Flavonoids and wound healing as an orchestrator of anc scar formation: a Flavonoidd of the literature. Many studies are currently being conducted to determine the effect of flavonoid-rich dressings on scar-free regeneration. Gan TJ.

Flavonoids and wound healing -

National Library of Medicine. Toggle navigation MyMedR. Browse Help Login. Fulltext Flavonoids as Potential Wound-Healing Molecules: Emphasis on Pathways Perspective. Zulkefli N 1 , Che Zahari CNM 2 , Sayuti NH 1 , Kamarudin AA 3 , Saad N 4 , Hamezah HS 1 Show all authors , Bunawan H 1 , Baharum SN 1 , Mediani A 1 , Ahmed QU 5 , Ismail AFH 6 , Sarian MN 1.

Int J Mol Sci , Feb 27;24 5. MeSH terms. Results: Fifty-five 55 articles met the established inclusion and exclusion criteria. Flavonoids presented effects in respect of the inflammatory process, angiogenesis, re-epithelialization and oxidative stress. They were shown to be able to act on macrophages, fibroblasts and endothelial cells by mediating the release and expression of TGF-β1, VEGF, Ang, Tie, Smad 2 and 3, and IL Moreover, they were able to reduce the release of inflammatory cytokines, NFκB, ROS and the M1 phenotype.

Conclusion: Flavonoids are useful tools in the development of therapies to treat skin lesions, and our review provides a scientific basis for future basic and translational research. Keywords: Chronic wounds; Flavonoids; Natural products; Skin lesions; Wound healing.

Abstract Background: Flavonoids are a class of compounds with a wide variety of biological functions, being an important source of new products with pharmaceutical potential, including treatment of skin wounds.

Background: Dodonaea Vibrant vegetable salads Jacq. However, wwound date Flavohoids is no experimental evidence on its flavonoid-rich Flavonoids and wound healing of D. viscosa formulation as an agent for healing wounds. Objective: The present study aimed to evaluate the wound healing effect of ethyl acetate fraction of D. viscosa leaves on dermal wounds.

Flavonoids and wound healing -

Toggle navigation MyMedR. Browse Help Login. Fulltext Flavonoids as Potential Wound-Healing Molecules: Emphasis on Pathways Perspective.

Zulkefli N 1 , Che Zahari CNM 2 , Sayuti NH 1 , Kamarudin AA 3 , Saad N 4 , Hamezah HS 1 Show all authors , Bunawan H 1 , Baharum SN 1 , Mediani A 1 , Ahmed QU 5 , Ismail AFH 6 , Sarian MN 1.

Int J Mol Sci , Feb 27;24 5. The most common scar removal methods are laser or hormone treatment, but these treatments are costly and have side effects 7. If scarring could be prevented immediately throughout the wound healing process, patients would suffer less.

Researchers have made numerous explorations in this direction in recent years, and a variety of dressings have emerged, loaded with growth factors, stem cells, extracellular vesicles, and other substances to induce tissue regeneration.

However, due to uncontrollable potency or dysregulated stem cell differentiation, it is often difficult to move to the clinic, and research often focuses on rapid healing at the expense of controlling post-healing complications 8 , 9.

