Medicinal plants and their components for wound healing applications

Wound is an anatomical and functional disruption of the skin following an injury. In response to the injury, wound healing is a complex process of tissue repair or remodeling. Historically, plants and plant-based constituents have been extensively used for the treatment and management of different types of wounds. In the current times, different types of biopolymers are being researched for developing economical, sustainable, stable, and effective delivery system for the treatment of wounds. The present review article attempts to enlist medicinal plants which have been reported to be effective in the treatment of wounds. Plant constituent-based wound dressings have also been discussed systematically including patented formulations reported by different inventors. The compiled data aims to update the researchers/scientists which will be helpful in providing them a directional view in understanding the role and importance of plant-based components for the treatment and management of wounds.


Background
Medicinal plant materials and herbal remedies derived from them represent a substantial portion of the global medicinal market. Herbal remedies and drugs have played a significant role in curing diseases throughout the history of mankind. Though a large amount of literature is available on their curative properties, standard procedures for quality control of plant materials with respect to their identification (phytochemical, pharmacological, and therapeutic activity) are not available. Standardization of medicinal plants ensure their consistency and therapeutic effectiveness. Herbal products are evaluated for their identity (characterization), quality, and quality of the extracts present, as it is required to evaluate their therapeutic efficacy, i.e., to know their pharmacological action to evidence authenticity [1]. Herbal medicines have the potential to treat and cure illnesses like ulcers, healing of wounds, skin infections inflammation, scabies, leprosy, and venereal disease [2].. Herbal medicines in wound treatment or care include disinfection, debridement, and providing a moist atmosphere which facilitates development of appropriate natural healing climate. Folklore cultures employ a significant number of plants to treat cuts, wounds, and burns [3,4].
A wound is a disruption of living tissue's cellular, anatomical, and functional integrity caused by physical, chemical, electrical, or microbial threats to the tissue [5]. Wound healing is defined as a complex process occurring by regeneration or reconstruction of damaged tissue [6]. The normal response to wound healing is a concerted sequence of events that begins with an injury. When platelets come into contact with exposed collagen, the healing cascade is initiated, causing the accumulation of platelets as well as the release of coagulating factors which in turn result in the formation of a fibrin clot at the injury site. The fibrin clot functions as a temporary matrix which sets the tone for activities that accompany healing [7]. Inflammatory cells, along with the platelets provide essential signals known as cytokines or growth factors; also arrive at the injury site [8]. The fibroblast is the connective tissue responsible for collagen deposition that is needed to fix tissue damage. Collagen provides strength, integrity, and structure in normal tissues. Collagen is required to repair the defect and restore anatomical structure and function when tissues are damaged after injury [9,10]. If healing does not progress stepwise in the usual way, then it can lead to chronic growth of wounds. Reported patents and articles state that various herbal formulations help accelerate the wound healing process and are useful in its treatment. Medicinal plants such as Curcuma longa (L.), Terminalia arjuna, Centella asiatica, Bidens Pilosa, Aloe barbadensis, and Rauwolfia serpentine have confirmed wound healing activity and are found to be effective in the treatment of wounds.
The review article starts with the classification of wounds followed by various factors affecting the wound healing process along with the mechanism have been explained systematically. Various medicinal plants and their herbal components effective in the management and treatment of wounds have been suitably discussed in text and tabular form. Finally, plant-based dressing and the patented technologies have also been listed.

Classification of wounds
Wounds are generally classified according to the underlying cause of the development of wounds.

Acute wounds
In acute wounds, there is tissue damage/injury that generally occurs through an orderly and time-reparative phase that results in the anatomical and functional integrity being restored sustainably. Acute wounds are typically caused by the cuts or surgical incisions [11].

Closed wounds
The blood escapes from the circulatory system in closed wounds but stays inside the body. It becomes evident in the form of bruises.

Open wounds
Blood leaks from the body through an open wound and bleeding is clearly noticeable. The open wound may be divided further into categories according to the source causing the wound.

