Abstract
Purpose
Chronic diseases often hinder the natural healing process, making wound infections a prevalent clinical concern. In severe cases, complications can arise, potentially leading to fatal outcomes. While allopathic treatments offer numerous options for wound repair and management, the enduring popularity of herbal medications may be attributed to their perceived minimal side effects. Hence, this review aims to investigate the potential of herbal remedies in efficiently treating wounds, presenting a promising alternative for consideration.
Methods
A literature search was done including research, reviews, systematic literature review, meta-analysis, and clinical trials considered. Search engines such as Pubmed, Google Scholar, and Scopus were used while retrieving data. Keywords like Wound healing ‘Wound healing and herbal combinations’, ‘Herbal wound dressing’, Nanotechnology and Wound dressing were used.
Result
This review provides valuable insights into the role of natural products and technology-based formulations in the treatment of wound infections. It evaluates the use of herbal remedies as an effective approach. Various active principles from herbs, categorized as flavonoids, glycosides, saponins, and phenolic compounds, have shown effectiveness in promoting wound closure. A multitude of herbal remedies have demonstrated significant efficacy in wound management, offering an additional avenue for care. The review encompasses a total of 72 studies, involving 127 distinct herbs (excluding any common herbs shared between studies), primarily belonging to the families Asteraceae, Fabaceae, and Apiaceae. In research, rat models were predominantly utilized to assess wound healing activities. Furthermore, advancements in herbal-based formulations using nanotechnology-based wound dressing materials, such as nanofibers, nanoemulsions, nanofiber mats, polymeric fibers, and hydrogel-based microneedles, are underway. These innovations aim to enhance targeted drug delivery and expedite recovery. Several clinical-based experimental studies have already been documented, evaluating the efficacy of various natural products for wound care and management. This signifies a promising direction in the field of wound treatment.
Conclusion
In recent years, scientists have increasingly utilized evidence-based medicine and advanced scientific techniques to validate the efficacy of herbal medicines and delve into the underlying mechanisms of their actions. However, there remains a critical need for further research to thoroughly understand how isolated chemicals extracted from herbs contribute to the healing process of intricate wounds, which may have life-threatening consequences. This ongoing research endeavor holds great promise in not only advancing our understanding but also in the development of innovative formulations that expedite the recovery process.
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Introduction
Wounds encompass a spectrum, ranging from minor cuts to severe injuries like punctures, lacerations, or burns [1]. Factors like diabetes, atherosclerosis, and venous insufficiency in an aging population have led to a surge in chronic wounds [2]. Delayed wound healing escalates risks, potentially culminating in severe complications, including infection, sepsis, and, in extreme cases, necessitating amputation [3]. Pediatric orthopedic surgery for early-onset scoliosis, while often necessary, carries a substantial risk of wound-related complications, averaging an incidence of 15.5% [4]. The rise in chronic wounds has heightened awareness of their associated morbidity and financial burdens over recent decades [5]. Chronic wounds and burns significantly diminish patients’ quality of life, underscoring the need for innovative, cost-effective technologies and treatments to sustain national health systems [6]. Opportunistic bacteria like Staphylococcus aureus and Pseudomonas aeruginosa, due to their inflammatory response-triggering ability, may play a role in sustaining chronic wounds. Research also indicates therapeutic potential in bacterial and host extracellular vesicles, with applications ranging from vaccine candidates to agents modifying bacterial species in chronic wound biofilms [7]. Patients with biofilms, responsible for 60% of burn-related fatalities and contributing to rapid antibiotic resistance spread, require isolation and specialized treatment before full admission to the hospital [8]. Infections in wounds lead to prolonged healing, chronicity, increased hospitalization, potential amputation, and elevated medical costs; biofilm presence exacerbates these issues, underscoring the critical importance of early detection and treatment for improved outcomes [9]. Implementing a structured assessment framework like the Tissue, Inflammation or Infection, Moisture, and Edge of the wound and Epithelial advancement model can enhance wound care, facilitating the detection of deviations from normal healing, including those arising from species-specific factors, and thereby averting potential delays in recovery or further tissue damage, beyond the influence of intrinsic and extrinsic factors [10]. Macrophages play a crucial role in regulating inflammation, fibrosis, and wound healing, owing to their phagocytic capabilities and secretion of cytokines and growth factors [11]. Growth factors serve as primary human regulators in wound healing, while fibroblasts, highly active cells, play a vital role in tissue fibrosis and the healing process [12]. Additionally, platelets, neurons, and glial cells not only aid in tissue repair but also establish the wound microenvironment, influencing the growth of immune cells, fibroblasts, and keratinocytes [13]. The dynamic expression of Programmed Death Ligand-1 on fibroblast-like cells within the granulation tissue during wound healing serves to establish an immunosuppressive microenvironment, facilitating the modulation of macrophage polarization from M1-type to M2-type and initiating the resolution of inflammation, ultimately expediting the wound healing process [14]. Tryptase, a mast cell mediator, triggers bronchial epithelial cells to enhance migration and proliferation, partially regulated by protease-activated receptor-2, ultimately enhancing epithelial wound healing [15]. Mesenchymal stem cells hold promise for cell-based therapy, primarily relying on their paracrine actions for wound healing and tissue repair [16]. Moreover, adipose-derived mesenchymal stem cell exosomes have recently demonstrated involvement in various wound-healing pathways, particularly aiding in the healing of diabetic wounds [17]. Thymosin-4, a naturally occurring protein abundant in various body fluids and cells, especially platelets, plays pivotal roles in wound healing, actively promoting angiogenesis while inhibiting fibrosis, apoptosis, and inflammation [18].
