Abstract
Diabetes mellitus is a prevalent cause of mortality worldwide and can lead to several secondary issues, including DWs, which are caused by hyperglycemia, diabetic neuropathy, anemia, and ischemia. Roughly 15% of diabetic patient’s experience complications related to DWs, with 25% at risk of lower limb amputations. A conventional management protocol is currently used for treating diabetic foot syndrome, which involves therapy using various substances, such as bFGF, pDGF, VEGF, EGF, IGF-I, TGF-β, skin substitutes, cytokine stimulators, cytokine inhibitors, MMPs inhibitors, gene and stem cell therapies, ECM, and angiogenesis stimulators. The protocol also includes wound cleaning, laser therapy, antibiotics, skin substitutes, HOTC therapy, and removing dead tissue. It has been observed that treatment with numerous plants and their active constituents, including Globularia Arabica, Rhus coriaria L., Neolamarckia cadamba, Olea europaea, Salvia kronenburgii, Moringa oleifera, Syzygium aromaticum, Combretum molle, and Myrtus communis, has been found to promote wound healing, reduce inflammation, stimulate angiogenesis, and cytokines production, increase growth factors production, promote keratinocyte production, and encourage fibroblast proliferation. These therapies may also reduce the need for amputations. However, there is still limited information on how to prevent and manage DWs, and further research is needed to fully understand the role of alternative treatments in managing complications of DWs. The conventional management protocol for treating diabetic foot syndrome can be expensive and may cause adverse side effects. Alternative therapies, such as medicinal plants and green synthesis of nano-formulations, may provide efficient and affordable treatments for DWs.
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Introduction
Diabetes is a complex metabolic disorder that affects a vast number of people worldwide, with more than 340 million individuals currently living with it. Unfortunately, over 20% of these individuals suffer from diabetes-related injuries, with the most common being leg or foot ulcers (World Health Organization 2014). The ability of people with diabetes to metabolize glucose is significantly impaired, and hyperglycemic conditions make the process of wound healing even more challenging. This often results in persistent and delayed injuries, which can have a significant impact on the quality of life. Unfortunately, the incidence of delayed healing in people with diabetes is increasing globally due to a lack of preventative and control measures.
This is a significant concern as approximately 2.5% to 15% of the global health budget is spent on diabetes mellitus annually, and diabetic wounds account for a significant proportion of this expenditure. According to a World Health Organization (WHO) study, diabetes could become the 7th leading cause of death by 2045. In 2014, around 9% of the global population suffered from diabetes, and this condition caused the death of 1.5 million patients in 2012 alone. Unfortunately, more than 80% of diabetes-related fatalities occur in low- and middle-income countries (World Health Organization 2013, 2014). One of the most significant risks of diabetes is the development of wounds in the legs and feet. These injuries can damage the skin, soft tissues, and even the bones, which can lead to an increased risk of infections in diabetic patients. In severe cases, amputations of the lower limbs may be necessary. Recent studies have revealed that around 60–80% of these wounds are capable of healing, but 10–15% of them may remain active, and 5–24% may ultimately result in leg amputations. It is crucial for diabetic patients to take measures to prevent such wounds from occurring, such as adopting a healthy lifestyle, monitoring blood glucose levels regularly, and seeking timely medical attention if any signs of injury or infection arise.
Proper care and management can minimize the risk of complications and improve the overall quality of life for people with diabetes (Vijayakumar et al. 2019; Talukdar et al. 2021; Yadav et al. 2022d). Diabetic wounds pose a significant health risk to individuals living with diabetes. In fact, more than 85% of all amputations in diabetic patients are preceded by ulceration that progresses to severe gangrene or infection. Shockingly, diabetic ulcers are estimated to affect around 6.4% of the world's population, with annual incidence rates ranging from 2 to 5% (Brocco et al. 2018; Adeleke et al. 2022; Ansari et al. 2022b). The prevalence of diabetic wound disease is alarming, as it is estimated that between 19 and 34% of diabetes patients may suffer from this condition at some point in their lives. It is particularly prevalent in males, with 4.5% of men being affected, compared to 3.5% of women. Additionally, patients with type II diabetes (T2DP) are more likely to develop diabetic wounds, with 6.4% of cases compared to only 5.5% of cases in patients with type I diabetes (T1DP) (Talukdar et al. 2021).
Despite the high prevalence of diabetic wounds, epidemiological studies on this condition remain limited. This underscores the need for a more comprehensive and detailed understanding of the global impact of diabetic foot, which would be instrumental in devising effective prevention and treatment strategies. Improved healthcare practices and early intervention can minimize the financial burden on diabetic patients and promote better health outcomes (Zhang et al. 2017b; Yadav et al. 2022a). To accelerate the healing process of diabetic foot ulcerations, various interventions, such as control blood glucose level, wound debridement, off-loading pressure therapy, wound dressings, negative pressure wound therapy, hyperbaric oxygen therapy chamber, antibiotic therapy, platelet-rich plasma therapy, laser therapy, electrical stimulation therapy, growth factor therapy, stem cell therapy, bioengineered skin substitutes, and in extreme situations surgery, have been implemented (Alexiadou and Doupis 2012; Bekele and Chelkeba 2020).
In many countries, treating diabetic wound (DWs) through conventional methods is difficult due to its high cost, undesirable side effects, and shortage of vascular surgeons. This issue is particularly challenging in developing nations. As a result, there has been a growing interest in finding alternative remedies, such as medicinal plants, and their active constituents to help manage and prevent DWs complications (Ahmadian et al. 2021; Ansari et al. 2022a). Herbal remedies have been used for centuries to treat various ailments, including diabetes and diabetic wounds. With advances in modern research, we now have a better understanding of the pharmacological properties of phyto-compounds, the active compounds found in plants that can be effective for preventing and treating DWs conditions (Arumugam et al. 2013; Gaonkar and Hullatti 2020; Ansari et al. 2022a). Various plants including, Globularia Arabica, Rhus coriaria L., Neolamarckia cadamba, Olea europaea, Salvia kronenburgii, Moringa oleifera, Syzygium aromaticum, Combretum molle, Myrtus communis, Terminalia chebula, Stryphnodendron adstringens, Euphorbia hirta Linn., Aloe Vera, Azadirachta indica, Teucrium polium, Gynura procumbens, Quercus infectoria, Pimpinella anisum, Punica granatum, Cycas thouarsii, and Ocimum sanctum, have demonstrated potential for treating diabetic wounds by exhibiting anti-inflammatory, antimicrobial, antioxidant, and antibacterial, stimulating the blood coagulation and other anti-diabetic properties. These plants are relatively safe and have little-to-no side effects, suggesting that they may be effective treatments for diabetic wounds and speed up healing (Oguntibeju 2019; Sharma et al. 2021a; Vitale et al. 2022). Numerous natural compounds, such as quercetin, pongamol, neferine, plumbagin, luteolin, kirenol, kaempferol, arnebin-1, 20(S)-protopanaxadiol, myricetin, rutin, mangiferin, ginsenoside Rb1, berberine, and curcumin, have been isolated from plants and possess the potential to promote diabetic wound healing. These compounds can be utilized as an effective treatment throughout various stages of the wound-healing process, and there are numerous reports in the literature supporting their efficacy (Ansari et al. 2022b; Herman and Herman 2023). Clinical trials investigating the use of natural products in combination with modern drugs, as well as the development of improved delivery mechanisms, show great promise as a significant area for drug discovery from natural products. This represents an exciting avenue for the advancement of research in the field (Amirah et al. 2022).
The objective of this review article is to investigate the potential of traditional medicinal plants and their isolated phyto-compounds in the prevention and management of diabetic foot syndrome, as well as to analyze their future prospects as anti-diabetic medications.
Diabetic wounds (DWs)
DWs are a common type of skin injury that occurs in individuals with diabetes. Due to factors such as impaired blood flow and diabetic neuropathy, these wounds can be slow to heal and can lead to serious complications, such as infections and even amputation. Proper wound care, controlling blood sugar levels, off-loading, infection control, debridement, and wound closure are all essential components of treatment. Detecting and treating diabetic wounds early are vital to prevent further complications (Patel et al. 2019; Burgess et al. 2021). In DWs, persistent infections and microbial films are typical, and they are often associated with age, venous ulcers, high blood pressure, obesity, and diabetes (Avishai et al. 2017; Yadav et al. 2022c). The inflammatory phase in these wounds is disrupted, leading to an increase in neutrophils which release MMPs, creating an overabundance of reactive oxygen species (ROS), such as peroxide anion, hydroxyl ion, and superoxide anion (Sahakyan et al. 2022). This, in turn, leads to the destruction of ECM components, such as collagen, fibronectin, and vitronectin, along with an increase in inflammatory cytokines due to the excessive increase in pro-inflammatory macrophages, further maintaining the inflammatory phase (Zhao et al. 2016; Spampinato et al. 2020). Keratinocytes are hyperproliferative in diabetic wounds, but angiogenesis is compromised, and re-epithelialization is challenging. Managing these wounds requires a multi-faceted approach that addresses the various factors that contribute to their development and slow healing (Hosseini Mansoub 2022; Fang and Lan 2023). Illustration of the DWs is shown in Fig. 1.
In diabetic wounds, persistent inflammation and infections are common. Additionally, these wounds may exhibit hyperproliferative epidermis, fibroblast senescence, impaired migration, and elevated levels of matrix metalloproteinase. Abbreviations: IL-7, interlukin-7; IL-17, interlukin-17; MMPs, matrix metalloproteinase; ROS, reactive oxygen species; TNF-α, tumor necrosis factor-α
Pathophysiology of diabetic wound
Diabetic wound healing requires harmonious interplay between biochemical mediators, inflammatory cells. This harmonious metastasis is triggered by various factors. The main contributors to this process are cellular macrophages derived from monocytes, which function as the primary sources of key pro-inflammatory cytokines. These cytokines, such IL-1β, IL-6, IGF-1, TGF-β, TNF-α, and VEGF, play pivotal roles in both normal wound healing and the distinct healing processes observed in diabetic condition (Veves et al. 2012). The detailed pathophysiology of DWs is explained through the schematic representation in Fig. 2.
