Topical Aloe Vera Gel for Accelerated Wound Healing of Split-Thickness Skin Graft Donor Sites: A Double-Blind, Randomized, Controlled Trial and Systematic Review

Abstract

Background: 

Aloe vera has been used to treat wounds since ancient times. However, data regarding the efficacy of aloe vera for burns and split-thickness skin graft donor sites are inconclusive.

Methods: 

A double-blind, randomized, controlled trial was conducted. Patients who underwent split-thickness skin graft harvesting from the thigh were included. Split-thickness skin graft donor sites were divided into two groups: the aloe vera group and the placebo group. The visual analogue scale score was used to evaluate pain, and complete epithelialization was assessed. The authors searched electronic databases and included only international clinical trials published in the English language.

Results: 

Twelve patients with 24 donor sites participated. Times to complete epithelization for the aloe vera and placebo groups were 11.5 ± 1.45 and 13.67 ± 1.61 days, respectively (p < 0.05). Visual analogue scale scores after wound dressing for the aloe vera and placebo groups were 17.18 ± 13.17 and 18.63 ± 11.20, respectively. No statistical significance was found between groups. Five articles met the inclusion criteria: four involved burns and one involved split-thickness skin graft donor sites. Three studies of burn wounds demonstrated improved epithelization and one did not. The split-thickness skin graft donor-site study indicated that wound healing time for the control group was significantly different from that of the aloe vera and placebo groups. The healing rate was not statistically different between groups.

Conclusion: 

Topical aloe vera gel significantly demonstrated accelerated split-thickness skin graft donor-site healing but did not show significant pain relief.

CLINICAL QUESTION/LEVEL OF EVIDENCE: 

Therapeutic, I.

In Brief

Video Discussion by Anthony Youn, M.D., is Available Online for This Article.

Aloe vera is a cactus herb that grows in tropical climates. It has been used to treat acute wounds since ancient times. Numerous medicinal products are made from its mucilaginous tissue, called aloe vera gel, which is located in the center of the aloe vera leaf.¹ Aloe vera contains 75 potentially active constituents, including vitamins, enzymes, minerals, sugars, lignin, saponins, salicylic acids, and amino acids.² Its prostaglandin and bradykinin-hydrolyzing enzymes, carboxypeptidase and bradykinase, have pain- and inflammation-relief properties.^3,4 Mannose-6-phosphate, a polysaccharide, supports the epithelialization process and tissue reorganization, induces fibroblast proliferation, activates collagen deposition, and accelerates wound healing.^3,5,6 Acemannan, which is another polysaccharide, is a white blood cell activator that has an important role in the activation of the wound healing process.^6,7 Anthraquinones, which have antibacterial properties, help to prevent wound infection.⁶

Only minimal adverse reactions (e.g., mild pain or a sense of discomfort) were found, without statistical significance, with the use of aloe vera.⁸ Furthermore, all adverse effects were reversible, and aloe vera was generally very well tolerated.⁹

The properties of aloe vera have led to the hypothesis that application of topical aloe vera accelerates epithelialization of split-thickness skin graft donor sites. Therefore, aloe vera has been studied in vitro and in animal models as an accelerator of wound healing. Obviously, such animal experiments are not a substitute for clinical trials evaluating its efficacy.⁹ Surprisingly, there are only a few clinical studies of the effects of aloe vera on reepithelialization. Moreover, the effects of aloe vera for partial-thickness burns and split-thickness skin graft donor sites have failed to show any significant advantages and are inconclusive, and the dosage and mode of application of aloe vera are controversial. There are no double-blind, randomized, controlled trials that have demonstrated the validity of this hypothesis.

PATIENTS AND METHODS

Part 1: Clinical Study of the Effects of Aloe Vera Gel on Split-Thickness Skin Graft Donor Sites

This study was approved by the ethics committee of Phramongkutklao Hospital and College of Medicine. This prospective, double-blind, randomized, placebo-controlled clinical trial was conducted from February of 2015 to January of 2016.

Patient Control

Patients who underwent split-thickness skin graft harvesting from the thigh were included. All patients provided written consent before enrollment. Demographic data were recorded. Exclusion criteria were pregnancy, breastfeeding, immunocompromise, nonresponsiveness, and allergy to aloe vera.