Empirical and anecdotal evidence support the use of herbs in encouraging wound healing, and extensive research into the effect and mechanism of herbs in tissue regeneration is underway However, because of the complicated compound composition, current research tends to focus more on the special natural compounds that are more easily controlled, inexpensive, and biocompatible Hemostasis, inflammatory response, proliferation, re-epithelialization, and remodeling are five processes in the wound healing process that are all regulated by multiple signaling pathways that recruit immune cells, fibroblasts, stem cells, and endothelial cells for repair in response to changes in the regenerative environment 12 , These cells work together to trigger signaling pathways such as transforming growth factor-β1 TGF-β1 that regulate fibroblast proliferation, migration, and collagen synthesis, resulting in fast healing and scarring Flavonoids are a class of molecules that are extensively found in plants and consist of C3-C6-C3 linked carbon chains with two benzene rings, which are classified based on how the two benzene rings are joined, their structure, and the hydroxylation or glycosylation of the benzene rings However, a good drug delivery platform that exerts a gradual local release, enhances bioavailability, and improves the physicochemical features of the drug itself, such as water-solubility, is required for clinical translation of flavonoids for scar-free regeneration Biomaterial drug delivery can improve water-solubility, provide sustained release systems, and enable targeted medication delivery by encapsulating drugs, as well as provide many advantages of their own Ideal biomaterials have antibacterial, anti-inflammatory, and hemostatic properties in addition to providing scaffold and room for cell growth The hydrogel dressing exemplifies the advantages of biomaterials, including absorbing exudate from wounds and providing a moist, sterile environment for wound healing Electrostatic spinning technology utilizes electrostatic fields to synthesize nanofiber biomaterials, enhancing the surface area to volume ratio, encouraging cell adhesion and aggregation while reducing bacterial invasion, inflammatory factor expression, scar tissue development, and improving skin tensile strength As novel bio-encapsulation materials, cellulose-based nanoparticles have excellent biocompatibility and facilitate cell-tissue contact with porous architectures to achieve diverse effects such as antibacterial, drug delivery, and wound healing There are also a variety of materials that act as a barrier to aberrant fibroblast adhesion and invasion, allowing for scar-free regeneration However, biomaterials alone lack good efficacy in inducing scarless regeneration on their own, and biomaterials combined with induction factors are a better match Therefore, we review the current state of flavonoid dressing research, as well as the five dimensions of flavonoids in wound healing: anti-inflammatory antioxidant, antibacterial, antifungal, and regulation of fibroblasts, as well as the current mechanisms of action for flavonoids in scarless regeneration.

In addition, we discuss the benefits of biomaterials that release flavonoids, especially some advancements of scar-free regeneration. The mechanism of action of many natural compounds is better understood thanks to the molecular docking experiments and other methods, and the major functional group action features can be gradually generalized.

This, combined with the multifunctional biomaterials, will aid in the realization of ideal scar-free regenerative treatments. Flavonoids have the sibling nucleus flavanone 2-phenylchromanone and are built on a flavonoid backbone of C6 A ring -C3 C ring -C6 B ring , where the hydrogen in the backbone is usually replaced by different groups such as hydroxyl, methoxy, and glycosyl groups, which affect their biological activity Depending on the backbone structure and hydroxyl group position, flavonoids, including orangiferin, apigenin, quercetin, catechin, and silymarin, can be classified as flavones, flavonols, flavanones and so on As secondary metabolites of plants, flavonoids are widely distributed in plants; for example, quercetin is abundant in rutin and hawthorn, apigenin in high amounts in chamomile, catechins can be recovered from green tea, and Silybum marianum is produced from the fruits of the plant Silybum marianum.

Meanwhile, flavonoids are also widely found in foods such as legumes, fruits, and vegetables, beverages, and especially in herbal medicines. With the development of biotechnology, the purification of flavonoids has become easier and faster Natural flavonoids have been discovered to exhibit a wide range of biological and pharmacological activities, including antioxidant and anti-inflammatory capabilities, as well as anticoagulant, antiplatelet, anti-obesity, and immunomodulatory properties Similarly, flavonoids derived from plants such as buckwheat have been shown to efficiently lower blood glucose levels and have anti-diabetic properties Flavonoids can also interfere with cell signaling pathways during tumor invasion and growth, lowering cancer risk by preventing tumor cell proliferation and differentiation Furthermore, study of flavonoids, such as epigallocatechin gallate EGCG , in the field of wound healing have been proved and reviewed comprehensively.