Schematic representation of the pathophysiology of DWs. Abbreviations: AGE, advanced glycation end-products; FFAs, free fatty acids; IL, interleukin; LDL, low-density lipoprotein; LOX-1, lectin-like oxidized low-density lipoprotein receptor-1; MMP-9, matrix metalloproteinase-9; NF-kB, nuclear factor kappa-B; RAGE, receptor for advanced glycation end-products; ROS, reactive oxygen species; STAT-1, signal transducer and activator of transcription-1; TLR4, toll-like receptor 4; TNF-α, tumor necrosis factor-α; UDP-GlcNAc, uridine diphosphate N-acetylgalactosamine; VEGF, vascular endothelial growth factor
DWs manifest as an intricate interplay of numerous factors, encompassing complications like diabetic neuropathy (DN), peripheral vascular disease (PVD), retinopathy, myopathy, and nephropathy. This intricate mechanism involves deficiencies in the angiogenic response, impaired functioning of neutrophils and macrophages, the generation of pro-inflammatory cytokines, and microvascular complications such as atherosclerosis. Additionally, compromised production of growth factors, hindered proliferation, and migration of fibroblasts and keratinocytes occur in diabetic wound-healing models. The cascade of events encompasses the blockade of nitrous oxide, inflammatory dysfunction of cells, hyperglycemia, hemoglobin glycation, impairment in cytokine production, dysfunction of MMPs, impaired collagen accumulation, down-regulation of neuropeptide expression, and an inflammatory response. Furthermore, there is a deficiency in the fibrinolysis inhibitor, pDGF modification, reduced epidermal nerve levels, and an imbalance between the ECM and MMPs (Yadav 2023).
Complications in diabetic wound
DWs are a significant contributor to diabetic wounds, often causing a delayed healing process that impacts patients' daily lives, morbidity, and mortality. These wounds can be categorized as delayed acute or chronic wounds, which compromise the healing process, resulting in impaired tissue generation. Diabetes also causes recurrent inflammation, hindering the development of mature granulation tissue and decreasing wound tensile strength, often attributed to ischemia-induced vascular disruption (Singh et al. 2023). It is essential to provide immediate treatment for all wounds, as they can be classified as either external or internal. External wounds, such as cuts, burns, bruises, and fractures, can go unnoticed in diabetic patients due to peripheral neuropathy. In contrast, internal wounds, such as ulcers and calluses, pose a high risk of bacterial infection, leading to tissue and skin damage (Petkovic et al. 2020; Fang and Lan 2023). Some of the factors responsible for DWs development are summarized in Fig. 3.
Factors responsible for diabetic wound
Diabetic wound mechanistic insight
Diabetes-related non-healing wounds can lead to a range of issues, including mental health concerns, such as anxiety and depression, functional limitations, difficulty with walking, and infection, which can manifest as cellulitis, abscesses, osteomyelitis, gangrene, and septicemia (Alsaimary 2010). While it is known that diabetic wound healing is impaired, the exact relationship between pathophysiology and wound healing in diabetes is still unclear. The healing process requires the cooperation of irritant cells and biochemical mediators. However, in diabetic patients, changes in cellular and metabolic processes and activities have been linked to the inability to heal wounds (Casqueiro et al. 2012).
Wound healing is a complex process that involves various cell types working together to repair the wound. These cells produce and regulate a range of cytokines and growth factors, including IL-1β, TNF-α, IL-6, VEGF, IGF-1, and TGF-β (Han et al. 2018). Monocytes, which eventually differentiate into macrophages, are responsible for the production of these factors in both diabetic and non-diabetic individuals. In addition to T-cells and B-cells, neutrophils also play a crucial role in producing TNF-α and IL-10. Other cell types, such as keratinocytes, fibroblasts, and mast cells, are also involved in the wound-healing process. The synthesis of VEGF, IGF-1, and TGF-β by these cells is equally important for effective wound healing (Babaei et al. 2013). Macrophages play a crucial role in the wound-healing process. However, changes in blood glucose levels and oxidative stress can cause alterations in the epigenetic coding, leading to changes in macrophage polarization and their control over this process. Dysregulated macrophage polarization is a primary cause of delayed wound healing (Maruyama et al. 2007; Basu Mallik et al. 2018). In diabetic individuals, wound healing is delayed due to complex chemical processes at the cellular level. Diabetic animal models have shown disruptions in healing-related factors such as growth factor production (Alavi et al. 2014). Activities, such as sustained production of pro-inflammatory cytokines, reduced angiogenic response, and microvascular complications, have also been reported in diabetic animal models (Loots et al. 2002). When it comes to the healing of diabetic wounds, a range of factors can impede the process. These include metabolic abnormalities, altered physiological responses, such as hypoxia resulting from glycation of hemoglobin and changes to red blood cell membranes, and the constriction of vascular passages (Brem and Tomic-canic 2007). Hypoxia occurs due to restricted blood flow, leading to a reduction in oxygen supply to the wound site. Hemoglobin glycation also reduces the availability of oxygen and nutrients to the affected tissue, leading to longer healing times (Avishai et al. 2017). The accumulation of unfolded proteins in the endoplasmic reticulum (ER) triggers a stress response in cells, known as unfolded protein response-8 (UPR8). This activation of unfolded protein response (UPR) is associated with the generation of pro-inflammatory mediators after tissue or skin damage. In diabetic wounds, the activation of UPR is prolonged compared to normal wounds, leading to increased production of pro-inflammatory chemokines (Schürmann et al. 2014). A summary of diabetic wound-healing mechanistic insights is illustrated in Fig. 4.
Diagrammatical schematic representation of diabetic wound healing mechanistic insights. Abbreviations: AMPK, adenosine monophosphate activated protein kinase; AKT, protein kinase B; ERK, extracellular signal-regulated kinase; FGF-1, fibroblast growth factor; GTP, guanosine triphosphate; GDP, guanosine diphosphate; IGF-1, insulin-like growth factor-1; IL-6, interleukin-6; IL-1β, interleukin-1β; mTORC1, mammalian target of rapamycin complex 1; MMPs, matrix metalloproteinase; MEK, mitogen-activated protein kinase; Ras, rat sarcoma virus; Raf, rapidly accelerated fibrosarcoma; RSK, ribosomal S6 kinase, ROS, reactive oxygen species; PI3K, phosphatidylinositol 3 kinase; Rheb, ras homolog enriched in brain; TNF-α, tumor necrosis factor-α; TGF, transforming growth factor; TGF-β, transforming growth factor-β; UPR, unfolded protein response; VEGF, vascular endothelial growth factor
Microvascular problems in diabetes can significantly slow down the process of wound healing. miRNAs, which are noncoding RNAs of 19–24 nucleotides, play a crucial role in a wide range of physiological activities. Altered levels of miRNAs have been linked to disturbed wound healing and a variety of illnesses (Moura et al. 2014). Hence, one of the miRNAs, MiR-210, is elevated in hypoxia and targets E2f3, which inhibits keratinocyte proliferation during wound healing (Biswas et al. 2010). Another miRNA, MiR-200b, targets globin transcription factor-2 (GTF-2) and vascular endothelial growth factor receptor-2 (VEGFR-2), inhibiting angiogenesis. There are several types of miRNAs like miR-21, miR-130a, miR146a, miR-198, and miR-26 involved in diabetic wounds that regulate various processes, such as epithelialization, keratinocyte migration, fibroblast migration, re-epithelialization, and angiogenesis (Bhattacharya et al. 2015; Icli et al. 2016).
Diabetic patients often experience slow healing of wounds, and there are various factors that contribute to this phenomenon. Physiological factors, such as increased levels of serum MMP-9, impaired collagen accumulation, variation in collagen types, dysregulated neuropeptide expression in the skin, suppressed inflammatory response, deficiency of thrombin-activatable fibrinolysis inhibitor (Verkleij et al. 2010), and AGE11 modification of pDGF (Nass et al. 2010), are some of the factors responsible for delayed wound healing (Pradhan et al. 2011; Li et al. 2013). Furthermore, diabetic patients may also have decreased epidermal nerves, impaired epidermal barrier function, and an imbalance between the accumulation of ECM components and their remodeling by matrix metalloproteinase, which can also contribute to slow wound healing (Nass et al. 2010; Gooyit et al. 2014).
Treatment strategies for diabetic wound
Conventional therapies for DWs’ complications
DWs are a common and challenging complication of diabetes mellitus, affecting an estimated 25% of patients with diabetes during their lifetime. These wounds often have poor healing rates, leading to prolonged hospital stays, increased healthcare costs, and decreased quality of life for patients. The treatment of diabetic wounds is complex and often requires a multi-faceted approach. In this study, we will review the current treatment strategies for diabetic wound complications, based on the available literature. It is important to note that the specific treatment plan for diabetic wound complications may vary depending on the individual patient's condition and the severity of the wound. A healthcare professional will typically assess the wound and develop a personalized treatment plan based on the patient's needs. Table 1 summarizes an overview of the conventional therapies for diabetic wound healing, including their description, benefits, and drawbacks.
Control blood glucose levels
Control of blood sugar levels is the cornerstone of DWs management. Elevated blood sugar levels can impair wound healing by decreasing collagen synthesis, impairing angiogenesis, and promoting oxidative stress. Medication, diet, and exercise are all essential components of blood sugar control in DWs care (Wang et al. 2023). Metformin, and other oral hypoglycemic drugs are commonly used medications for diabetes, which have been shown to improve wound healing by reducing inflammation and promoting angiogenesis. Insulin therapy is also commonly used to manage hyperglycemia in diabetic patients with wounds. Diet and exercise modifications can help control blood sugar levels and improve wound healing (Liu et al. 2022). A balanced diet rich in protein, vitamins, and minerals is essential for wound healing. Exercise has been shown to improve circulation and promote wound healing in patients with diabetes.
Metformin therapy
Metformin is a medication commonly used to treat type 2 diabetes. While its primary use is to help control blood sugar levels, some studies suggest that it may also have benefits for wound healing in people with diabetes. Metformin has been shown to have anti-inflammatory properties and may improve blood flow to damaged tissues, which could potentially aid the healing process (Shi et al. 2022a). Some studies have also suggested that metformin may have antibacterial, anti-inflammatory, and diabetic wound-healing properties, which could help prevent infections in wounds.
Han et al. (2017) investigated wound healing, angiogenesis, and the number of circulating endothelial precursor cells (EPCs) in db/db mice, and the impact of metformin treatment on these parameters. Metformin therapy in these mice led to faster wound healing, improved angiogenesis, and increased circulating EPCs. The in-vitro experiments revealed that metformin treatment improved the function of bone marrow‑derived EPCs (BM-EPCs) isolated from db/db mice, as shown by enhanced tube formation and NO production, and decreased levels of O2.− Furthermore, metformin therapy significantly decreased the expression of TSP-1 in cultured BM-EPCs. These results suggest that metformin treatment may promote wound healing and angiogenesis in T2DM by stimulating NO production and inhibiting O2− and TSP-1 expression and inflammation in EPCs isolated from db/db mice (Han et al. 2017). In an another study, Cam et al. (2021) evaluated the efficacy of incorporating pioglitazone, metformin, and glibenclamide into chitosan/gelatin/polycaprolactone and polyvinyl pyrrolidone/PCL composite nano-fibrous scaffolds for diabetic wound healing. The combination therapy resulted in the formation of hair follicles and improved regeneration of the dermis and epidermis in type-1 diabetic rats, while also reduced inflammatory cell infiltration and edema compared to single drug-loaded scaffolds. Furthermore, the combination therapy increased scaffold wettability and hydrophilicity, sustained drug release, and demonstrated high tensile strength and cyto-compatibility (Cam et al. 2021). Furthermore, Du et al. (2023) suggested that metformin (MTF) can work in coordination with mesenchymal cells (MSCs) to promote angiogenesis and wound healing in diabetic patients. The researchers found that MTF treatment activated the Akt/mTOR signaling pathway in MSCs, which in turn led to increased production of VEGF. VEGF is a key factor in promoting the growth of new blood vessels, which is essential for proper diabetic wound healing (Du et al. 2023).
