Current scenario of traditional medicines in management of diabetic foot ulcers: A review

Abstract

Diabetic foot infections and diabetic foot ulcers (DFU) cause significant suffering and are often recurring. DFU have three important pathogenic factors, namely, microangiopathy causing local tissue anoxia, neuropathy making the foot prone to injuries from trivial trauma, and local tissue hyperglycaemia favouring infection and delaying the wound healing. DFU have been the leading cause for non-traumatic amputations of part or whole of the limb. Western medicines focus mainly on euglycaemia, antimicrobials, debridement and wound cover with grafts, and off-loading techniques. Advances in euglycaemic control, foot care and footwear, systemic antimicrobial therapy, and overall health care access and delivery, have resulted in an overall decrease in amputations. However, the process of wound care after adequate debridement remains a major cost burden globally, especially in developing nations. This process revolves around two basic concerns regarding control/eradication of local infection and promotion of faster healing in a chronic DFU without recurrence. Wound modulation with various dressings and techniques are often a costly affair. Some aspects of the topical therapy with modern/Western medicines are frequently not addressed. Cost of and compliance to these therapies are important as both the wounds and their treatment are “chronic.” Naturally occurring agents/medications from traditional medicine systems have been used frequently in different cultures and nations, though without adequate clinical base/relevance. Traditional Chinese medicine involves restoring yin-yang balance, regulating the ‘chi’, and promoting local blood circulation. Traditional medicines from India have been emphasizing on ‘naturally’ available products to control wound infection and promote all the aspects of wound healing. There is one more group of chemicals which are not pharmaceutical agents but can create acidic milieu in the wound to satisfy the above-mentioned basic concerns. Various natural and plant derived products (e.g., honey, aloe vera, oils, and calendula) and maggots are also used for wound healing purposes. We believe that patients with a chronic wound are so tired physically, emotionally, and financially that they usually accept native traditional medicine which has the same cultural base, belief, and faith. Many of these products have never been tested in accordance to “evidence-based medicine.” There are usually case reports and experience-based reports about these products. Recently, there have been some trials (in vitro and in vivo) to verify the claims of usage of traditional medicines in management of DFU. Such studies show that these natural products enhance the healing process by controlling infection, stimulating granulation tissue, antimicrobial action, promoting fibroblastic activity and collagen deposition, etc. In this review, we attempt to study and analyse the available literature on results of topical traditional medicines, which are usually advocated in the management of DFU. An integrated and ‘holistic’ approach of both modern and traditional medicine may be more acceptable to the patient, cost effective, and easy to administer and monitor. This may also nevertheless lead to further improvement in quality of life and decrease in the rates of amputations for DFU.

Key Words: Diabetic foot infections, Diabetic foot ulcers, Management, Traditional medicines, Topical agents, Wound healing

Core Tip: The chronicity, cost, and compliance issues complicate the management of diabetic foot ulcers. These patients prefer traditional medicines with the same cultural base and belief. This article focuses on the role of and results of comparative studies about usage of traditional medicines in managing diabetic ulcers. Topical formulations from Chinese and Ayurved systems, honey, plant products, which are commonly used and studied, will be discussed regarding their observed efficacy in wound healing.

INTRODUCTION

Projections for the increasing prevalence of diabetic patients and prediabetic individuals are alarming. Presently, patients from low- and middle-income countries comprise about 81% of the total prevalence. About 665.5 million people from these nations will be at risk for diabetes by 2045. Nations like China and India will continue to have the maximum number of adult diabetics. Almost a trillion US dollars are spent globally as annual direct expenditures for managing diabetes and its complications[1]. Peripheral vascular and neurological complications in diabetic patients account for more than a third of these expenditures[2]. The world has seen many improvements and advances concerning the diagnosis and management of diabetes. Control for euglycaemia is now an easily achievable goal. The management of diabetes-related complications is still a herculean task. The complex plethora of diabetic foot ulcers (DFU) is one of them. One-third of diabetic patients will eventually develop a foot ulcer sometime in their life[3]. The morbidity and eventual mortality due to DFU are just next to those of cancers[4].

DFU: A WOUND CONTINUUM

Multiple factors act collaboratively to cause the complex pathology of DFU (Figure 1), especially diabetic microangiopathy and neuropathy[1,5]. Diabetic microangiopathy leads to compromised tissue perfusion and makes the foot prone to poor local immunity, infection, and delayed healing. Diabetic neuropathy, especially sensory loss, makes the foot more prone to repeated trauma and poor foot care. Disturbed glycaemic metabolism makes the tissue prone to infection. Due to peripheral insulin resistance, type 2 diabetics are more likely to suffer from long-term complications of vasculopathy, neuropathy, and diabetic ulcers in the lower limbs[1,6]. Irrespective of age, gender, region, or culture, the pathophysiology of a DFU remains the same. Two or more risk factors, often peripheral neuropathy and frequently vasculopathy, are always present[6] (Figure 1).

Figure 1 Pathogenesis of diabetic foot ulcers.