Hemostasis, inflammation, proliferation, re-epithelialization, and remodeling are the five basic stages of wound healing, and regulating these processes is expected to achieve scar-free regeneration Bleeding is unavoidable after a skin injury, and then the body triggers a coagulation reaction to stop the bleeding in the first place Neovascularization promotes tissue regeneration and remodeling by delivering nutrients and oxygen to the tissues External factors that negatively influence these processes, such as bacterial infections and oxidative stress, contribute to the formation of scarring Following that, we will discuss the mechanisms by which flavonoids promote wound healing and reduce scarring through anti-inflammatory, antioxidant, antibacterial, antifungal, and fibroblast modulation, respectively Figure 1.

Figure 1. The five major effects of flavonoid-laden dressings are: the hydroxyl substituents of flavonoids can inhibit bacterial nucleic acid synthesis, cell membrane function, and energy metabolism to provide antibacterial functions, as well as the phenolic hydroxyl groups can combine with reactive oxygen species ROS to adsorb surrounding free radicals and exert an antioxidant effect.

Flavonoids can reduce inflammatory factors, regulating fibroblasts, inhibiting extracellular matrix ECM deposition, and promoting scarless healing. Flavonoids can also be antifungal by interfering with folate metabolism and inhibiting biofilm formation. ATP, adenosine triphosphate; ADP, adenosine diphosphate; CD80, cluster of differentiation 80; CD86, cluster of differentiation 86; TGF-β1, transforming growth factor-β1; THF, tetrahydrofolate; DHF, dihydrofolate; dTMP, deoxythymidine phosphate; dUMP, deoxyuridine phosphate; ECM, extracellular matrix; NADPH, nicotinamide adenine dinucleotide phosphate.

Damaged tissues and clots in wounds will attract inflammatory cells, promoting the absorption and evacuation of necrotic tissue and foreign substances The initial recruited neutrophils trigger the inflammatory response by releasing chemokines, which attract mononuclear macrophages and other innate immune cells to clear cellular debris and microorganisms, and these immune cells eventually leave or undergo apoptosis after the foreign substances are cleared and eliminated Early activation of the inflammatory response aids wound healing, but in order to eliminate the foreign substances quickly, the body responds with an abnormally hyperactive anti-inflammatory response TGF-β1 and platelet-derived growth factor, both released by macrophages and others, activate fibroblasts, and scarring is exacerbated by excessive collagen production or impaired regression For scarless regeneration, regulating inflammation during wound healing is critical Nuclear factor kappa κB NF-κB is a transcription factor that increases the expression of many pro-inflammatory genes in cells, regulates protein kinases, and has a direct impact on cell activation and proliferation 43 , The cytokine interleukin IL promotes the release of the inflammatory factor tumor necrosis factor-α TNF-α from immune cells Flavonoids can affect the expression of genes, including NF-κB and IL They also have been proven in numerous clinical trials to considerably reduce TNF-α Furthermore, flavonoids have inhibitory effects on phosphodiesterases, delaying the expression of cyclic AMP cAMP , a key pro-inflammatory messenger In addition, flavonoids have long-term effects on immune cell activation and maturation According to studies, macrophages are the key target cells for the anti-inflammatory actions of flavonoids.

Whereas, on dendritic cells, flavonoids can block cluster of differentiation 80 CD80 and CD86, which results in the inhibition of dendritic cell maturation 49 , Flavonoids such as apigenin have been shown to have anti-inflammatory properties by decreasing NO release from macrophages and considerably lowering levels of pro-inflammatory cytokines IL-6 and TNF-α Flavonoids may also modulate inflammation selectively, such as EGCG, which is hypothesized to have a pro-inflammatory effect when the level of inflammatory makers is low and a counter-inflammatory effect as inflammatory markers rise These efficacies are better attuned to the various stages of wound healing and help to reduce scarring.