Herbal medicine is increasingly explored for its diverse therapeutic potential, with certain medicinal plants showing significant wound-healing effects in experimental studies [19]. These herbs, supported by evidence-based medicine, offer viable treatment options in various healthcare contexts [20]. For instance, the ancient text, Sushruta Samhita, highlights various medicinal plants with potential for wound cleansing and healing, although no current published data validate these properties [21]. Traditional Persian medicine also provides valuable insights into natural remedies for wound healing [22]. Additionally, research on wound healing agents is a burgeoning field in biomedical sciences, with Chinese medicinal herbs showing promise, particularly bioactive polysaccharides derived from natural resources [23]. Plants like Acacia modesta, Aloe barbadensis, Azadirachta indica, Ficus benghalensis, Nerium oleander, and Olea ferruginea are extensively utilized for wound healing and demonstrate high use values in traditional practices [24]. Certain herbs like Vitis vinifera, Quercus spp., Punica granatum, Polygonum spp., Lilium spp., Gentiana lutea, Arnebia euchroma, Aloe spp., and Caesalpinia spp. possess verified biological and pharmacological mechanisms for wound healing [25]. Similarly, compounds from the convolvulaceae family such as Evolvulus alsinoides, Evolvulus nummularius, Argyreia cuneata, and Ipomoea carnea exhibit notable antidiabetic and wound healing activity, showing potential in diabetic wound care [26].
Antioxidants such as astaxanthin, beta-carotene, epigallocatechin gallate, delphinidin, and curcumin have shown efficacy in promoting cell proliferation, migration, angiogenesis, and inflammation control, presenting a promising approach for developing innovative treatments for cutaneous conditions [27]. Natural dietary antioxidants rich in flavonoids have been shown to influence keratinocyte physiology demonstrating notable skin repair benefits across different stages of the wound-healing process, including cell-cell and cell-matrix interactions, as well as collagen synthesis [28, 29]. In addition, numerous polyherbal formulations have demonstrated the ability to expedite wound healing in experimental models [30]. The effectiveness of combined herbal medications may be attributed to the synergy of diverse plant classes, each contributing different mechanisms that collectively lead to a more comprehensive therapeutic outcome [31]. These formulations show promise in enhancing wound healing by stimulating various physiological functions, warranting clinical trials for further validation and upscaling production, potentially revolutionizing the development of polyherbal wound healing products [32]. For example, polyherbal formulations like Jathyadi Thailam and Jatyadi Ghritam from Indian traditional medicine demonstrate potent antibacterial and anti-inflammatory properties, suggesting their potential as an external adjunct therapy for chronic wound management, particularly in cases of multidrug-resistant bacterial infections [33]. This review aims to investigate the potential of herbal extractions, their combinations (polyherbal formulations), and new developments in wound healing technology to enhance wound recovery abilities.
Methods
Literature search strategy
Database searches were conducted in PubMed and Google Scholar to identify articles published between 2014 and 2023, focusing on wound healing, herbal wound treatments, herbal wound dressings, nanotechnology, and wound dressings. Studies concerning the efficacy of herbal drugs in wound treatment were included, while non-English publications were excluded. Initially, 103,911 articles were identified. After removing duplicates, unrelated articles, and those with irrelevant titles, 476 articles remained for eligibility assessment. Ultimately, 282 articles were selected for inclusion in this review. Advanced filters in PubMed and Google Scholar were utilized during the screening process, followed by a manual assessment for eligibility. Data extraction was carried out using spreadsheet software like Microsoft Excel and Google Sheets. The flowchart detailing article inclusion is represented in Fig. 1. This review aimed to evaluate the significant effectiveness of medicinal plants in wound care and explore advancements in wound dressing technology to enhance wound healing capabilities.