Procedure Preparation

All patients underwent a skin test to determine any allergy to aloe vera gel. Aloe vera gel was applied to the medial aspect of the arm. Patients who had allergic reactions such as rash, itching, or any inflammatory reactions were excluded.

Split-thickness skin grafts with a depth of 0.008 to 0.014 inch (0.20 to 0.40 mm), depending on the skin thickness in each patient, were harvested with the Air Zimmer Dermatome skin grafting system (Zimmer Ltd., Swindon, United Kingdom) by a single surgeon.

Randomization

The split-thickness skin graft donor sites were equally divided and randomized by a random numbers table into two groups: the aloe vera group and the placebo group. The 2-cm width at the midline was defined as the border between groups and was not included in the evaluation (Fig. 1).

Fig. 1.: Area divided into two groups. The 2-cm width at the midline was defined as the border between groups and was not included in the evaluation.

Double Blinding

The placebo agent used was sterilized glycerine (AQUAGEL, Ecolab Ltd, Leeds, England), which has lubricant and emollient properties, is odorless, and produces no reaction or harm to human skin. This agent has been widely used for medical lubrication. The aloe vera gel (Governmental Pharmaceutical Organization, registration number G 418/41) comprised aloe vera 87.399%. Both the placebo and aloe vera were prepared by a single surgeon.

The dressing was performed by a second surgeon blinded to the agent. In group A, placebo was applied to the wound. Then, paraffin gauze and cover with 20 layers of dry gauze was performed. Finally, an elastic bandage was placed over the gauze. In group B, aloe vera gel was applied to the wound, and all of the wound care procedures were performed as for group A.

The wound dressing was changed once daily. The second surgeon removed the elastic bandage and dry gauze. The top-dressing layer was removed and only one layer of the paraffin gauze was left (so as not to interfere with epithelialization). The aloe vera gel or placebo was then applied and covered with 10 layers of dry gauze.

Evaluation

The 100-mm visual analogue scale was used to evaluate the pain level. The visual analogue scale results were collected by the second surgeon before and after wound dressing. The 2-cm width at the midline was defined as the border between groups and was not included in the evaluation. The patients were asked about the visual analogue scale on the upper and lower parts of the donor site. The wound healing period was recorded by the second surgeon by taking photographs with a Sony camera (model Alpha 5100, 24.3 Megapixels APS-C CMOS sensor, Bionz X image processor; Sony Corp., Tokyo, Japan). The focal distance was approximately 30 cm. The wound healing processes were assessed by computer-assisted planimetry to determine complete epithelialization, which was defined as the entire split-thickness skin graft donor site covered by epithelium. Complications were recorded and used to evaluate treatment results.

Statistical Analyses

For comparative statistics, the paired t test was used. A value of p < 0.05 was considered statistically significant.

Part 2: Review of the Literature

We searched the electronic databases of the Cochrane Wounds Group Specialized Register (searched January 31, 2015), the Cochrane Database of Systematic Reviews (1996 to 2014), the Cochrane Central Register of Controlled trials (1966 to 2014), the Central Cumulative Index to Nursing and Allied Health Literature (to December of 2014), MEDLINE (to January of 2015), and Embase (to January of 2015). We used the Medical Subject Headings “aloe vera,” “burn or skin graft,” and “epithelization.”

We included only international clinical trials of aloe vera or aloe vera–derived products for burns or split-thickness skin graft donor sites published in the English language. Articles published between 1990 and 2015 were evaluated by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist. The inclusion criteria were full-length articles and sufficient data. The exclusion criteria were incomplete or interim data, abstract-only studies, and non–English language articles. Two authors independently evaluated the eligibility of all studies identified using the predetermined selection criteria.

RESULTS

Part 1

Twelve patients with 24 donor sites were included in the study. Six patients received aloe vera gel on the proximal part and six patients received placebo on the proximal part. There were 10 men and two women (Table 1). The mean age was 48.33 ± 19.24 years. No allergy against aloe vera was noted during the skin test. Patient characteristics and causes of disease are demonstrated in Table 2. The mean surface area of the donor site was 73.16 cm² (Table 2).