Insulin therapy
Insulin has been found to accelerate wound healing by controlling oxidative and inflammatory reactions. In rats with burn wounds, insulin therapy has been shown to decrease the levels of reactive oxygen species that can cause harm to lipids, proteins, and deoxyribonucleic acid (DNA) (Dhall et al. 2015). Additionally, insulin treatment has been observed to raise the levels of M2 macrophages and interleukin-10, leading to an anti-inflammatory effect that facilitates the removal of necrotic tissue from the wound (Chen et al. 2012). In addition, Vatankhah et al. (2017) investigated whether different diabetic treatment regimens have an impact on the healing of DWs. The researchers followed 107 diabetic foot ulcers in 85 patients until the wounds had healed, amputation was required, or a non-healing wound developed. The study found that insulin therapy significantly increased the wound-healing rate compared to other diabetic treatment regimens. After adjusting for multiple confounding co-variates, they also found that systemic insulin treatment can improve wound healing in DWs. The authors concluded that insulin therapy should be considered as a part of diabetic management for patients with DWs (Vatankhah et al. 2017). Furthermore, Yang et al. (2020a, b) demonstrated that the insulin-containing dressing could promote re-epithelialization, angiogenesis, and the deposition of extracellular matrix, specifically collagen, leading to accelerate wound healing. The researchers also found that HIF-1α, an important regulator of wound healing, was stable and accumulated in wound cells treated with the insulin-containing dressing, but was significantly unstable in the control group. Furthermore, the study showed that insulin could counteract the destabilization of HIF-1α caused by methylglyoxal (MGO), a major form of AGEs in the diabetic state. Insulin facilitated the expression of HIF-1α target genes, promoting angiogenesis and extracellular matrix deposition, which are critical to wound healing (Yang et al. 2020a).
Wound debridement
Wound debridement is another essential component of diabetic wound care. Debridement is the removal of dead or infected tissue from the wound to promote healing. Surgical, mechanical, and enzymatic debridement are all effective methods of wound debridement (Bellingeri et al. 2016). Surgical debridement is the most invasive and is typically reserved for wounds with a significant amount of necrotic tissue. Mechanical debridement involves the use of a dressing or irrigation to remove dead tissue. Enzymatic debridement involves the application of topical enzymes to the wound to break down necrotic tissue (Haycocks and Chadwick 2012; Lázaro-Martínez et al. 2020) A retrospective study of patients with DWs treated for biofilm-associated infections found that sharp debridement combined with meshed skin grafts and negative pressure wound therapy (NPWT) resulted in a mean wound-healing time of 3.5 ± 1.8 weeks (Namgoong et al. 2020). Further analysis of debridement modalities found that surgical debridement was associated with shorter healing time, but there is a lack of strong evidence to support its efficacy in promoting wound healing (Elraiyah et al. 2016). However, various studies in both porcine and human models have shown that enzymatic debridement is another effective form of debridement that may reduce wound size, decrease inflammation, and increase granulation tissue. However, a secondary dressing may be required to penetrate the deeper layers of the wound to effectively control the biofilms present (Davis et al. 2017). Moreover, hydro-active dressings soaked with polyhexamethylene biguanide have shown promising results in promoting macrophage activation in the wound, inhibiting bacterial proliferation, and reducing inflammation in human studies (Mancini et al. 2017; Johani et al. 2018; Bain et al. 2020). In summary, while sharp debridement combined with meshed skin grafts and NPWT is effective in promoting wound healing in patients with DWs, other forms of debridement such as enzymatic debridement may also be effective. The use of hydro-active dressings soaked with polyhexamethylene biguanide is also a promising approach to promote wound healing and reduce inflammation.
Off-loading pressure therapy
Off-loading pressure therapy is also an essential component of DWs care. DWs often occur on the feet and can be exacerbated by pressure from walking or standing. While casting and non-removable walkers have traditionally been the go-to options for reducing plantar pressures in patients with diabetes, "diabetes footwear" has emerged as a promising alternative (van Netten et al. 2018). This type of footwear, including shoes and insoles designed to alleviate stress on the foot, has been shown to effectively reduce plantar pressures in a recent review and meta-analysis. The study highlighted the importance of features, such as metatarsal additions, apertures, and arch profiles for optimal results (Collings et al. 2021). Aside from footwear modifications, surgical off-loading is a viable option for patients suffering from diabetic foot ulcers (Ahluwalia et al. 2021). Achilles tendon release and foot reconstruction are two examples of surgical procedures that aim to optimize the foot for long-term off-loading. Studies have suggested that surgical off-loading may result in significantly better healing and amputation rates compared to non-surgical treatments. However, specialized footwear, custom orthotics, or a wheelchair/crutches can all be used to reduce pressure on the wound site and promote healing (Yammine and Assi 2022).
Wound dressings
The treatment and care of DWs present a significant global challenge due to their high amputation, recurrence, and mortality rates. Wound dressings have become a crucial aspect of DWs treatment, and continuous innovation has led to the development of advanced wound dressings with remarkable properties (Wang et al. 2021a). Among these, hydrogel, alginate, hydrocolloid, and foam dressings have gained popularity due to their exceptional moisture retention, biocompatibility, and therapeutic capabilities. In recent years, the pathogenesis of DWs has been better understood, leading to the development of functionalized dressings that have shown promising results in treating DWs. These advancements have brought significant benefits to the management and improvement of DWs (Ribeiro et al. 2009; Wang et al. 2021a).
Hydrogel dressings
The unique potential of hydrogels for effective DWs dressing development lies in their remarkable ability to retain oxygen, absorb wound exudate, and maintain the moist environment that supports normal physiological processes in the wound bed (Kumar et al. 2017a). Moreover, hydrogels have shown promising results as antimicrobial substrates that help avoid tissue death and accelerate regular wound repair, and their porous structure promotes adequate exchange of gases, allowing the wound to breathe throughout wound healing and closure (Güiza-Argüello et al. 2022). For instance, Lei et al. (2017) evaluated the ability of collagen hydrogels to promote angiogenesis and wound healing in diabetic rat models. Toward this, full-thickness wounds were induced and externally treated with a collagen hydrogel loaded with recombinant human epidermal growth factors. After 14 days of treatment, the rats treated with the fabricated hydrogel showed significantly smaller wound areas, indicating accelerated injury regeneration, relative to the group that did not receive a hydrogel treatment. Regarding angiogenesis, the proposed hydrogel dressing supported endogenous collagen synthesis, as well as the formation of vascularized scar tissue (Lei et al. 2017). In addition, Nilforoushzadeh et al. found that the use of pre-vascularized collagen/fibrin hydrogels on DWs patients resulted in increased hypodermis thickness and an accelerated wound-healing process (Nilforoushzadeh et al. 2020).
Alginate hydrogel dressings
Alginate is a substance that has been extensively studied for its potential applications in tissue repair. One of its key properties is its ability to facilitate the attachment and activation of platelets and erythrocytes, which are crucial for wound healing. Alginate has been used to immobilize cells, enzymes, and peptides, and as a supporting matrix for drug delivery systems. Another advantage of alginate is that it is hydrophilic, which means that it can provide a moist environment that supports wound re-epithelialization and reduces the risk of bacterial infection (Sharmeen et al. 2019). Tellechea et al. (2015) investigated the use of alginate hydrogels to encapsulate anti-inflammatory substances: Substance P and Neurotensin, as well as human umbilical cord-derived outgrowth endothelial cells. The study used a mouse model of diabetes and found that the alginate hydrogels allowed continuous release of neuropeptides over a period of 10 days. This led to a significant reduction in wound size by approximately 80%. Furthermore, the addition of VEGF to the hydrogel improved and accelerated wound healing, resulting in a 40% decrease in wound size just after 4 days of treatment. These findings indicated a synergistic effect of the combination therapy, which supported the formation of new blood vessels (neovascularization) and promoted wound healing (Tellechea et al. 2015).
Hydrocolloid dressings
Hydrocolloid dressings are occlusive dressings usually composed of a hydrocolloid matrix bonded onto a vapor-permeable film or foam backing. When in contact with the wound surface, this matrix forms a gel to provide a moist environment. Takeuchi et al. (2020) investigated the efficacy of hydrocolloid dressings combined with hydrogel in treating wounds in diabetic mice. The study revealed that the hydrogel treatment facilitated the formation of new blood vessels (angiogenesis) at the wound site. Moreover, the treatment boosted the proportion of macrophages with M2 polarization, which are known to support tissue repair and healing. As a result, there was an increase in the proliferation of fibroblasts, which are essential for wound healing. The study concluded that the use of hydrocolloid dressings with hydrogel can be an effective approach to promote the healing of non-infected DWs, even in the presence of high blood sugar levels (Takeuchi et al. 2020).
Negative pressure wound therapy (NPWT)
NPWT is a treatment approach used in the management of wounds, whether acute or chronic, for both short- and long-term care. NPWT involves the use of a specialized dressing that applies negative pressure to the wound bed, which can facilitate the removal of excess fluid, reduce inflammation and swelling, and promote the development of granulation tissue. These factors can lead to an acceleration of the healing process (Ji et al. 2021). In addition, Liu et al. (2017) performed a meta-analysis of randomized controlled trials to assess the effectiveness, safety, and cost-effectiveness of NPWT in treating lower leg ulcers caused by vascular issues, such as DWs. The results showed that NPWT had a positive impact on healing time and was well tolerated by patients, suggesting it as a promising therapeutic option for DWs (Liu et al. 2017). In an analysis of 11 trials, it was observed that NPWT was more effective than standard dressings in promoting complete ulcer healing, accelerating wound healing, and reducing wound surface area, without a substantial increase in adverse events. Similarly, Wynn and Freeman's (2019), extensive review found that NPWT was superior to standard treatment for treating DWs (Wynn and Freeman 2019). NPWT is typically continued as part of standard medical practice. It is important to note that NPWT may have additional benefits beyond promoting wound healing. Patients treated with NPWT showed earlier achievement of discharge criteria and the formation of granulation tissue, as well as significant reductions in leukocyte count, discomfort, and systemic inflammatory response (Gonzalez et al. 2017). There is ongoing debate about the impact of NPWT on tissue perfusion and oxygenation, as the results of various research methods have been inconsistent. While laser Doppler and thermal imaging have shown increased blood flow during NPWT (Wackenfors et al. 2005; Kairinos et al. 2013), transcutaneous partial oxygen pressure measurements have revealed a significant reduction in tissue oxygenation levels in DWs (Jung et al. 2016). However, this decrease in tissue oxygenation may actually be beneficial, as relative ischemia can stimulate neovascularization.
