Herbal Products and Their Active Constituents for Diabetic Wound Healing—Preclinical and Clinical Studies: A Systematic Review

The purpose of this review is to provide verified data on the current knowledge acquired in preclinical and clinical studies regarding topically used herbal products and their active constituents (formulations and dressings) with diabetic wound healing activity. Moreover, herbal products and their active constituents used for diabetic wound infections, and various cellular and molecular mechanisms of their actions will also be described. The electronic databases were searched for articles published from 2012 to 2022. Publications with oral or systemic administration of herbal products in diabetic wound healing, published before 2012, available only as an abstract, or in languages other than English were excluded from the study. The 59 articles comparing topically used herbal products in diabetic wound healing treatment versus control treatments (placebo or active therapy) were selected. Herbal products through different mechanisms of action, including antimicrobial, anti-inflammatory, antioxidant activity, stimulation of angiogenesis, production of cytokines and growth factors, keratinocytes, and fibroblast migration and proliferation may be considered as an important support during conventional therapy or even as a substitute for synthetic drugs used for diabetic wound treatment.


Introduction
Diabetes is a metabolic disorder associated with the endocrine system that resulted in hyperglycemic conditions. Prolonged and untreated hyperglycemia or uncontrolled glucose levels leads to serious diabetic complications, such as nephropathy, neuropathy, retinopathy, hypertension, hyperlipidemia, increased risk of cardiovascular disease, and heart attacks [1]. The most costly and devastating complication of diabetes is delayed wound healing processes which can lead to serious complications such as a high risk of bacterial infections, gangrene, limb amputations, sepsis, and even death [2]. About 15% of diabetic patients have diabetic foot ulcers (DFU), and 14-24% of these patients subsequently experience a lower extremity amputation, with the mortality rate from amputation approaching 50-59% five years post-amputation [3]. Therefore, acceleration of wound healing should be a priority in preventing diabetes complications.
Wound healing difficulties in diabetes patients are multidirectional. The hyperglycemic condition in the wound site leads to chronic inflammation, impaired vascularization and tissue regeneration, reduced production of growth factors, excessive protease activity, and oxidative stress [4]. Moreover, open wounds are particularly prone to infection, especially by bacteria, and provide an entry point for systemic infections. Aerobic or facultative pathogens such as Staphylococcus aureus, Pseudomonas aeruginosa, and β-hemolytic

Animal-Based Studies
Animal-based studies are important in the research on the use of herbal products and their active constituents for diabetic wound healing (Tables 1-3). The most described animal studies are based on diabetes induced by streptozotocin (STZ) and alloxan monohydrate. Alloxan monohydrate and STZ are the most popular diabetogenic agents used for assessing the anti-diabetic or hypoglycemic capacity of test compounds. These compounds are cytotoxic glucose analogs that preferentially accumulate in pancreatic β cells via the GLUT2 glucose transporter [12]. STZ is a glucosamine-nitrosourea compound, a cytostatic antibiotic produced by Streptomyces achromogenes, used clinically as a chemotherapeutic agent in the treatment of pancreatic β-cell carcinoma. STZ damages pancreatic β cells, resulting in hypoinsulinemia and hyperglycemia [13]. Moreover, STZ induces type 1 and 2 diabetes in rodents [14]. Alloxan monohydrate, a urea derivative, selectively inhibits glucose-induced insulin secretion through its ability to inhibit the β cell glucose sensor glucokinase [12]. Inhibition of glucokinase reduces glucose oxidation and ATP generation, thereby suppressing the ATP signal that triggers insulin secretion [12]. Alloxan monohydrate can induce type 1 diabetes [15]. In a few reported studies, induction of diabetes was based on the combination of STZ with a high-fat diet (STZ/HFD) [16] or carried out on genetically modified animals with diabetes (leptin receptor-deficient (Leprdb/JNju, db/db) mice) [17]. Due to single-gene mutations that lead to the lack of action by the satiety factor leptin or its cognate receptor, these rodents spontaneously develop severe hyperphagia leading to obesity and manifest some type 2 diabetes mellitus (T2DM)-like characteristics [18].
The wound healing activity of herbal products and their active constituents conducted on animals with induced diabetes are mainly based on the excision wound model and one study on the punch wound model [19]. The excision wound model is induced by the removal of some part of the skin at the depth of the epidermis and upper dermis (a partial thickness (or split-thickness) wound) or both epidermis and dermis up to the fascia or subcutaneous tissue (a full-thickness wound) [20]. Excision wounds well illustrate the skin defects that can be observed in diabetic wounds and allow the evaluation of re-epithelialization and wound closure. All herbal products and their active constituents (Tables 1-3) showed wound contraction in a shorter time, increased wound breaking strength, increased re-epithelialization, and better granulation compared to that of standard drugs (5% and 10% povidone-iodine, 1% silver nitrate, 1% silver sulfadiazine, 2% mupirocin, 8.5% mafenide, bacitracin) and commercially available wound dressings (Comfeel-hydrocolloid dressing, Kaltostat-alginate dressing) as positive controls.