Incised wounds
This is a wound with no loss of tissue and minor damage to tissue. It is caused primarily by sharp objects like a scalpel or knife.

Tear or laceration wounds
This is the non-chirurgical injury in conjunction with other types of trauma which results in tissue loss and damage.

Puncture wounds
These are caused by an object which, like a nail or a needle, which punctures the skin. Since dirt may penetrate deep into the wound, chances of infection are common in them.

Abrasive or superficial wounds
Sliding slip onto a rough surface induces abrasion. During this time, abrasion is scraped off the top layer of the skin, i.e., epidermis which exposes nerve endings resulting in a painful injury.

Penetration wounds
Penetration wounds are chiefly caused by an object like a knife going in and out of the skin.

Gunshot wounds
They are typically produced by bullet or similar projectile which drives through or into the body.

Chronic wounds
Chronic wounds are wounds that have not gone through the usual healing stages and hence reach a state of pathologic inflammation. They need extended healing time [12].

Factors affecting wound healing Oxygenation
Oxygen is essential for the metabolism of cells, particularly the production of energy through ATP, and is necessary for almost all wound healing processes. It protects wounds from infection, causes angiogenesis, increases differentiation of keratinocytes, migration and re-epithelialization, improves proliferation of fibroblasts and synthesis of collagen, and facilitates contraction of wounds. The microenvironment of the early wound is deprived of oxygen and is very hypoxic owing to ingestion by metabolically active cells. Several systemic disorders will produce reduced vascular flow, including advancing age and diabetes, thereby setting the stage for inadequate oxygenation of the tissue. This superposition of inadequate perfusion produces a hypoxic wound in the sense of recovery. Chronic wounds are hypoxic in particular; tissue oxygen concentrations were measured transcutaneous in chronic wounds of 5 to 20 mm Hg, relative to control tissue concentrations of 30 to 50 mm Hg.

Infections
Micro-organisms that are typically sequestered on the skin surface gain access to the underlying tissues until the skin is wounded. If the wound is listed as having inflammation, colonization, local invasion/critical colonization, and/or spreading invasive infection determines the state of infection and replication status of the micro-organisms. Contamination is the presence of non-replicating microbes on a wound, while colonization is characterized as the presence without tissue damage of replicating microorganisms on the wound. An intermediate stage is local infection/critical colonization, with proliferation of microorganisms and the beginning of local tissue responses. The involvement of replicating organisms inside a wound with subsequent damage to the host is known as invasive infection. Inflammation is a natural part of the woundhealing process and is necessary for the elimination of micro-organisms that are infected. However, inflammation can be prolonged in the absence of successful decontamination, because microbial clearance is incomplete. The sustained elevation of pro-inflammatory cytokines such as interleukin-1 (IL-1) and TNF-alpha will contribute to both bacteria and endotoxins and elongate the inflammatory process. The wound can reach a chronic state and refuse to heal if this persists. In addition, this prolonged inflammation contributes to an elevated level of matrix metalloproteases (MMPs), a protease family that can degrade the ECM. A decreased level of the naturally occurring protease inhibitors occurs in combination with the increased protease content. This change in protease equilibrium may cause the rapid deterioration of growth factors that occur in chronic wounds.

Age
The elderly population (people over 60 years of age) is growing more than any other age group (a significant risk factor for delayed wound healing is the World Health Organization and elevated age). Several cellular and molecular-level clinical and animal studies have explored age-related changes and delays in wound healing. It is widely accepted that the impact of aging induces a transient pause in wound healing in stable older people, but not a genuine disability in terms of the consistency of healing.

