Medicinal Plants as Efficacious Agents for Diabetic Foot Ulcers: A Systematic Review of Clinical Studies

Diabetes mellitus (DM) is a substantial health problem worldwide. In 2015, approximately 415 million patients were identified as having DM; this number is estimated to increase to 642 million by 2040.^1,2 This sharp rise in worldwide prevalence of DM will exacerbate the deleterious complications related to chronic hyperglycemia, such as microvascular and macrovascular problems.³ A diabetic foot ulcer (DFU), which is one of the most disturbing complications of DM, is a common result of diverse etiological pathways such as neuropathy, ischemia, and infection.¹ The prevalence of DFU in the diabetic population is estimated to be 4% to 15%, affecting the elderly in particular.^4,5 The risk of foot ulcer is 25% higher in persons with DM than in persons without DM.⁶ According to the World Health Organization, patients with DM are 10 to 20 times more likely than patients without DM to require lower extremity amputation owing to infected, nonhealing foot ulcers.⁷ These ulcers may strongly affect health disbursement owing to hospitalization and amputation, which cause an overall reduction in patients’ quality of life resulting from high rates of morbidity and mortality.^8-10 

Standard care for DFU includes offloading and debridement. In addition, some adjuvant therapies such as modern dressings, electrophysical therapy, negative pressure wound therapy, biological and hyperbaric oxygen therapies, and some Chinese herbal medications have been shown to have positive effects on healing DFU.^11-15 Of note, this paper identifies herbal treatments as medicinal treatments; while recognized in many parts of the world, these herbal treatments are not classified as such in Western medicine at this time. 

Since approximately the year 2000, several studies have shown a 40% to 60% reduction in rates of amputation among adult patients with DM in high-income countries.⁷ Ten percent to 15% of these wounds are of the chronic, nonhealing type,⁴ and 5% to 24% of patients with DFU undergo limb amputation as a result.¹⁶ As of 2020, reports on the use of hyperbaric oxygen therapy indicate that its treatment effects are not yet conclusive,¹⁷ and this therapy is not recommended as a routine part of DFU management.¹⁸ Similarly, only 3 of 7 high-quality clinical trials support the efficacy of negative pressure wound therapy.¹⁹ Thus, there is an urgent need to find an alternative and efficacious strategy for better management of DFU.

Herbal medicines have been used as reliable treatments for various health problems since ancient times. Currently, many studies indicate that bioactive molecules from medicinal plants have multiple pharmacological properties that can prevent several types of destructive cellular damage, including chronic wounds. For instance, debridement is a primary standard treatment for DFU; sometimes this treatment is performed by enzymatic means, in which proteolytic enzymes such as papain and bromelain are used.⁴ Papain and bromelain are natural, plant-derived enzymes obtained from papaya and pineapple, respectively. The selective removal of necrotic tissue without affecting healthy tissue suggests that this method is a valuable treatment for DFU.⁴ Medicinal plants are traditionally used as different topical preparations to treat burns, infected wounds, skin irritations, and inflammations.^20-24 The traditional use of plants as wound healing remedies has also been demonstrated by in vitro, in vivo, and clinical studies.^22,25,26

Use of medicinal plants alone or as an adjuvant therapy along with current therapeutic approaches has been shown to reduce the complications of DFUs in patients with DM.^27-29 The present review provides information on herbal medicinal options for the management of DFUs based on currently available clinical evidence. Outcomes considered for study selection included but were not limited to reduction in wound healing time, wound area, markers of inflammation, and oxidative stress, as well as the number of patients who required amputation.

The literature search was performed via screening electronic databases, including PubMed, Scopus, and Cochrane Library. The keywords were “diabetic foot ulcer” in the title and/or abstract, and “plant,” “phytochemical,” “extract,” or “herb” in the whole text. The search was conducted from inception through May 2019. The inclusion criteria consisted of controlled or before-after clinical trials in the English language in which a medicinal plant or polyherbal preparation was evaluated as an intervention for DFUs in humans. Human studies other than clinical trials (ie, case reports, case series, cohort studies) as well as non-herbal interventions were excluded. Final eligible studies were reviewed regarding the medicinal plant name, study design, study population, intervention, outcomes, and possible side effects. The Jadad score was used to assess the quality and methodological rigor of included clinical trials. The Jadad score is a system of scoring clinical trials from zero to 5 considering randomization, blinding, and withdrawal. A higher Jadad score shows a stronger design of the trial regarding the 3 mentioned items. The Figure presents the flow diagram of the literature search.

