I got a shock the first time I took off a patient’s dressing and found something like this over a wound. The patient had cut open a large leaf from her Aloe Vera plant and was using it as a wound treatment. I will admit that her innovation was driven in part by the fact that she was having problems getting needed surgical dressings paid for by her insurance. However, let’s leave that issue for another time. I mentioned the Aloe Vera dressing to my longtime friend and colleague, Dr. Tom Bozzuto, who’s written about this topic. Tom sent me an article of his on the use of Aloe in wound care. There is growing interest (bad pun) in plant-based wound treatments. Stay tuned for more about that interesting topic!

–Caroline

Aloe is a cactus-like plant that grows in hot, dry climates such as Africa and India. In the United States. It is cultivated in Florida, Texas, and Arizona.¹ Aloe is in a plant family with over 360 species.² The applicable part of aloe is the leaf. From the leaf, multiple components of aloe can be extracted. Most aloe-containing products use aloe gel or aloe latex. The forms of aloe contain different active constituents and have different pharmacological effects. Aloe gel is the clear, jelly-like substance obtained from the thin-walled mucilaginous cells in the center of the leaf.^3,4 This form of aloe is often found in topical formulations and in cosmetics. Aloe latex is an intensely bitter, yellow sap or juice produced in the peripheral bundle sheath cells just beneath the leaf skin.⁴ It drains from cut leaves and dries to form solid granules, sometimes referred to as “aloes.” References to aloe juice or aloe sap are usually describing aloe latex products. Some products contain a homogenized total leaf extract which contains constituents of both the gel and the latex.^3,4

Aloe latex contains up to 30% anthraquinones, including glycosides such as barbaloin (aloin), isobarbaloin, emodin, and free anthraquinones (aglycones) such as aloe-emodin, anthranol, and chrysophanic acid.4 It also contains resins and aloesin. Aloe gel does not contain the anthraquinones found in aloe latex. Aloe gel contains mono- and polysaccharides, including acemannan, aloeride, and maloyl glucans, tannins, sterols and enzymes, including cyclooxygenase, amylase, lipase, alkaline phosphatase, and carboxypeptidase; amino acids, saponins, salicylic acid, arachidonic acid, lipids, vitamins, and minerals.^{1, 2, 6} Sterols in aloe include lophenol, 24-methyl-lophenol, 24-ethyl-lophenol, cycloartenol, and 24-methylene-cycloartanol.⁷

Acemannan is a polysaccharide reported to be one of the active components contributing to fibroblast proliferation and type I collagen synthesis.⁷ The clinical study by Khorsani et al. (2009) demonstrated this reduction in healing time following A. vera application when compared to silver sulfadiazine; all 30 patients (100%) in the A. vera group, compared to 80% of the silver sulfadiazine group, demonstrated complete wound healing with 19 days. This healing difference was more pronounced at the healing rate within 16 days, with 83% and 23% for the A. vera group and silver sulfadiazine group, respectively. A study by Fox et al. (2017) demonstrated that both the gel and whole-leaf material exerted a beneficial wound repopulation response. However, the Aloe gel treatments were superior to the whole-leaf materials in the induction of wound closure, assessed using an in vitro scratch wound assay with epidermal keratinocytes (HaCaTs).¹¹ Due to the importance of establishing the protective outer barrier of the skin, stimulating the migration of epidermal keratinocytes over the wound site is essential for the re-epithelialization process. This allows the re-established epidermis to prevent water loss from the tissue, whilst also providing a barrier to any microbial organisms.^11,12

Another important aspect of wound repair is the proliferation and migration of fibroblasts into the wound site and the subsequent deposition of extracellular matrix, replacing the temporary fibrin scaffold.12 The effect of A. vera on fibroblast function was assessed by Shafaie et al. (2020) through use of the colorimetric MTT viability assay. The addition of A. vera gel was shown not to impair the viability of the fibroblasts and even appeared to stimulate their proliferation, particularly at 24 h. A. vera gel also appeared to stimulate the migration of fibroblasts into the denuded space within 24 h, assessed using an in vitro scratch wound assay. However, part of this enhanced migratory response could be a result of the induced proliferative potential.¹³ The gene expression of integrins ɑ1 and β1 significantly increased following treatment with A. vera gel, which corroborates the wound repopulation response observed in the scratch assay due to their role in fibroblast migration.^{13, 14} Therefore, A. vera gel could stimulate the proliferation and migration of fibroblasts independently, resulting in a further enhanced response.