Hyperbaric oxygen therapy chamber (HOTC)
HOTC involves breathing pure oxygen in a pressurized chamber to increase oxygen delivery to the wound site and promote healing. This therapy stimulates tissue growth and reduces the risk of infection, but it can be expensive and requires specialized equipment. According to recent studies, HOTC may have beneficial effects on patients with Wagner grade 3 and 4 ulcers, resulting in improved levels of HbA1c, leukocytes, and serum creatinine. However, it should be noted that there is a limited number of high-quality studies available on the use of HOTC for this purpose (Erdoğan et al. 2018). A meta-analysis conducted by Sharma et al. (2021a, b), has demonstrated a positive correlation between HOTC and improved rates of complete healing of DWs, as well as a reduction in the incidence of major amputations. However, the analysis did not show a significant decrease in the rates of minor amputations, overall amputations, or mortality, and the average ulcer percentage did not show improvement. Additionally, it was found that the HOTC group experienced more side effects compared to the group receiving conventional therapy. Thus, caution should be exercised when using HOTC in the treatment of DWs. Furthermore, there is an urgent need for well-designed, adequately sized, multicenter studies using rigorous methodology to assess the efficacy and safety of HOTC as an adjunctive therapy for DWs (Sharma et al. 2021b). A small-scale study consisting of 17 patients revealed that HOTC led to an increase in levels of VEGF, IL-6, insulin-like growth factor binding protein-3, fibrosis, angiogenesis, and adiponectin, while decreasing IFN-γ levels. Additionally, the therapy caused the NF-κB to localize and resulted in translocation of HIF-1α into the cytoplasm (Burgess et al. 2021). Furthermore, studies have demonstrated that prolonged HOTC treatment reduces neutrophil recruitment and adhesion, enhances oxygen dispersion to damaged tissues, diminishes inflammation, and modulates the healing process in patients with DWs (Chen et al. 2017; Baiula et al. 2020).
Antibiotics
Antibiotic treatment is often utilized as an adjunctive therapy in the management of DWs healing. Diabetic patients are particularly susceptible to bacterial infections, which can delay the healing process and increase the risk of complications. Antibiotics can help to eradicate bacteria and reduce the risk of infection, allowing the wound to heal more effectively (Perez-Favila et al. 2019). However, the use of antibiotics should be carefully considered and prescribed judiciously, taking into account factors, such as the type and severity of the infection, the patient's medical history, and potential side effects or adverse reactions. Additionally, the overuse or misuse of antibiotics can lead to the development of antibiotic resistance, emphasizing the importance of proper antibiotic stewardship in the treatment of DWs (Ramirez-Acuña et al. 2019). Although there is a dearth of prospective comparative studies, various antibiotics have shown efficacy in treating diabetic foot infections. Nafcillin, flucloxacillin, and dicloxacillin, as well as ceftazidime, cefazolin, and ceftriaxone, have been utilized with success. In addition, newer antibiotics, such as dalbavancin, oritavancin, and telavancin, have also demonstrated efficacy in treating diabetic foot infections (Singh and Gupta 2017). Nevertheless, it is important to exercise caution when prescribing antibiotics, taking into account factors, such as drug efficacy, safety, and potential for development of antibiotic resistance. Furthermore, future research efforts should aim to provide further insight into the optimal antibiotic treatment options for DWs (Lipsky et al. 2016).
Platelet-rich plasma therapy (P-RP)
For more than 3 decades, the use of autologous P-RP and platelet gel products have been found to accelerate the healing of DWs. This is attributed to the presence of numerous growth factors, such as PDGF, TGF-β1, and EGF, as well as antimicrobial actions, which are responsible for various positive outcomes, such as tissue regeneration, cell proliferation and differentiation, α-degranulation, and chemotaxis. These factors play a vital role in promoting wound healing by aiding in the repair and regeneration of damaged tissues, promoting the growth of new blood vessels, and reducing inflammation (Babaei et al. 2017; Hirase et al. 2018). Additionally, Mehrannia et al. (2014) reported a clinical case involving a 71-year-old man with type II diabetes who had severe foot injury due to his inability to sense hot surfaces. Despite receiving treatment at the hospital, the patient's condition did not improve. Consequently, P-RP therapy was chosen as a treatment option. The standard P-RP methodology (Bio-Act. Bio-Jel. Inc.) was employed to isolate the P-RP, which was then injected 4 mm into the wound. Within 20 d, signs of tissue regeneration were evident, and by the 8th week, the tissue had completely returned to its normal state (Mehrannia et al. 2014). In the study conducted by Ahmed et al. (2017), patients treated with P-RP gel demonstrated a significantly faster healing rate compared to the control group (68% vs. 86%). The use of P-RP gel resulted in accelerated recovery from DWs and a decreased risk of infection when compared to standard control treatments (Ahmed et al. 2017). Both topical and injectable P-RP treatments have demonstrated potential as a novel approach for treating DWs, with benefits that include accelerated healing and antimicrobial properties. However, additional research is necessary to determine the true efficacy of P-RP in the treatment of wounds. Further studies should focus on refining P-RP treatment protocols, identifying the optimal dosage and frequency of treatment, and investigating its long-term effectiveness and safety.
Laser therapy
Laser therapy has been used as a potential treatment option for DWs’ healing. Diabetic wounds are a common complication of diabetes and can be slow to heal due to poor circulation, nerve damage, and other factors.
Low-level laser therapy (LLLT)
LLLT, also known as cold laser therapy, has been shown to promote wound healing by increasing blood flow, reducing inflammation, and stimulating cell growth and repair. LLLT uses low-intensity lasers or light-emitting diodes to stimulate the cells in the affected area. Several studies have shown promising results for the use of LLLT in DWs’ healing (de Sousa and Batista 2016). Kaviani et al. (2011) conducted a randomized, double-blind clinical trial involving 23 patients with DWs who received either placebo treatment (n = 10) or LLLT in addition to conventional care (n = 13) for at least 3 months. The LLLT used had a wavelength of 685 nm and an energy density of 10 J/cm2. The results showed that LLLT reduced the healing time for DWs, as evidenced by a significant reduction in wound size compared to the placebo group after week four of treatment. After 20 weeks, eight patients in the LLLT group achieved full wound healing, while only three patients in the placebo group did so. Although there was no statistically significant difference between the LLLT and placebo groups, the LLLT group had a shorter mean time to full recovery 11 weeks, compared to the placebo group 14 weeks (Kaviani et al. 2011). In another study, conducted by Schindl et al. (1999) evaluated the number of treatments needed to achieve complete wound closure in 20 patients with ulcers of different underlying causes, including diabetes (n = 8), vascular insufficiency (n = 5), radio damage (n = 4), and autoimmune vasculitis (n = 3). The results of the study showed that radiation injury ulcers healed at a faster rate compared to diabetes-related ulcers. Additionally, wound healing was significantly slower in patients with autoimmune vasculitis compared to those with radio-dermatitis. The study also revealed that wound size was a significant factor affecting healing time (Schindl et al. 1999). The promising outcomes reported in the current research on the use of LLLT for DWs highlighted the need for more comprehensive investigations in this domain. To obtain definitive evidence regarding the efficacy of LLLT as a treatment for DWs, there is a requirement for high-quality studies that are randomized, controlled, and double-blinded, with adequate designs and statistical significance. Furthermore, research is needed to gain a deeper understanding of the mechanism of action of LLLT in relation to DWs.
Photo-bio-modulation therapy (PBMT)
The use of PBMT, utilizing red and near-infrared (NIR) wavelengths, is being examined as a promising therapy for enhancing the speed of DWs. PBMT regulates the expression of genes responsible for various cellular processes, such as cell division, migration, and differentiation, thereby promoting cell growth. Effective wound repair requires a coordinated process of cell proliferation, differentiation, and migration, all of which can be modulated by PBMT (Oyebode et al. 2021). Numerous experiments utilizing NIR lasers have been conducted Maiya et al., (2005) studied the impact of PBMT on DWs healing in alloxan-induced diabetic rats by applying PBMT at a visible wavelength (632.8 nm, He–Ne laser) with a fluence of 4.8 J/cm2 for 5 d a week. According to the findings, wounds treated with lasers healed substantially more quickly and more effectively than those in the untreated control group (Maiya et al. 2005). In another study conducted by Houreld and Abrahamse (2007), the same wavelength (632.8 nm) was utilized, but the researchers applied significantly lower (5 J/cm2) and higher (16 J/cm2) fluences. The results of the study revealed that at a fluence of 5 J/cm2, IL-6 expression, proliferation, and migration were all higher compared to those observed at 16 J/cm2. While selecting the appropriate fluence and wavelengths may accelerate the healing process, it is crucial to carefully consider these factors when implementing PBMT (Houreld and Abrahamse 2007).
Electrical stimulation therapy (EST)
Diabetes can lead to the development of chronic wounds that are challenging to manage due to poor circulation and reduced sensation. In recent years, electrical EST has emerged as a non-invasive treatment option for DWs. By applying low-level electrical currents, EST can stimulate the healing process in these difficult-to-treat wounds. EST has been found to be effective in promoting wound healing by increasing blood flow to the affected area, promoting cell growth, fibroblast growth, and reducing inflammation. These benefits make EST a promising therapy for DWs healing (Melotto et al. 2022). In a recent study, Abedin-Do et al., (2021) investigated the impact of EST on diabetic human skin fibroblasts (DHSF) cells that play a crucial role in wound healing. The study examined how different intensities of direct current EST (100, 80, 40, and 20 mV/mm) affected the ability of DHSF to stick together and grow, as well as their production of cytokines and growth factors. Using various assays, the study found that EST at 20 and 40 mV/mm promoted the ability of DHSF to stick together, grow, and remain viable. Additionally, EST reduced the release of pro-inflammatory cytokines IL-6 and IL-8, while increasing the release of the growth factor FGF-7 in the 48 h following EST. The study also showed that the beneficial effects of ES on DHSF growth persisted for up to 5 days after the treatment (Abedin-Do et al. 2021). Recent, findings of a meta-analysis conducted by Zheng et al. (2022), suggest that EST may offer therapeutic benefits for the treatment of diabetic foot ulcers. Despite the high degree of variability observed among the included studies, EST treatment was found to be effective in reducing ulcer size and promoting ulcer healing. Moreover, the meta-analysis identified pulsed current EST as having the potential to improve ulcer healing compared to direct current EST. However, to fully assess the safety and efficacy of EST in the treatment of DWs, further large-scale clinical trials are necessary (Zheng et al. 2022). Wang et al. (2021a, b) conducted a study to investigate the effects of high-voltage monophasic pulsed current (HVMPC) on the proliferation and migration of human umbilical vein endothelial cells (HUVECs). The study found that HVMPC stimulated the PI3K/Akt and extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathways, leading to increased cell proliferation and migration. Overall, these findings suggested that the use of ES-chitosan dressing may offer promising therapeutic benefits for the treatment of diabetic wounds (Wang et al. 2021b).