Herbal Products and Their Active Constituents Loaded in Dressings Used for Diabetic Wound Healing
There is quite a lot of research on medicinal plant-based dressings for wound healing applications [81][82][83]. Some of them refer to diabetic wounds healing, including gauze, foams, drug-impregnated dressings (iodine, silver, polysaccharides), natural polymerbased dressing (hydrocolloids and hydrogel-based alginate, chitosan, collagen, cellulose), synthetic polymer-based dressings (poly (lactide-co-glycolide), polyurethanes, polyetheneglycols), and electrospun scaffolds [84]. Unfortunately, some types of traditional dressings can protect the wounds from the external environment but do not respond well to the wound-healing process. The most popular dressings for diabetic wounds based on herbal products and their active constituents are hydrogels, hydrocolloids, foams, and different nanofiber-based scaffolds (Table 3). Hydrogels consist of natural or synthetic polymers and up to 70% water. These structures maintain a moist wound environment, which significantly accelerates the regeneration of the epidermis, prevents the risk of necrotic tissue formation, stimulates the process of autolytic wound cleansing, and inhibits the development of pathogens, which reduces the risk of wound infection, allergic reactions, and pain in the wound [85]. The advantages of hydrogels translate into the popularity of their use in the treatment of diabetic wounds. It was shown that polysaccharides isolated from Periplaneta americana and loaded onto a hydrogel (carbomer 940, carboxymethyl cellulose) [69], Blechnum orientale extract in a hydrogel (sodium carboxymethyl-cellulose) [61], apigenin-loaded hydrogel (gellan gum-chitosan with polyethylene glycol as a cross-linker) [60], and hydroxysafflor yellow A and deferoxamine loaded into hydrogels (chitosan/gelatin) [65] effectively stimulated wound contraction.
Hydrocolloids can absorb minimal to moderate amounts of wound fluids, and they can prevent water, bacteria, and oxygen from entering into the wound, as well as reduce the pH of the wound, inhibiting bacteria growth [84]. Unfortunately, hydrocolloid dressings are not appropriate for deeper and infected wounds that need oxygen to increase the healing rate of the wound. Moringa oleifera aqueous leaf extract (0.5%)-loaded hydrocolloid film dressings had proven to be the most promising approach to accelerate the diabetic wound healing process in both full-thickness excisions and partial thickness abrasion wounds in the HFD/STZ-induced diabetic type 2 model with comparable activity to commercial Kaltostat dressings [16]. In addition, vicenin-2 hydrocolloid film (sodium alginate) enhanced diabetic wound healing through increased cell proliferation, migration, and wound contraction [71].
Foam dressings consist of a porous structure that is excellent for absorbing large amounts of exudates, providing occlusion, protecting against bacteria and other infectious agents, promoting autolysis debridement, permeability to gases and water vapors, and are easy to remove [86]. Gastrodia elata extract and tea tree EO loaded in foam dressing containing silk fibroin protein accelerated wound recovery and achieved full closure of the wound within 21 days [87]. Moreover, histological analysis of regenerated skin tissues indicated that foam dressings enhanced the generation of thicker, denser, and more abundant collagen fibers in the dermis layer in comparison with the positive and negative control groups.
Nanofiber-based scaffolds offer a large surface area-to-volume ratio to allow cell adhesion and increase their exudate-absorbing capacity, antibacterial properties, and encapsulation of drugs for the desired period which helps in achieving their controlled release [88]. This release-controlling property is not provided by any of the dressings mentioned above nor by existing novel drug delivery systems (e.g., liposomes, nanostructured lipid carriers, nanoparticles, and dendrimers) used for topical applications [84]. Recently, wound dressings based on electrospun nanofiber scaffolds have attracted researchers' attention since they replicate the characteristics of skin, have a high surface area-to-volume ratio, and tunable porous structure for easy nutrient infiltration and gas exchange [89]. Moreover, bilayer nanofibrous scaffolds reduce the frequency of dressing changes and minimize patients' discomfort. Curcumin-loaded poly (ε-caprolactone) nanofibers as diabetic wound dressing increased the rate of wound closure and sustained release of curcumin for 72 h [90]. In addition, curcumin loaded in chitosan nanoparticles impregnated into collagen-alginate scaffolds [62] and bilayer nanofibrous scaffolds containing curcumin and Lithospermi radix extract (gelatin/poly(vinyl alcohol) solution with curcumin electrospun onto chitosan scaffolds) [64] showed faster diabetic wound closure. Polyurethane-based nanofiber wound dressings containing Malva sylvestris extract improved diabetic wound healing better than gauze bandage-treated wounds [66]. H. perforatum oil gel-based electrospun nanofibers showed better wound healing activity than Aloe vera gel-based electrospun nanofibers [59]. It was also shown that Astragalus polysaccharide-loaded tissue engineering scaffolds mimicked the structure of extracellular matrices and restored skin microcirculation, and increased collagen synthesis, wound closure, and appendage and epidermal differentiation [67]. The use of the antimicrobial activities and wound healing properties of herbal products and their active constituents loaded in dressing is a promising approach in diabetic wound healing and requires further research.

