Herbal Innovations in Diabetic Wound Care Novel Drug Delivery Approaches A Review

Abstract

The discovery of herbal drugs has traditionally relied on ethnobotanical knowledge and experimental screening; however, these approaches are often time-consuming, resource-intensive, and limited in their ability to explore the vast chemical diversity of medicinal plants. Recent advances in artificial intelligence (AI) and computational methodologies have transformed natural product research by enabling faster, data-driven, and more precise identification of bioactive phytoconstituents. This integrative review critically examines the role of AI-based and in-silico approaches in the discovery and development of herbal drugs. Key computational techniques, including machine learning, deep learning, molecular docking, pharmacophore modelling, quantitative structure–activity relationship (QSAR) analysis, and network pharmacology, are discussed in the context of herbal medicine research. The review highlights how these tools facilitate target identification, activity prediction, toxicity assessment, and optimization of lead phytochemicals, while reducing experimental cost and failure rates. Additionally, the integration of big data resources such as phytochemical databases, omics platforms, and traditional medicine repositories is explored, emphasizing their contribution to predictive modelling and multi-target drug discovery. Challenges related to data quality, model interpretability, standardization of herbal datasets, and regulatory acceptance are also addressed. By bridging traditional herbal knowledge with modern computational intelligence, AI-driven approaches offer a promising pathway for accelerating herbal drug discovery and supporting evidence-based development of safe and effective phytopharmaceuticals. This review underscores the potential of AI and computational tools to reshape the future of herbal medicine research and innovation.

Keywords

Introduction

One of the most frequent complications among diabetics is diabetic foot ulcers (DFU). 6.3% of diabetic people worldwide have chronic foot ulcers, according to a meta-analysis . Diabetic patients may experience complications such as chronic sores on their feet as a result of prolonged periods of high blood glucose . High blood sugar causes peripheral neuropathy, or the degeneration of the peripheral nerve system, and peripheral vascular disease [1]. Due to poor peripheral sensory nerve system function, people with diabetes are more likely to sustain foot injuries without realizing they have them. In addition to the degeneration and constriction of the blood vessels supplying the toes, damage to the motor nervous system of the foot muscles also frequently results in deformity of the foot structure and the formation of chronic wounds that are difficult to heal and more prone to infection[2].These issues lead to slower-than-normal wound healing in patients with diabetes. It should be noted that the incidence of obesity and chronic illnesses like diabetes, venous and arterial insufficiency, have increased substantially in recent years, which has led to a rapid increase in the frequency of persons with chronic wounds. The main topics covered in this review are the wound healing process, the limitations of current wound treatments, and the state of the art in nano-DDSs, with a particular emphasis on liposomes, polymeric nanoparticles, lipid nanoparticles, nanofibrous structures, and nanohydrogel. Due to the remarkable and inventive advancement of nanotechnology, a multitude of nano-drug delivery systems (nano-DDSs) have been developed and used  to skin regeneration[3].Because of their many notable benefits, nano-DDSs have been shown to expedite wound healing and enhance the quality of healing. Specifically, they have been shown to be non-toxic, to be completely compatible with skin, and to favorably create a moist environment that is conducive to the activation and acceleration of the wound healing process. In order to increase drug retention, certain particular nano-DDSs have the capacity to activate particular transport systems or penetrate cellular barriers to access the cytoplasmic space .  