During the inflammatory response phase of wound healing, platelets accumulate in large numbers at the wound site and activate neutrophils and macrophages, while the expression of NADPH oxidase in these cells increases dramatically NADPH is produced by neutrophils and macrophages via NADPH oxidase, which converts molecular O 2 in the phagosome to superoxide radical anions, which are rapidly dismutated to hydrogen peroxide H 2 O 2 , and these chemically active oxygen-containing molecules combine to form reactive oxygen species ROS Moderate or basal levels of ROS can maintain normal cellular function and homeostasis and are thought to be crucial for local clearance of foreign bodies by macrophages, but an over-activated inflammatory response can induce excessive levels of ROS ROS have active electrons and are highly reactive in nature, reacting immediately with a wide range of chemicals High levels of ROS near the wound site inhibit cell growth, damage proteins and nucleic acids, cause apoptosis, and prolong the inflammatory process, all of which contribute to scarring Furthermore, high amounts of free radicals cause fibroblasts to convert to the adherent type, which promotes scarring by increasing collagen synthesis and deposition Antioxidant enzymes are able to be activated in a physiological environment, breaking free radicals and reducing ROS, and their increased levels can provide adequate conditions for wound healing.

Flavonoids have phenolic hydroxyl groups, and the hydrogen atoms on these groups can combine with ROS radicals to generate flavonoid radicals, which attract more radicals to complete the reaction and protect tissue cells from free radical damage The flavonoid catechin has more than 20 times the antioxidant potential of vitamin C Atala et al.

Furthermore, flavonoids inhibit the expression of ROS synthase-related genes or up-regulate the expression of antioxidant synthases Silymarin, a polyphenolic flavonoid lignan, in a random group of patients with type 2 diabetes, and compared to those taking placebo, the oral silymarin group increased superoxide dismutase, glutathione peroxidase activity, and total antioxidant capacity by When compared to controls, patients with pulmonary tuberculosis who received a combination of catechins and antituberculosis showed a significant increase in blood levels of reduced glutathione, an antioxidant effect that plays an important role in the human oxidative stress mechanisms In addition, the levels of ROS metabolites such as F2-isoprostaglandins are considerably reduced when flavonoids are consumed over time 69 , Wound infection is a major issue during the healing of skin defects, and the emergence of drug-resistant bacteria poses a challenge for wound debridement and antibacterial agents Escherichia coli E.

coli and Staphylococcus aureus are common bacteria that cause wound infections, the metabolic substances produced by these bacteria cause inflammation and exudation, for example, the overproduction of matrix metalloproteinases MMPs attracts more inflammatory neutrophils into the wound, impeding the growth and migration of cells in the basal skin layer, while a large influx of fibroblasts repairs the void and forms proliferative scars Furthermore, the bacterial metabolite lipopolysaccharide LPS is able to significantly reduce local macrophage recruitment to the wound, inhibit wound collagen deposition, and increase apoptotic cells in both the dermis and granulation tissue at the wound edges, resulting in a sustained inflammatory response and prolonged wound healing However, some current antibacterial ingredients may have an impact on the physiological activity of normal cells, for example, silver causes cytotoxicity to keratin-forming cells and fibroblasts subsequently impairing wound healing and leading to scars Cushnie et al.

reviewed that flavonoids exert antibacterial effects through three mechanisms of action: suppression of bacterial nucleic acid synthesis, cell membrane function, and energy metabolism For example, flavonoids can inhibit pore proteins on the bacterial outer membrane to directly affect the activity of E.

coli , which is equivalent to cutting off the energy source of E. coli such as glucose and amino acids Flavonoids also protect cells by inhibiting bacterial adherence to cells and reducing the production of bacterial toxin products Clinical studies have shown that using flavonoid-rich mouthwash reduces the oral plaque index and the number of Streptococcus mutans bacteria, effectively inhibiting the formation of dental plaque biofilm Acne patients used quercetin patches versus placebo preparations on the right and left sides of their faces, respectively, and after 8 weeks, the quercetin group had a Meanwhile, in animal models, Vikram et al.