PRISMA flowchart of included article
Wound healing process
The epidermis, our body’s outermost layer commonly known as the skin, plays a crucial role as a protective barrier, preventing harmful substances, pathogens, and environmental toxins from infiltrating our system [34]. It also plays a pivotal role in temperature regulation, managing heat loss through mechanisms like sweating and blood vessel constriction or dilation [35]. Being the most exposed organ, the skin is susceptible to various forms of injury and damage [36]. Any harm to this protective shield, be it cuts, burns, or wounds, can impair its safeguarding functions [37]. A wound, defined as any injury leading to a break in the skin or mucous membranes, can stem from a range of causes, from abrasions to surgical incisions [38, 39]. Following skin damage, a complex sequence of cellular and molecular events is set into motion, kickstarting the wound-healing process and fortifying the body against infections and further harm [40]. The skin, an intricate organ with diverse cell types, signaling pathways, and functions, makes wound healing a sophisticated undertaking [41]. Effectively enhancing cutaneous wound healing necessitates a diverse array of approaches that acknowledge the intricate nature of the skin and its healing mechanisms [42]. This process hinges on a dynamic interplay of cellular elements, growth factors, cytokines, antioxidants, and essential metal ions [43]. Wound healing, a meticulously organized procedure, seeks to reinstate the skin’s barrier function and mechanical integrity. It unfolds through a well-coordinated series of stages, each playing a pivotal role in repairing tissue damage [44]. Restoring the skin’s integrity and function post-injury is paramount for both wound healing and overall health. This intricate process involves the phased reconstitution of a functional epidermis and other skin layers [45], as depicted in Fig. 2.
Wound healing process (A) Homeostasis: After injury, the body initiates homeostasis to stop bleeding and form a blood clot at the wound site. B Inflammation: The inflammatory phase involves the recruitment of immune cells to the wound to combat potential infections and clear debris. C Proliferation: During this stage, new tissue is generated to fill the wound gap. Cells such as fibroblasts produce collagen to build a new extracellular matrix, and new blood vessels form through angiogenesis. D Remodeling: In the final phase, the wound undergoes remodeling as the newly formed tissue matures and gains strength. Collagen fibers realign, and the wound’s overall tensile strength improves
Comprehensive strategies for wound management
Comprehensive wound management encompasses the intricate multi-stage healing process, distinguishing between acute (pain, redness, warmth, and pus) and chronic infections (slow healing, discolored tissue, clear discharge, pockets, and an unpleasant odor) by their respective symptoms, with Fig. 3 illustrating diagnostic methods to identify wound infections [46]. Optimal wound management prioritizes creating a warm, moist environment to facilitate natural healing, with a strong emphasis on hygiene to reduce infection risks. This comprehensive approach involves crucial steps such as debridement [47,48,49] and the application of advanced treatments including wound bed preparation, antimicrobial dressings, and silver-based products [50,51,52]. In burn cases, topical antimicrobial agents like silver sulfadiazine cream play a pivotal role due to the heightened risk of bacterial infections, however, this approach has faced criticism for potential drawbacks including antimicrobial resistance, delayed healing, and cytotoxic effects on host cells [53]. While advanced therapies like negative pressure, growth factors, hyperbaric oxygen, and skin grafts present viable secondary options [54,55,56,57,58,59,60,61,62,63], their accessibility is limited by high costs and associated complications, including systemic issues, tissue availability, and donor-site morbidity, particularly in resource-poor settings. This underscores the urgent need for affordable wound treatments [64, 65]. Cost-effective clinical dressings like gauze sterilized absorbent cotton, and bandages offer valuable physical protection in wound healing and infection prevention. However, their adherence to the wound can sometimes lead to secondary damage upon separation [66]. Given the constraints of current wound healing agents, there is a critical imperative for the development of natural products to address non-healing wounds [67, 68].