The Table details the final included clinical trials assessing the effect of single and polyherbal preparations in the management of DFU. 

Single herbal preparations for the management of DFU

Actinidia deliciosa (A. Chev.)
C.F. Liang & A.R. Ferguson 

Kiwifruit or Actinidia deliciosa is a member of the family Actinidiaceae, which originated in China.⁴⁴ Several animal studies have demonstrated beneficial effects of kiwifruit in healing burn wounds, including its use in debridement and its proangiogenic and antibacterial properties.^45,46 The most important constituent of the fruit is actinidin enzyme, which is similar to the more common protease, papain (from papaya fruit). Actinidin is a cysteine protease responsible for the debridement properties of kiwifruit.^44,30

In a randomized, controlled clinical trial of 37 patients with DFUs, the wound healing activity of a 3-mm-thick layer topical dressing of kiwifruit along with standard treatment (surgical debridement, ciprofloxacin 500 mg twice daily, and clindamycin 600 mg 3 times daily) was compared with standard care in control patients. In the treatment group, kiwifruit dressing was used twice a day after standard treatment. After 21 days of treatment, the intervention group showed a significant decrease in both ulcer size and time to wound closure compared with the control group (P < .0001). Additionally, there were significant improvements in vascularization and granulation (P = .03), collagen formation (P =. 0001), and inflammation (P = .001) at wound sites of patients in the intervention group in comparison to their baseline values. The kiwifruit exhibited no antibacterial activity; thus, the wound healing properties of this plant are independent of any antimicrobial activity.³⁰ 

Ageratina pichinchensis (Kunth)
R.M. King & H. Rob

Ageratina pichinchensis, which belongs to the Asteraceae family, is an important medicinal plant in Mexican traditional medicine. The aqueous extract of A. pichinchensis protects skin injuries against fungal infections and has wound healing properties, as demonstrated by several in vitro and in vivo studies.⁴⁷ The anti-inflammatory activity and stimulatory effects on cell growth are the main mechanisms of the wound healing properties of this plant.⁴⁸ Additionally, the pro-proliferative activity of the extract is mainly attributed to the flavonoid derivative 7-O-(β-D-glucopyranosyl)-galactin, which suggests that flavonoid structures play an important role in wound healing.⁴⁹

Romero-Cerecero et al³¹ conducted a randomized, double-blind, controlled, pilot study of 30 patients with DFUs to investigate the efficacy and tolerability of A. pichinchensis as a topical wound healing agent. The n-hexane/ethyl acetate extract of A. pichinchensis was topically administered as a 5% cream formulation to patients in the study group, and the control patients received 1% micronized silver sulfadiazine once a week. After 6 weeks, wound healing had occurred in 77.5% of patients in the intervention group compared with 69.8% of patients in the control group. The average time to wound healing was approximately 65 days for the intervention group and 77 days for the control group. 

Although none of these results were statistically significant (P > .05), they can be clinically valuable. With the disabling impact of a DFU, an 11-day reduction in time to wound healing³¹ would be beneficial for patients. Moreover, the study compared the herbal cream and silver sulfadiazine (which is a criterion standard antimicrobial preparation, not a placebo) and suggests the efficacy of the herbal cream is equal to the criterion standard treatment. This study had a relatively low sample size.³¹ Larger studies are necessary to further evaluate this treatment.

Linum usitatissimum L. 

Linum usitatissimum, which is Latin for very useful, is the scientific name of the flax plant from the Linaceae family. It is grown in different parts of the world, mostly in North America, China, and India.⁵⁰ In traditional Chinese medicine and Ayurveda, the oil of L. usitatissimum seeds (flaxseed oil) is used for skin injuries. Flaxseed oil is a source of natural phenolic compounds such as flavonoids, lignans such as secoisolariciresinol diglucoside, polyphenols such as p-coumaric acid and ferulic acid,⁵¹ tannins, and fatty acids with previously demonstrated wound healing properties.^52,53