DFU are a wound continuum starting from a very superficial ulcer and progressing to a deep-tissue infection and then osteomyelitis. The mere presence of an ulcer or bioburden does not qualify for the definition of DFU. The evidence of manifestations of an inflammatory process in any tissue below the malleoli in a diabetic person is a must. The presence of systemic manifestations of these inflammatory responses itself indicates severe infection[6,7]. Unfortunately, sometimes, despite all possible locoregional treatment, amputating the affected part becomes the sole option. But then this option has a lingering threat of non/delayed healing of the stump.

The wound, on its own, is responsible for producing key molecular regulators like growth factors, chemokines, and cytokines, which affect wound healing[8]. In the wound healing continuum, chronic wounds are stuck in the proliferative phase and are not progressing through the remodelling phase. Chronic wounds have low mitotic activity, highly inflammatory cells, and high protease and cytokine activity[8-10]. These wounds have senescent cells, irresponsive to the signals for clearing inflammation and epithelization[8,9]. The exudate itself is antiproliferative and hampers the extracellular matrix (ECM) production[10]. Undermined edges, friable granulation tissue, foul odour, or exudative floor also denote infection in chronic wounds and contribute to non-responsiveness[8]. Bed preparation in chronic wounds should focus on improving the molecular and cellular environment similar to that in acute healing wounds so that the natural healing can progress[8,11].

Biofilms are complex protective matrix composed of bacterial colonies and various extracellular polymeric substances, sugars, lipids, and glycocalyx, imparting eco-physical and immunological protective and adhesive abilities[12-15]. Biofilm allows the bioburden to flourish, which in turn allows the biofilm to further stabilise, adhere, and progress. Biofilm also contributes to persistence of chronic inflammation (abnormal neutrophilic infiltration and subsequent production of high levels of reactive oxygen species and proteases)[13,14]. It also facilitates horizontal transfer of antimicrobial resistance. Wound exudate also nourishes the biofilm[13]. Apart from the standard definition, biofilm is quandary in terms of detection and evaluation of clearance. Clinical assessment can confirm these issues. Physical debridement of biofilm helps to decrease bioburden and local chronic inflammation, converts the chronicity to a favourable active healing milieu, and improves action of antimicrobials. Available topical drugs like silver, cadexomer, polyhexamethylene biguanide, etc. have variable effects, hence drugs or phytochemicals with hygroscopic or surfactant action are under evaluation[12,13].

Systemic management is usually the control of hyperglycaemia and coexisting nephropathy and vasculopathy. Wound management in DFU is tailored according to the TIME (Tissue control, Inf-ection/inflammation, Moisture balance, Edge of the wound) concept with the prime aim to restore the balance of key molecular regulators. The TIME concept focuses on tissue control (wound debridement and cleaning), infection/inflammation complex (control of bioburden continuum), moisture-exudate balance, and epithelial advancement (Figure 2)[8,12]. There is a plethora of research on different aspects of DFU (microbiota, risks, care, management, burden, outcome, newer trials, etc.) with an overflowing armamentarium of existing and advanced wound-care products. Irrespective of the choice of dressing material used, its basic function will always be to control the bioburden. The efficient role of one over other dressing materials in wound healing is yet unproven[4,14].

Figure 2 Tissue control, infection/inflammation, moisture balance, edge of the wound concept for managing diabetic foot ulcers. TIME: Tissue control, Infection/inflammation, Moisture balance, Edge of the wound.

CHALLENGES DURING MANAGEMENT OF DFU

DFU are chronic wounds, and so is their treatment. DFU management cannot be set in rigid protocols due to many issues (resistant strains, polymicrobial infection, appropriate tissue/pus sampling, antibiotic stewardship and misuse, unpredictable recurrence, etc.)[3,16-20]. The adverse effects of topical antimicrobials are concerning[21]. The exact duration of antibiotics for different severities of DFU infections is unknown[8,22]. The cost-factor and compliance issues are significant and interlinked problems when prescribing any DFU treatment[1,3,23-25].

Newer trends show the rising preference for multidisciplinary integration, including biomechanics, biotechnology, and natural material sciences. Sociocultural beliefs sometimes warrant for integrating traditional and Western medicinal options. Evidence defining the valid statistical efficacy of such treatments is lacking. We have observed that patients with DFU are so exhausted physically, emotionally, and financially that they usually accept native traditional medicine with the same cultural base, belief, and faith. Other reasons for medical pluralism are the impulse to try all possible options, fear of side effects of allopathic medicines, cost, recommendations by family members and peers, etc.[25]. We have experienced that people with DFU consider these options patient-friendly because of easy availability, accessibility, and affordability. Many times, care providers also prefer experience-based therapy over evidence-based.

In this narrative review, we attempt to analyse the available literature on topical traditional medicine usually advocated for managing DFU. We have preferred appropriately framed clinical trials and good-quality case series, specific to DFU. We have excluded the literature about personal experiences, multiple therapeutics, individual case reports, and data in non-English languages.