A randomized clinical study performed by Khorsani et al. (2009) assessed the potential of an A. vera cream against topical silver sulfadiazine on burn injuries. Silver sulfadiazine is used to prevent the microbial contamination of the burn site but impairs wound healing.8 Given the long history associated with the use of A. vera on minor burns, there was validity in the assessments; a systematic review indicated a reduction in the healing time of burn injuries following A. vera treatment.¹⁰

A rodent study assessing a hydrogel preparation of A. vera, Restauder®, demonstrated a significantly enhanced reduction in wound size through 91.6% wound reduction, compared to 83.99% reduction in the untreated control.¹⁵ A benefit of this hydrogel preparation is being able to exert this healing response using previously manufactured batches, as opposed to freshly obtained A. vera, increasing the availability of A. vera products within the community. An in vitro study assessing the effect of A. vera on dermal fibroblasts and epidermal keratinocytes observed a significant stimulation of fibroblast and keratinocyte proliferation following treatment with 3% or 1% A. vera, respectively.16 These same concentrations of A. vera also significantly stimulated the migration of fibroblasts and keratinocytes into denuded scratch sites within 24 h, compared to controls.¹⁶ The migration of keratinocytes is vital for re-epithelialization, along with proliferation at the wound site. Additionally, the migration of fibroblasts to the wound site and subsequent proliferation is required to synthesise the extracellular matrix needed to replace the temporary fibrin scaffold produced following injury.^12,17

Constituents in aloe may play a role in the reduction of pain and itching associated with inflammation, as shown in laboratory research. The carboxypeptidase and salicylate components of aloe gel were shown to inhibit bradykinin, a pain-producing agent. The presence of magnesium lactate can inhibit histamine, which may reduce itching.¹⁸ A C-glucosyl chromone component appears to reduce topical inflammation.¹⁹ In colorectal mucosa in vitro, aloe gel has an antioxidant effect, decreasing levels of colorectal prostaglandin E2 and interleukin-8. These effects may explain why aloe gel seems to help some patients with inflammatory bowel disease.²⁰ Salicylic acid and other antiprostaglandin compounds in aloe may be responsible for aloe’s local anti-inflammatory activity, possibly due to an inhibitory effect on the arachidonic acid pathway via cyclooxygenase²¹. In vitro, the maloyl glucan components of aloe also had anti-inflammatory effects.⁶

Preliminary data suggest that anthraquinones may have mutagenic and carcinogenic effects, and may promote tumor growth, although some data are conflicting.^22-24 Possible mechanisms include intercalation of the tricyclic anthraquinone structure into DNA, inhibition of topoisomerase II, and induction of cell signaling and growth. Also, the constituent aloe-emodin is thought to induce DNA damage through the generation of reactive oxygen species.²⁴

However, some evidence suggests that aloe or its constituents may have anticancer effects. In vitro, individual maloyl glucans had antagonistic effects on cell proliferation, with one stimulating and one inhibiting, suggesting a mechanism by which aloe may have both pro-cancer and anti-cancer effects.6 Antileukemic and antimutagenic effects of aloe have been shown in vitro and attributed to di-(2-ethylhexyl) phthalate (DEHP).²⁵ Another constituent, aloe-emodin, has been shown to promote apoptosis by various mechanisms, including the involvement of p53.^26-28 Also, in vitro, aloe-emodin had anti-angiogenesis effects, possibly by affecting urokinase secretion and tubule formation of endothelial cells.²⁹ In animal research, aloe itself appears to affect detoxification of reactive metabolites by liver and other organs.³⁰