Soleimani et al³³ conducted a randomized, double-blind, placebo-controlled clinical trial to assess the effect of supplemental use of flaxseed oil omega-3 fatty acids in 60 patients with Wagner grade 3 DFUs. The supplement was orally administered in the form of 1000 mg capsules twice a day. After 12 weeks of treatment, use of flaxseed oil resulted in decreased ulcer size, serum insulin concentration (P = .002), hemoglobin level (P = .01), and serum high-sensitivity C-reactive protein level (P = .01). Moreover, significant increases occurred in insulin sensitivity based on quantitative insulin sensitivity check index (P = .002), plasma total antioxidant capacity (P < .001), and glutathione concentrations (P < .03). These results indicate the effect of this supplement on wound healing by improvement of metabolic profile in patients with DM.³³

Major constituents of flaxseed oil include polyunsaturated fatty acids, of which omega-3 fatty acids are the most abundant. Dietary intake of omega-3 has an important role in the inflammation process. This conclusion came from a study on the low incidence of autoimmune and inflammatory disorders, including type 1 DM, in the population of Greenland.⁵⁴ Intake of omega-3 fatty acid food derivatives was found to contribute to the reduction of pro-inflammatory cytokines such as interleukin-1 and tumor necrosis factor (TNF), which in turn ameliorates inflammation. In addition, the anti-inflammatory effects of polyunsaturated fatty acids, such as omega-3, are related to the ability of these compounds to inhibit the conversion of arachidonic acid to the pro-inflammatory lipid mediators, which consequently interrupts the pro-oxidant and pro-inflammatory nuclear factor (NF)-κB signaling pathway and activates the AMP-activated protein kinase.⁵⁵ Additional effects of flaxseed oil fatty acids on skin care include decreased transepidermal water loss and subsequent improvement of skin hydration and elasticity.^50,52

Melilotus officinalis (L.) Pall.

Semelil (ANGIPARS; Nano Hayat Darou) (Product A) is a commercial product derived from the extract of Melilotus officinalis (Fabaceae) for use as a wound healing agent owing to its anti-inflammatory and proangiogenic effects. Oral, topical, and parenteral formulations have been developed for use in patients with DFUs.⁵⁶

In a non-controlled clinical trial including 10 patients with DFUs, Masoompour et al³⁴ reported that daily intravenous infusion of Product A had a significant effect on the reduction of wound size compared with baseline values (P = .009). To confirm the results of this study, another clinical trial with a randomized, controlled, multicenter design was carried out in which the wound healing efficacy of Product A was compared with conventional therapy.³⁵ The intervention group received 4 mL of Product A once a day, diluted in 50 mL to 100 mL of normal saline and infused over 1 hour. Both the control and the intervention group received conventional therapy, including wound dressing, debridement, and systemic antibiotic therapy. After 4 weeks of treatment, significant decrease in wound surface area was observed in the intervention group compared with baseline values (P = 0.000). Additionally, patients in the intervention group showed a 64% wound closure rate, compared with a 25% wound closure rate in the control group (P = .015). 

Bahrami et al³⁶ conducted a randomized, single-blind, parallel groups clinical trial to compare the wound healing effect of oral and topical forms of Product A in 21 patients with DFUs. The patients were divided into 3 groups and treated with conventional therapy alone (control), conventional therapy plus oral Product A (oral), or conventional therapy plus oral and topical Product A (oral plus topical). The oral intervention was administered as 100 mg capsules twice daily, while the topical form was administered as 3% topical gel. After 6 weeks of treatment, complete wound healing, defined as a wound closure rate of 70% or more, was observed in 22%, 83.3%, and 100% of patients in the control, oral, and oral plus topical treatment groups, respectively (P = .002 between interventions and control). There was no statistically significant difference between the 2 intervention groups concerning ulcer condition. That is, the addition of topical gel did not induce a statistically significant additive effect to the therapeutic effect of the oral formulation. It should be reiterated, however, that oral plus topical intervention resulted in complete wound healing in all patients in that group; although that result is not statistically significant, it is an important clinical consideration. None of these trials reported significant side effects for the preparation, which confirms the safety of this product in patients with DFUs. Overall, Product A has demonstrated positive results in patients with DFUs; however, larger studies are needed to further investigate its efficacy.¹⁵  

Olea europaea L.