TRADITIONAL CHINESE MEDICINES

Traditional Chinese medicines (TCM) may be described as multicomponent, multitarget, and multi-effect. TCM perspective involves restoring yin-yang balance, regulating the ‘chi’, and promoting local blood circulation. TCM system suggests that treating DFU should focus on improving and regulating qi, nourishing the yin, resolving the dampness, improving the spleen, and activating stagnant blood[26,27]. TCMs are available and advocated as an oral decoction, foot bath, and topical applicants (ointment and solutions). We have restricted our literature search for topical applications, especially comparative studies.

Multicomponent

Various herbs are utilised for producing active compounds or final drugs.

Actions (multitarget/multi-effect)

Effects in proliferative phase: A preliminary study on effect of Hongyou ointment and Shengji powder on Wnt signalling pathway proteins, observed that refractory wounds have characteristically abnormal β-catenin expression and over-expressed c-myc and K6. These were downregulated to normal levels after usage of the above formulation[28]. PA-F4 from the ON101 and WH-1 creams, significantly attenuates M1 macrophages by suppressing the NLRP3/interleukin (IL)-1β and IL-6 mediated inflammatory responses[29]. S1 extract of Centella asiatica stimulates fibroblast proliferation, collagen synthesis, and keratinocyte migration[30]. The Kangfuxin solution (KFS), from extracts of Periplaneta americana L., contains many active ingredients (peptides, polyols, and sticky sugar amino acid), which promote granulation tissue, neovascularisation, and neutrophilia, nourishes yin, and has myogenic effects, ultimately promoting rapid wound healing[31].

Antibacterial effects: Although there is no significant data on the actions of individual herbal products for DFU healing, in vitro experiments have shown that extracts from Phellodendri Cortex or Huangbai have an antimicrobial role against Pseudomonas, Staphylococcus aureus (MRSA), Pneumococcus, C. diphtheriae, Streptococcus, etc.[32-34].

Anti-inflammatory effects: Lianqiao has a detoxifying effect and reduces swelling. Jinyinhua soothes the skin itching such as eczema and alleviates swollen ulcers and cellulitis. Wugong also has detoxifying and anti-inflammatory effects[32]. Tangzu Yuyang ointment contains many phytochemical components (berberine, ferulic acid, ginsenoside, phellodendrine, obaculactone, etc.), which exert anti-inflammatory, antibacterial, antioxidant, and analgesic actions on the wound bed[35].

In animal models, Zizhu ointment resulted in rapid wound healing, and downregulated the expression of the Notch4 gene and its target genes and ligands and promoted the proliferation of M2 macrophages and other anti-inflammatory effects[36]. Components of Shenghong liquid (SH) have an anti-inflammatory effect and improve local circulation[37].

Human trials

Commonly used topical ointment, cream, and solutions[28,32,35-39] for DFU are mentioned in Table 1. The available and accessible literature about human clinical trials[28,32,35,37,39-41] for TCM in DFU is scanty with a very small number of test subjects (Table 2). The therapy is well-tolerated and results are promising but need further high-volume studies.

Table 1 Contents of formulations used in managing diabetic foot ulcers.

Name of formulation	Contents
Hongyou ointment[28]	Jiuyi Pellet (Gypsum Fibrosum: hydrargyrum oxydatum crudum), Dong Pellet (main ingredients: sminium), and Vaseline
Shengji powder[28]	Gypsum Fibrosuum, Resina Draconis, Resina Olibanum, Myrrh, and Borneolum syntheticum
Cortex Phellodendri Compound Fluid[32]	Huangbai (Phellodendron Chinese Schneid), Lianqiao (Forsythia suspensa), Jinyinhua (Lonicera japonica Thunb), Pugongying (Taraxacum mongolicum Hand. -Mazz), and Wugong (Scolopendra)
Tangzu Yuyang ointment[35]	Coptis chinensis Franch (Huanglian), Ligusticum chuanxiong Hort. – (Chuanxiong), Atractylodes lancea (Thund.) DC. (Cangzhu), Panax notoginseng (Burk.) F.H. Chen. (Sanqi), Angelica sinensis (Oliv.) Diels. (Danggui), Arnebia euchroma (Royle) Johnst. (Zicao), Phellodendron chinense Schneid. (Huangbo), Rheum officinale Baill. (Dahuang), Borneolum syntheticum (Bingpian), Daemonorops draco Bl. (Xuejie), Gypsum fibrosum praeparatum (Duanshigao), and Sesame oil and Beeswax served as bases
Zizhu ointment[36]	Cinnabar (Zhusha), Astragalus mongholicus (Huangqi), Arnebia guttata (Zicao), Donkey hide gelatin (Ejiao), Borneol (Bingpian), and Dragon’s Blood (Xuejie)
Shenghong liquid[37]	Radix rehmanniae, Carthamus tinctorius, Coptis chinensis, Rheum officinale, Radix lithospermi, Fructus gardenia, and licorice
WH1 and ON101 creams[38,39]	PA-F4 from an extract of Plectranthus amboinicus and S1 from an extract of Centella asiatica.
Panchvalka[104,109]	Stem bark of Ficus benghalensis, F. glomerata, F. religiosa, F. virens, and Thespesia populnea
Jatyadi tailam[105,109]	Chameli (Jasminum grandiflorum) Neem (Azadirachta indica) Patol (Trichosanthes Dioica), Karanj (Pongamia glabra), Yashtimadhu (Glycyrrhiza glabra), Haridra (Curcuma longa), Daruharidra (Berberis aristate), Kutki (Picrorhiza kurrooa), Manjistha (Rubia cordifolia), Padmakh (Prunus cerasoides), Lodhra (Symplocos racemose), Haritaki (Terminalia chebula), Nilofer (Nymphaea alba), Tutiya (Copper sulfate), Sariva (Hemidesmus indicus), Mom (Wax), Chandan Oil (Santalum album), Kumari oil, and Sesame oil