treated rats infected with Salmonella typhi with the flavonoid naringenin and found that naringenin specifically inhibited 24 genes in the pathogenicity island of Salmonella and attenuated the virulence and cell motility viability of the bacteria In addition to inhibiting bacterial activity through direct inhibition, flavonoids have been shown to exert synergistic effects with antibiotics, such as inhibiting the expression of β-lactamases that produce antibiotic resistance in bacteria To inhibit drug resistant bacteria, flavonoids can serve as inhibitors of bacterial efflux pumps and virulence factors, for example, quercetin strongly reduces extracellular matrix targeting to disrupt E.

coli colonic biofilms, whereas apigenin restores antibiotic susceptibility to drug-resistant bacteria and limits the spread of drug-resistant bacteria by activating the host innate immune system Also, flavonoids have antibacterial effects in slightly alkaline conditions.

The phenolic hydroxyl groups of EGCG are deprotonated and microorganisms are scavenged by redox processes in buffer solutions with pH values near to or greater than the pKa of EGCG pH 7. Fungi can quickly invade burns and severely traumatized skin wounds, resulting in widespread wound infections Fungal cell walls are made up of many layers of carbohydrates such α-mannan and β-glucan α-Mannan binds to dendritic cell-associated C-type lectin-2 dectin-2 , activates the NF-κB pathway, induces overproduction of the inflammatory cytokine TNF-α, and inhibits angiogenesis and myofibroblast proliferation Natural flavonoids of plant origin can cause apoptosis and reduce biofilm formation, resulting in antifungal actions via multi-targeting Flavonoids destroy fungal biofilms by blocking the essential enzyme isocitrate lyase ICL , which permits Candida albicans to exist and proliferate in a nutrient-limited environment within phagocytes such as macrophages and neutrophils, resulting in cell shrinkage and internal component leakage Meanwhile, flavonoids can inhibit the folic acid synthesis pathway and prevent fungal reproduction.

Navarro-Martinez et al. co-cultured EGCG with dihydrofolate reductase from Candida albicans at various concentrations and found an inhibition constant Ki of 0.

Furthermore, clinical trials utilizing a rutin-rich plant ointment to treat canine wounds revealed much higher wound retraction rates than controls, as well as powerful antifungal activity against Candida krusei around the wounds The amount of collagen accumulated was proportional to the number of mobilized fibroblasts The proportion of En1-positive and negative fibroblasts in skin defects is the main cause of scarring En1-positive fibroblasts are activated by inflammation, ROS, bacteria, and wound tension Furthermore, recruitment of deeper dermal fibroblasts, which are larger, slower to proliferate, and secrete vast amounts of collagen fibers while inhibiting collagen degradation through reduced release of cellulase, occurs when wounds are deeper and under greater tension The activation of these pro-scar-forming fibroblasts is a mechanism for the organism to protect against infection and recover quickly, yet scars can become a repair endpoint due to the large synthesis and deposition of extracellular matrix In addition to regulating inflammation, ROS, and infection during wound healing, flavonoids are also engaged in how to enhance healing without producing excessive fibrosis and scar formation.

Flavonoids have been proven in studies to lower TGF-β1 and IL-1β production, limit extracellular matrix ECM secretion, and prevent excessive fibrous connective tissue deposition For example, while maintaining the viability of fibroblasts, safranin inhibits TNF-α expression, reduces ECM protein synthesis and improves wound healing Pinocembrin, the most abundant flavonoid compound in propolis, has anti-fibrotic properties, inhibiting TGF-β1 signaling and impairing TGF-β1-induced proliferation and activation of abnormal skin fibroblasts, effectively alleviating bleomycin an antibiotic -induced excessive skin fibrosis Furthermore, quercetin treatment of mice wounds resulted in the same duration and rate of wound healing as the control group, but with less ECM deposition in vivo , and quercetin was able to modify effective adhesion and migration of fibroblasts as well as resist scar tissue fibrosis Transforming growth factor-β TGF-β , which comes in three types: TGF-β1, 2, and 3, is the most essential regulatory factor in tissue repair.