Herbal Products and Their Active Constituents Used for Diabetic Wound Infections
Prolonged diabetic wound infections are a factor in the delayed wound healing process. Moreover, if infected diabetic wounds are not treated properly, they could lead to systemic infection, sepsis, and even death. Furthermore, diabetic foot infections are the main cause of leg amputation. Diabetic wounds are more prone to microbial infections than normal wounds due to the high levels of blood glucose in the wound fluids that allow microbes to grow rapidly [91]. It was shown that an infected diabetic wound is more difficult and longer to heal compared to an uninfected diabetic wound. Kandimalla et al. [34] observed that fungal-infected wounds were not healed for up to 21 days whereas in non-infected diabetic wounds were healed by this period. Histopathology of the wound showed a wide area of necrosis with no signs of wound healing in infected diabetic wounds compared to normal diabetic wounds. Therefore, it is very important to implement a strict program for the prevention and treatment of diabetic foot ulcers, as well as proper management of microbial infections.
Topical antimicrobial therapy is one of the most important methods of diabetic wound care. Herbal products and their active constituents are known to possess antimicrobial activity, even against resistant strains, making them a reliable source to combat diabetic wound infections [8,98]. Some researchers found that herbal products and their active constituents have strong antimicrobial activity against microorganism isolated from diabetic wounds or applied on infected diabetic wounds. It was found that quercetin and its esterified complex with 4-formyl phenyl boronic acid (4FPBA−Q) showed a remarkable effect against bacterial suspensions (1 × 10 5 CFU/mL) containing Gram-positive (S. aureus) and Gram-negative (P. aeruginosa, S. typhi) bacteria isolated from diabetic foot ulcers [99]. Malva sylvestris extract loaded in polyurethane/carboxymethylcellulose nanofibers showed antibacterial against S. aureus and E. coli [66]. The aqueous fraction of Moringa oleifera was found to be active against S. aureus, P. aeruginosa, and E. coli [41]. Hydrogels with water extracts of Blechnum orientale [61] and Quercus infectoria [100] was active against the MRSA strain. Curcumin-loaded electrospun nanofibers showed antibacterial activity against MRSA and ESBL Gram-negative bacteria [63]. An herbal ointment with ethanol extracts of Salvia kronenburgii and Salvia euphratica showed antibacterial activity against S. aureus, E. coli, A. baumannii, A. hydrophila, and M. tuberculosis, as well as antifungal activity against C. glabrata, C. parapsilosis, and C. tropicalis [48]. Besides bacterial infections, diabetic wounds are complicated by fungal infections. Candida species are the most common yeast that infects diabetic wounds which leads to delays in the wound healing process [101]. Cymbopogon nardus EO dispersed in olive oil attenuated the growth of fungi (C. albicans, C. glabrata, C. tropicalis) on chronic diabetic wounds and simultaneously reduced the inflammation which led to acceleration of the wound healing process [34].