Table 1.: Demographic Data

Table 2.: Patient Characteristics, Cause of Disease, and Surface Area of the Donor Site

The times to complete epithelization for the aloe vera and placebo groups were 11.5 ± 1.45 and 13.67 ± 1.61 days, respectively (Table 3 and Figs. 2 through 4). Statistical significance was found between the aloe vera and placebo groups. The average visual analogue scale scores before dressing for the aloe vera and placebo groups were 8.57 ± 6.9 and 9.05 ± 6.01, respectively (Table 4 and Fig. 5). No statistical significance was found between the aloe vera and placebo groups. The average visual analogue scale scores after wound dressing for the aloe vera and placebo groups were 17.18 ± 13.17 and 18.63 ± 11.20, respectively. No statistical significance was found between the aloe vera and placebo groups. Statistical significance was found before and after wound dressing for both the aloe vera and the placebo groups. No infection, seroma, rash, or itching of the donor sites was detected in the groups. No allergy against aloe vera was found in our study.

Table 3.: Time to Complete Epithelization

Table 4.: Pain Associated with Wound Dressing

Fig. 2.: Split-thickness skin graft donor site of the placebo group (left) compared with that of the aloe vera group (right) immediately after surgery and on postoperative days 3, 6, 9, 11, and 13.

Fig. 3.: Complete epithelization of the right side (aloe vera group) on postoperative day 11 (left) and complete epithelization of both sides on postoperative day 13 (right).

Fig. 4.: Correlation between the days to complete epithelialization in each case.

Fig. 5.: Correlation among the mean visual analogue scale scores of pain before and after dressing and the day after surgery.

Part 2

Five articles met the inclusion criteria (Fig. 6). Four studies were about burns and one was about split-thickness skin graft donor sites (Table 5).^8,10–13 Studies by Khorasani et al.,¹¹ Visuthikosol et al.,⁸ and Shahzad and Ahmed¹³ regarding burn wounds demonstrated improved epithelization.

Table 5.: Results of the Literature Review

Fig. 6.: Flow diagram to depict the studies used in the systematic review. STSG, split-thickness skin graft.

Khorasani et al.¹¹ conducted a clinical study to evaluate the efficacy of aloe vera cream compared with silver sulfadiazine for partial-thickness burn wounds. Thirty patients with similar types of second-degree burns at two sites on different body parts were included. Each patient had one burn treated with topical silver sulfadiazine and one treated with aloe cream, randomly. The results showed that the rate of reepithelialization and healing of the partial-thickness burns was significantly faster in the site treated with aloe cream than with silver sulfadiazine (15.9 ± 2 versus 18.73 ± 2.65 days, respectively; p < 0.0001). They concluded that aloe cream demonstrated greater efficacy than silver sulfadiazine cream for treating second-degree burns.

Visuthikosol et al.⁸ studied 27 patients with partial-thickness burn wounds treated with aloe vera gel compared with petroleum jelly gauze. Aloe vera gel resulted in faster healing than did petroleum jelly gauze. The average healing times for aloe gel and petroleum jelly gauze were 11.89 days and 18.19 days, respectively. Two of 27 patients had minimal transient pain that was relieved by oral paracetamol. No allergic reaction or eczema was seen in the study.

The study by Shahzad and Ahmed¹³ involved 50 burn patients: 25 patients applied aloe vera gel twice daily and 25 patients applied silver sulfadiazine twice daily. In the aloe vera group, epithelialization began at day 5, and in all patients healing was complete by day 40, whereas in the silver sulfadiazine group, healing was prolonged. Moreover, they demonstrated that the price of 1000 ml of aloe vera gel was $4.55, whereas the price of 250 g of silver sulfadiazine was $5.85. The cost of dressing per percentage body surface are burned per silver sulfadiazine dressing was $0.05 for 2 g of ointment and $0.02 for 5 ml of aloe vera gel. They concluded that aloe vera gel showed earlier wound epithelialization, earlier pain relief, and cost-effectiveness for thermal burn patients than did 1% silver sulfadiazine.