Olea europaea, or the olive tree from the family Oleaceae, is a well-known evergreen tree widely distributed in the Mediterranean region.⁵⁷ Several experimental studies have demonstrated the role of olive oil in chronic wound healing. It has been suggested that olive oil results in improved reepithelialization, tissue blood flow, cell migration, and dermal reconstitution and can aid in the prevention of inflammatory responses in the healing of burns, pressure ulcers, and cutaneous wounds.^58,37 Oleic acid and phenolic compounds such as tyrosol and its derivatives are major antioxidant components in olive oil that can prevent oxidative damage and that exhibit anti-inflammatory effects in chronic wound healing.⁵⁸

Refined olive oil was assessed in a randomized, double-blind clinical trial involving 30 patients with DFUs.³⁷ Topical application of olive oil was performed daily for a period of 4 weeks along with conventional therapy and the results compared with those of a control group treated with conventional therapy alone. Use of olive oil plus conventional therapy significantly decreased wound size (P = .01) and depth (P = .02) compared with conventional therapy alone. Additionally, 73.3% of the patients treated with olive oil showed complete wound healing, compared with only 13.3% in the control group (P = .003). It should be noted that since polyphenolic compounds have significant antioxidant activity and are found in high concentration in extra-virgin olive oil, it may be interesting to evaluate this type of olive oil in future studies.

Tinospora cordifolia (Willd.) Miers

Tinospora cordifolia (T. sinensis), commonly known as amritaor guduchi and known as the Rasayana plant in Ayurvedic medicine, belongs to the Menispermaceae family. The health benefits of this plant species are due to the immunomodulatory properties attributed to its phytochemicals, such as different terpenes, glycosides, alkaloids, steroids, and flavonoids.^59,60

In a randomized, double-blind, placebo-controlled clinical trial involving 45 patients, the oral consumption of T. cordifolia aqueous extract significantly decreased the number of required surgical debridements in patients with DFUs (P = .03).³⁹ The effects on ulcer size and depth, neutrophil count, and bacterial clearance were not statistically significant, however. It was suggested that the significant phagocytic activity enhancement of polymorphonuclear cells served as a regulator to promote wound healing. The dosage of the supplement is not mentioned in this study, however, and further research on the safety and efficacy of this plant is required.

Vasconcellea cundinamarcensis
V.M. Badillo

Vasconcellea cundinamarcensis or V. pubescens is a member of the Caricaceae family and originates from South America.⁶¹ This plant is commercially cultivated in Peru and Chile.⁶² The unripe fruits of the genus Carica are rich in proteolytic enzymes. The proteolytic fraction from latex of V. cundinamarcensis (P1G10) has been evaluated for its beneficial pharmacological properties and has demonstrated antifungal and antithrombotic activities.^61,63 Experimental studies on animals and cell lines have demonstrated proangiogenic and mitogenic properties of P1G10, as well as stimulating effects on fibroblast proliferation.^64,65 Previous literature has shown that the use of P1G10 on dermabrasion, burn, excisional lesion, and DFU has resulted in accelerated wound healing.^65,66  

In a randomized, double-blind, controlled trial, the wound healing efficacy and safety of a topical formulation prepared with 0.1% P1G10 in Polawax (Belo Horizonte) (3 times weekly for 16 weeks) was compared with hydrogel therapy in 39 patients with DFUs.⁴⁰ Patients in the control group received a standard hydrogel treatment for DFUs containing collagen, panthenol, and allantoin. The number of patients in the P1G10 group with complete and partial wound healing was twofold and threefold higher, respectively, than in the control group (P = .03). Wounds worsened in 6 patients in the control group, compared with 2 patients in the intervention group. The toxicity of topical P1G10 was evaluated for 1 month before the trial; no significant changes in blood parameters were shown. This study demonstrates the effect of P1G10 in patients with DFUs; P1G10 likely acts via enzymatic debridement of necrotic tissue and prevention of biofilm formation. Additional studies are needed to assess the microbial contamination of the wounds and clarify the exact mechanism of action.