Mechanism of Action of Herbal Products and Their Active Constituents Used for Diabetic Wound Healing
Wound healing involves a complex sequence of events involving cellular and biochemical processes including four overlapping phases; (1) homeostasis (coagulation which controls excessive blood loss from the damaged vessels) (few minutes); (2) inflammatory (influx of macrophages and proteases to clean up debris and pathogens, secretion of growth factors and pro-inflammatory cytokines) (0-3 days); (3) proliferative (fibroblast migration, extracellular matrix formation, granulation, re-epithelialization, neoangiogenesis) (3-21 days), and (4) maturation or remodeling that occurs within the dermis (collagen crosslinking and reorganization, increase in the tensile strength of the extracellular matrix, scar formation) (21 day-2 years) [4,102]. These overlapping phases of wound healing as well as their length in diabetes patients are disturbed. Diabetic patients have a reduced ability to metabolize glucose resulting in hyperglycemic conditions which further complicate the wound healing process [103]. Hypoxia due to glycation of hemoglobin, leads to the alteration of red blood cell membranes and the narrowing of blood vessels, which further leads to a deficient supply of nutrients and oxygen to the tissue [104]. This local ischemia due to microvascular complications in diabetes considerably delays the wound healing processes. Serum glucose concentrations of more than 150 mL/dL were considered indicative of immune system dysfunction and leads to long-term inflammatory disease [105]. Microvascular complications, irregular inflammatory responses, impaired angiogenesis, tissue oxidative stress, impaired production of cytokines and growth factors, reduction of nitric oxide, impaired keratinocytes and fibroblast migration and proliferation, and abnormal levels of matrix metalloproteinases are the main factors that disturb the diabetic wound healing process [4]. Herbal products and their active constituents, through different mechanisms of action, affect the cellular and biochemical processes occurring in the different phases of wound healing (Figure 2). through different mechanisms of action, affect the cellular and biochemical processes occurring in the different phases of wound healing (Figure 2).

Free Radicals and Oxidative Stress
Oxidative stress is caused by an increase in free radicals, reactive oxygen species (ROS), and/or reactive nitrogen species (RNS) in the body, which leads to intercellular biochemical dysregulation of the redox status [106]. The antioxidant system includes the major ROS-scavenging enzymes such as superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH), and prevents damaging effects of oxidative stress [107]. An imbalance of free radicals and antioxidants in the body results in the overproduction of ROS which leads to cell/tissue damage, inflammation, neuropathy, ischemic lesion, and topical infection, delaying diabetic wound healing [108]. Therefore, decreasing ROS levels through antioxidative systems may improve diabetic wound healing.
Herbal products and their active constituents are well known for their antioxidant activity [109,110]. Annona squamosal ethanolic extract promoted increased levels of enzymatic and non-enzymatic antioxidants in wound tissues, thus detoxifying free radicals to promote better wound healing in normal and diabetic rats [26]. An ointment containing luteolin (0.5% w/w) and the flavonoid fraction (0.5% w/w) isolated from Martynia annua [55], a resveratrol solution, resveratrol-loaded microparticles, and resveratrol-loaded microparticles impregnated in a dermal matrix [70] enhancing diabetic wound healing through free radical scavenging. Piper betel paste significantly decreased the oxidative stress markers such as SOD and expression of 11β-hydroxysteroid dehydrogenase type 1 (11b-HSD-1) in diabetic wounds compared to untreated diabetic wounds [44]. Apigenin from Morus alba loaded into a hydrogel effectively stimulated diabetic wound contraction with significant antioxidant activity through increased levels of SOD and CAT in granuloma tissue [60]. Pongamol and flavonoid-rich fractions from Tephrosia purpurea ointment stimulated diabetic wound healing through antioxidant activity by increasing SOD, CAT,