Growth factors
The process of wound healing involves a harmonious interplay of various biological agents, such as growth factors, MMPs, cytokines, inflammatory cells, keratinocytes, fibroblasts, and endothelial cells. Growth factors, which are polypeptides with biological activity, play a pivotal role in all stages of the healing process (Barrientos et al. 2008; Zubair and Ahmad 2019). In the process of tissue development, the granulation phase is marked by the initiation of the early inflammatory phase, which is augmented by the activity of growth factors. However, growth factor deficiencies in compromised wounds can result from various factors, including inadequate expression, generation, release, or excessive degradation of these critical agents (Crovetti et al. 2004). The synthesis of ECM during the healing process requires a delicate balance between matrix production and degradation. This regulation is influenced by various factors, such as VEGF (Frank et al. 1995), IGF-I, IGF-II (Xie et al. 2013), TGF-β (Bitar and Labbad 1996), KGF (Werner et al. 1994), pDGF (Beer et al. 1997), EGF (Burstein 1987), and FGF (Hosokawa et al. 2000; Parkar et al. 2001). Interestingly, individuals with diabetes tend to exhibit significantly lower levels of both TNF-α and IL-6. Growth factors are crucial not only in initiating the wound-healing process, but also in sustaining it throughout its various stages. Autologous keratinocytes, fibroblasts, and stem cells have a crucial role in directly interacting with growth factors, such as pDGF, EGF, VEGF, FGF, and KGF, which are essential for healing diabetic wounds. Moreover, many agents can indirectly affect molecular targets, thereby influencing the expression of growth factors, cytokines, MMPs, NO, and angiogenesis-promoting factors. These indirect effects can have significant implications for biological processes, whether they are direct or indirect. Table 2 summarizes the various growth factors-based therapy for the treatment of diabetic wound.
Platelet-derived growth factor (pDGF)
In DWs, the down-regulation of growth factor receptors and rapid degradation of growth factors contribute to the slowed healing process. One such critical growth factor is pDGF, a serum mitogen released by platelets, which plays a key role in stimulating fibroblast proliferation, matrix formation, and connective tissue maturation (Greenhalgh et al. 1990). During the late inflammatory phase, macrophages produce pDGF in the wound environment, attracting fibroblasts and inflammatory cells due to its cell proliferation stimulating properties. This, in turn, facilitates the synthesis of collagen, glycosaminoglycans, proteoglycans, and glycan’s, ultimately leading to the production of granulation tissue proteins, provisional ECM, and angiogenesis (Doxey et al. 1995). The reduced expression of pDGF and its receptors in diabetic wounds further emphasizes the importance of this growth factor in the healing process. Several clinical trials have demonstrated the efficacy of pDGF in speeding up the wound-healing process (Lobmann et al. 2006; Li et al. 2008).
Basic fibroblast growth factor (bFGF)
The bFGF plays a critical role in various biological processes, such as the development and differentiation of fibroblasts, proliferation of vascular smooth muscle cells and endothelial cells, metabolism of extracellular matrix, growth of mesodermal cells, and cell movements. It stimulates these cellular activities and facilitates the formation of granulation tissue, thereby accelerating the healing process. The increased pace and intensity of granulation tissue formation induced by bFGF contributes significantly to the wound-healing process (Tsuboi and Rifkin 1990).
Vascular endothelial growth factors
VEGF is a potent angiogenic cytokine that is abundantly present in the skin, and its concentration in a wound plays a crucial role in the healing process. It supports the rate-limiting phases of vasculogenesis and angiogenesis by promoting the proteolytic degradation of the extracellular matrix of existing blood vessels and stimulating the migration and proliferation of capillary endothelial cells (Presta et al. 1997). In DWs, VEGF increases capillary density, enhances blood flow and metabolic rate, and promotes the formation of granulation tissue. Additionally, this protein regulates the re-vascularization and permeability of the wound site. VEGF receptor-1 and -2 activation can induce inflammation and angiogenesis, respectively (Angelo and Kurzrock 2007). However, diabetes can impair wound healing by reducing the local levels of VEGF. Studies have shown that aberrant VEGF receptor patterns, reduced VEGF mRNA levels, increased VEGFR-1 levels, and decreased VEGFR-2 levels are the primary reasons for non-healing wounds (Zhou et al. 2015).
Endothelial growth factors, Insulin-like growth factor, and transforming growth factor-β
Activation of the EGF receptor by platelets leads to the secretion of EGF, which in turn stimulates epidermal cell growth, cellular motility, migration, mesenchymal regeneration, angiogenesis, and cell proliferation (Hardwicke et al. 2011). The insulin-like growth factor complex, comprising IGF-1 and IGF-2 peptides, is also involved in diabetic wound healing. IGF-1 plays a critical role in the granulation and re-epithelialization of cells, enhances the chemotaxis of endothelial cells, and promotes the proliferation of keratinocytes and fibroblasts, thereby facilitating wound repair. In contrast, diabetic individuals exhibit reduced expression of IGF-1, suggesting that an aberration in cell granulation may contribute to the pathogenesis of diabetes. Additionally, the pH of the wound environment significantly influences the binding affinities of these growth factors (Brown et al. 1997; Bruhn-Olszewska et al. 2012). Studies have shown that both diabetic animals and humans have lower levels of IGF-1 and TGF-β in their wound tissue, which is associated with delayed healing process (Bhora et al. 1995; Galiano et al. 2004). TGF-β plays a critical role in wound healing by promoting the recruitment of inflammatory cells, such as neutrophils, macrophages, lymphocytes, and keratinocytes, stimulating fibroblasts, and generating growth factors. These events accelerate vascularization, angiogenesis, and ECM synthesis while inhibiting ECM breakdown (Roberts 1995). Reduced TGF-β concentration is a potential reason for delayed healing in diabetes patients. Notably, several studies have demonstrated that TGF-β1-dependent inhibitory elements in the promoter region of MMP-encoding genes can reduce MMPs production, leading to excessive degradation of growth factors (Veves et al. 2012). Transcription factors, such as Smad-2, Smad-3, and Smad-4, can either activate or repress TGF-β target genes, including those encoding for MMPs and collagen (Hozzein et al. 2015). Decreased TGF-β1 levels enhance the activation of inflammatory cells, leading to a delay in the healing process in diabetic wounds. Diabetics are hypothesized to have lower levels of TGF-β1 and higher levels of TGF-β3, resulting in increased macrophage activity, higher production of reactive oxygen species, and prolonged inflammation (Jude et al. 2002; Heublein et al. 2015). In summary, decreased levels and expression of growth factors, such as TGF-β and IGF-1, contribute to the delayed wound healing observed in diabetes.
Stem cell therapy
Stem cell treatment has an advantage over growth factor therapy in DWs, because stem cells can govern tissue regeneration in a comprehensive manner by refining the microenvironment at the wound site. While neither therapy is perfect in repairing DWs, stem cell therapy has a higher success rate. Stem cells have been found to exert a beneficial influence on a range of pathophysiological processes, such as wound healing, by enhancing cellular activities required for tissue repair, augmenting the formation of extracellular matrix, and stimulating angiogenesis in ischemic tissue. Animal experiments have revealed that implantation of stem cells can improve circulation in previously ischemic extremities by creating a favorable wound site microclimate (El Hage et al. 2022).
Kirana et al. (2012) evaluated the efficacy, safety, and viability of bone marrow-derived cellular product transplantation in improving microcirculation and reducing amputation rates in diabetic subjects with critical limb ischemia and diabetic ulcers. The study included two groups: one receiving Bone Marrow Mesenchymal Stem Cells (BM-MSCs) and the other receiving expanded bone marrow cells enriched in CD90+ tissue repair cells (TRCs). Patients were followed up for 52 weeks following treatment, and wound healing, ankle-brachial index and TcPO2, reactive hyperemia, and angiographic imaging were measured before and after cell therapy. The results showed that both treatments were safe and feasible, with subjects undergoing BM-MSCs treatment showing significantly improved outcomes in ulcer-healing rate and ankle–brachial index compared to TRCs. However, there was no significant difference in TcPO2. Microcirculation improved in some transplanted patients in both groups, but some patients experienced adverse events, such as subarachnoid bleeding and death due to multiple organ failure following sepsis (Kirana et al. 2012). In a mouse model of DWs, Kim et al. (2012) discovered that intradermal injections of human amniotic mesenchymal stem cells (MSCs) were more effective in promoting wound healing compared to human autologous adipose-derived stem cell (ADSCs) or human dermal fibroblasts (Kim et al. 2012). In addition, Ren et al. (2019a, b) demonstrated that utilizing adipose stem cell-derived microvesicles for wound treatment substantially increased the production of growth factors, such as VEGF, pDGF, EGF, and FGF2. This led to enhancements in epithelialization, angiogenesis, and collagen deposition, ultimately resulting in an accelerated wound-healing rate (Ren et al. 2019b). In another research study, Li et al (2018) conducted research demonstrating that adipose-derived stem cell-secreted exosomes reduced ulcer size in diabetic mice by promoting angiogenesis, granular tissue development, immunosuppression, and a reduction in oxidative stress-related proteins (Li et al. 2018).
ADSCs have emerged as a promising therapeutic avenue for tissue regeneration. Recently, Shi et al. (2022a, b) demonstrated that a circular RNA known as Snhg-11, secreted from ADSCs, could enhance DWs healing by potentially inducing M2 macrophage polarization through modulation of the miR-144-3p/HIF-1α/STAT-3 signaling pathway (Shi et al. 2022b). In another study, Ouyang et al. (2022) demonstrated that overexpression of hematopoietic Prostaglandin-D synthase (HPGDS) in ADSCs accelerated the healing of DWs. HPGDS is a cytosolic protein that can convert prostaglandin H-2 (PGH-2) to prostaglandin-D-2 (PGD-2). The study found that HPGDS overexpression improved the anti-inflammatory state and promoted M2 macrophage polarization, contributing to faster wound healing (Ouyang et al. 2022).