Table 2 Results of various trials that used traditional Chinese medicines topically.

Ref.	Test group	Control group	Results
Li et al[28]	Hongyou ointment and Shengji powder (CM group) (n = 27)	WM (mupirocin ointment, growth factor, and vaseline gauze) (n = 26)	Overall effective rate (healed and completely effective) in CM group (22/27, 81.48%) was significantly higher than that in WM group (15/26, 57.69%, P = 0.04). The mean wound healing time was 22.71 ± 5.46 d in CM group vs 26.56 ± 7.56 d in WM group (t = 2.13, P = 0.04)
Liu et al[32]	CPCF	KFS	CPCF group: Initial wound area was 7.58 ± 2.13 cm2, improved to 3.83 ± 3.13 cm2 on 14th d, 2.39 ± 2.53 cm2 on 21st d, and 1.18 ± 2.49 cm2 on 28th d. The mean wound area of 7.73 ± 2.11 cm2 in KFS group had improved through 5.66 ± 2.58 cm2 on day 14, 4.42 ± 2.87 cm2 on day 21, and 2.78 ± 3.32 cm2 on 28th d (P < 0.05)
Huang et al[39]	ON101 cream (n = 118)	Sodium carboxymethyl cellulose absorbant dressing (n = 112)	At 16 wk, 74 patients (60.7%) of ON101 group and 40 (35.1%) of comparison group had achieved ulcer closure (OR = 2.84; 95%CI 1.66-4.84; P < 0.001). No difference between rates of 50% ulcer reduction at 16 wk (82.8% vs 86.0%)
Li et al[35]	TYO (n = 24)	SWT (n = 24)	Improved healing rate of only 4% (37.5% TYO group vs 33.3% SWT group). Significant improvement in TYO group at 12 wk (79.2% vs 41.7%; P = 0.017) and 24 wk (91.7% vs 50%; P = 0.003)
Xie et al[37]	SH (n = 30)	Recombinant human basic FGF gel ( n = 30)	Significant reduction in ulcer size by 4, 8, and 12 wk. Ulcer size was reduced from 15.90 ± 3.27 cm2 to 2.75 ± 1.08 cm2 in the SH group and from 15.72 ± 3.11 cm2 to 8.36 ± 2.07 cm2 in controls (P < 0.001)
Jiang et al[40]	Jingwanhong ointment (n = 67)	Sulphadiazine zinc ointment (n = 64)	Epithelization was complete by 46.5 ± 15.6 d in Jingwanhong group and 67.9 ± 17.9 d in sulfadiazine zinc group (P < 0.05)
Cao et al[41]	Unspecified TCM ointment (n = 20)	Topical ethacridine lactate (n = 20)	Better wound healing at 10, 20, and 30 d in TCM group

FGF: Fibroblast growth factor; CM: Chinese medicine; WM: Western medicine; CPCF: Cortex Phellodendri Compound Fluid; KFS: Kangfuxin solution; TCM: Traditional Chinese medicines; TYO: Tangzu Yuyang Ointment plus standard therapy; SWT: Standard wound therapy; SH: Shenghong liquid.

Li et al[28] observed that Hongyou ointment and Shengji powder have a higher overall effective rate, shorter mean healing time, and no adverse reactions or long-term complications when compared to Western medicine.

The Cortex Phellodendri Compound Fluid (CPCF) was superior to the KFS in reducing ulcer area, and increasing growth factor content and total effective rate (P < 0.05). In these groups, serum VEGF (vascular endothelial growth factor), EGF (epidermal growth factor), and bFGF (basic fibroblast growth factor) levels increased significantly after treatment (higher in CPCF group)[32].

Kuo et al[38] studied the effects of WH-1 cream dressings (n = 11) against hydrocolloid dressings (n = 10) in Wagner grade-3 DFU. With no significant difference in the size reduction, improvement of Wagner grade was marginally higher in the WH-1 group but not statistically significant. Huang et al[39] used ON101 cream with same TCM composition as WH-1 cream. The healing rate was statistically significant in the ON101 group, without any significant adverse reactions.