Drugs are shielded from degradation caused by proteases in wounds when combined with bioactive substances, which significantly increases therapeutic efficacy [4].Diabetes-related wound healing has a complicated and multifaceted pathophysiology that includes inflammatory response, decreased collagen production, and impaired angiogenesis. Due to the chronic nature of these wounds and the underlying metabolic disorders linked to diabetes, traditional therapeutic approaches frequently prove ineffective. Effective alternative therapy approaches that might speed up recovery and reduced problems are therefore desperately needed. The use of many commonly used herbs and spices are claimed to have wound healing effects with various mechanisms since long time. The treatment with herbal drugs can improve the quality of life of diabetic foot ulcer patients with less adverse effects [5].
2.Pathophysiology of Diabetic Wound
The process of wound healing is intricate and requires the cooperation and interaction of several bodily cell types as well as inflammatory mediators. Skin tissue healing is initiated by signals from injured cells in the wound region, which take the form of growth factors and cytokines. The degree of tissue damage and the existence of foreign antigens that cause the activation of acute inflammatory cells determine how quickly the body recovers . The initial function of platelet fragments is to stop bleeding (hemostasis) by starting the coagulation cascade after being triggered by endothelium. Pro-inflammatory cytokines such IL1b, TNFa, IL 6, and IL 8 are released by activated platelets, keratinocytes, and damaged or hypoxic endothelium. These cytokines draw neutrophil and macrophage cells to the wound site.In people with diabetes, the normal path to repair skin integrity is slowed down and changed. particularly when renal failure, angiopathy, and neuropathy develop as side effects[6]. Denervated feet are more prone to damage due to intrinsic muscular weakness, deformity, lack of protective sensibility, and reduced moisture. As a result, ulcers will develop in these feet. Callus production and improper pressure to the plantar side of the foot were caused by the foot deformity. Chronically high pressure over the bony prominence and in dry skin will result in disintegration and subcutaneous skin hemorrhage. Due to the hypoxic and hypercoagulant state, normal neutrophil and macrophage inflow has diminished, and keratinocyte, platelet, and endothelium synthesis of mediators has been compromised .For the appearance of a DFU, the convergence of several factors is necessary: usually, an initial injury (trauma) that is not detected by the patient because of an existing neuropathy, together with a peripheral vascular disease [7].
3. Foot Ulcer
Twenty to forty percent of health care resources are used to treat diabetic foot infections, indicating that complications from foot ulcers are the primary cause of hospitalization and amputation in diabetes patients. They also result in large health care expenses. as "ulceration of the foot associated with neuropathy and different grades of ischemia and infection," per the World Health Organization . Foot conditions include ulcers, infections, and illnesses that result in hospitalization for individuals with diabetes mellitus [8]. Unfortunately, a pointednumber of these patients may need to have their feet or ankles amputated due to peripheral ischemia or serious infections. One of the risk factors for ulcers and amputations is neuropathy. By supplying various essential elements ( proteins,vitamins and minerals) needed at various phases of wound regeneration and proliferation, the herbs also speed up tissue repair. It has also been shown that herbal remedies areaffordable and safe than allopathic ones. The potential use of herbs in treating DFUs along with their mechanisms is covered in this review [9].
 