Bioengineered skin substitutes
Managing DWs using the conventional therapy approaches can be problematic due to their poor healing potential. However, recent advancements in tissue engineering, bioengineered skin substitutes, and genetic growth factors have resulted in significant breakthroughs for addressing this challenge. These technological innovations have played a pivotal role in improving the treatment outcomes of DWs (Ren et al. 2022). Santema et al. (2016) conducted a systematic review to evaluate the effectiveness of skin substitutes in addition to standard care for treating DWs, using the Cochrane Collaboration's methodology. Seventeen randomized clinical trials comprising 1655 participants were included in the review, and the risk of bias varied across the studies. Thirteen studies compared standard care to skin substitutes and found that the use of skin substitutes in conjunction with standard care significantly increased the likelihood of full wound closure at 6–16 weeks compared to standard care alone [risk ratio 1.55, 95% (confidence interval) 1.30–1.85]. No significant differences in efficacy were found between different skin substitutes in the four studies that compared two different products. Two studies reported lower limb amputation rates, and when the results were combined, the rate was significantly lower in patients treated with skin substitutes (risk ratio 0.43, 95% CI 0.23–0.81), although the absolute risk difference was minor (− 0.06, 95% CI − 0.10 to − 0.01). Therefore, the review provides evidence that using skin substitutes in combination with standard care can enhance complete ulcer closure in diabetic foot ulcers (Santema et al. 2016). In an another meta-analysis, Gordon et al (2019) analyzed 25 studies that assessed wound closure rates after 12 weeks and found that biologic dressings were 1.67 times more effective than standard of care dressings in promoting healing of diabetic wounds, with a statistical significance of (p < 0.00001). Additionally, their analysis of 5 trials demonstrated that biologic dressings were 2.81 times more likely to result in complete wound closure at 6 weeks compared to standard of care (SOC) dressings, with a statistical significance of (p = 0.0001). The majority of the 31 studies, which evaluated the healing time of diabetic wounds, indicated that biologic dressings were more effective than SOC dressings, with 29 out of 31 studies recommended biologic dressings as the preferred treatment option (Gordon et al. 2019).
Nutritional supplements
The process of wound healing is intricate and necessitates adequate nutrients to repair damaged soft tissues. Unfortunately, malnutrition is a prevalent and often overlooked issue among patients suffering from diabetes and chronic wounds. Furthermore, there is currently a lack of clear guidance or reliable data regarding the use of nutritional supplements to enhance wound healing in individuals with DWs. Various nutritional supplements, such as proteins, vitamins, and amino acids, are discussed as potential adjuncts to promote the healing of DWs (Da Porto et al. 2022).
Protein and amino acid supplements
Proteins and amino acids are commonly used as nutritional supplements to accelerate the healing of diabetic foot wounds, owing to their established effectiveness. Notably, there are randomized controlled trials (RCTs) specifically examining the impact of protein or amino acid combination supplementation on wound healing among individuals with DWs. Basiri et al. (2020) investigated the impact of combining a nutrient-dense formula with nutrition education on wound healing in patients with DWs. The study enrolled 29 patients who were randomly assigned to either the treatment group (n = 15) receiving nutritional supplements and education or the control group (n = 14) receiving only standard care. Wound healing was evaluated through planimetry at baseline and every 4 weeks for up to 12 weeks. No significant differences were observed between the groups at baseline for age, body mass index (BMI), duration of diabetes, wound age estimation, or wound area. The treatment group demonstrated a significantly faster wound-healing rate, with a 6.43 mm2/week more reduction in wound area compared to the control group. The mean reduction in wound area during the first 4 weeks was almost 13 times greater in the treatment group (18.0 mm2/week) compared to the control group (1.4 mm2/week). The study findings suggested that combining nutrition supplementation with education can significantly accelerate wound healing in DWs patients compared to standard care alone (Basiri et al. 2020, 2022). In another study, Armstrong et al. (2014) conducted a randomized controlled trial with 270 patients, to investigate the impact of arginine, glutamine, and b-hydroxy-b-methyl butyrate supplementation on healing of DWs. No significant differences were observed between the groups in wound closure or healing duration after 16 weeks. However, subgroup analysis revealed that patients at risk of limb hypo-perfusion and/or hypoalbuminemia demonstrated accelerated healing of DWs, when these supplements were added to the standard treatment (Armstrong et al. 2014). Wong et al. (2014) found that after 2 weeks of supplementation with beta-hydroxy-beta-methylbutyrate (HMB), arginine (Arg), and glutamine (Gln), there was a statistically significant increase in the percentage of viable tissues (p = 0.02). Additionally, the experimental group showed a significant increase in pressure ulcer scale for healing (PUSH) scores within 1 week of supplementation (p = 0.013). Although wound size and PUSH scores did not appear to decrease with the administration of specialized amino acid supplements, tissue viability may have increased after 2 weeks (Wong et al. 2014).
Vitamin “C and D” supplement
Vitamin C, also known as ascorbic acid, is a vital water-soluble nutrient that is essential for numerous tissue repair and maintenance functions, including collagen synthesis, immune system regulation, and the health of cartilage and bones. In addition, bone development requires two minerals, calcium and phosphorus, and the absorption of these minerals is facilitated by vitamin D, a fat-soluble vitamin with well-established benefits (Bechara et al. 2022).
Yarahmadi et al. (2021) found that the administration of vitamin E (200 IU/day) and vitamin C (250 IU/day) supplements for 8 weeks, along with platelet-rich plasma-fibrin glue dressing and negative pressure wound therapy device, significantly improved wound healing in patients with non-healing DWs (Yarahmadi et al. 2021). Kostadinova et al. (2019) reported that in recent RCTs with limited sample sizes, vitamin C supplementation may expedite the healing of DWs. One such trial conducted in Australia involved seven patients with DWs receiving (500 mg) of slow-release vitamin C capsules twice a day for 8 weeks, which resulted in a greater percentage reduction in ulcer volume compared to the placebo group in a randomized, placebo-controlled study (Gordon et al. 2019). Currently, only a few randomized controlled trials (most of which involve the same study group) have evaluated the effects of vitamin D supplementation on wound healing in DWs. However, a double-blind, placebo-controlled, RCTs conducted on 60 patients with grade 3 DWs based on “Wagner-Meggitt” criteria showed that after 12 weeks of intervention, vitamin D supplementation resulted in a significant reduction in ulcer length, width, depth, and erythema rate compared to the placebo (Razzaghi et al. 2017). According to Karonova et al. (2020), administering high-dose cholecalciferol therapy (40,000 IU/week) for a period of 24 weeks resulted in the normalization of 25(OH)D levels and led to improvements in neuropathy severity, skin microcirculation, and cytokine profile. Specifically, there was a reduction in pro-inflammatory IL-6 and an increase in anti-inflammatory IL-10. These findings suggested that vitamin D insufficiency may be a treatable factor that affects diabetic peripheral neuropathy, and highlighted the need for prompt identification and treatment with cholecalciferol at doses greater than 5000 IU/day (Karonova et al. 2020).
Surgery
Diabetic wound-healing surgery aims to promote healing of wounds in diabetic patients that are not healing properly on their own (Yang et al. 2016). The underlying theory is that diabetes can cause damage to blood vessels and nerves, leading to poor circulation and decreased sensation in the feet and legs. This can result in wounds that are slow to heal and prone to infection (Ji et al. 2022). Surgical intervention can help to address these issues and promote healing. Debridement (Yammine and Assi 2022), for example, can remove dead or infected tissue from the wound, allowing healthy tissue to grow and heal. Skin grafting can provide a new, healthy layer of skin to cover the wound and promote healing. NPWT can promote healing by removing excess fluid and increasing blood flow to the wound. HOTC can promote healing by increasing oxygen levels in the body, which is important for wound healing (Han and Ceilley 2017; Everett and Mathioudakis 2018). It is important to note that diabetic wound-healing surgery is typically only considered after non-surgical treatments have been tried and failed. Proper wound care, including keeping the wound clean and dry and changing dressings regularly, is also crucial for successful wound healing. Additionally, maintaining good blood sugar control is important in promoting healing and reducing the risk of complications (Kavitha 2014; Rezvani Ghomi et al. 2019).
Alternative therapies for DWs’ complications
Natural plants and their active constituents-based treatment strategy in diabetic wound healing
Animal (pre-clinical) in-vitro and in-vivo based studies
The delayed and impaired wound-healing process is a major issue in diabetic wounds (Kulprachakarn et al. 2017). Medicinal plants are a well-known source of therapeutic treatments, utilized in both conventional and alternative medicine (Ansari et al. 2022a). These traditional remedies possess several therapeutic properties, including wound-healing, antioxidant, antimicrobial, anti-inflammatory, and anti-hyperglycemic activities. Studies indicate that natural remedies are generally used for wound dressing, with few taken orally to treat DWs (Oguntibeju 2019). Traditional healthcare practices such as Ayurveda, Unani, traditional Chinese medicine, and other traditional health systems have significantly contributed to the healing of wounds in diabetic foot syndrome. In western nations, these medical systems are regarded as conventional and alternative medicine, as they incorporate medicinal herbs, acupuncture, dietary therapy, massage, and therapeutic exercise for treating and preventing diseases (Li et al. 2011). Chinese herbal medicine, a primary component of traditional Chinese medicine, is widely used in clinical practice to treat DWs (Debnath et al. 2014; Wang et al. 2019). The healing process is accelerated by medicinal herbs due to their active constituents, which act in various ways. These include promoting the proliferation of fibroblasts, initiating the early expression of growth factors, exhibiting free radical scavenging or antioxidant activity, halting wound bleeding, preventing microbial growth, enhancing collagen synthesis and strength, increasing blood flow to wounds, reducing cellular damage, promoting DNA synthesis, facilitating wound contraction and epithelialization, and stimulating the production and migration of keratinocytes (Veves et al. 2012; Pis and Altunkaynak 2014).