Free Radicals and Oxidative Stress
Oxidative stress is caused by an increase in free radicals, reactive oxygen species (ROS), and/or reactive nitrogen species (RNS) in the body, which leads to intercellular biochemical dysregulation of the redox status [106]. The antioxidant system includes the major ROSscavenging enzymes such as superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH), and prevents damaging effects of oxidative stress [107]. An imbalance of free radicals and antioxidants in the body results in the overproduction of ROS which leads to cell/tissue damage, inflammation, neuropathy, ischemic lesion, and topical infection, delaying diabetic wound healing [108]. Therefore, decreasing ROS levels through antioxidative systems may improve diabetic wound healing.
Herbal products and their active constituents are well known for their antioxidant activity [109,110]. Annona squamosal ethanolic extract promoted increased levels of enzymatic and non-enzymatic antioxidants in wound tissues, thus detoxifying free radicals to promote better wound healing in normal and diabetic rats [26]. An ointment containing luteolin (0.5% w/w) and the flavonoid fraction (0.5% w/w) isolated from Martynia annua [55], a resveratrol solution, resveratrol-loaded microparticles, and resveratrol-loaded microparticles impregnated in a dermal matrix [70] enhancing diabetic wound healing through free radical scavenging. Piper betel paste significantly decreased the oxidative stress markers such as SOD and expression of 11β-hydroxysteroid dehydrogenase type 1 (11b-HSD-1) in diabetic wounds compared to untreated diabetic wounds [44]. Apigenin from Morus alba loaded into a hydrogel effectively stimulated diabetic wound contraction with significant antioxidant activity through increased levels of SOD and CAT in granuloma tissue [60]. Pongamol and flavonoid-rich fractions from Tephrosia purpurea ointment stimulated diabetic wound healing through antioxidant activity by increasing SOD, CAT, and GSH levels [57]. Hydrogels with 4% w/w Blechnum orientale extract exhibited stronger antioxidant activity compared to standards (ascorbic acid, α-tocopherol, BHT as butylohydroksytoluen, and Trolox-C as an analog of vitamin E) and effectively treated diabetic ulcer wounds [61]. An herbal formulation of Cassia auriculata, Mangifera indica, Ficus banghalensis, Cinnamomum tamala, and Trichosynthis diocia) [32], a mixture of alcoholic herbal extracts (Plantago lanceolata, Arnica montana, Tagetes patula, Symphytum officinale, Calendula officinalis, Geum urbanum) loaded onto chitosan [45], ethanol extracts of Salvia kronenburgii and Salvia euphratica ointment [48], Cotinus coggygria ointments [33], Quercus infectoria formulations [51], and kaempferol ointments [52] showed significant antioxidant activity and improved diabetic wound closure.

Impaired Inflammatory Cell Response
An increase in glucose levels and free fatty acids promotes the activation of macrophagemediated inflammation in diabetes, contributing to the elevated production of pro-inflammatory cytokines [111]. M1-like macrophages with pro-inflammatory activity produce cytokines (IL-12, IL-1β, IL-6, TNFα, iNOS), while M2-like macrophages with anti-inflammatory activity are dominant in the proliferative phase of diabetic wound healing [112,113]. These recruit macrophages and immune cells that serve a pivotal role in orchestrating the appropriate healing of diabetic wound [114]. It was shown that macrophage dysregulation [115] and macrophage-derived IL-1β [116,117] lead to a prolonged inflammatory phase and impaired diabetic wound healing.

Impaired Growth Factors Production
Growth factors play a critical role in initiating and sustaining the different phases of wound healing [120]. Several growth factors that are released at the wound site are presumed to be necessary for wound healing such as transforming growth factor (TGF), epidermal growth factor (EGF), fibroblast growth factor (FGF), insulin-like growth factor (IGF), keratinocyte growth factor (KGF), platelet-derived growth factor (PDGF). and vascular endothelial growth factor (VEGF) [120]. The down-regulation of growth factor receptors and rapid degradation of growth factors leads to delayed wound healing in diabetics [121]. TGF-β recruits and promotes the stimulation of inflammatory cells including neutrophils, macrophages, and lymphocytes, as well as keratinocytes, fibroblasts, and induces the production of growth factors [122]. The reduced concentration of TGF-β has been reported in diabetic wounds [123]. EGF is associated with the systemic attenuation of pro-inflammatory markers and antioxidant effects in diabetic foot ulcer patients [124]. Moreover, EGF stimulates fibroblast replication, collagen formation, and re-epithelialization which promote diabetic wound healing [125]. Lack of FGF-7 [126] and KGF [127] inhibited cell proliferation and delayed diabetic wound healing.

Impaired Keratinocyte and Fibroblast Proliferation and Migration
During the proliferative phase of wound healing, keratinocytes (epidermal skin cells), endothelial cells (the primary vascular cell type), and fibroblasts (the primary cell type in connective tissues) proliferate, migrate, and differentiate, which enables the formation of granulation tissue, reconstitution of the dermal matrix, restoration of surface integrity, and promotion of wound closure [128]. These processes may be supported by herbal products and their active constituents. Ointments containing Aloe vera or Teucrium polium alone and in combination triggered diabetic wound healing through fibroblast proliferation and collagen deposition [24]. Topical application of Hypericum perforatum in olive oil showed significantly higher tensile strength, tissue hydroxyproline concentration, and collagen density compared to the control group [36]. Hypericum perforatum gel improved tissue regeneration by enhancing fibroblast proliferation and collagen synthesis [37]. Camellia sinensis extract increased collagen and fibronectin deposition [31]. Blechnum orientale hydrogel exhibited re-epithelialization and higher fibroblast proliferation and collagen synthesis [61]. Curcumin from Curcuma longa loaded into electrospun nanofibers stimulated wound closure with well-formed granulation tissue areas dominated by fibroblast proliferation, collagen deposition, rapidly regenerated epithelial layer, and formation of sweat glands and hair follicle tissues [63]. Polysaccharides from Astragali Radix loaded into tissue engineering scaffolds increased collagen synthesis, wound closure, and appendage and epidermal differentiation [67].