Stress
Stress has a considerable influence on human well-being and social behavior. Stress is associated with multiple disorders, such as cardiovascular disease, cancer, compromised wound healing, and diabetes. Several studies have reported that stress-induced neuroendocrine immune equilibrium dysfunction is critical for well-being. Stressors can contribute to harmful mental conditions, such as depression and anxiety, which can in turn alter physiological mechanisms and/or behavioral behaviors that affect health outcomes. Stressed people are more likely to have risky behaviors, including irregular sleep schedules, insufficient diet, less exercise, and a higher risk for consumption of alcohol, nicotine, and other medications, in addition to the direct effects of anxiety and depression on endocrine and immune function.

Body type
Body form can also influence the healing of wounds. For instance, an obese patient can experience a compromise in wound healing due to low adipose tissue blood supply. In addition, there is protein malnutrition in some obese patients, which further impedes recovery. Conversely, the absence of oxygen and nutrition stores can interfere with wound healing when a patient is emaciated.

Chronic diseases
A few of the chronic conditions that can compromise wound healing include coronary heart disease, peripheral vascular disease, stroke, and diabetes mellitus. To have the right plan, patients with chronic illnesses should be monitored closely through their course of care.

Vascular insufficiency
Various wounds or ulcers-such as arterial, diabetic, pressure, and venous ulcers-can affect the lower extremities. Decreased blood supply is a common cause of these ulcers. The clinician must identify the type of ulcer to ensure appropriate topical and supportive therapies.

Nutrition
Food has been recognized for more than 100 years as a very significant aspect that impacts wound healing. The most apparent thing is that malnutrition or specific nutritional shortages following trauma and surgery can have a profound impact on wound healing. Special nutrients are also needed in patients with chronic or non-healing wounds and with nutritional deficiencies. The metabolism of energy, carbohydrates, proteins, fats, vitamins, and minerals will all affect the healing process [13].

Mechanism/pathophysiology of wound healing
Wound healing is a complex mechanism that can be categorized as an allergic response, propagation, and remodeling in three parallel phases. The inflammatory process initiates a proliferative wound repair response further characterized by vascular responses like blood coagulation and hemostasis. Cellular activities include leukocyte infiltration with the release of antimicrobials and cytokines. During the proliferative process, the epithelium is formed to coat the wound surface with the subsequent growth of granulation tissue to fill the wound space. The generation of granulation tissue includes fibroblast proliferation, collagen deposition as well as other extracellular matrices, and the development of new blood vessels [14]. The remodeling process begins to restore structural integrity and functional competence to the tissue when the new tissue is established inside the wound. The 3 stages of wound healing, however, are not simple linear procedures, but instead, vary in time. Acute wounds, like burns, other severe injuries, and wounds sustained by surgery, relate to those injuries that heal quickly. An example of a typical acute wound is a neat and uninfected incisional surgical wound approximated by operative sutures. While the desired end product of organized healing is tissue production with similar structure and functions as with retained skin, but regeneration is rare (with significant exceptions, such as early fetal healing). Thus, healing results in an outcome that is structurally and functionally adequate but not equivalent. Wound healing processes tend to be strictly regulated at the wound site by various growth factors and cytokines released. Changes that interfere with regulated timely healing processes increase tissue damage and delay recovery [15].
The different phases (inflammatory phase, proliferative phase, remodeling phase) of wound healing are described in Fig. 1. Blood-borne cells-neutrophils, macrophages, and platelets-play crucial roles during the coagulation and inflammatory phases (A) of the healing. These cells provide the growth factors and interim matrices required for the recruitment into the wound bed of epidermal and dermal cells. The proliferative process (B) starts around 3 days after injury and is characterized by increased rates of proliferation, migration, and extracellular matrix (ECM) synthesis of keratinocytes and fibroblasts in response to autocrine, juxtracrine, and paracrine growth factors. In this process, angiogenesis/neovascularization occurs too. The tissue has a granular texture (granulation tissue), due to the involvement of blood vessels. Eventually, inside the granulation tissue, differentiated fibroblastic cells (myofibroblasts) begin to remodel the extracellular matrix at about 1 to 2 weeks after injury. Extracellular matrix remodeling accompanied by resident cell apoptosis leads to an acellular scar formation [17,18]. Medicinal plants and their metabolites used in the treatment of different types of wounds are depicted in Table 1.