Li et al[35] studied Tangzu Yuyang Ointment (TYO) as an adjuvant to standard wound therapy in Wagner grades 1-3 DFU but could not find any statistical difference in the improvement of ulcer size or Wagner grade nor the incidence of study-related adverse effects or ulcer recurrence. In another study, Wagner grades 1-3 DFU were ultrasonically debrided and the effect of Shenghong liquid (SH) vs recombinant human basic fibroblast growth factor was studied. The SH group had higher and faster rates of ulcer healing[37].

A multicentric study of 229 patients with non-severe ischaemic DFU, observed a statistically significant effective rate (80.54%) in the TCM group compared to the conventional treatment group (68.00%)[42]. Kangfuxin and other extracts from Periplaneta americana are under research for an integrated approach for manufacturing a composite biodegradable hydrogel dressing with promising results in promoting wound healing[43-45].

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HONEY

Actions

Apart from dextrose and levulose, honey contains many vitamins, trace minerals, prostaglandins, flavonoids (rutin, kaempferol, catechin, genistein, chrysin, etc.), and polyphenolic compounds (ferulic acid, coumaric acid, gallic acid, abscisic acid, vanillic acid, hydroxycinnamic acid, etc.)[46]. Phenolic acids mainly contribute to the antioxidative and anti-inflammatory actions through various signalling pathways[46].

Honey has antibacterial efficacy against many aerobes and anaerobes[47-51]. This action is attributed to acidic pH, hyperosmolarity, inhibins, antioxidants, H₂O₂, and various enzymes[46,52-54]. Different studies reported anti-Pseudomonal activity at minimum inhibitory concentrations (MIC) of 11%-40%[50-52,55,56]. Hygroscopic action due to high osmolarity improves lymphatic and blood circulation[57,58]. Hygroscopic action and facilitatory actions for protease activity allow for autolytic debridement[59]. Low concentrations of H₂O₂ in honey may promote fibroblastic proliferation and neoangiogenesis[60]. Improvements in epithelization, neoangiogenesis, and better collagen synthesis via various growth factors/chemokines (TNF-α, TGF-β, VGEF, IL-6, IL-12, etc.) and signalling pathways, all contribute to the ameliorated healing action of honey[46,61-63].

By using various types of honey in animal studies, many researchers have confirmed faster and higher wound epithelization and contraction, when compared to other topical applicants[64-68].

Human studies in DFU

The various studies comparing honey against povidone[57,69,70] and other dressings[71-74] are summarized in Table 3. Hammouri et al[69] had noted significantly better mean healing time and shorter hospital stay in the honey group as against povidone and H₂O₂. Fourteen patients had allergic reactions to povidone, but honey dressings were well-tolerated. Eight refractory cases in the povidone group then used honey till healing[69].

Table 3 Results of various trials that used honey topically.

Ref.	Test group	Control group	Results
Shukrimi et al[57]	Honey	Povidone iodine	Mean time for "ready for surgical closure" 14.4 d in honey group vs 15.4 d in povidone group (P < 0.005). Less pain and faster improvement in oedema and foul exudation in honey group. No significant changes in bioburden isolation before and after therapy
Hammouri et al[69]	Honey and normal saline (n = 100)	Povidone and H2O2 (n = 100)	Mean healing time 21 (7-70) d, hospital stay 13 (7-42) d, and low treatment costs in honey group. In povidone group, the mean healing time was 32 (7-90) d with a mean hospital stay of 23 (7-56) d (P < 0.001)
Jan et al[70]	Honey (n = 50)	Povidone iodine (n = 50)	Faster wound healing at various intervals. Healing at end of 8-10 wk: All patients in honey group and 74% in povidone group (P < 0.0001). No difference in amputation rates
Imran et al[71]	Honey (n = 179)	Saline dressings (n = 169)	By 120 d, complete healing in 136 (75.97%) wounds in honey group vs 97 (57.39%) wounds in saline group (P < 0.001). Mean wound healing time: 18 (6-120) d in honey group vs 29 (7-120) d in saline group (P < 0.001)
Kamaratos et al[72]	Manuka honey (n = 32)	Saline dressings (n = 31)	No statistical difference in the total healed ulcers (97% in honey vs 90% in saline group). Mean healing time: 31 ± 4 d in honey group vs 43 ± 3 d in saline group (P < 0.05)
Al Saeed et al[73]	Honey (n = 32)	Tulle grass dressings (n = 27)	Faster wound healing in honey group than simple tulle grass dressings [(61.3% vs 11.5%; P < 0.05) at 6 wk and (87.1% vs 42.3%; P < 0.05) at 6 mo]. Hospital stay and incidence of amputation were also lower in honey group
Siavash et al[74]	5% Royal jelly (bee product)	Placebo	No statistical difference regarding size reduction and complete healing (P > 0.5)

In a pilot study, Abdelatif used honey in 60 cases of DFU (Wagner grades 1-5). Patients with Wagner grades 1-2 DFU showed a 100% response given the complete healing by 9 wk, whereas those with Wagner grade 3 DFU had a 92% response at the end of 9 wk. The patients with Wagner grades 4-5 DFU underwent surgical debridement followed by topical honey application and showed a 100% response without a need for amputation[75].