Aloe is commonly used as an ingredient in skin care products. In human research, aloe gel has been shown to reduce ultraviolet (UV)-induced erythema ³¹ and increase water content of the stratum corneum.³² Oral intake of aloe vera gel powder has also been shown to increase skin elasticity, skin hydration, and collagen content of the dermis and reduce trans epidermal water loss and markers of skin fatigue.^33,34 When applied to psoriatic plaques, aloe extract cream seems to reduce cellular desquamation, erythema, and infiltration. This results in reduction or resolution of the plaque.35 In an in vitro model of psoriasis, which used tumor necrosis factor (TNF) alpha to stimulate over-production of cultured human keratinocytes, a polysaccharide extract of aloe mixed into the culture medium in a concentration of 20-80 mcg/mL produced a dose-dependent reduction in keratinocyte proliferation, and a reduction in levels of inflammatory mediators such as interleukins 8 and 12.³⁶

Some clinical evidence suggests that aloe may prevent mucositis associated with radiation therapy.^37,38 In vitro, radioprotective effects of aloe polysaccharides were associated with modulation of the cell cycle.^{39, 40}

Aloe gel might inhibit the synthesis of thromboxane A2, a potent vasoconstrictor and thereby increase microcirculation and prevent ischemia in wounds. This may speed the healing of burns and frostbite.41-44 In animal models, aloe seems to prevent the inhibition of wound contraction caused by silver sulfadiazine (SSD). SSD is often applied to wounds, especially burn wounds, to prevent infection. But SSD seems to slow wound healing by inhibiting contraction and epithelialization. Applying aloe in conjunction with SSD seems to improve the speed of wound healing compared to SSD alone.⁴⁵ However, there is also evidence SSD improves the rate of wound healing better than aloe when each product is used alone.⁴⁶ This suggests that there might be a synergistic effect when SSD and aloe are used together. In animal models of frostbite, aloe gel seems to be more effective for improving tissue survival than pentoxifylline. The combination of pentoxifylline plus aloe gel seems to be better than either agent alone. Topical aloe’s anti-inflammatory properties do not appear to interfere with wound healing but rather increase wound tensile strength,⁴⁷ possibly due to the fibroblast-stimulating activity of mannose-6-phosphate.⁴⁸ Polysaccharides such as mannose stimulate the activity of fibroblast growth factor and increase collagen production. Aloe gel also seems to increase collagen crosslinking, accelerating wound healing.⁴⁹

In a study using cultures of human skin fibroblasts and keratinocytes, adding aloe vera gel 2-3% to the culture medium increased proliferation and migration of both types of cells, suggesting the gel could increase the rate of epithelialization of wounds.^50,51
When aloe latex is used orally in high doses. Ingesting aloe latex 1 gram daily for several days can cause nephritis, acute kidney failure, and death.52 Oral ingestion is not recommended for pregnant or lactating women.

Most common side-effects:

• Orally: Aloe latex may cause abdominal pain, cramps, and diarrhea.
• Topically: Burning, erythema, and itching. Contact dermatitis in sensitive individuals.

HERB-DRUG INTERACTIONS:

• ANTICOAGULANTS/ANTIPLATELET DRUGS – (increases potential for bleeding),
• DIABETIC MEDICATIONS – (increases the change of hypoglycemia),
• DIGOXIN – (increases effect),
• DIURETICS – (potentiates and increases likelihood of hypokalemia),
• STIMULANT LAXATIVES – (potentiates effect and increases likelihood of fluid and electrolyte imbalance),
• WARFARIN – (increases effect).

These effects are only applicable if Aloe is ingested, not applied topically.

HERB-LAB TEST INTERACTIONS: None known.