Traditional use of medicinal plants in wound healing
For more than 5000 years, Egyptians, indigenous peoples of Africa, Asia, Romans, and the Americas have used medicinal plants as first-line therapy for inflammation, burns, ulcers, and surgical wounds. They contain many natural bioactive compounds that help fasten the process of wound healing and regenerate tissue at the wound site. Some examples of medicinal plants and their wound healing effects are listed below [50].

Centella (Centella asiatica)
This was also known as Asian pennywort, used to facilitate healing of wounds. To facilitate the healing of the chronic ulcers in terms of their distance, depth, and scale, extracts from the Centella asiatica aerial sections are reported. Asiaticoside isolated from the Centella asiatica has been shown to promote epithelialization and collagen deposition in a punch type wound. Centella asiatica isolated triterpenes improve collagen remodeling and the synthesis of glycosaminoglycans. In addition, it has been shown that oral administration of madecassoside from Centella asiatica promotes collagen synthesis and angiogenesis at the wound site [51].

Turmeric (Curcuma longa)
Curcumin has been used as a remedy and as a food seasoning for many years, being an active agent found in the Curcuma longa root and a member of the ginger tribe. Curcumin is used by conventional Ayurvedic medicine practitioners to treat asthma, respiratory diseases, liver disorders, diabetes, and skin injury [52]. Curcumin is a popular remedy in traditional Chinese medicine for stomach pain. Curcumin has been commonly used for decades by different ethnic groups and are among the most widely studied nutraceuticals. A highly pleiotropically molecule has been shown to interact at transcription, translation, and post-translation levels with key cellular pathways. Proinflammatory cytokines, apoptosis, NF-yB, cyclooxygenase 2, 5-LOX, STAT3, C-reactive protein, prostaglandin E2, cell adhesion molecules, phosphorylase kinase, β-transforming growth factor, triglycerides, ET-1, creatinine, heme oxygenase-1, AST, and ALT are found in the goal pathways. Experimental findings from various in vivo trials and in vitro tests show that by altering the pericellular and extracellular matrix, curcumin produces much of its beneficial effects. It may not be surprising, therefore, that curcumin stimulates fibroblast proliferation, the development of granulation tissue and the deposition of collagen in the healing of cutaneous wounds [53].

Bay (Sphagneticola trilobata)
Plant, Wedelia trilobata, also known as Sphagneticola trilobata, was originally native to the tropical Americas; however, it is now widespread in the tropics as one of the world's most invasive plants. Extracts of alcohol from the Wedelia trilobata leaves have been used to treat rheumatism, persistent wounds and sore arthritic joints. Luteolin, a flavonoid in the leaves, has been shown to contribute to Wedelia trilobata medicinal benefit, conferring neuroprotective, anti-cancer,  antioxidant, and immunomodulatory activities. Traditional healers treat skin wounds using the Wedelia trilobata leaves. Luteolin inhibits the expression of NF-κBregulated proinflammatory cytokines, a characteristic feature of skin infection and psoriasis. In a study designed to validate this traditional use, Balekar et al. [54] fractionated ethanolic extracts from the leaves of Wedelia trilobata and assayed them in vitro. Specific subfractions were found to support fibroblast viability, proliferation, and migration. Different subfractions were also found to be active against Staphylococcus aureus and Staphylococcus epidermidis.