Moghazy et al[76] observed that honey dressings significantly reduce the exudation in the wound bed, ulcer dimensions, and surrounding inflammation. In that study, each wound had a different bacterial isolate, but after 2 mo, most wounds (28, 93.3%) had Staphylococcus epidermidis. Pseudomonas aeruginosa was isolated from only two ulcers. The authors noted significant improvement from a severe to favourable grade of the DFU[76]. Kamaratos et al studied the beneficial effects of manuka honey but did not mention the outcome about antibacterial effect against specific bacterium[72].

In an open-label randomized controlled trial (RCT) with three parallel groups (nanosilver, manuka honey, and conventional dressings), cumulative healing, ulcer reduction, and clinical wound infection after 12 wk were measured. Although the nanosilver group had the highest proportion of wound healing, the cumulative healing was not statistically significant (P = 0.26). Rapid ulcer reduction was present in the nanosilver group (97.45% vs 86.24% in the honey group vs 73.91% in the conventional group). Bioburden was significantly reduced in the nanosilver and honey groups. The authors observed that nanosilver and manuka honey were only 1.3 and 1.1 times, respectively, more effective than conventional paraffin tulle dressings[77]. Saeed observed similar results when using nanosilver vs manuka honey dressings[78].

Shrivastava studied the effects of tannin-rich plant extract in one group (n = 69 ulcers) and honey and glycerol in another group (n = 49 ulcers) of a RCT. In that study, 67% of the wounds were DFU. Tannin-rich extracts were better than honey for reducing wound surface area (97.87 vs 33.37%, respectively) and maintaining wound humidity after 6 wk of treatment. The study did not mention the details of progression/outcomes in the DFU patients[79].

ALOE VERA

Clinical metabolites contributing to antibacterial, anti-inflammatory, and antioxidant actions are lupeol, salicylic acid, urea nitrogen, cinnamomic acid, phenols, sulfur, vitamins, enzymes, mineral, lignin and amino acids, bradykinase, anthraquinones, dihydroxyanthraquinones, saponins, aloin emodin, and many others[80-82].

Antibacterial effects

Nejatzadeh-Barandozi et al[80] and Danish et al[83] studied the antibacterial effect against various Gram-positive and Gram-negative bacteria by disc diffusion techniques. Nejatzadeh-Barandozi et al[80] observed that acetone extracts of aloe vera were better than ethanol or aqueous extracts. The zone of inhibition for acetone and ethanol extracts against Pseudomonas was 19 ± 0.57 mm and 14 ± 0.53 mm, respectively[80]. Aloe vera root and leaf ethanol extracts exhibited good antibacterial activity with a zone of inhibition of > 13 mm at a concentration of 30 mg[83]. Arbab et al[84] also concluded that ethanol extracts are more efficacious than conventional extracts. Antifungal activity was noted against Fusarium and Aspergillus[83]. Goudarzi et al had observed favourable activity against multidrug-resistant P. aeruginosa at a MIC ≤ 400 µg/mL[82]. Distillate form of Aloe vera was effective against Staphylococci including methicillin-resistant MRSA and Gram-negative microbes like K. pneumoniae and P. aeruginosa[85]. Aloe vera had a 100% in vitro activity against Pseudomonas compared to vancomycin (72.2%) but less for Staphylococci and Streptococci (75.3% vs 80.5% of vancomycin)[86].

Action on wound healing

Throughout the study duration, Chithra et al[87] observed that the collagen, protein, and DNA levels were significantly higher in the aloe vera gel group compared to the control group. The period of epithelization was 22.2 ± 92.3 d in the aloe vera gel group and 24.8 ± 92.4 d in the control group (P < 0.05), indicating significantly faster healing[87]. The same authors also noted a positive impact on the production of glycosaminoglycans, especially hyaluronic acid and dermatan sulphate, and proteoglycans in the wound bed[87,88].

Shafaie et al[89] studied the effects of aloe vera on fibroblasts against controls. Fibroblast proliferation and migration were significantly promoted. Aloe-treated fibroblasts were morphologically better and had significantly higher expression of Integrins α1 and β1 and PECAM-1 gene, which are integral for proliferation, differentiation, migration, and formation of granulation tissue and the ECM. The study concluded that aloe vera is efficient in proliferative, reepithelization, and remodelling phases of wound healing[89].

Takzaree et al[90] observed that the augmented TGF-β gene expression in the aloe vera gel-treated group resulted in rapid formation of granulation tissue, angiogenesis, and epithelialization in rats. Daburkar et al[91] observed significantly higher levels of glycosaminoglycans, rapid wound contraction, and increased breaking (tensile) strength by the ninth day (P < 0.0001) in aloe-treated DFU. In an Indonesian experimental rat study, Sari et al[92] compared the effects of topical aloe vera vs Nigella sativa oil vs untreated group. They noted significantly smaller wounds by the seventh day, better fibroblastic infiltration, and better reepithelization in the aloe vera group[92].