Alsarayreh et al. (2022) demonstrated the wound-healing potential of a 10% plant extract from G. arabica in non-diabetic and diabetic rats. The healing process was notably associated with the utilization of a 10% plant extract, leading to a substantial improvement in wound contraction, as evidenced by statistically significant p values (< 0.025) in both non-diabetic and diabetic rats. This highlights the robust wound-healing capabilities of G. arabica extract. The treatment also demonstrated an increase in hydroxyproline and collagen expression, further emphasizing its effectiveness. In both non-diabetic and diabetic rat models, G. arabica extract exhibited significant wound-healing properties, as evidenced by enhanced wound contraction and elevated levels of hydroxyproline and collagen expression (p values < 0.025). This underscores the potent wound-healing capacity of the plant extract. Notably, during the initial phases of wound healing, G. arabica treatment upregulated IL-6 levels, contributing to the observed positive effects on wound contraction and hydroxyproline and collagen content. This suggests that the induction of cytokine production, such as IL-6, may play a role in expediting the wound-healing process. Furthermore, in this study explored the impact of G. arabica extract on a fibroblast cell line. Treatment with a 20 µg/ml methanolic extract resulted in a significant increase in cell migration (p values < 0.035), indicating substantial wound-healing activity. This finding further supports the notion that G. arabica extract promotes efficient wound healing, potentially through the stimulation of fibroblast migration (Alsarayreh et al. 2022). Moreover, Yadav et al. (2022a, b, c, d) reported the wound-healing potential of Neolamarckia cadamba extract in diabetic rats. Phytochemical analysis showed the presence of alkaloids, flavonoids, phenols, saponins, steroids, glycosides, and tannins in the extract. The extract caused significant wound contraction in both oral (28.70%, 36.80% at doses of 200, 400 mg/kg/day) and topical (23.08%, 31.21% at doses of 5%, 10% w/w/day) treated groups compared to the diabetic control. The oral treatment with the extract also decreased serum glucose levels and improved biochemical and enzymatic status in the body. Histopathological investigations demonstrated a dose-dependent improvement in wound healing by re-epithelialization, collagenation, and vascularization of damaged skin samples. These findings suggested that Neolamarckia cadamba extract may be effective in promoting wound healing in diabetic rats (Yadav et al. 2022b). In addition, Elnahas et al. (2021) evaluated the antimicrobial and wound-healing potential of Tanta LEM crude extract, obtained from olive leaves, against Methicillin-resistant S. aureus (MRSA). The extract showed significant antimicrobial activity against MRSA with an MIC value of 15.6 mg/ml. The checkerboard dilution technique demonstrated a synergistic interaction between Tanta LEM crude extract and Ciprofloxacin. The extract also exhibited high scavenging activity against 2,2-Diphenyl-1-picrylhydrazyl (DPPH) free radicals. In-vivo experiments on normal and diabetic rats treated with a combination of Shea butter and Tanta LEM extract showed the maximum wound contraction and healing activity. These findings suggested that Tanta LEM crude extract may be a promising agent for the treatment of MRSA infections and diabetic wound healing (Elnahas et al. 2021). Moreover, De Souza de Aguiar et al. (2021) investigated the wound-healing potential of alcoholic extract from Stryphnodendron adstringens (SAHE). Phytochemical analysis showed the presence of phenolic compounds, tannins, and flavonoids in the extract. SAHE showed strong antioxidant activities and induced fibroblast proliferation without being cytotoxic. The combination of SAHE and hydrogen peroxide showed a more pronounced healing activity than other treatments in both non-diabetic and diabetic animals, promoting angiogenesis and re-epithelialization. These findings suggest that SAHE may be a promising agent for promoting wound healing (De Souza de Aguiar et al. 2021). In a study, Hashemnia et al. (2019) examined the effect of Pimpinella anisum treatment on wound healing in 60 rats. The treated animals showed significantly reverted oxidative changes of total antioxidant capacity, malondialdehyde, and glutathione peroxidase induced by diabetic wounds (p < 0.05). Furthermore, it significantly increased the dry matter and hydroxyproline contents at various stages of wound healing (p < 0.05). Additionally, Pimpinella anisum treatment resulted in significant improvements in re-epithelialization, tissue alignment, collagen fiber maturity, and large capillary-sized blood vessels compared to the control group (Hashemnia et al. 2019). In another study, Marchianti et al. (2021) investigated the effectiveness of different Mm (Lour.) gel formulations on wound healing in diabetic rats. Histopathology observation, VEGF expression, and hydroxyproline levels showed a significant acceleration of wound healing in all treatment groups compared to the negative control group. The study concluded that all Mm (Lour.) gel formulations were effective in restoring the delayed healing process on wounds in diabetic rats and were equally effective in accelerating wound healing. Among the formulations, sodium carboxymethyl cellulose (CMC) Na was found to be the most preferable because it did not cause any irritation. Therefore, Mm (Lour.) gel formulations could be considered a promising option for wound healing in diabetic patients (Marchianti et al. 2021). Due to their beneficial properties and other positive effects, medicinal plants are now being used to treat DWs problems and may serve as potential alternatives to the conventional anti-diabetic medications in the future. Many modern phytomedicines have been developed based on traditional medicinal plants (Ansari et al. 2022a). The formulation of phytomedicines may be either single or poly-herbal. Several marketed poly-herbal formulations including Angipars (Res and I-iii 2011), WinVivo (Ongarora 2022), Jathyadi Thailam, Jatyadi Ghritam (Mandrika et al. 2021), and others have been employed to heal DWs. These products are typically composed of individual ingredients sourced from different anti-diabetic herbs, and often come with instructions on dietary modifications, exercise, and rest. These adjustments can ultimately aid patients in re-establishing a healthy lifestyle (Petchi et al. 2014). Medicinal plants and their active constituent responsible for diabetic wound-healing effect are summarized in Table 3.
Naturally isolated compounds-based treatment strategy in diabetic wound healing
The theory behind the potential of natural isolated compounds for diabetic wound healing lies in their ability to target various biological pathways involved in the wound-healing process. In diabetic individuals, wound healing is often impaired due to several factors, including poor blood flow, increased oxidative stress, and chronic inflammation. Natural isolated compounds were found to have antioxidant and anti-inflammatory properties, which can help to reduce oxidative stress and inflammation in the wound bed, allowing for more efficient healing. Additionally, these compounds have been found to stimulate angiogenesis, which is important for the formation of new blood vessels to supply oxygen and nutrients to the wound. Furthermore, these compounds have been found to promote collagen deposition, which is necessary for the formation of new tissue in the wound bed. Collagen is a major component of the ECM and is essential for the structural integrity of the skin (Agyare et al. 2019). For instance, Ahmad et al. (2017) found that quercetin has a hypoglycemic effect in STZ-induced diabetic rats and normalized plasma lipids and protein profiles. Additionally, when applied topically to the wound area, quercetin also showed an excellent wound-healing property in diabetic rats. Overall, these findings suggested that quercetin may have potential therapeutic benefits for diabetes management and wound healing (Ahmad et al. 2017). Moreever, Lodhi et al. (2013), evaluated the wound-healing properties of flavonoid-rich fraction and pongamol from Tephrosia purpurea (TPF) in diabetic rats. Ointments of pongamol and flavonoid-rich fraction were prepared and applied to excision wounds in STZ-induced diabetic animals. The results showed that percent wound contraction were observed significantly (p < 0.01) greater in MAF fraction and 0.5% w/w of luteolin treatment groups. Presence of matured collagen fibers and fibroblasts with better angiogenesis were observed in histopathological studies (Lodhi et al. 2013). Shao et al. (2019) suggested that Plumbagin administration can enhance wound-healing activity and serve as a potent anti-diabetic and anti-inflammatory agent in diabetic rats. The diabetic rats showed delayed wound healing, decreased epithelialization, collagen and protein content, reduced serum insulin levels, increased glucose and lipid levels, lowered antioxidant levels, and upregulated levels of inflammatory markers. Plumbagin treatment resulted in increased epithelialization, collagen deposition, increased serum insulin levels, increased antioxidant status, lowered lipid peroxides and lipid levels, lowered inflammatory markers, and increased growth factors’ expressions. Therefore, Plumbagin could be a potential therapeutic agent for the treatment of diabetes and wound healing (Shao et al. 2019). In another study, Chen et al. (2021) indicated that luteolin, when administered, had the potential to improve the delayed wound-healing process in streptozotocin induced diabetic rats. The positive impact of luteolin on wound healing was attributed to its anti-hyperglycemic, anti-inflammatory, and anti-oxidative properties. The study also delves into the underlying mechanisms through which luteolin exerted its effects, such as the inhibition of NF-κB expression, leading to the down-regulation of inflammatory mediators, and the activation of nuclear-related factor-2 (Nrf-2) phosphorylation, resulting in the upregulation of antioxidant enzymes. Furthermore, the study provided biomarkers that may help in determining the status of recovery in diabetic wound healing, such as angiogenesis and neuronal regeneration. Overall, the study highlighted luteolin's potential as a therapeutic agent for treating diabetic wound injury (Chen et al. 2021). The naturally isolated compounds have been found to promote wound healing by stimulating the migration of cells, re-epithelialization, angiogenesis, increase growth factors, reduced inflammation, collagen deposition, and new tissue formation. Table 4 provides a summary of recent in-vitro and In-vivo studies that have investigated the diabetic wound-healing properties of various naturally isolated compounds by oral/topical route administration.
Green-synthesized nanoparticle-based treatment strategy in diabetic wound healing
Nanoparticle-based treatments have gained significant attention in the field of wound healing due to their unique properties, such as high surface area-to-volume ratio, size, and surface chemistry. One promising area of research in this field is the use of green-synthesized nanoparticles for the treatment of diabetic wounds. In the case of diabetic wounds, green-synthesized nanoparticles have been shown to possess antimicrobial, antioxidant, and anti-inflammatory properties, which are essential for promoting wound healing. For instance, silver, gold, titanium dioxide (TiO2), copper, and zinc oxide nanoparticles synthesized using plant extracts have been shown to exhibit strong antimicrobial activity against a wide range of bacteria, including drug-resistant strains, which are commonly found in diabetic wounds (Ezhilarasu et al. 2020; Sharma et al. 2022). This makes them particularly attractive for wound-healing applications, as they can penetrate the skin and reach deep tissues, where they can release therapeutic agents and promote tissue regeneration (Qin et al. 2022). Green synthesis methods involve using natural sources, such as plant extracts, to reduce and stabilize the nanoparticles. This approach offers several advantages over conventional chemical synthesis methods, including improved biocompatibility, reduced toxicity, and cost-effectiveness (Hajialyani et al. 2018). In the context of diabetic wound healing, green-synthesized nanoparticles have been found to have anti-inflammatory, antioxidant, and antimicrobial properties, which can help to address the impaired wound healing process in diabetic individuals. Additionally, these nanoparticles can enhance angiogenesis and stimulate collagen production, which are essential for wound healing (Ezhilarasu et al. 2020). Ahmad et al. (2022) investigated the use of Ocimum sanctum leaf extract to synthesize TiO2 nanoparticles for diabetic wound healing. The study found that the synthesized TiO2 nanoparticles were spherical and polygonal in shape with sizes ranging from 75 to 123 nm. The developed TiO2 nanoparticles, when incorporated into 2% chitosan (CS) gel, exhibited desirable thixotropic properties with pseudo plastic behavior. In-vivo wound-healing studies and histopathological investigations of healed wounds demonstrated that the TiO2 nanoparticles-containing CS gel had excellent wound-healing efficacy in diabetic rats. The study's findings highlight the potential of using green-synthesized TiO2 nanoparticles-containing CS gel for diabetic wound healing (Ahmad et al. 2022).
Bai and Jarubula (2023) conducted a study on the synthesis of zinc oxide nanoparticles (ZnO NPs) using the leaf extract of the Nigella sativa. The researchers found that these ZnO NPs had the ability to restore levels of glycogen, insulin, and blood glucose, indicating their potential as a cost-effective and efficient treatment for diabetes and diabetic wounds. Moreover, the study suggested that ZnO NPs could be applied in the field of diabetic wound care during athletic training (Bai and Jarubula 2023). For SNPs, Mojally et al. (2022) conducted a study to assess the effectiveness of Mentha piperita and silver nanoparticle hydrogel films in treating wounds in diabetic rats. The researchers prepared the hydrogel films using a solvent- and diluent-free process that was environmentally friendly. Thirty rats were randomly assigned to one of five groups, and the results showed that Gel-I and fucidin groups had fully healed wounds after 22 days, whereas Gel-II groups healed by Day 16 (compared to Group 1st to day 25). Group-II diabetic rats took over 25 days to recover, but Gel-II improved wound healing. Both Gel-I and Gel-II also decreased fasting blood glucose levels, indicating that the Mentha piperita and SNPs effectively maintained their concentration at the wound site with low toxicity (Mojally et al. 2022). Furthermore, for the GNPs, Ponnanikajamideen et al. (2019) observed that administering gold nanoparticles to diabetic mice over a period of 21 days resulted in significant improvement in blood glucose, glycogen and insulin levels, and wound healing. These findings suggested that gold nanoparticles have the potential to be an effective treatment option for managing diabetes mellitus and reducing the size of wounds (Ponnanikajamideen et al. 2019). The green-synthesized nanoparticles have been found to promote wound healing by stimulating the migration of cells, re-epithelialization, angiogenesis, increase growth factors, reduced inflammation, collagen deposition, and new tissue formation. Table 5 provides a summary of recent in-vitro and in-vivo studies that have investigated the diabetic wound-healing properties of various green-synthesized nanoparticles.