 

 
4.Phases of Wound Healing 
The four steps of this healing phases  are: hemostasis (platelet aggregation) and inflammation (prevention of infection), proliferation (wound contraction) and new tissue formation, maturation (remodeling) to strengthen the tissue, and scar formation wound healing phases [10].

 
Table no: 1 Phases of Wound Healing 
Phase    Description    Key Processes and Components    References
Hemostasis and Inflammation    Impact of blood vessel injury, platelet aggregation, and prevention of infection.    Platelet growth factors, clot formation, release of platelet-α-granules, cytokines, growth factors (PDGF, TGF-β), PAF    [11]
Proliferation Phase    Revascularization and angiogenesis at the wound site, fibroblast proliferation, and formation of new tissue.    Fibroplasia, angiogenesis, endothelial cell migration, cytokine production, chemotaxis in low-oxygen environments    [12]
Remodeling and Maturation    Maturation of new tissue, strengthening of wound area through matrix deposition and remodeling.    Fibroblasts, fibronectin, glycosaminoglycan, thrombospondin, matrix components    [13]
 
5. Factors influencing chronic wound ulcers 
Research and scientific data show that the healing process for continuous diabetic wounds and other continuous wounds differs from that of severe wounds [14].
5.1.Vasculopathy
Ischemic stroke Microvascular health issues resulting from type 1 diabetes were evaluated, and it was shown that non-diabetic individuals distal veins seemed sluggish in response to both fantastic O2 and nutritional supplements at the wound site. The distal veins were altered by the continuous diabetic wound, starting with the metatarsal canal, tarsal, and femoral veins [15].
5.2.Nervopathy
Reduced nerves are the autonomic and sensorimotor fibres. Patientsinability to detect pressure, temperature, or other external stimuli stems from their lack of sensory organs, which makes wound healing more challenging.Inhibiting pathogenesis, wound development, and force perception is achieved by the combination of unanticipated vasodilatory autoreceptors that attenuate pain [16].
5.3.Infection
Weakness in people afflicted is often caused by infectious infections, relocation, hospitalization, and a protracted healing period. Unexpectedly, the illness may show up in diabetic ulcers and abrasions. Prompt treatment is necessary for conditions such inflammation, cellulitis, and osteomyelitis [17].
6.Current Diabetic Wound Treatment 
Reducing scars and suffering for patients, accelerating wound healing, and preventing serious infection are the ultimate goals of wound management.There are currently a number of approaches for managing wounds, the most common ones being debridement, autografts, and the use of therapeutic drugs. Furthermore, a few cutting-edge novel treatments like gene therapy, photothermal therapy, stem cell therapy, and photodynamic treatment is becoming more and more important function in some complex wound care [18]
6.1.Debridement 
Using a traditional debridement technique, necrotic or diseased tissue that might limit wound closure, prolong the inflammatory phase, or cause re-epithelialization is removed improving the wound bed to promote healing . Debridement, including surgical, autolytic, mechanical, enzymatic, and maggot methods, typically entails applying more wound dressing.Despite debridement, particularly the pointed debridement, which is widely recognized as the gold standard in order to quickly remove necrotic tissue and avoid despite the possibility of infection, it still faces several limitations: the severe, long-lasting agony that occasionally be intolerable for patientsnecessitating seasoned medical professionals and certain resources in order to avert a second trauma. Consequently, the strategy used should be consistent with the wound assessment [19].
6.2.Autografts and allografts
The gold standard for skin regeneration continues to be the use of autografts and allografts. Synthetic and autologous methods primarily obtain full-thickness fascia from a patient's or another donor's donor location and transplant it throughout the intended area. Autografts are well-known. for superior wound site adherence and improved Cosmetic outcomes, substantially easing discomfort and lowering refusal . Nonetheless, the strict donor requirements website restricts their use, and these skin transplants further carry the unwanted level of scarring and severe skin conditions in the last stages of wound healing, in addition to the expensive hospitalization . Regarding allografts, the primary benefit is the short-term mitigation of dehydration from wounds and pollution as well as the advantageous wound-healing fitness [20].
7.Herbal Remedies/Drugs 
Many different plants and herbs with medicinal compounds, both known and unknown, are recommended for wound healing. The use of herbs in ulcer treatment and care includes the removal and killing of bacteria, creating a good environment for healing. The components of medicinal herbs are considered to be less toxic and have fewer side effects than traditional drugs, which explains the interest in the use of medicinal herbs and their application in drug therapy in diabetic and non-diabetic patients . Poor wound healing due to diabetes is considered by doctors worldwide as a major health problem, sometimes associated with non-specific causes. Therefore, one of the treatment methods, especially in rare regions, is the use of medicinal herbs. Here are some plants with good wounds [21]
7.3.Phytochemicals and Their Mechanisms in Wound Healing
Flavonoids are polyphenolic chemicals, which are present in chamomile and calendula, have the ability to neutralize reactive oxygen species, which lowers inflammation and aids in the healing ofwounds.Tannins are found in Terminalia chebula, tannins have astringent and antibacterial properties that aid in the development of a protective layer over wounds and help ward against infections.Aloe vera contains saponins, which increase fibroblast activity, encourage the creation of collagen, and strengthen the tensile strength of wounds [22].

8.Nano-Drug Delivery System
Nano-DDSs can maintain drug release and prevent drug degradation, they have enormous potential to improve the efficacy of medication therapy. The use of therapeutic agent-carrying nano-DDSs is increasing. in a way never seen before and used to encourage wound healing and skin regeneration—primarily using liposomes lipid,inorganic, and polymeric nanoparticles .Nanoparticles, nanostructures made of nanofibers,and nanohydro gel [23].
8.1.Liposomes :
Liposomes, which are bilayer vesicles made of phospholipids and other amphiphilic compounds, are one of the most promising nanocarriers for topical medication administration. They are biocompatible, harmless, and biodegradable. skin, and having the ability to accept both hydrophilic medications (such as growth hormones) in the bilayer's hydrophobic agent and inner water cavity[24].Furthermore, liposomes effectively cover wound and create moist environment on wound surface after application, which is very conducive to wound healing . Taking advantage of all these merits, liposomes have been universally applied in wound treatment and skin regenerationprepared a novel liposome with hydrogel core of silk fibroin which effectively encapsulated bFGF[25].
 