Aloe (Aloe vera)
Aloe vera comprises of many natural bioactive compounds, including basic and complex such as glycosides, polysaccharides, saponins, pyrocatechol, anthraquinones, acemannan, phytol, oleic acid, and water-soluble polysaccharides. Acetone extracts from Aloe vera leaves show greater antimicrobial activity than that of alcohol and aqueous extracts. Aloe vera tends to be more susceptible to gram-positive bacterial species than gram-negative species. Saponins, acemannan, and anthraquinone derivatives are compounds with a proven antimicrobial activity. Acemannan, a large Aloe vera mucopolysaccharide (mesoglycan), is an effective stimulator for the operation of macrophages and T cells and induces the transcription of proinflammatory mRNAs (including IL-1af, IL-1β, IL-6, TNF-af, PGE2, and nitrous oxide). Mesoglycan moieties bind and absorb endogenous mitogenic inhibitors and species of reactive oxygen, which promote phagocytosis. Coincidentally, glycans stabilize, prolonging their function, the secreted cytokines, growth factors, and other bioactives [39,55]. Topically applied acemannan, acting through cyclin D1 and AKT/mTOR signaling pathways has been documented to significantly reduce the time for wound closure [56].

Burdock (Arctium lappa)
This, generally referred to as burdock, is a commonly grown perennial weed. Arctium lappa is used in the treatment of sore throats and skin pathologies such as boils, rashes, and acne in North America, Europe, and Asia. In a clinical trial, the antioxidant, antimicrobial, anti-inflammatory, anti-diabetic, antiviral, anti-cancer, and hepatoprotective effects of Arctium lappa were detected. It has been shown that Arctium lappa root extract greatly enhances dermal ECM metabolism, affects glycosaminoglycan turnover and decreases visible in vivo wrinkles in human skin. Arctium lappa has also been reported to control cell adhesion and gene expression in canine dermal fibroblasts, influencing the Wnt/β-catenin signaling pathway, known to be a key wound cure regulator. In a pilot study of one medical drug, namely, Arctium lappa, burns and wounds topical ointment (B&W), discomfort and healing of human first and seconddegree burns was found to be handled more efficiently than the control procedure [57].

Ginseng (Panax ginseng)
In China, Japan, Korea, and Eastern Siberia, it is one of the most popular medicinal plants consumed. It is also assumed that recollection increases immunity and physical agility and reduces fatigue. Therefore, Panax ginseng is used to cure depression, anxiety, and chronic fatigue disorders. It has been shown that Panax ginseng causes vasodilatation, controls blood lipids, decreases inflammation, and confers antioxidant, anti-cancer, antibacterial, anti-allergic, anti-aging, and immunomodulatory capacity [58]. Panax ginseng comprises many bioactive compounds, of which the most potent active constituent of Panax ginseng is a family of saponins (called ginsenosides by Asian researchers and panaxosides by Russian scientists). Panax ginseng root extracts have been shown to protect the skin from acute UVB irradiation and significantly improve healing following laser burning and excisional wound injury. Studies indicate that extracts of Panax ginseng strengthen keratinocyte migration and induce proliferation and in vitro increase collagen production in human dermal fibroblasts. It has also shown, however, that ginsenoside Rb2, isolated from Panax ginseng, induces the development of epidermis in raft culture by increasing epidermal growth factor and receptor expression, fibronectin and the receptor, and keratin and collagenase I, all of which play vital/critical roles in wound cure [59].

Neem (Azadirachta indica)
In wound dressing, it was well known as anti-ulcer, antifungal, antibacterial, antiviral, anticancer, and antioxidant. Viji et al. [60] evaluated nitric oxide scavenging activity in RAW 264.7 cell lines. The nitric oxide concentration was found to be 10 μg/mL in wells with collagen integrated with 1000 μg/mL of neem extract in them. The biocomposite film has good anti-inflammatory activity and nitric oxide scavenging activity. In further tests, the authors performed the antioxidant activities and the biocompatibility test using the neem-incorporated collagen film RAW 264.7 cell lines. The integrated collagen films of the neem extract (400 μg/mL) showed an 80 percent increase in the operation of DPPH scavenging and had a cell viability of more than 80 percent via MTT assay. Researchers examined the capacity for electrospinning four different plant extracts, namely, A. Indica, Indigofera aspalathoides, Memecylon edule (ME), PCL for skin tissue engineering, and Myristica andamanica. A cell proliferation test was used to determine the capacity of human dermal fibroblasts (HDFs) to live on nanofibrous scaffolds, and F-actin and collagen staining evaluated the relationship between HDF and scaffolds. The proliferation of HDF on M from the experiments was apprehensible. The PCL integrated by Edule was the lowest of all and was 31 percent higher than PCL nanofibers after 9 days. M. Edule-incorporated PCL had better cell density, and sufficient cell to cell contact was verified by F-stain analysis. Collagen staining showed that the extracellular matrix (ECM) was secreted by the cells in M. Edule-incorporated PCL. M. Edule extract containing nanofibers has also served as a slot for stem cells that supports epidermal differentiation markers found by separating epidermal lines from human adipose derived stem cells (ADSC) [61].