Polyherbal preparations for management of DFU

Leung et al^{27, 41} conducted randomized, placebo-controlled clinical trials to evaluate the safety and efficacy of an oral polyherbal preparation in 80 patients with DFUs. The herbal formula contained Radix Astragali, Radix Rehmanniae, Rhizoma Atractylodis Macrocephalae, Radix Stephaniae Tetrandrae, Radix Polygoni Multiflori Preparata, Rhizoma Smilacis Chinensis, Poria Rhizoma Dioscoreae, Fructus Schisandrae Chinensis, Cortex Moutan, Fructus Corni, and Rhizoma Alismatis in equal proportions. All patients received sufficient antidiabetic and antibiotic medications with daily dressing and cleaning with 1% chlorhexidine gluconate solution. For 4 weeks, the herbal drink preparation was orally administered twice a day to those in the treatment group, while the control group received placebo. By the end of week 4, TNF-α levels had decreased significantly in the intervention group administered the polyherbal preparation compared with the control group (42% and 10%, respectively; P = .037), showing the significant anti-inflammatory properties of the supplement. Additionally, surface oxygen tension was significantly improved in the intervention group compared with baseline values (P = .005); no significant change occurred in the placebo group (P = .76).⁴¹ Rapid wound healing was observed in the intervention group, but this result was not significantly different from that of the placebo group. A dramatic increase in limb salvage occurred in the intervention group (P = .007), which supports the healing properties of the supplement in the setting of DFU. The safety of the herbal drink was also confirmed by evaluating the biomarkers of hepatic and renal function.²⁷

In a single-center, open-label, phase III clinical trial, Viswanathan et al⁴² compared the daily topical application of a polyherbal formulation with silver sulfadiazine cream in 38 patients with DFUs. The polyherbal cream consisted of Glycyrrhiza glabra, Musa paradisiaca, Curcuma longa, Pandanus odoratissimus, Aloe vera, and Cocos nucifera oil, all of which have antibacterial and anti-inflammatory properties. In both groups, the off-loading method was used and dressings were replaced daily with a thin layer of cream after irrigation with normal saline. At 5-month follow-up, a significant decrease in wound size compared with baseline values was observed in both groups (P < .001). The mean healing time was approximately 43 days in both groups, which demonstrates that the polyherbal formulation is as effective as the criterion standard (silver sulfadiazine cream), with no considerable side effect.

A prospective, randomized, controlled, and add-on clinical trial was conducted in 7 centers in China to investigate the efficacy and safety of the topical Chinese herbal preparation, Tangzu Yuyang Ointment (Product B), compared with standard wound therapy including local debridement, off-loading, and dressings.⁶⁴ The constituents of Product B include root of Coptis chinensis Franch, Ligusticum chuanxiong Hort, Atractylodes lancea (Thunb.) DC, Panax notoginseng (Burk.) F.H Chen, Angelica sinensis (Oliv.) Diels, Arnebia euchroma (Royle) Johnst, Rheum officinale Baill and bark of Phellodendron chinense C.K.Schneid., Borneolum syntheticum (borneol), Daemonorops draco (Willd.) Blume, and Gypsum fibrosum praeparatum (calcium sulfate). The formulation base was sesame oil plus beeswax and was prepared in a bacteria-free environment. A total of 48 patients with DFUs were included in this trial. Nine patients were lost to follow-up. The treatment group received standard wound therapy (saline gauze) along with application of a 1-mm-thick layer of Product B to the ulcer surface. In contrast, patients in the control group received only standard wound care. After 24 weeks, the healing rate was significantly higher in the intervention group than in the control group (91.7% vs 62.5%, respectively; P = .036).⁴³

Kuo et al³⁸ conducted a randomized, single-center, controlled, open-label clinical trial to evaluate the effectiveness and safety of an herbal cream in comparison to hydrocolloid fiber wound dressing (a standard DFU treatment procedure) in 21 patients. Three patients were lost to follow-up. The 1.25% cream was formulated from the most active fractions of Plectranthus amboinicus (Lour.) Spreng. and Centella asiatica (L.) Urban in proportion of 1:4, respectively, in a simple cream base. In the intervention group, the herbal cream was applied to the wound surface in a 2-mm-thick layer 2 times a day for 2 weeks. In the control group, a hydrocolloid fiber dressing was used once a week. At 2-week follow-up, there was no significant difference in wound size between the 2 groups, which shows the herbal cream to be as effective as the standard treatment. Although better improvement in Wagner grade was observed in wounds treated with the herbal cream, this improvement was not statistically significant. The treatment period of 2 weeks in this study is relatively short compared with other clinical studies on DFUs, and thus, future studies with longer follow-up periods are needed to better determine the effect of this herbal preparation compared with a standard treatment. 