  
Figure 2: Thin Film Hydration 
8.2.Polymeric nanoparticles
Biocompatible colloidal systems known as polymeric nanoparticles are gaining popularity in the domains of bioengineering and biomedicine. When integrated or medicines are pro when used with these polymeric devices. shielded against deterioration by the proteases found in the wound and released in a regulated way so as to lower the frequency of administration.[26]
8.3.Inorganic nanoparticles
The term "inorganic nanoparticles" describes particles that have been stripped of inorganic components, such as metallic, carbon-based, and ceramic nanoparticles. etc.Inorganic nanoparticles have both wound healing and antibacterial properties, with silver nanoparticles being used as antimicrobial treatments. Inorganic nanoparticles can synergistically promote both materials and medications, making them a popular combination in research.[27]
 
 
Figure 3: Inorganic nanoparticles preparation
 
8.4. Nanofibrous structures
Natural and artificial continuous polymer chains are used to create nanofibers, which may then be deployed as 3D scaffolds or nanofibrous sheetsin tissue engineering. Such nanofibrous structures are made to resemble the ECM and offer favorable circumstances for cell adhesion and increase cell-drug interface, acting as a substitute for synthetic dermal comparable [28]. 
8.5.Nanohydrogel
Three-dimensional polymeric nets called nanohydrogel are thought to be the best formulation for managing wounds because of their porous nature it is  having the capacity to absorb aqueous fluids, prior to releasing moisture from wounds and generating a useful moist setting to promote healing of wounds; its non its adhesive properties enable it to maintain the wound bed. while preserving the oxygen's penetration, which is vital for the healing of wounds[29].
8.6.Micelles Polymeric
Micelles are widely used in preclinical studies to develop poorly soluble drugs for diabetic wounds. They are developed using the self-adaptation of amphiphilic polymers in superficial true compositions. The extensive availability of hydrophobic and, to some extent, hydrophilic polymer blocks allow researchers to investigate various polymer combinations for maximum loading, stability, systemic circulation, and shipping to the goal of wound restoration in diabetic rats [30].
9.Recent advancement 

Formulation    Effect on Wound Healing    Model Used    Reference
Curcumin-loaded nanoparticles    Accelerated wound healing by promoting angiogenesis and collagen deposition    Diabetic rat models    [31]
Aloe vera-loaded hydrogels    Enhanced wound healing by increasing fibroblast proliferation and re-epithelialization    Diabetic rat models    [32]
Centella asiatica nanofibers    Promoted wound contraction and improved tensile strength    Diabetic wound in vivo study    [33]
Green tea polyphenols in liposomes    Enhanced antioxidant activity, reduced oxidative stress, and accelerated wound closure    Diabetic wound models    [34]

Table no 2: Recent advancement in wound healing
 
CHALLENGES OF HERBAL-BASED NDDS:
It is challenging to guarantee constant effectiveness in herbal extracts since environmental influences frequently cause compositional variations in these extracts.Stability: In order to preserve the stability of many herbal chemicals, which are susceptible to deterioration when exposed to light, heat, or oxygen, sophisticated formulation processes are needed.Obstacles related to regulations: The regulatory clearance procedure for herbal based NDDS is made more difficult by the unpredictability and lack of uniformity in herbal goods.Toxicity: Although typically regarded as harmless, some herbal components have the potential to trigger allergic responses or interfere with other drugs, therefore extensive toxicity studies are necessary [35].
CONCLUSION 
The treatment of diabetic wound ulcers (DWUs) might be greatly enhanced by the combination of herbal medicine and innovative drug delivery systems (NDDS).Nano-DDSs have significant potential, but lack international standards and evaluation methods for toxicology, biocompatibility, and targeting efficiency. Additionally, their complex preparation procedures limit industrial production. The anti-inflammatory, antibacterial, and wound-healing qualities of herbal substances can be enhanced even further by using cutting-edge delivery systems such hydrogels, liposomes, nanoparticles, and electrospun nanofibers.The progressive expansion of nano-DDSs in recent years has provided new insights for wound skin regeneration: these drug carriers prolong drug release, protect drugs from degradation, and improve skin retention, resulting in an enhancement of the therapeutic power of biological and synthetic molecules (e.g., reduction or eradication of wound bacterial load and improved re-epithelialization). By offering targeted distribution, enhanced bioavailability, and regulated release, these NDDS technologies overcome many of the drawbacks of conventional herbal uses.
FUTURE PROSPECTS AND RESEARCH DIRECTION
Personalized medicine are adapting herbal remedies to each patient's unique requirements taking into account their genetic, metabolic, and wound-specific characteristics.Large-scale clinical studies to confirm the safety and effectiveness of herbal NDDS in the treatment of diabetic wounds, more stringent human trials are required.Advanced formulations creating NDDS that are sensitive to changes in wound-specific stimuli, including pH or infection state, in order to release herbal bioactives, may improve treatment results .Combination therapy researching the potential benefits of combining herbal extracts with other established medicines, including growth factors or antimicrobial peptides, may speed up the healing of diabetic ulcers .
CONFLICT OF INTEREST 
The authors declare no conflicts of interest. 
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