German chamomile (Chamomilla recutita)
Researchers studied the effect of nanofibrous membranes of electrospun poly caprolactone/polystyrene (PCL/PS) as chamomile-containing active wound dressings. Therapy qualities C. Recutita (L.) Rauschert, a member of the Asteraceae family, is present because of specific phenolics and flavonoids, apigenin, quercetin, patuletin, luteolin, and their glucosides. Apigenin is the rarest flavonoid in chamomile flora and has a remarkable effect on the wound healing process. Studies of antibacterial and antifungal in vitro demonstrated nanofibers' efficacy against microorganisms, Bacteria S. aureuas, and C. Albicans (fungi) with inhibitory zones approximately 7.6 mm in diameter. MTT assay demonstrated the adhesion of in vitro cells and the viability of mesenchymal stem cells on the nanofibers. The nanofibers, according to the authors with 15 percent chamomile extract, up to 99 ± 60.5 percent of the wound could be cured after 14-day post-treatment periods which were confirmed using a rat wound model. This wound examination showed the accretion of reepithelization and collagen in the dermis tissue, and also the absence of necrosis [62]. Different types of dressings loaded with herbal constituents for the treatment/management of wounds are shown in Table 2. Patents on herbal formulation for wound healing Phillip Roy et al. 2010 [75] patented that honey could be used in dressings. The dressing consists of an alginate fiber sheet with honey completely impregnated into the fiber sheet. As a result, the dressing has porous surfaces and the dressing becomes gel-like when the exudate gets absorbed upon application to the wound. This patent includes 11 claims describing how honey is impregnated into the dressings. It can be used for treating acute as well as chronic wounds. Michael Koganov et al. 2013 [76] patented "Bioactive compositions from theacea plants for the treatment of wounds and cuts." The invention relates to the bioactive topical formulation containing the bioactive fractions from theacea plants. The bioactive fraction from theacea plants shows anti-inflammatory action on the skin and normalizing skin damage or tissue injury.
Suresh Balkrishna et al. 2013 [77] patented a "Novel herbal composition for the treatment of wound healing." Their innovation includes a new, synergistic, herbal composition as a regenerative medicine consisting of a mixture of therapeutically efficient quantities of extracts obtained as a basis from Curcuma longa, Glycyrrhiza glabara, Hamil tonia suaveolens, Tipha angustifolia, and Azadirachta indica, as well as an optional basis consisting of Pig fatin Sesamum indicum (Til) oil, useful for wound cure care.
Parveen Walia et al. [78] patented a "Multifunctional natural wound healing matrix" which consists of a wound pad made of hydrophilic cotton fabric coated on one side with zwitterionic low molecular weight chitosan and lined with organic-synthesized silver nanoparticles on top. Curcumin particles and tulsi extracts are used to further improve their properties with herbal medicinal principles and to have a synergistic impact with all the ingredients working together to provide better results for healing.
Suresh Balkrishna et al. [79] also patented "A regenerative medicine, the herbal composition for the treatment of wound healing." This herbal composition is a combination of therapeutically effective amounts of extracts obtained from Curcuma longa, Glycyrrhiza glabara, Hamil tonia suaveolens, Tipha angustifolia, and Azadirachta indica, mainly used for the treatment of wounds and wound therapy. This includes 27 claims and 6 drawing sheets shows testing on different wounds. The invention shows novel synergism and effective composition of herbs as a regenerative medicine. This also offers a preparation method for the herbal composition.