Clinical human studies

With very few trials, aloe vera had shown promising results in improving healing in DFU, but there are only few human trials[93-95] (Table 4) with small sample size, inadequate data, and low-level evidence. Worasakwutiphong et al[96] conducted a small pilot study by using blended silkworm fibroin and aloe gel extract for the dressing of five hard-to-heal DFU (Wagner grade 1). Spectroscopic analysis and tensile strength analysis showed favourable results. Clinically, three DFU had a significant reduction in wound size and healed within 3 wk. The other two had healed by 4 wk[96].

Table 4 Results of various trials that used aloe and ayurvedic medicines topically.

Ref.	Test group	Control group	Results
Panahi et al[93]	AVO cream	Topical phenytoin	At 4 wk, wound healing scores (overall BJUA score, size, depth, slough, adjacent tissue inflammation) in AVO group were significantly better (P < 0.001) than the pre-treatment score and as compared with the phenytoin group
Avijgan et al[94]	Aloe vera ointment with conventional treatment	Only conventional treatment	At 3 mo, 28 (93.3%) patients in aloe vera group vs 14 (46.7%) from control group had complete wound healing (P < 0.05). The overall mean healing time and average cost were significantly lesser in aloe vera group
Najafian et al[95]	Aloevera/ Plantavera major gel (n = 20)	Placebo (n = 20)	After 4 wk, significant reduction of ulcer surface in the Plantavera group than in placebo group (P = 0.039). No statistical difference in ulcer depth
Tamoli et al[109]	Aerosol sprays (containing Panchvalka Kwatha and Jatyadi Taila) (n = 12)	Standard care (n = 14)	BJUA score: 30.59 ± 7.11 on the first day in herbal group, improved to 23.45 ± 8.79, and 15.32 ± 7.63 on days 30 and 90, respectively. In control group, score: 30.58 ± 8.72 and improved to 21.05 ± 9.78 and 14.92 ± 7.69 on days 30 and 90, respectively. Healing time was better in the aerosol spray group
Ajmeer et al[110]	Katupila Kalka (paste of S. leucopyrus leaves) with Tila Taila (sesame oil) (n = 13)	Betadine ointment (n = 10)	Complete healing was noted in 92.3% of cases of group A compared to 20 % of group B. Weekly improvement in exudate and peri-wound skin and size reduction were statistically significant in group A

AVO: Aloe vera-olive oil; BJUA: Bates-Jensen ulcer assessment.

CALENDULA

Calendula officinalis (Asteraceae family) has been used as a medicinal plant in many traditional systems. Hydroglycolic extracts of calendula flower contain various bioactive terpene alcohols, flavonoids, oligoglycosides, and mono-ester triterpenoids that contribute to the anti-inflammatory, antioxidant, and wound healing actions[97]. Calendula promotes neoangiogenesis via upregulation of VEGF and other angiogenic factors in animal models[98]. Calendula has a broad antimicrobial effect against various Gram-positive and Gram-negative bacteria as well as fungi like Candida and Aspergillus[99].

There are many studies about the efficacy of calendula in non-diabetic wounds but those for DFU are very limited. Carvalho et al[100] conducted a four-arm randomized control trial on diabetes patients with leg ulcers for ulcer size reduction. Four groups, each containing eight patients, were calendula extract oil group, the low-level laser therapy group, a combination of both, and a standard-care control group. At the end of 3 wk, the calendula group did not show a significant reduction from baseline wound size (pre- vs post-treatment). The combination group and laser alone group had statistically better results[100]. Chitosan based hydrogels loaded with calendula have been studied with promising results[101].

Effects of Ageratina pichinchensis extracts (also from Asteraceae family) were compared with those of silver sulfadiazine cream on DFU in a small pilot study. Wounds had healed in a shorter period in the intervention group (65.47 ± 47.08 vs 77.46 ± 50.8 d, P = 0.509)[102].

TOPICAL AYURVEDIC MEDICINES

Principles of Ayurved for managing DFU, focus on restoring tissue perfusion, improving circulation, and controlling the inflammatory processes[103]. The phenolics and tannins in Panchvalka have free-radical scavenging activity comparable to ascorbic acid[104]. Jatyadi oil formulations contain various alkaloids, phenols, tannins, sterols, glycosides, saponins, terpenoids, flavonoids, and anthocyanins which contribute to the anti-inflammatory and antimicrobial activities. Jatyadi oil is effective against Gram-positive microbes, even against MRSA and, to a lesser extent, against Gram-negative bacteria[104,105]. Mandrika et al[105] observed that in vitro, Jatyadi formulations downregulate the proinflammatory cytokines IL-6, IL-1β, and TNF-α, and related chemokines.