One burn study did not demonstrate improved healing. Puvabanditsin and Vongtongsri¹⁰ studied the efficacy of aloe vera cream for 20 volunteers with burns from ultraviolet light. Aloe vera cream was applied using a randomized, double-blind technique on the test sites 30 minutes before, immediately after, or both before and after serial exposures to ultraviolet light. Erythema and pigmentation were evaluated by a visual grading score of 1 to 4. Aloe vera cream was applied continually at the test sites twice daily for the next 3 weeks. The results showed that aloe vera cream provided no sunburn or suntan protection and no efficacy for sunburn treatment compared to placebo. It also had no bleaching effect.

Only one article¹² studied the split-thickness skin graft donor site. Forty-five patients involved in a randomized clinical trial were divided into three groups: control group (without topical agent), placebo group (base cream without aloe vera), and aloe vera cream group. All patients underwent split-thickness skin grafting for various reasons, and the skin graft donor-site wounds were covered with a single layer of gauze without any topical agent, with aloe vera, or with placebo cream. Donor sites were assessed daily postoperatively until complete healing was achieved. The mean durations to complete reepithelialization were 17 ± 8.6, 9.7 ± 2.9, and 8.8 ± 2.8 days for the control, aloe vera, and placebo groups, respectively. Mean wound healing duration for the control group was significantly different from that of the aloe vera and placebo groups (p < 0.005). The healing rate was not statistically different between the aloe vera and placebo groups. This study showed significantly shorter wound care time for skin graft donor sites of patients who were treated with aloe vera and placebo creams. The moisturizing effects of these creams may have contributed to wound healing.

DISCUSSION

The split-thickness skin graft procedure is a basic reconstructive method. There are many treatment methods for the split-thickness skin graft donor site; however, which method is the best has not been determined.¹⁴ Novel wound dressing methods are being developed to achieve the ideal donor-site dressing. The principal aims of the donor-site dressing are to promote epithelialization and the healing process, to reduce bacterial infection, to provide optimal moisture, and to relieve pain. Aloe vera use for first- and second-degree burns has pharmacologic actions such as antibacterial and antiinflammatory effects. However, there is insufficient clinical trial evidence regarding the effects of aloe vera topical agents for the treatment of acute wounds in humans.

In our study, the difference in epithelialization rate was statistically significant in favor of the aloe vera group. However, one of the major concerns regarding the daily dressing was pain when changing the dressing. Although statistical significance was found for the pain score before and after dressing, most patients did not need any analgesia. A study by Mantha et al.¹⁵ showed that the pain score was clinically significant when it was more than 30; therefore, the daily dressing with aloe vera gel can be performed without clinically significant pain.

Although aloe vera has been used since ancient times to treat acute wounds, there are few clinical studies about its therapeutic indications. Moreover, the evidence for aloe vera effectiveness was inconclusive. In vitro studies have demonstrated the benefits of aloe vera. Aloe vera gel at various concentrations can be used as an effective antibacterial agent to prevent wound infection.¹⁶ Furthermore, bioadhesive films containing vitamin E acetate and aloe vera could be an innovative therapeutic system for the treatment of burns.¹⁷

Most studies of the effectiveness of aloe vera involving animal models for burn wound healing have demonstrated faster healing compared with the use of silver sulfadiazine and petroleum jelly gauze.^18–24 Although most investigations have reported the beneficial effects of aloe vera, some suggest that aloe vera may slow wound healing.^21,25,26 This controversy was supported by the study of Cuttle et al.²⁷ In that study, dressings infused with aloe vera, saliva, and tea tree oil were applied as first aid to a porcine deep dermal contact burn. The alternative treatments did significantly decrease the subdermal temperature within the skin during the treatment period. However, they did not decrease the microflora or improve reepithelialization, scar strength, scar depth, or cosmetic appearance of the scar, and they cannot be recommended for the first aid treatment of partial-thickness burns.