Human (clinical trial) in-vivo-based studies
A common and serious complication of diabetes is the development of diabetic wounds, especially in the lower limbs, which can be challenging to heal and may result in severe infections and amputations. Indian traditional medicines have utilized natural products for wound care for a long time, and many of these products possess properties, such as antimicrobial, anti-inflammatory, and antioxidant that could potentially aid in the treatment of diabetic wounds (Bandyk 2018). Several human-based studies have investigated the use of natural products in the treatment of diabetic wounds. These studies have generally focused on topical applications of natural products, such as creams, ointments, and dressings (Sharma et al. 2021a; Herman and Herman 2023). Some of the most promising natural products studied in this context include, study conducted by Najafian et al. (2018), who found that the use of Plantavera gel significantly reduced the total ulcer score and ulcer surface in patients with diabetic wounds compared to the control group, without causing any side effects. However, no significant difference was observed in terms of ulcer depth between the two groups (Najafian et al. 2018). In addition, Tonaco et al. (2018) analyzed the results of intention-to-treat analysis on patients with ulcers in the control and P1G10 groups. The P1G10 group was found to be 2.95-fold more effective in achieving 100% healing and 2.52-fold more effective in achieving 80% healing compared to the control group (Tonaco et al. 2018). The study by Jayalakshmi et al. (2021), found that the neem leaves extract showed significant improvement in wound-healing score (PUSH score) and other wound variables compared to the control group (p < 0.001) (Jayalakshmi et al. 2021). Moreover, Ghanadian et al. (2022) showed that Plantago extract gel was significantly more effective than the control group in reducing wound size after the first and second week of treatment (p < 0.001). Moreover, the drug group had a significantly higher number of patients with complete wound healing compared to the control group (OR: 3.129, 95% CI: 1.685–5.809, p < 0.001) (Ghanadian et al. 2022). These products have been shown to improve wound healing and reduce the risk of infection in patients with diabetic wounds. While the exact mechanisms underlying the therapeutic effects of natural products in diabetic wound healing are not fully understood, it is thought that their antimicrobial, anti-inflammatory, and antioxidant properties may play important roles. Additionally, some natural products may stimulate the growth and differentiation of cells involved in wound healing, such as fibroblasts and keratinocytes. The natural products have been found to promote wound healing by stimulating the migration of cells, re-epithelialization, angiogenesis, increase growth factors, reduced inflammation, collagen deposition, and new tissue formation. Table 6 provides a summary of recent clinical trial studies that have investigated the diabetic wound-healing properties of various natural products.
Future therapeutic strategies
Diabetes, peripheral neuropathy, peripheral vascular disease, and foot conditions are all risk factors for DWs. However, despite the widespread adoption of standard care for DWs and the development of technologies such as bioengineered skin cells, diabetic patients continue to experience a less than 50% rate of wound healing. Natural product-based treatments for DWs have been used for centuries in traditional medicine, and recent research has shown their potential as a complementary therapy for diabetic patients. Several plants, including aloe vera, Curcuma longa, Neem, and Annona squamosa, have been studied for their diabetic wound-healing properties. Natural products are bioactive compounds that have been shown to have anti-inflammatory, antioxidant, and antibacterial effects, making them promising candidates for treating DWs. In addition to traditional plant-based treatments, advances in biotechnology have led to the development of plant-based wound dressings. These are made from natural materials, such as chitosan, collagen, and alginate, and have been shown to promote wound healing and reduce the risk of infection. Nevertheless, non-traditional therapeutic approaches, including single and dual growth factors, skin substitutes, cytokine stimulators and inhibitors, matrix metalloproteinase inhibitors, gene and stem cell therapy, extracellular matrix, and angiogenesis stimulators, are rapidly advancing DWs research. Recombinant growth factors, platelet-rich plasma, sphingosine 1-phosphate, stem cell therapy, matrix metalloproteinase inhibitors, shock-wave therapy, laser therapy, and natural products are among the emerging therapeutic strategies for DWs. Laser therapy, in particular, shows promise as a future therapeutic option. These techniques are essential for developing more convenient, safe, and effective therapies for DWs. Despite being mostly experimental, these techniques have shown great potential in clinical trial. However, most of these methods are still in the early stages of development.
Conclusion
Diabetes is a prevalent cause of impaired wound healing, which can have devastating consequences for patients. Over the past few years, there has been a surge of research in the field of DWs’ treatment. Many studies have pointed out several factors that contribute to slow healing in diabetic patients. Fortunately, there has been significant progress in developing novel treatment techniques and products for wound healing in diabetics. One promising avenue for treatment is the use of natural products and their bioactive constituents. These can be used either as a supplement to standard therapy or as an alternative to synthetic drugs, as they offer a wide range of potential therapeutic benefits. These benefits include antimicrobial, anti-inflammatory, antioxidant, angiogenic, keratinocyte and cytokine stimulation, and growth factor modulation, which can promote fibroblast migration and proliferation. While several approaches, such as growth factors and other cytokine modulators, anti-inflammatory medications, MMP inhibitors, angiogenesis stimulators, and ECM stimulators, have been tested, none have shown significant success. However, recent research has shown that combinational techniques have outperformed the traditional approaches, which has given researchers optimism for creating innovative carriers while also understanding the fundamental methodology. Looking ahead, future research in the treatment of diabetic wounds could benefit from a combination of treatments, resulting in faster healing. Researchers should continue to identify different substances that can aid wound healing at various stages in diabetic patients. As healing progresses, improved clinical methods and systems may help reveal the full extent of healing. Overall, with continued research and development, there is hope for finding better treatment and improving the quality of life for patients suffering from diabetic wounds.
Data availability
The data that supports the findings are available in the manuscript.
Abbreviations
- AGEs:
-
Advanced glycation end-products
- ADSCs:
-
Adipocyte-derived stem cells
- CAT:
-
Catalase
- DWs:
-
Diabetic wounds
- DNA:
-
Deoxyribonucleic acid
- ECM:
-
Extracellular matrix
- EGF:
-
Epidermal growth factor
- EMT:
-
Epithelial–mesenchymal transition
- EPCs:
-
Endothelial progenitor cells
- EST:
-
Electrical stimulation therapy
- FGF:
-
Fibroblast growth factor
- FTIR:
-
Fourier transform infrared spectroscopy
- FESEM:
-
Field emission scanning electron microscopy
- GSH:
-
Glutathione
- GPx:
-
Glutathione peroxidase
- GLUT-1:
-
Glucose transporter-1
- GNPs:
-
Gold nanoparticles
- HIF-1α:
-
Hypoxia inducible factor-1α
- HOTC:
-
Hyperbaric oxygen therapy chamber
- HVMPC:
-
High-voltage monophasic pulsed current
- IL:
-
Interleukin
- IRF:
-
Interferon regulatory factor
- IFN-γ:
-
Interferon-γ
- IGF-1:
-
Insulin-like growth factor-1
- JAK/STAT:
-
Janus kinase/signal transducers and activators of transcription
- LLLT:
-
Low-level laser therapy
- MAPK:
-
Mitogen-activated protein kinase
- miRNA:
-
Micro-ribonucleic acid
- MDA:
-
Malondialdehyde
- MMPs:
-
Matrix metalloproteinase
- NGF:
-
Nerve growth factor
- NPWT:
-
Negative pressure wound therapy
- NF-κB:
-
Nuclear factor kappa B
- PAD:
-
Peripheral arterial disease
- PLGA NPS :
-
Poly-lactic-co-glycolic acid nanoparticle
- PBMT:
-
Photo-bio-modulation therapy
- pDGF:
-
Platelet-derived growth factor
- PGH2:
-
Prostaglandin H2
- PK-C:
-
Protein kinase-C
- ROS:
-
Reactive oxygen species
- SEM:
-
Scanning electron microscope
- SNPs:
-
Silver nanoparticles
- SOD:
-
Superoxide dismutases
- STZ:
-
Streptozotocin
- TNF-α:
-
Tumor necrosis factor-α
- TEM:
-
Transmission electron microscopy
- TGF:
-
Transforming growth factor
- T1DP:
-
Type-1 diabetic patients
- T2DP:
-
Type-2 diabetic patients
- TcPO2:
-
Transcutaneous oxygen pressure
- UPR:
-
Unfolded protein response
- UV–Vis:
-
Ultraviolet–visible spectroscopy
- VEGFR-2:
-
Vascular endothelial growth factor receptor-2
- WHO:
-
World Health Organization
- XRD:
-
X-ray diffraction
- ZnO NPs:
-
Zinc oxide nanoparticles
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Acknowledgements
The authors are very thankful to Shalom Institute of Health and Allied Sciences, Sam Higginbottom University of Agriculture, Technology, Prayagraj, India for facilitating research facilities. The authors extend sincere appreciation to the Honorable Vice Chancellor and the Dean of Rama University for their invaluable support and guidance throughout this project. Furthermore, the author would like to express gratitude toward our esteemed Dean, Prof. Dr. Sonia Pandey, and the faculty of Pharmaceutical Sciences, Kanpur, for their provision of state-of-the-art research facilities and all necessary resources required for conducting this review. The authors are also thankful to GITAM University and DST-FIST Central University of Punjab, for providing necessary fatalities to execute this research.
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Conceptualization and supervision: Dinesh Kumar Patel; DATA collection: Jagat Pal Yadav and Ankit Kumar Singh; writing the manuscript: Jagat Pal Yadav; Sketching of figures: Jagat Pal Yadav, Ankit Kumar Singh; writing, review, and final editing of the manuscript: Amita Verma, Vikas Kumar, Prateek Pathak, Pradeep Kumar, Maria Grishina, and Dinesh Kumar Patel.
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Yadav, J.P., Singh, A.K., Grishina, M. et al. Insights into the mechanisms of diabetic wounds: pathophysiology, molecular targets, and treatment strategies through conventional and alternative therapies. Inflammopharmacol 32, 149–228 (2024). https://doi.org/10.1007/s10787-023-01407-6
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DOI: https://doi.org/10.1007/s10787-023-01407-6