Radix Astragali and Radix Rehmanniae are the roots of Astragalus membranaceus (Fisch.) Bge. and Rehmannia glutinosa Libosch, belonging to Fabaceae and Scrophulariaceae families, respectively.⁶⁷ These 2 Chinese medicinal herbs in a 2:1 proportion (named NF3) were shown to accelerate DFU healing in an animal model.⁶⁸  Several in vitro and in vivo studies have demonstrated that NF3  is beneficial for DFU healing because it activates the transforming growth factor-β pathway and genes attributed to fibroblast migration and proliferation; promotes extracellular matrix synthesis, thereby triggering angiogenesis; and promotes anti-inflammatory activities by inhibition of nitric oxide production.^67,69 In a randomized, double-blind, placebo-controlled clinical trial, NF3 formulation was administered to evaluate its wound healing properties in 16 patients with DFUs.³² Each NF3 sachet contained 5 g of granulated extract powder. Administration of this preparation (2 sachets per day) for 6 months resulted in a significant decrease in TNF-α level (P = .034) and regulation of the expression of genes related to fibroblast proliferation. Significant improvement occurred in the intervention group from baseline to 6-month follow-up in terms of the number of negative tests for sensory neuropathy using monofilament (from 27% to 7%; P < .001), whereas only slight improvement occurred in the control group during the same period (from 37% to 35%). 

Chronic hyperglycemia leads to major microvascular and macrovascular complications. Ulcerated feet in patients with DM are associated with high rates of morbidity and mortality and are financially burdensome for both patients and the health care system because of the chronic nature of DFUs and long hospitalization time.^3,70 Chronic wounds likely result from an imbalance between pro-inflammatory and anti-inflammatory mediators, which interferes with the wound healing process. In this context, plant metabolites such as different alkaloids, flavonoids, terpenes, and lignans are helpful because of their various stimulatory effects on fibroblast proliferation and activity through induction of collagen synthesis, migration, and reepithelization as well as their antimicrobial and antioxidant properties.⁷¹ Inflammation, impaired angiogenesis, oxidative damage, and infection are the main reasons for abnormal wound healing in DFUs. There are several medicinal plants with previously demonstrated beneficial effects on the regulation of the aforementioned mechanisms; their possible therapeutic effects in the setting of DFU can be evaluated in cellular and animal models.^{27-29,32,72,73}

The plants of the Caricaceae family are rich in proteolytic enzymes, and use of V. cundinamarcensis is among the most effective interventions evaluated in the studies included in this review as it had a significant effect on accelerating wound healing. The amount and activity of cysteine proteases in latex of V. cundinamarcensis are fivefold to sevenfold higher compared with these enzymes in V. papaya.⁷⁴ In a study published in 2011, Correa et al⁶⁴ found these enzymes to have a debridement effect on lesions and to promote stimulatory activity in the form of fibroblast proliferation, both of which had a positive effect on wound healing. Vasconcellea monoica, V. stipulata, and V. × heilbornii are other species of this genus with higher content of cysteine protease enzymes.⁷⁴ The present authors believe these species warrant further study in animals and in human patients with DFUs. Another effective treatment that might act via the same mechanism is the proteolytic enzyme actinidin, another type of papain-like cysteine protease enzyme mostly found in kiwifruit. Use of kiwifruit has also demonstrated significant improvement in patients with DFUs compared with control patients.⁴⁶ Based on the positive results of these 2 clinical studies,^46,74 it can be concluded that herbal protease enzymes may be a valuable group of natural agents that hold promise for aiding in the management of DFUs through enzymatic debridement of the wounds. Future studies on other plant species containing such enzymes are highly encouraged. 