Haridra (curcumin) is used in many traditional systems independently as well as in polyherbal formulations. Curcumin has antioxidant and anti-inflammatory (reduction of TNF-α and IL-1 cytokines) properties and promotes granulation formation, fibroblastic migration, collagen synthesis, and epithelization[106].

Polyherbal creams are being studied in animal models and have shown statistically better results than conventional topical creams[107]. Jatyadi Ghrita has a significant role in improving moisture and reepithelization in a rat model study[108]. Only a few comparative studies are available about the role of topical ayurvedic (poly-herbal) preparations (Table 1) in DFU. Data from available trials[109,110] (Table 4) warrants further research. Honey and curcumin are being studied for producing an effective and biodegradable hydrogel sponge for improved wound care[111].

ACIDS IN WOUND HEALING

Conventionally available and naturally occurring acids are also used for the topical management of chronic and infected wounds like DFU. The acidic milieu favours wound healing by antimicrobial action as well as promoting inflammatory and proliferative phases[21].

Antimicrobial action

The wound bed is improved into a ground unfavourable for bacterial proliferation, thereby controlling the bioburden. Eliminating biofilms, altering the protease activity, allowing autolytic debridement, decreasing the local toxic effects of bacterial end products, and improving tissue oxygenation, are other notable actions[112-116]. The citric acid (MIC: 500-2500 μg/mL) and hypochlorous acid have antibacterial actions against common culprits in DFU. Despite being very effective against Pseudomonas, the action of acetic acid against other microbes is limited[21]. Boron derivatives (boric acid and sodium pentaborate pentahydrate) have broad antibacterial and antifungal actions[117]. Nagoba et al[118] observed favourable antimicrobial action of citric acid in hard-to-heal DFU with multidrug-resistant MRSA infection.

Wound healing

Citric acid and to some extent, hypochlorous acid both augment fibroblastic growth and promote healthy angiogenesis and epithelization[119,120]. Hyaluronic acid stimulates cell migration, keratinocyte proliferation and maturation, scar remodeling, and free radical scavenging[121]. In vitro and in vivo studies on diabetic rats revealed that low concentrations of boric acid promote the proliferation of dermal cells, stimulate migration, improve expression of ECM proteins, and downregulate the expression of pro-inflammatory nitric oxide synthase and cyclooxygenase-2. Boron derivatives augment the synthesis of various growth factors[117].

Human trials

Fejfarová et al[122], in a small pilot study of 32 DFU (17 patients received topical 1% acetic acid) found better improvement and easy and cheap usage in the acetic acid group, but the results were not statistically significant. Agrawal et al[123] observed that 1% acetic acid is efficient against many bacteria (MRSA, Pseudomonas spp., Klebsiella, Acinetobacter, E.coli, etc.) and fungi (Candida, Aspergillus, and Cryptococcus spp.). After 14 d of daily acetic acid applications, 64/100 wounds were sterile. Along with the reduction in ulcer size, there were reductions in exudation and surrounding inflammation[123]. Similar effects were also noted with the usage of citric acid in 115 DFU patients with Wagner 1-3 grades[116]. Alginic acid alone is rarely used for DFU, but alginic acid-based preparations are widely used in research and practice.

Despite adequate evidence, the absence of good quality human studies with greater sample size marks the usage of acids in DFU as an unexplored avenue.

MAGGOTS, LARVAE, AND LEECHES

Larval or maggot debridement therapy is a biological debridement by the sterile larvae of green bottle fly (Lucilia species)[124-126]. Infection control is achieved by debridement, ingestion of bacteria, and antimicrobial action of the maggot secretions facilitating the action of topical antimicrobials[125-127]. Despite acceptable and relatively painless debriding action, maggots are not socio-culturally accepted as traditional medicine by patients and health-care personnel in many communities. Maggot secretions might induce endothelial proliferation to improve neo-granulation tissue[128]. Maggot therapy related trials in DFU are very few with very small sample size. Overall debridement effect was in 50%-80% patients with an average healing duration of 8-14 wk[125,129]. There is heterogenous data on slough vs total wound area, dose/exposure per cm², and duration of usage and healing. Definite guidelines and adequate evidence are lacking from the available literature. Leeches have no topical action in diabetic wounds.

CONCLUSION

DFU have complex pathogenesis and even more complex treatment protocols. Ultimately what matters is salvaging the limb. Refractory wounds with resistant microbes and exhausted resources may benefit from traditional medicine systems, especially if integrated with Western medicine. Experts in such systems should come forward with better trials for the ultimate goal of DFU treatment. The results of available clinical trials on traditional medicines in DFU are not always accessible. Unrestricted availability of observations from such trials will be undoubtedly valuable for researchers around the globe. Traditional medicine systems have a long way to go in terms of large, well-designed, human RCT. Till then, only at the hands of an expert, experience-based DFU treatment may be better than evidence-based treatment.

ACKNOWLEDGEMENTS

The authors wish to thank Mr. Vinod Jogdand and Mr. Dipak Badne from Department of Medical Education for their assistance in preparation of the manuscript.