Traditional Herbal Medicines, valued for their cultural significance and minimal side effects, have been esteemed for their proven efficacy, accessibility, growing scientific validation, and commercial viability [69,70,71,72]. These traditional therapies include herbal- and animal-derived compounds, living organisms, and traditional dressings [73]. Medicines with bioactive compounds from traditional sources hold promise in treating chronic wounds by reducing inflammation, promoting re-epithelization, and acting as potent antiseptics, even against antibiotic-resistant bacteria [74]. Herbal products and their active constituents like Aloe barbadensis, Adiantum capillus, Commiphora molmol, henna, Nigella sativa, Teucrium polium, Nelumbo nucifera and Boswellia carteri exhibit superior wound healing effects, surpassing the efficacy of standard antimicrobial agents (e.g., silver nitrate, povidone-iodine, silver sulfadiazine, mafenide, mupirocin, bacitracin) and commercially available wound dressings (Comfeel—hydrocolloid dressing, Kaltostat—alginate dressing) [75]. Ayurveda and folk medicine traditions incorporate potent healing agents like Honey, Ghee, and revered medicinal plants including Glycyrrhiza glabra and Nerium indicum, known for their well-established wound-healing properties with minimal adverse effects [76]. Allium sativum, Aloe barbadensis, Centella asiatica, and Hippophae rhamnoides exhibit potent burn wound healing due to their diverse phytochemical composition engaging in antimicrobial, anti-inflammatory, antioxidant, collagen synthesis stimulation, cell proliferation, and angiogenic mechanisms [77]. Incorporating bioactive natural compounds within wound dressings, in forms like nanofiber, hydrogel, film, scaffold, and sponge, coupled with bio- or synthetic polymers, shows remarkable promise in augmenting wound healing by addressing oxidative stress, inflammation, and microbial activity throughout distinct phases of the healing process [78]. Critical to tissue repair, maintaining proper nutrition with adequate protein, vitamin C, zinc, and hydration is essential [79, 80]. Active patient engagement, encompassing vigilant wound care, infection monitoring, timely dressing changes, and knowing when to seek medical help, plays a pivotal role in the recovery process [81, 82].
Diagnostic methods for identification of wound infections. Note: BPA: Bacterial protease activity; CRP: C-reactive protein; PCR: Polymerase chain reaction; PCT; Procalcitonin, CT: Computed tomography; MRI: Magnetic resonance imaging; PET: Positron emission tomography; SFDI: Spatial frequency domain imaging
Herbs used for wound management
Plant-based medications are gaining prominence for their perceived effectiveness, cost-effectiveness, and safety in treating chronic wounds [83]. Research highlights flavonoids, glycosides, saponins, terpenes, and phenolic compounds as key contributors to herbal remedies’ efficacy in wound management, exerting diverse beneficial effects at different stages of the healing process (Table 1).
Polyherbal a synergistic combination for wound management
Polyherbal compositions, also known as polyherbal therapy, have gained global recognition for their enhanced therapeutic potential compared to individual plant-based treatments, as they harness synergistic effects to amplify medicinal activity while reducing toxicity within specific proportions [144, 145]. This approach offers distinct advantages over single herbal formulations, demonstrating a more potent therapeutic outcome and necessitating lower quantities for desired pharmacological effects, thereby minimizing potential side effects [146, 147]. These collective benefits have substantially bolstered the market appeal of polyherbal remedies. In the context of wound infections, diverse herbal blends tailored for specific effects are available, as detailed in Table 2.
Recent advances in wound dressing technology for enhanced wound healing capacity
A wound dressing applied directly to a wound plays a crucial role in expediting healing and preventing complications associated with untreated wounds [172]. Wound healing involves four primary stages: hematoma creation, inflammation, neotissue formation, and tissue remodeling [173], with the involvement of macrophages being instrumental [174]. There’s been significant development in wound dressings and technologies aimed at enhancing the body’s natural healing and tissue regeneration processes [175]. Nanotechnologies have emerged, offering unique properties to address issues in wound repair mechanisms [176]. In fields like biomedicine, pharmaceuticals, and medicine, there’s a growing emphasis on nano-formulations for wound care, particularly in cases of diabetes-induced wounds [177]. Herbal preparations have gained attention due to their diverse phytoconstituents and broad pharmacological activity compared to synthetic drugs. They are considered safe for extended use, leading to increased focus on designing herbal-loaded wound dressings [178]. Accelerated wound healing has also been associated with various substances including probiotics, food supplements, metal nanoparticles, polymers, and others [179].
Nanoparticle-based materials excel in wound healing due to their antibacterial properties, compatibility with the body, and ability to provide mechanical strength [180]. Soft nanoparticles, derived from organic sources, encompass liposomes, micelles, nanoemulsions, and polymeric nanoparticles [181]. When incorporated into hydrogels, they show potential for enhancing wound healing, offering improved texture, adherence, skin penetration, controlled drug release, and enhanced user comfort compared to traditional forms [182]. While epidermal growth factor (EGF) is highly effective in wound healing, challenges such as vulnerability to enzymatic degradation and maintaining therapeutic levels at the wound site have been significant hurdles. Encapsulating EGF within chitosan nanoparticles has shown promise, significantly increased wound closure rates, and promoted re-epithelialization and collagen deposition, ultimately contributing to a more efficient wound healing process [183]. The use of silver-modified chitosan and alginate-integrated nanoparticles in wound care provides supplementary benefits, including inhibiting bacterial growth, accelerating re-epithelialization, reducing inflammation, and enhancing collagen fiber deposition [184].