References

1. Cosmetic Ingredient Review Expert Panel. Final report on the safety assessment of AloeAndongensis Extract, Aloe Andongensis Leaf Juice,aloe Arborescens Leaf Extract, Aloe Arborescens Leaf Juice, Aloe Arborescens Leaf Protoplasts, Aloe Barbadensis Flower Extract, Aloe Barbadensis Leaf, Aloe Barbadensis Leaf Extract, Aloe Barbadensis Leaf Juice,aloe Barbadensis Leaf Polysaccharides, Aloe Barbadensis Leaf Water, Aloe Ferox Leaf Extract, Aloe Ferox Leaf Juice, and Aloe Ferox Leaf Juice Extract. Int J Toxicol 2007;26 Suppl 2:1-50.
2. Vogler BK, Ernst E. Aloe vera: a systematic review of its clinical effectiveness. Br J Gen Pract 1999;49:823-8
3. Reynolds T, Dweck AC. Aloe vera leaf gel: a review update. J Ethnopharmacol 1999;68:3-37
4. Vogler BK, Ernst E. Aloe vera: a systematic review of its clinical effectiveness. Br J Gen Pract 1999;49:823-8
5. Newall CA, Anderson LA, Philpson JD. Herbal Medicine: A Guide for Healthcare Professionals. London, UK: The Pharmaceutical Press, 1996.
6. Esua, M. F. and Rauwald, J. W. Novel bioactive maloyl glucans from aloe vera gel: isolation, structure elucidation and in vitro bioassays. Carbohydr Res 2-27-2006;341(3):355-364
7. Liang, J.; Cui, L.; Li, J.; Guan, S.; Zhang, K.; Li, J. Aloe vera: A Medicinal Plant Used in SkinWound Healing. Tissue Eng. Part B Rev. 2021, 27, 455–474.
8. Khorasani, G.; Hosseinimehr, S.J.; Azadbakht, M.; Zamani, A.; Mahdavi, M.R. Aloe Versus Silver Sulfadiazine Creams for Second-Degree Burns: A Randomized Controlled Study. Surg. Today 2009, 39, 587–591.
9. Kaminaka C, Yamamoto Y, Sakata M, et al. Effects of low-dose Aloe sterol supplementation on skin moisture, collagen score and objective or subjective symptoms: 12-week, double-blind, randomized controlled trial. J Dermatol. 2020
10. Maenthaisong, R.; Chaiyakunapruk, N.; Niruntraporn, S.; Kongkaew, C. The efficacy of aloe vera used for burn wound healing: A systematic review. Burns 2007, 33, 713–718.
11. Fox, L.T.; Mazumder, A.; Dwivedi, A.; Gerber, M.; du Plessis, J.; Hamman, J.H. In vitro wound healing and cytotoxic activity of the gel and whole-leaf materials from selected aloe species. J. Ethnopharmacol. 2017, 200, 1–7.
12. Velnar, T.; Bailey, T.; Smrkolj, V. TheWound Healing Process: An Overview of the Cellular and Molecular Mechanisms. J. Int. Med. Res. 2009, 37, 1528–1542.
13. Shafaie, S.; Andalib, S.; Shafaei, H.; Montaseri, A.; Tavakolizadeh, M. Differential Biological Behavior of Fibroblasts and Endothelial Cells under Aloe vera Gel Culturing. Int. J. Mol. Cell. Med. 2020,9.
14. Koivisto, L.; Heino, J.; Häkkinen, L.; Larjava, H. Integrins in Wound Healing. Adv. Wound Care 2014, 3, 762–783.
15. Meza-Valle, K.Z.; Saucedo-Acuña, R.A.; Tovar-Carrillo, K.L.; Cuevas-González, J.C.; Zaragoza-Contreras, E.A.; Melgoza-Lozano, J. Characterization and Topical Study of Aloe Vera Hydrogel on Wound-Healing Process. Polymers 2021, 13, 3958.
16. Teplicki, E.; Ma, Q.; Castillo, D.E.; Zarei, M.; Hustad, A.P.; Chen, J.; Li, J. The Effects of Aloe vera on Wound Healing in Cell Proliferation, Migration, and Viability. Wounds 2018, 30, 263–268.
17. Olczyk, P.; Mencner, A.; Komosinska-Vassev, K. The Role of the Extracellular Matrix Components in Cutaneous Wound Healing. Biomed. Res. Int. 2014, 747584.
18. Klein AD, Penneys NS. Aloe vera. J Am Acad Dermatol 1988;18:714-20.