TGF-β1 is highly expressed in adult wound healing, but TGF-β3 is broadly expressed in newborn and child wound healing TGF-β1 and TGF-β3 share receptors but have opposing roles in scar repair TGF-β1 stimulates fibroblast activation, proliferation, and anti-apoptosis by phosphorylating smad proteins and facilitating cell aggregation at the wound site TGF-β1 activation also boosts fibroblast collagen fiber synthesis while lowering collagenase activity, and TGF-β1 stimulates fibroblasts to develop into myofibroblasts, which compress the wound and induce scar formation Specific TGF-β1 inhibitors are currently being developed, but TGF-β1 serves a crucial physiological function in cells, direct blockage will result in aberrant cell behavior such as apoptosis Natural compounds have many groups on them, and different groups play different roles, forming hydrogen bones, π bonds, or other forces with various genes to enhance or inhibit their expression.

The capacity of catechins to selectively regulate TGF-β1 and TGF-β3 expression is promising, but the exact mechanism must be explored in its organic form Transforming growth factor-β1 TGF-β1 can also activate phosphatidylinositol 3-kinase PI3K , which causes activation of protein kinase B Akt , and an abnormally active Akt will promote proliferation and motility of fibroblasts and speed up the formation of proliferative scarring Signal transducer and activator of transcription 3 STAT3 is important for fibroblast proliferation, migration, and collagen synthesis EGCG was discovered to influence fibroblast proliferation and migration primarily through its inhibitory effect on STAT3, which causes reversible cell cycle when inhibited by PI3K and STAT3 inhibitors Activin receptor-like kinase 5 Alk5 is also involved in scar formation, and Alk5 knockdown in a wound healing model resulted in a considerable reduction in scars When TGF-β1 is active, Alk5 is activated in a cascade, and transcription of pro-fibrosis genes begins At lower doses 5.

Integrins αV and β1 control fibroblast proliferation, migration, and the production of extracellular matrix Focal Adhesion Kinase FAK is an essential step in the integrin-mediated signaling cascade during integrin-extracellular matrix interactions, and it promotes wound healing to form scars FAK knockout mice had much lower levels of fibrosis and inflammation, as well as less scarring.

FAK inhibition has emerged as a unique strategy for preventing scarring Quercetin and other antioxidants have been demonstrated to increase integrin αV expression while lowering integrin β1 in dermal cells by phosphorylating two sites, and , of the FAK complex Furthermore, the sarcoma gene Src is a complex kinase that frequently works in a functional protein complex with FAK.

Src inhibition resulted in decreased myofibroblast and macrophage aggregation, as well as a significant reduction in extracellular matrix deposition and scarring Molecular docking investigations revealed that flavonoids like quercetin, apigenin, and catechin have a high binding energy to Src ; Figure 2.

Figure 2. Flavonoids promote scar-free regeneration by regulating signaling pathways. Catechin, by binding to Scr, reduces extracellular matrix deposition and enhances scar-free wound healing. FAK, Focal Adhesion Kinase; Src, Sarcoma gene; Erk, Extracellular regulatxory protein kinase; MAPK, Mitogen-activated Protein Kinase; Alk5, Activin receptor-like kinase 5; PI3K, Phosphatidylinositol 3-kinase; Akt, Protein kinase B.

When flavonoids are utilized alone to regenerate tissue, they frequently encounter issues such as limited water solubility, low bioavailability, and unstable physicochemical qualities.

Encapsulating chemicals with biomaterials can improve their water solubility and stability, make them easier to absorb in the body, avoid premature degradation, and prolong circulation time.

Furthermore, after being bioencapsulated, these chemicals will effectively target recipient cells, improve their penetration in damaged tissues, and increase therapeutic bioavailability, lowering toxicity Therefore, the use of flavonoids and other chemicals in combination with biomaterials is predicted to improve drug water solubility, increase drug loading, provide a sustained-release platform, and enable targeted administration.