Hydrogels, known for their high-water content and excellent flexibility, stand out as highly promising materials for wound dressings. They regulate inflammation by scavenging free radicals, sequestering chemokines, and promoting macrophage transition, thereby promoting effective wound healing [185, 186]. Bioactive polypeptide hydrogel, composed of silk fibroin and angiogenic peptide, demonstrates impressive wound healing capabilities. It effectively reduces inflammation, stimulates angiogenesis, and leads to notable improvements in vessel formation and wound area reduction in a mouse skin wound model [187]. Peptide-based hydrogels, known for their biocompatibility and biodegradability, offer unique benefits in ligand-receptor recognition and stimulus-responsive self-assembly. This makes them highly promising for wound treatment [188]. Stimuli-responsive hydrogels, known as “smart hydrogels,” have gained traction for diabetic wound healing as they possess the unique ability to alter mechanical properties, swelling behavior, hydrophilicity, and permeability to bioactive molecules in response to stimuli like temperature, pH levels, protease activity, and other biological factors [189].
Growth factors hold promise for tissue regeneration, but their instability and rapid clearance from tissues pose significant challenges [190]. Utilizing liposomal drug delivery systems to encapsulate and deliver growth factors has emerged as a potential solution to address these limitations [191]. Liposomes, composed of bilayered lipids, are versatile carriers capable of encapsulating both lipophilic and hydrophilic drugs. This makes them an excellent choice for delivering substances like curcumin effectively [192]. Citicoline-loaded chitosan-coated liposomes have demonstrated remarkable efficacy in enhancing skin wound healing in diabetic rats through a multi-faceted approach, including inflammation reduction, accelerated re-epithelization, enhanced angiogenesis, increased fibroblast proliferation, and improved connective tissue remodeling [193].
Polysaccharide nanofibers, created through electrospinning for wound dressings, hold significant promise for wound healing. They facilitate cell adhesion and proliferation in the wound bed and provide a permeable network structure that mimics the natural extracellular matrix [194]. Polymeric nanofibers are highly prospective as scaffolds for wound healing due to their ability to replicate the extracellular matrix [195]. Another promising avenue lies in hierarchical structure dressings. The top layer, made of hydrophobic polycaprolactone, prevents foreign microbe adherence. The middle layer comprises hydrophilic Janus nanofibers, produced through electrospinning. The bottom layer, consisting of hydrophilic gelatin, creates a moist nurturing environment for the wound [196]. A new class of nanomaterial, electrospun nanofibers, shows great promise in various biological processes. This includes tissue redesigning, using bandages and scaffolds for wound repair, and enabling multimodal drug delivery [197]. Utilizing hyaluronic acid-based nanofibers, which release nitric oxide due to their biodegradable nature, can help control inflammation and eliminate bacterial infections, making it valuable for wound healing [198].
Nanocomposite hydrogels incorporating polymeric micelles offer a dual advantage. They enhance the mechanical, self-healing, and chemical properties of hydrogels while also improving the in vivo stability of the micelles themselves [199]. Polymeric micelles have emerged as a highly auspicious drug delivery platform, particularly for poorly soluble, potent, and potentially toxic compounds. They efficiently encapsulate such molecules [200]. Their strong core-shell structure, exceptional kinetic stability, and innate ability to solubilize hydrophobic drugs make them stand out in this field [201]. Polymeric micelles form through the self-assembly of amphiphilic polymers with both hydrophilic and hydrophobic segments, occurring when polymer concentrations exceed critical micelle concentrations [202]. An innovative approach involves a novel hybrid hydrogel sheet, composed of polyethylene glycol-grafted chitosan and a reactive polymeric micelle. This combination enhances the material’s functionality and improves therapeutic outcomes [203].