19. Hutter JA, Salman M, Stavinoha WB, et al. Antiinflammatory C-glucosyl chromone from Aloe barbadensis. J Nat Prod 1996;59:541-3.
20. Langmead L, Makins RJ, Rampton DS. Anti-inflammatory effects of aloe vera gel in human colorectal mucosa in vitro. Aliment Pharmacol Ther 2004;19:521-7
21. Vazquez, B., Avila, G., Segura, D., and Escalante, B. Antiinflammatory activity of extracts from Aloe vera gel. J Ethnopharmacol. 1996;55(1):69-75.
22. Nusko G, Schneider B, Schneider I, et al. Anthranoid laxative use is not a risk factor for colorectal neoplasia: results of a prospective case control study. Gut 2000;46:651-5.
23. Mueller SO, Stopper H. Characterization of the genotoxicity of anthraquinones in mammalian cells. Biochim Biophys Acta 1999;1428:406-14.
24. Schorkhuber M, Richter M, Dutter A, et al. Effect of anthraquinone laxatives on the proliferation and urokinase secretion of normal, premalignant and malignant colonic epithelial cells. Eur J Cancer 1998;34:1091-8
25. Lee, K. H., Kim, J. H., Lim, D. S., and Kim, C. H. Anti-leukaemic and anti-mutagenic effects of di(2-ethylhexyl)phthalate isolated from Aloe vera Linne. J Pharm Pharmacol 2000;52(5):593-598.
26. Pecere, T., Sarinella, F., Salata, C., Gatto, B., Bet, A., Dalla, Vecchia F., Diaspro, A., Carli, M., Palumbo, M., and Palu, G. Involvement of p53 in specific anti-neuroectodermal tumor activity of aloe-emodin. Int J Cancer 10-10-2003;106(6):836-847.
27. Lin, S. Y., Yang, J. H., Hsia, T. C., Lee, J. H., Chiu, T. H., Wei, Y. H., and Chung, J. G. Effect of inhibition of aloe-emodin on N-acetyltransferase activity and gene expression in human malignant melanoma cells (A375.S2). Melanoma Res 2005;15(6):489-494
28. Lin, J. G., Chen, G. W., Li, T. M., Chouh, S. T., Tan, T. W., and Chung, J. G. Aloe-emodin induces apoptosis in T24 human bladder cancer cells through the p53 dependent apoptotic pathway. J Urol 2006;175(1):343-34
29. Cardenas, C., Quesada, A. R., and Medina, M. A. Evaluation of the anti-angiogenic effect of aloe-emodin. Cell Mol.Life Sci 2006;63(24):3083-3089
30. Singh, R. P., Dhanalakshmi, S., and Rao, A. R. Chemomodulatory action of Aloe vera on the profiles of enzymes associated with carcinogen metabolism and antioxidant status regulation in mice. Phytomedicine 2000;7(3):209-219.
31. Reuter J, Jocher A, Stump J, et al. Investigation of the anti-inflammatory potential of Aloe vera gel (97.5%) in the ultraviolet erythema test. Skin Pharmacol Physiol. 2008;21:106-10
32. Dal’Belo SE, Gaspar LR, Maia Campos PM. Moisturizing effect of cosmetic formulations containing Aloe vera extract in different concentrations assessed by skin bioengineering techniques. Skin Res Technol. 2006;12:241-6
33. Tanaka M, Yamamoto Y, Misawa E, et al. Effects of aloe sterol supplementation on skin elasticity, hydration, and collagen score: a 12-week double-blind, randomized, controlled trial. Skin Pharmacol Physiol. 2016;29(6):309-17.
34. Kaminaka C, Yamamoto Y, Sakata M, et al. Effects of low-dose Aloe sterol supplementation on skin moisture, collagen score and objective or subjective symptoms: 12-week, double-blind, randomized controlled trial. J Dermatol. 2020
35. Syed TA, Ahmad SA, Holt AH, et al. Management of psoriasis with Aloe vera extract in a hydrophilic cream: a placebo-controlled, double-blind study. Trop Med Int Health 1996;1:505–9