Another scientist, Melikoglu et al. [80], patented "Herbal formulation for topical wound treatment" in this interval with new herbal formulas, which have proved beneficial for the topical treatment of skin wounds and oral mucosal wounds. For the preparation, a solution or gel composed of poly hexamethylene biguanide as an anti-microbial agent and poloxamer as an emulsifier and a product includes at least one herbal ingredient (Comfrey Symphytum officinale L. extract and/or Commiphora molmol tincture) with analgesic, antibacterial, antifungal, and anti-inflammatory effects can be used to enhance analgesic, antibacterial, and anti-inflammatory effects. Poly hexamethylene biguanide (PHMB) was used as a protective agent, algaecide, bactericide/bacteriostatic, fungicide/fungistatic, and microbicide/microbiostatic.
Kerri-Anne et al. [81] patented a "Topical herbal formulation" particularly suitable for the treatment of wounds and skin disorders. This comprises of Gotu kola (Centella asiatica), Figwot (scrophularia nodosa), yarrow (Achillea millefolium), Plantago major, and Echinacea purpurea. The formulation has both anti-inflammatory and anti-microbial properties. It was found particularly effective as a synergistic healing agent in the treatment of wounds, prevention of scar formation, and promotion of hair regrowth in the wound area. It was also found suitable for the treatment of general skin disorders in humans including eczema and nappy rash.
Kenneth A. et al. [82] invented and patented "Buckwheat honey and bacitracin wound-healing dressing." The invention has been found efficacious in the treatment of acute and chronic wounds and skin conditions and regeneration of skin and/or dermal tissue in a chronic wound. The product comprises a composition or formulation mixture of buckwheat honey and bacitracin. In one unique embodiment, the composition is gelled. The composition is applied directly to a wound or a patient's skin or is impregnated on gauze or other similar material on a bandage or dressing for application to an exuding or non-exuding acute or chronic wound or skin condition.
Dinesh Upendra et al. [83] patented "Herbal oil formulation for topical use and medicinal applications thereof." The invention includes a herbal oil solution based on Heterophragma roxburghii bark extract, which can be used topically and can be used to manage and repair numerous skin abnormalities and infections, all types of wounds, and other medical problems associated with diminished human and animal blood supply. The topical herbal oil formulation is an important natural curing therapy for different medical conditions such as, but not limited to, diabetic gangrene, dry gangrene, wet gangrene, athlete's foot, burn wounds, diabetic foot ulcer, bedsore, untreated open wounds, snakebite wounds, and cellulite-formed gangrene.
Mikolaj Tomulewicz et al. [84] patented "Herbal preparation for accelerating wounds and skin inflammations healing and its application." The invention involves a medicinal preparation that can be used in the treatment of wounds and skin inflammation. The herbal Use of honey in dressings Honey of preferred consistency and viscosity is envisaged and will be used in combination with a variety of medicinal and suitable surgical dressings and will be used as a wound healing buffer.
[ 75] 2. US 2013/ 0146481 A1 Boiactive compositions from theacea plants and processes for their production and use The innovation is based on isolated bioactive compounds comprising theoretical plant bioactive fractions. This procedure is also meant to prevent inflammatory behavior along with shielding a mammal's skin tissue from damage caused by UV light and also normalizing skin disorders.
[ This invention concerns modern herbal formulas, which are particularly useful for topical treatment of skin and oromucosal wounds. Formulations may be either a solution or a gel form consisting of an anti-microbial agent, polyhexamethylene biguanide, and poloxamer amer.