A newly developed composite biological dressing, composed of polyvinyl alcohol, carbon nanotubes, and epidermal growth factor, demonstrates a uniformly distributed structure. It effectively releases the epidermal growth factor at a steady rate, creating an environment conducive to expedited wound healing [204]. Even at low concentrations, nanocomposites like carbon nanotube-loaded hydrogels can substantially enhance cell migration within the hydrogel, leading to accelerated tissue regeneration and wound healing [205]. Both single-wall and multi-wall carbon nanotubes, when complexed with chitosan, enhance the re-epithelization of wounds and contribute to increased fibrosis, indicating a positive effect on wound healing and tissue regeneration [206]. The incorporation of zinc oxide nanoparticles and multiwall carbon nanotubes as nanofillers in gellan gum alters the film microstructure, creating a sponge-like texture. This transformation enhances fluid uptake capacity, making it particularly beneficial for wound healing applications [207]. A gold-halloysite nanotubes-chitin composite hydrogel demonstrates dual benefits, exhibiting strong hemostatic activity while also promoting wound healing. This combination maintains low cytotoxicity, making it highly promising for biomedical applications [208]. Advancing the field of biomaterial scaffolds for effective wound healing involves microfabricating biomaterials into various forms, such as 3D-bioprinted structures, microneedles, and electrospun scaffolds [209].
Silicon-based wound dressings, developed into different kinds of scaffolds, are of interest due to their high biocompatibility and mechanical strength [210]. Non-crosslinked collagen-based bi-layered composite dressings have shown promise in promoting wound healing and expediting re-epithelialization [211]. Hydrogels, meticulously designed and prepared to possess specialized qualities, have demonstrated significant promise for skin wound healing [212]. Researchers are increasingly exploring the use of biopolymers in fiber production and their potential applications in wound treatment [213]. Biopolymers like alginate, chitosan, collagen, and hyaluronic acid are frequently employed in wound therapy due to their biocompatibility, biodegradability, and similarity to biomolecules recognized by the human system [214]. The rapidly evolving field of adjustable bioelectronics, with benefits including daily wear, affordability, and easy application, also presents a significant possibility for customized wound therapy [215]. Figure 4 and Table 3 provide examples of advancements in wound dressing technology that have contributed to enhanced wound healing capacity.
Nanotechnology used as drug delivery systems (Created by Biorender.com)
Discussion
Wounds, encompassing damage to skin integrity from incisions, burns, scalds, or specific lesions (e.g., diabetic foot ulcers, venous ulcers, pressure sores) [229], require proper treatment to prevent complications like bleeding, infection, inflammation, and scarring. These complications can impede angiogenesis and tissue regeneration [230]. Effective wound management plays a crucial role in healthcare, as prolonged healing periods can lead to increased burdens on institutions, healthcare professionals, patients, and their families, both economically and socially [231, 232]. Maintaining proper hygiene is foundational in wound care to minimize infection risks. Wound healing therapies, categorized into traditional and modern (skin grafts, modern dressings, bioengineered skin substitutes, and cell or growth factor therapies), vary in efficacy, clinical acceptance, and side effects notably. The wound management process begins with debridement, involving the removal of necrotic tissue, followed by the application of topical treatments like antimicrobial dressings and products containing silver sulfadiazine, which actively promote optimal wound healing [233]. In cases where wound healing stalls, advanced techniques become crucial. These include negative pressure therapy, growth factors, hyperbaric oxygen, and skin grafts [234]. However, it’s important to note that these treatments may come with a higher cost and limited accessibility, particularly in low-resource settings. Additionally, they carry potential risks such as bleeding, infection, barotrauma, and even the potential development of cancer [235, 236]. Silver dressings are highly effective due to their antimicrobial properties, ease of use, and cost-effectiveness in wound healing, however, their application requires careful consideration, as improper usage may lead to potential cytotoxic effects [237]. Biomaterial-based dressings, including grafts and engineered skin substitutes, play a crucial role in restoring tissue function, especially in cases of severe burns or chronic wounds with significant skin loss but these solutions face challenges such as limited vascularity, weaker mechanical strength, and potential risk of immune rejection [238]. Also, cell and growth factor therapy hold promise for regenerating chronic wounds, but the presence of chronic wound fluid can lead to the rapid degradation of growth factors, hindering stem cell proliferation [239, 240]. Similarly, artificial dressings made from polymers can mimic tissue properties, but they may also lack bioactive components critical for optimal wound healing [241]. Considering the limitations of current wound healing treatments, there is a crucial need for the development of natural products to effectively address wound healing [242,243,244]. Traditional therapies hold significant value due to their safety, accessibility, established effectiveness, and natural origins, effectively addressing the drawbacks associated with modern approaches, which often entail high costs, lengthy production processes, and the rising challenge of bacterial resistance [245,246,247,248,249]. Recognizing this potential, the World Health Organization advocates for the integration of traditional methods into formal health systems and underscores the power of phytochemicals in not only combating infections but also in supporting the intricate process of wound healing [250]. Ayurveda attributes unique medicinal properties to individual herbs, yet it believes that combining these herbs, termed polyherbal formulations, in specific ratios and proportions can amplify their therapeutic benefits while reducing potential toxicity [251, 252].
