulation of inflammation, increased wound contraction and epithelialization, decreased and better organized scar, that ultimately results in a greater maximum wound strength and elasticity, when wounds were treated with Aloe vera [53]. Aloe vera and its extract isolates are associated with decreased pain, shorter healing time, improved wound contracture, and increased breaking tensile strength [22] [52] [53]. Proliferative   [56]. This is likely due to a common issue with many natural product medications: a lack of standardization of extract concentrations. It is possible that some of these studies used Aloe extracts with insufficient concentrations of active compounds that have the known anti-inflammatory and proliferative effects. The study performed by Cuttle et al. also had the Aloe vera mixed further with other alternative therapies such as saliva and tea tree oil impregnated dressing [57].

Aloe vera Uses and Potential Uses
Because the concentration of active ingredients in plants may vary depending on age, growing environment, and extraction methods, it is beneficial to extract the ingredients as a concentrate before application [52] [58]. This is seen with the use of Dermaide Aloe  , a commercially purified extract, which when compared to other crude extracts, was shown to have higher antimicrobial effects with lower doses of the product [59]. Active ingredients in Aloe extracts also deteriorate with time [52] [60]. Auto-degradation of the mucilage polysaccharides can be retarded with the addition of microalgae polysaccharides [60].
What also differentiates Aloe vera products and its derivatives from other topical medications is low side effect profile and a lack of serious adverse reactions. Adverse effects noted by patients include transient burning sensation after application, skin hyperpigmentation, contact dermatitis, mild itching, and transient leukocytosis [6] [52] [61]. Some of the skin irritation such as the itching and burning may be associated with wound inflammation itself. The transient leukocytosis is likely due to the immunostimulating compounds, such as acemannan. Reynolds et al. noted some cytotoxic effects found in several other studies, but these were more associated with chemical solvents used during commercial processing [6]. The use of Aloe vera is not limited to high temperature thermal injuries.
Much of the tissue damage caused by frostbite is due to partial thawing and refreezing-or recurring frostbite-which is the result of progressive thrombosis of microvasculature [62]. The frostbite pathophysiology of progressive tissue ischemia is not unlike the mechanisms of other burn wounds. Evaluation of frostbite blister fluid revealed similar enzymes and inflammatory mediators [12] [62]. Similar to thermal burn wounds, there is a balance between vasodilatory prostaglandins and vasoconstricting thromboxane present with frostbite injuries.
When comparing Aloe vera cream used in controlled rabbit frostbite wound models, tissue survival was up to four times greater when utilized as a cream [63]. Aloe vera is not effective in all types of thermal injuries. Liquid propane freeze injuries damage tissue differently than thermal burn wounds. Skin was unsalvageable and use of Dermaide Aloe  did not significantly improve outcomes [64].
A randomized controlled trial on split-thickness skin graft (STSG) donor site wound healing time was performed by comparing Aloe vera gel with a medical lubricant [65]. Similar in pathology to partial thickness burn injury, STSG donor site wounds require regular moist dressing changes as skin re-epithelialization occurs. The authors found statistical significance in the times to complete epithelialization, which demonstrated Aloe vera's efficacy in wound healing [65]. There is some evidence for potential Aloe vera use in the treatment of radiation-induced dermatitis [66]. However, this evidence seems inconclusive, as several other studies indicate damage from radiation therapy did not improve significantly with Aloe vera gel compared to control group [67] [68]. Given oral lyophilized Aloe powder dissolved in purified water, rat models with radiation exposure had significantly accelerated wound contraction [69]. Aloe-treated rats were shown to have increased TGF-β1 and bFGF activity with significantly less inflammatory cells, more fibroblasts and blood vessels 15 days post-wounding when compared to radiation exposure only rats [69].
Aloe vera's vasodilatory and angiogenic properties along with its other proliferative anti-inflammatory effects may have a role in microcirculatory disease and injury. Aloe vera has already been shown to decrease leukocyte adhesion and maintain increased arteriolar diameter and permeability in microcirculation of burn models [70]. Maintaining proper perfusion to skin flaps is a common challenge in plastic surgery, and microvascular thrombosis and endothelial cell injury have been implicated in ischemia [71]. Thrombogenic factors are increased at the anastomosis sites in the animal models with skin flaps. It has been shown that antithrombotic treatment modalities have an effect on thrombus formation and preventing ischemia-related injury [71] [72]; these modalities were further demonstrated to increase skin flap survival and decrease necrosis [73]. The antithrombotic effects of Aloe vera can be a similarly effective means of maintaining perfusion in thermal injuries [3] [18] [21]. Further studies may show a possible use of Aloe vera topical agents in maintaining skin flap perfu-  [76]. The vasospasm and lack of perfusion for long periods may eventually lead to digital ulcers, gangrene, and cutaneous infarction [5].
The pathophysiology of these disease processes is similar. As autoimmune disease processes, SSc and SLE produce autoantibodies against endothelial cells, causing vasculopathy, digital infarcts, thrombosis, and vasoconstriction [5] [77] [78] [79]. Endothelial damage and autoantibodies also lead to leukocyte recruitment and extravasation through the upregulation of adhesion molecules (E-selectin, ICAM-1, VCAM-1) and cytokines [79]. With elevated oxidized-LDL, scleroderma can induce a pro-inflammatory response and generation of free radicals, along with a pro-coagulative state from increased thrombogenic factors, to form atherosclerotic plaques [80] [81]. Vasospasm may occur in SSc, as damaged cells have decreased expression of nitric oxide (NO) and increased endothelin-1 (ET), leading to a vasoconstrictive, ischemic state.
Aloe vera may have efficacy in managing skin manifestations of these disease processes. Topical application of nitroglycerin paste has been shown to reduce digital ulcers and ischemia through localized venodilation and smooth muscle relaxation [82]. When comparing nitroglycerin with Aloe vera in wound healing, topical Aloe compound (Dermaide Aloe  ) appeared to promote wound healing faster than nitroglycerin while also having less systemic adverse effects [83] [84].
The progression of these diseases is related to the vasculopathy that occurs through endothelial damage, coagulation, vasospasm, inflammation, and dysre-

Conclusion
Aloe vera's complex chemistry has been shown to act directly on wound and pathological sites or synergistically with other medications. Its properties as an anti-inflammatory, anti-microbial, anti-oxidative, antithrombotic, vasodilatory, and tissue proliferative agent have been shown to significantly decrease skin

Disclaimer
The contents of this work do not represent the views of the Department of Veterans Affairs or the United States Government.