Vogler and Ernst⁹ reported a systematic review of clinical trials of the clinical effectiveness of aloe vera and found only 10 controlled clinical trial studies that met the criteria. They found that oral aloe vera might be a useful adjunct in diabetic and hyperlipidemic patients. Topical application of aloe vera was not an effective preventive measure for radiation-induced injuries; however, aloe vera cream resulted in shorter healing times for genital herpes and psoriasis. However, none of these results is sufficient to draw firm conclusions.⁹

In 2007, a systemic review of aloe vera used in controlled clinical trials for burn wound healing was published. Maenthaisong et al.¹ found that only four studies met the criteria. One study was available only in abstract form, two studies were published in local journals (Thailand and China), and only one study¹² was published in an international journal. They concluded that because of the differences of products and outcome measures, there is a paucity of evidence with which to draw a specific conclusion regarding the effect of aloe vera on burn wound healing. Furthermore, well-designed trials with sufficient details of the composition of aloe vera products should be carried out to determine its effectiveness.

In 2012, Dat et al.²⁸ studied the ability of aloe vera to treat acute and chronic wounds. They included all randomized, controlled trials that evaluated the effectiveness of aloe vera, aloe-derived products, and a combination of aloe vera and other dressings. There were no restrictions in terms of source, date of publication, or language. Seven trials were eligible for inclusion. Five trials with acute wounds evaluated the effects of aloe vera on burns, hemorrhoidectomy patients, and skin biopsy patients. Aloe vera did not increase burn healing compared with silver sulfadiazine. One trial of people with chronic wounds found no statistically significant difference in pressure ulcer healing with aloe vera; in a trial of surgical wound healing with a secondary intervention, aloe vera significantly delayed healing. There is currently an absence of high-quality clinical trial evidence to support the use of aloe vera topical agents or aloe vera dressings as treatments for acute and chronic wounds.

In our review, two clinical studies of aloe vera for partial-thickness burns compared it with silver sulfadiazine and one study compared it with petroleum jelly gauze. The results of these three studies indicated that application of aloe vera gel twice daily accelerated epithelization compared to silver sulfadiazine and petroleum jelly gauze.^8,11,13

Controversy was demonstrated in the study by Puvabanditsin and Vongtongsri.¹⁰ Their results showed that aloe vera cream provides no sunburn or suntan protection and has no efficacy for sunburn treatment compared with placebo.

No consensus exists regarding aloe vera gel and aloe vera cream for the treatment of partial-thickness burn or split-thickness skin graft donor sites. The aloe vera powder is extracted from aloe vera gel and is dissolved in sterile 0.9% saline to produce a solution with the concentrations of 50 mg of aloe vera per milliliter of saline (aloe vera cream contains 0.5% aloe vera gel powder). This concentration will have the biological activity of the aloe vera on wound healing.^23,29 We used aloe vera gel manufactured by a Governmental Pharmaceutical Organization, which comprised aloe vera 87.399%. Previously, three studies used 0.5% aloe vera cream^10–12 and two studies used aloe vera gel (85 to 98%).^8,13 Maenthaisong et al.¹ revealed that none of the included studies standardized the amount of active ingredients of aloe vera in the product. The amount of active ingredient in aloe vera varies depending on the age of plants, growing and harvesting conditions, parts of plants, and extraction methods. The standardization of product is necessary for the quality control of the products.

Furthermore, to our knowledge, only one study of aloe vera used at a split-thickness skin graft donor site has been reported. A study by Khorasani et al.¹² demonstrated that the healing rate was not statistically different between aloe vera and placebo, but it did show a significantly shorter healing time for split-thickness skin graft donor sites of patients treated with aloe vera and placebo creams. The difference in the findings might be explained by the difference in study design, products used, and mode of application of aloe vera.

We designed this double-blind, randomized, controlled trial to study the effects of aloe vera on epithelization at split-thickness skin graft donor sites for the same patients and made sure that all wounds were of the same depth to eliminate confounding factors. Faster epithelization with aloe vera can be used in partial-thickness facial burns. More comparative studies involving antibiotic ointments and large sample sizes may be advantageous in the future.

CONCLUSIONS

Application of topical aloe vera gel demonstrated significant acceleration of healing of split-thickness skin graft donor sites. However, significant pain relief was not observed.

ACKNOWLEDGMENT

The authors thank Supak Cae-ngow, statistician and research assistant at the Office of Research Development at Phramongkutklao College of Medicine, for kind help with the statistical analysis of this article.