This review offers valuable insights into a diverse range of natural remedies explored for wound healing. When focusing on studies of individual herbs (Fig. 5), a significant number of them were found to belong to the Asteraceae family, followed by the Fabaceae and Leguminosae families in terms of frequency. In the dataset (Fig. 6), the Apiaceae family emerges as predominant, with 24 studies utilizing polyherbal formulations for wound care. It is followed by the Burseraceae and Fabaceae families in terms of representation. When considering both single herbs and those utilized in polyherbal formulations, a total of 72 studies encompassing 127 different herbs (excluding any overlapping herbs) were examined. These herbs were predominantly from the Asteraceae family, followed by the Fabaceae and Apiaceae families (Fig. 7). Noteworthy, herbs with wound healing efficacy belonging to the Asteraceae family include Areca catechu, Calamus draco, Artemisia absinthium, Carthamus caeruleus, Dittrichia viscosa, Echinacea purpurea, Elephantopus scaber, Gynura procumbens, Launaea procumbens, Matricaria chamomilla, Siegesbeckia orientalis, Tridax procumbens, Xanthium strumarium, and Aster koraiensis. Likewise, in another study, the effectiveness of Ageratina pichinchensis and Calendula officinalis in wound healing underscores the potential of Asteraceae plants for the development of impactful wound-healing drugs [253]. Also, Achillea asiatica, commonly known as Asian yarrow, from the Asteraceae family, demonstrates the potential to stimulate wound healing and support the growth of keratinocytes, the predominant cells in the epidermis [254]. Additionally, a study conducted in 2020 focused on the plant’s wound-healing potential reported that the Fabaceae or Leguminosae family exhibited an abundance of herbs beneficial for wound healing [255]. Traditional remedies from the Fabaceae and Rosaceae families have a significant presence among plants used in traditional medicine for various health conditions, including wound care [256].
%age of individual herbs from the same botanical family exhibit wound healing properties
%age of herbs included in polyherbal formulations, which belong to the same botanical family, possess wound healing properties
%age of herbs, found in both individual herb and polyherbal formulation studies, and belonging to the same botanical family, demonstrate wound healing properties across a total of 72 studies, which encompass 127 unique herbs (excluding duplicates)
Figure 8 illustrates the sequential steps involved in evaluating the wound healing efficacy of bioactive compounds extracted from herbs. Among the various plant parts studied for wound healing efficacy, leaves were the most utilized, followed by roots, rhizomes, and fruits. These plant parts were initially extracted using solvents such as ethanol, methanol, and hydroalcoholic solvents. This choice of solvents can be attributed to their wide compatibility, high solubility, moderate toxicity, scalability, cost-effectiveness, and stability. Once bioactive compounds were extracted from different plant parts, they were further assessed using in-vivo rat wound models, including incisions, excisions, deep tissue pressure injuries, burns, and medically induced wounds. Additionally, in-vitro models were employed to measure enzyme levels and conduct various cell assays, representing the diverse mechanisms involved in promoting wound healing efficacy. The review highlighted the significant wound-healing efficacy of phenolic acids, flavonoids, glycosides, and other phytochemicals, contributing to wound-healing activity. They operate through diverse mechanisms, enhancing various stages of wound healing, including upregulating vital factors like VEGF and TGF-β, crucial for re-epithelialization, angiogenesis, granulation tissue formation, and collagen deposition. Other studies reported the presence of diverse polyphenols, alkaloids, saponins, terpenes, essential oils, and polyphenols in various plants positively impacts different stages of the wound healing process [257]. These compounds modulate steps in wound healing, including cell proliferation, fibroblast migration, reduction of oxidative stress, improvement of collagen synthesis, and modulation of the expression of various factors. Flavonoids also positively regulate pathways involved in wound healing [258]. Phytochemicals also act as inhibitors of inflammatory factors, conferring antioxidant and anti-inflammatory effects throughout the healing process [259]. Specific compounds like saponins, flavonoids, and quercetin signify the potential wound-healing properties of certain herbs [260]. Molecular approaches are now gaining importance in understanding the underlying mechanisms of action and assessing potential herbal or synthetic compounds for wound management [261]. Phytochemicals, with their potent antimicrobial, antioxidant, and wound-healing properties, play a vital role in encouraging blood clotting, combating infections, and expediting wound recovery. Medicinal plants rich in polyphenols demonstrate notable efficacy in this regard [262,263,264].