In the shape of an emulsifying agent and product that contains at least one herbal ingredient (Comfrey Symphytum officinale L. extract and/or Commiphora molmol tincture), which has analgesic, antibacterial, antifungal and anti-inflammatory properties to increase the treatment of the wound. [80] 7. WO 2019/ 078931 Al Buckwheat honey and bacitracin woundhealing dressing A means of treating acute and chronic wounds and skin disorders and regenerating skin or dermal tissue in a chronic wound is the latest innovation. A synthesis or preparation containing a mixture of buckwheat honey and bacitracin is used in the substance. The composition is gelled in one distinctive encarnation. The composition is applied directly to the wound or skin of the patient or impregnated with gauze or other similar material on the bandage or dressing for application to an acute or chronic wound or skin condition that is exuding or non-exuding. The present disclosure concerns a formulation of herbal oil based on Heterophragma roxburghii bark extract, which can be applied topically and can be used to treat and cure different skin conditions and diseases, all types of wounds, and other therapeutic conditions associated with decreased human and animal blood flow. For various therapeutic conditions such as, but not limited to, diabetic gangrene, dry gangrene, wet gangrene, athlete's foot, burn wounds, diabetic foot ulcer, bed sore, chronic open wounds, snake bite wounds, and gangrene formed due to cellulitis, the disclosed topical herbal oil formulation provides an inexpensive alternative healing therapy. preparation is distinguished by the fact that the preparation includes emulsified or suspended Melittis melissophyllum L. organic medium extract. Ten percent to 40% w/w and % to 20% w/w ethyl alcohol. Vaseline album was used as an organic medium in the case of an ointment from 40% to 70% w/w, 2% w/w triethylamine 2% w/w, hydroxy cellulose 1% w/w and filtered water, aqua purificata, from 30% to 35% w/w. Milind Omkar et al. [85] patented "Wakeri (Wagatea spicata Dalzell) for wound healing." The invention comprises Wakeri-fortified Kampillakadi Tailam/oil. The Wakeri fortification comprises oil extract of root bark powder of Wakeri being a component in the Kampillakadi oil. Kampillakadi oil being a medicinal oil comprising oil extract of Vavding, Kutaj, Kapilla, Trifala, Patolpatra, Bala, Nimsal, Lodhra, Nagarmotha, Charolya, Khadirsal, Dhayatiphul, Agaru, and Chandanadded with Sarjaras. The invention also includes a composition comprising Wakeri-fortified Kampillakadi oil for topical application; the compositions comprise (a) a tulle, (b) an ointment, (c) a liniment, (d) a capsule, (e) a wound healing spray, (f) a cream, and (g) a gel. The invention pertains to wound healing properties of Wakeri (Wagatea spicata Dalzell) Wight synonym of Moullava spicata (Dalzell Nicolson) with Kampillakadi Tailam (CHARAK SAMHITA CHIKITSA STHANAM). Table 3 enlists various plant constituent based patented technologies for wound healing applications.

Conclusion
Wound healing from ancient times remains a challenging clinical issue for effective wound treatment. Wound healing involves multiple populations of cells, the extracellular matrix and the action of soluble mediators like growth factors and cytokines. Much research has been centered on wound care, with emphasis on new therapeutic methods and the advancement of acute and chronic wound treatment techniques in Ayurveda (herbal). New formulas, dressings, and medicinal plant composition are being explored by researchers for developing cost effective, efficient, stable, and sustainable delivery system for the management/treatment of wounds. With the advent of nanotechnology and availability of novel materials, wound management is becoming more effective and patient-centric. Newer technologies like 3D printing are also providing advantageous options for developing different drug delivery systems for managing wounds. Tissue engineering and regenerative medicines are the futuristic view of technologies for developing wound healing systems. Better quality control techniques for identification, screening, and quantification herbal components along with well-designed pre-clinical and clinical studies will open new research gateways in wound care management.