Impaired Angiogenesis
Angiogenesis (or neovascularization) is an essential part of the wound healing process consisting of the formation of a new capillary network (microvasculature) in response to hypoxia or other stimuli [129]. The hypoxic conditions in diabetes induce macrophages to secrete pro-angiogenic growth factors such as FGF, VEGF, and PDGF and cytokines, such as TGF-β and IL-1 that are involved in the control of various aspects of angiogenesis [130,131]. VEGF is one of the most important angiogenic factors in wounds and its production lies downstream of hypoxia and hyperglycemia. Hypoxia following injury activates hypoxia-inducible factor-1 (HIF-1), a transcriptional activator that promotes angiogenesis by upregulating target genes such VEGF-A [132], while hyperglycemia induces indirect VEGF overexpression mediated by TGF-β [133]. In addition, the upregulation of FGF and PDGF is associated with angiogenesis in diabetes and stimulates wound healing in diabetic mice [134].
It is well known that chronic, non-healing diabetic wounds are closely linked to poor vascular networks. Herbal products and their active constituents are a rich source of novel angio-modulators that may affect the angiogenesis process in diabetic wound healing [135]. Camellia sinensis extract promotes the angiogenesis process and vascular remodeling via molecular control of circulating hypoxia-responsive microRNAs: miR-424, miR-210, miR-199a, and miR-21 in diabetic and non-diabetic wounds [31]. Topical application of the aqueous fraction of Moringa oleifera enhanced wound healing in diabetic rats through upregulation of VEGF and accelerating the angiogenesis process [41]. Blechnum orientale hydrogels [61], Hypericum perforatum gels [37], Malva sylvestris extract nanofibers [66], Salvia kronenburgii and Salvia euphratica ointments [48], a mixture of Agrimonia eupatoria, Nelumbo nucifera, Boswellia carteri, and pollen from Typhae angustifoliae [119] improved tissue regeneration by revascularization. 20(S)-protopanaxadiol from Panax notoginseng accelerated wound closure through elevation of VEGF expression and capillary formation, and stimulation of angiogenesis via HIF-1α-mediated VEGF expression by activating p70S6K through PI3K/Akt/mTOR and Raf/MEK/ERK signaling cascades [17]. Arnebin-1 from Arnebia euchroma in an ointment promoted wound healing by a remarkable degree due to neovascularization through the synergetic effects of arnebin-1 and VEGF [19]. Hydroxysafflor yellow A from Carthamus tinctorius and deferoxamine loaded in chitosan/gelatin hydrogels exerted a synergistic effect on enhancing angiogenesis by upregulation of HIF-1α expression [65]. Polysaccharides from Astragali Radix loaded onto tissue engineering scaffolds restored skin microcirculation [67], while polysaccharides from Periplaneta americana loaded in hydrogels effectively accelerated wound healing through inflammation alleviation, angiogenesis, and macrophage polarization [69]. Kirenol from Siegesbeckia orientalis [53], pongamol and the flavonoid-rich fraction from Tephrosia purpurea in an ointment [57], and curcumin from Curcuma longa loaded onto electrospun nanofibers [63] affected vascularization and angiogenesis in diabetic wounds.

Conclusions
There are numerous animal-based studies and only a few clinical trials confirming the activity of herbal products and their active constituents in the stimulation of diabetic wound healing. Topical applications of herbal products and their active constituents in formulation or loaded in various dressings seem to be a good alternative for the treatment of diabetic wounds. The new dressings offer several beneficial properties, such as absorbing excess discharge from the wound, maintaining a moist environment conducive to healing, creating a protective barrier against bacterial penetration, being suitable for wounds with necrosis, and affecting the release of active ingredients over time, which can positively affect diabetic wound healing. Herbal products and their active constituents through different mechanisms of action, including antimicrobial, anti-inflammatory, and antioxidant activities, stimulation of angiogenesis and keratinocytes, production of cytokines and growth factors, and promotion of fibroblast migration and proliferation, may be considered as an important support during conventional therapy or even as a substitute for synthetic drugs used for diabetic wounds treatment.