36. Leng H, Pu L, Xu L, Shi X, Ji J, Chen K. Effects of aloe polysaccharide, a polysaccharide extracted from Aloe vera, on TNF-a-induced HaCaT cell proliferation and the underlying mechanism in psoriasis. Mol Med Rep 2018;18(3):3537-43. doi: 10.3892/mmr.2018.9319
37. Worthington HV, Clarkson JE, Bryan G, et al. Interventions for preventing oral mucositis for patients with cancer receiving treatment. Cochrane Database Syst Rev. 2011;(4):CD000978
38. Puataweepong P, Dhanachai M, Dangprasert S, et al. The efficacy of oral Aloe vera for radiation induced mucositis in head and neck cancer patients: a double-blind placebo-controlled study. Asian Biomedicine 2009;3(4):375-382.
39. Wang, Z. W., Huang, Z. S., Yang, A. P., Li, C. Y., Huang, H., Lin, X., Liu, Z. C., and Zhu, X. F. [Radioprotective effect of aloe polysaccharides on three non-tumor cell lines]. Ai.Zheng. 2005;24(4):438-442
40. Wang, Z., Huang, Z., Wu, Q., Zhou, J., Zhu, X., Li, Q., and Liu, Z. [The modulating of aloe polysaccharides on the cell cycle and cycle regulating protein expression in X-ray irradiated non-malignant cells]. Zhong.Yao Cai. 2005;28(6):482-485
41. Klein AD, Penneys NS. Aloe vera. J Am Acad Dermatol 1988;18:714-20
42. Reynolds T, Dweck AC. Aloe vera leaf gel: a review update. J Ethnopharmacol 1999;68:3-37.
43. Kaufman T, Kalderon N, Ullmann Y, Berger J. Aloe vera gel hindered wound healing of experimental second-degree burns: a quantitative controlled study. J Burn Care Rehabil 1988;9:156-9
44. Miller MB, Koltai PJ. Treatment of experimental frostbite with pentoxifylline and aloe vera cream. Arch Otolaryngol Head Neck Surg 1995;121:678-80.
45. Muller MJ, Hollyoak MA, Moaveni Z, et al. Retardation of wound healing by silver sulfadiazine is reversed by Aloe vera and nystatin. Burns 2003;28:834-6
46. Kaufman T, Kalderon N, Ullmann Y, Berger J. Aloe vera gel hindered wound healing of experimental second-degree burns: a quantitative controlled study. J Burn Care Rehabil 1988;9:156-9.
47. Davis, R. H., DiDonato, J. J., Johnson, R. W., and Stewart, C. B. Aloe vera, hydrocortisone, and sterol influence on wound tensile strength and anti-inflammation. J Am Podiatr.Med Assoc 1994;84(12):614-621
48. Davis, R. H., Donato, J. J., Hartman, G. M., and Haas, R. C. Anti-inflammatory and wound healing activity of a growth substance in Aloe vera. J Am Podiatr.Med Assoc 1994;84(2):77-81.
49. Davis, R. H., DiDonato, J. J., Johnson, R. W., and Stewart, C. B. Aloe vera, hydrocortisone, and sterol influence on wound tensile strength and anti-inflammation. J Am Podiatr.Med Assoc 1994;84(12):614-621
50. Teplicki E, Ma Q, Castillo DE, et al. The effects of aloe vera on wound healing in cell proliferation, migration, and viability. Wounds 2018;30(9):263-8.
51. Levin NJ, Erben Y, Li Y, Brigham TJ, Bruce AJ. A systematic review and meta-analysis comparing burn healing outcomes between silver sulfadiazine and Aloe vera. Cureus 2022;14(10):e30815
52. Luyckx VA, Ballantine R, Claeys M, et al. Herbal remedy-associated acute renal failure secondary to Cape aloes. Am J Kidney Dis 2002;39:E13.

Caroline Fife, M.D.

Dr. Fife is a world renowned wound care physician dedicated to improving patient outcomes through quality driven care. Please visit my blog at CarolineFifeMD.com and my Youtube channel at https://www.youtube.com/c/carolinefifemd/videos