Herb-derived bioactive compounds for wound healing activity (from extraction to evaluation). The diagram illustrates the comprehensive process of harnessing bioactive compounds from selected herbs for wound healing. Primarily utilizing leaves, followed by roots, rhizomes, and flowers, the herbs undergo extraction with specific solvents. The extracted compounds are then utilized to prepare either individual herb formulations or polyherbal blends. These formulations are subsequently evaluated for wound healing efficacy through both in vivo and/or in vitro models, showcasing their diverse mechanisms in promoting wound recovery
Conventional treatments for chronic wounds, like skin grafting or negative pressure wound therapy, may lead to tissue damage or functional restrictions, prompting the exploration of nanobiotechnology, an interdisciplinary field integrating engineering, chemistry, and biology, for innovative biomedical applications [265]. By incorporating nanoparticles, both biopolymers and synthetic polymers have been tailored for use as wound dressings, addressing contemporary wound care challenges including tissue repair, scarless healing, and tissue integrity [266]. This review emphasizes advancements in utilizing nanotechnology-based wound dressings in herbal-based formulations to enhance targeted drug delivery and accelerate recovery. These innovative drug delivery systems, benefiting from high stability, extensive surface area, and customizable compositions, have shown promise in both in vitro and in vivo models. Materials for wound dressing include electrospun nanofiber guar gum and polyvinyl alcohol-based matrices, sodium alginate nanofiber mats, cellulosic textile nanoemulsions, polycaprolactone nanofibers with silver nanoparticles, and chitosan-polyvinyl alcohol hydrogel microneedles. In other studies, advanced techniques utilizing nanoparticles and hydrogels loaded with bioactive molecules and non-bioactive substances, particularly smart hydrogels, hold promise for enhancing diabetic wound healing. These approaches can be further enhanced with technologies like photothermal therapy, layer-by-layer self-assembly, and 3D printing [267]. Nanotechnology provides molecularly designed nanostructures for both therapeutic and diagnostic use in burns, categorized as organic and non-organic (e.g., polymeric and silver nanoparticles), with many exhibiting multifunctional properties [268]. Self-assembled nanomaterials, serving as wound dressings and growth factor carriers, characterized by superb biocompatibility and versatile functionalities like mimicking extracellular matrix, drug delivery, and adjustable mechanics, offer promising therapeutic prospects for chronic wound healing [269]. With rising clinical demands, botanical applications are increasingly integrating with nanotechnologies. This fusion, particularly through electrospinning, creates nanofibrous membranes ideal for skin wound healing [270]. Noteworthy breakthroughs in tissue regeneration and skin wound therapy, including 3D-printing, cell-imprinted substrates, nano-architectured surfaces, and gene-editing tools, hold substantial promise for advancing burn wound therapies [271].
Perspectives and future direction
Numerous preclinical research on herbs with shown wound healing properties have been undertaken. Several clinical studies employing single herbs or effective herb combinations have demonstrated efficacy in the therapy of wounds. Here, in “Table 4,” are some of the clinical experiments that were done to create safe medications (herbal or polyherbal formulations) and ensure the quickest recovery period. To achieve this and lessen the significant challenges associated with conducting clinical studies, an appropriate research design that mimics the wound conditions is needed. Future research is required to understand how these herbs’ isolated compound helps wound linked with disease heal and to develop new formulations containing herbal extracts and phytochemicals that will lessen the risk of medication resistance and drug allergies or many other associated factors that interfere with wound healing.
Conclusion
This critical overview highlights the multifaceted roles of medicinal plants in advancing wound healing technology. The rich repository of bioactive compounds found in these plants offers a promising avenue for promoting tissue regeneration, combating infections, and reducing inflammation. By leveraging the therapeutic potential of medicinal plants, we can address the complex challenges associated with wound care. There is a need for in-depth studies to unravel the specific mechanisms of action underlying the wound-healing properties of individual bioactive compounds in medicinal plants. This understanding will pave the way for the development of targeted interventions tailored to different types of wounds. Collaborative efforts between traditional healers and scientific researchers can lead to the identification of novel wound-healing agents and innovative treatment approaches.
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Pathak, D., Mazumder, A. A critical overview of challenging roles of medicinal plants in improvement of wound healing technology. DARU J Pharm Sci 32, 379–419 (2024). https://doi.org/10.1007/s40199-023-00502-x
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DOI: https://doi.org/10.1007/s40199-023-00502-x