Another valuable plant species discussed herein is M. officinalis. Product A is formulated based on the traditional use of this plant as a wound healing agent in Iran. The product is prepared in oral, topical, and injectable dosage forms, all of which showed significant effects on the wound healing process. ^34-36 Because the oral and topical forms are more convenient for the patient than the injectable form, they are preferred for clinical use.³⁶

Another important aspect of DFU healing is the prevention of xerosis, which can be achieved by use of medicinal plants.⁷⁵ Treatment with moisturizers has been shown to be an efficient means of maintaining water content to avoid loss of elasticity, skin cracks, and onset of infectious local wounds.⁷⁶ The study by Nasiri et al⁵¹ on the healing effect of olive oil in patients with DFUs demonstrates successful wound healing in part as the result of modulation of skin moisture content. Herbal oils such as canola oil (Brassica napus L.) and sunflower oil (Helianthus annuus L.), as well as mucilage obtained from plants such as Aloe vera L., all have been described as natural moisturizers useful in the prevention of xerosis in the skin recovery process in the setting of DFU.⁷⁵ These plants can be used instead of or in conjunction with currently available topical products in skin recovery; however, studies on the effects of these plants on DFUs are needed.

It is important to note that all interventions used in the studies included in this review were provided as adjuvant treatment; that is, both the intervention and the control patients received the conventional standard treatment for DFUs. This is because a DFU is a critical condition, and it is not ethically acceptable to deprive patients of standard therapy. Consequently, all the results provided in the Table concern improvements resulting from herbal medicine as an adjuvant therapy. For example, in the study by Nasiri et al,³⁷ despite receiving standard care, only 13.3% of patients in the control group had complete wound healing. In contrast, 73.3% of patients in the intervention group (who received topical olive oil in addition to standard care) had complete wound healing. This is a difference of 60%. The Table includes several other examples of the inability to achieve successful wound healing with standard care alone and the efficacy of natural therapies for a synergistic healing effect. 

It is also important to note that several of the efficacious treatments introduced in this review are systemic (oral) interventions (Table). Improvement in overall health through the antioxidant and anti-inflammatory effects of herbal supplements is critical in the healing of DFUs. Thus, use of oral plus topical supplementation with medicinal plants can improve the healing process of DFUs. Additionally, nearly all of the clinical trials included herein reported no adverse effects other than some mild and self-limiting gastrointestinal complications, which demonstrates the safety of these preparations. 

Animal studies have also demonstrated beneficial effects of medicinal plants on healing of DFUs. In one such study, use of methanolic extract of Lycium depressum Stocks leaves improved wound contraction and epithelialization time.⁷⁷Momordica charantia L. is another medicinal plant with significant beneficial effects on wound healing, and it was shown to cause elevated transforming growth factor-β expression in diabetic rats with foot ulcer.¹³ Mahboubi et al⁷⁸ reported use of a cream made of Oliveria decumbens Vent. and Pelargonium graveolens L’Hér. to achieve wound site repair in diabetic rats. Thus, there is currently a large body of evidence on the medicinal plants with beneficial effect in animal models of DFUs, which have not yet been clinically investigated. Such studies can introduce new candidates for future clinical studies on the safety and efficacy of medicinal plants in DFUs.

To develop a full picture of the capacity of medicinal plants to heal diabetic wounds, studies with larger sample sizes are needed. 

Medicinal plants provide a valuable source of natural compounds to use as adjuvants to standard wound care for the management of DFU. However, additional research is required that focuses on the precise evaluation of the most active extracts and/or fractions of medicinal plants for use in wound healing to minimize the possibility of side effects and other negative results. Future mechanistic pharmacological studies as well as well-designed clinical trials are essential to develop new herbal medicines for the management of DFUs. 

Authors: Roohollah Ahmadian, PhD Candidate^1,2; Roodabeh Bahramsoltani, PharmD, PhD³; André M Marques, Msc, PhD⁴; Roja Rahimi, PharmD, PhD³; and Mohammad Hosein Farzaei, PharmD, PhD^5,6

Affiliations: ¹Department of Pharmaceutics, Faculty of Pharmacy, Baqiyatallah University of Medical Sciences, Tehran, Iran; ²PhytoPharmacology Interest Group (PPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran; ³Department of Traditional Pharmacy, School of Persian Medicine, Tehran University of Medical Sciences, Tehran, Iran; ⁴Oswaldo Cruz Foundation (FIOCRUZ), Institute of Technology in Pharmaceuticals (Farmanguinhos), Rio de Janeiro, RJ, Brazil; ⁵Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran; ⁶Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran

Correspondence: Mohammad Hosein Farzaei, PharmD, PhD, Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran; mh.farzaei@gmail.com

Disclosure: The authors disclose no financial or other conflicts of interest.