Quercetin and rutin, two frequently used flavonoids, have limited water solubility and difficulties penetrating the lipid bilayer of cell membranes, limiting their bioavailability despite their anti-inflammatory and anti-oxidative stress properties in wound healing.

Cyclodextrins contain hydrophobic interior and hydrophilic external structures, and with the help of water-soluble external surfaces, they can form highly soluble inclusion complexes.

By freeze-drying and solvent evaporation, Başaran et al. prepared inclusion complexes of quercetin and rutin with hydroxypropyl—cyclodextrin, and in vitro tests revealed that the concentrations of both in aqueous solution increased from 1. Polyphenols such as EGCG, curcumin, and resveratrol are stable in acidic environments but degrade in neutral or slightly alkaline environments, whereas nanoparticles can encapsulate bioactive compounds to improve permeability of cell membranes.

And when nanoparticles are used to encapsulate polyphenols, their pH stability, water solubility, bioavailability, anti-inflammatory, and antioxidant bioactivities are all improved, and drug degradation is prevented For example, poor water solubility, low absorption, and quick enzymatic degradation limit curcumin, a polyphenolic molecule, in vivo Topical application of pure compounds has a short duration of action, low stability, and can cause undesirable side effects, whereas sustained release of bioactive drugs can maintain drug levels in vivo for a long time with little changes Chitosan CS is a natural, biodegradable, and biocompatible macromolecular molecule.

In vitro release results of chitosan nanoparticles CS-NPs prepared by the ionic gelation method as an effective carrier for quercetin revealed that the release of quercetin was The ionic interaction between quercetin and CS may be responsible for the prolonged release feature Meanwhile, Bose et al.

The pace of discharge comes to a halt between 24 and 30 h. This technique boosted skin tissue repair by prolonging the effect of quercetin in wounds Due to its instability and pH sensitivity, EGCG, a physiologically active tea polyphenol in green tea, has a high rate of breakdown and limited bioavailability in vivo.

To maximize drug bioavailability, it is necessary to facilitate targeted drug administration. Encapsulating the drug in biomaterials and surface functionalization, such as aptamer modification, are two methods for achieving targeted drug delivery.

Furthermore, depending on the parameters of the milieu, such as the pH of the microenvironment, or with the addition of external auxiliary light and heat, bioactive substances can be supplied to the target region to boost therapeutic effects and prevent adverse effects Due to rapid metabolism, quercetin, as one of the most prevalent flavonoids, has low targeting efficacy.

It does not easily concentrate intracellularly and is easily and quickly eliminated by the organism. The synthesis of phenylboronic acid conjugated zinc oxide nanoparticles PBA-ZnO using 3-carboxyphenylboronic acid PBA as an aptamer for targeting tumors would serve as an effective carrier for quercetin, while ZnO nanoparticles tend to accumulate in the acidic tumor microenvironment but have limited penetration.

The slightly alkaline conditions retain the hydroxyl groups of quercetin ionized, increase tumor cell death, and inhibit the proliferation of murine breast cancer cells, so this technique can successfully target quercetin delivery to sialic acid overexpressing cancer cells CD44 has a significant affinity for hyaluronic acid HA and is overexpressed on the surface of different tumor cells.

Mu et al. created HA-EGCG as an adriamycin delivery vehicle by incorporating EGCG into a CDmodified HA backbone with disulfide links. Targeting EGCG to tumor locations boosts the tumor treatment effect of adriamycin and magnifies the effect of oxidative stress Fucoidan is found in a variety of marine species, most often isolated from brown algae, and exhibits anti-inflammatory, antioxidant, and anti-cancer properties.

EGCG can be successfully administered to macrophages via the dual-targeted binding method of CS and HA to macrophages. Furthermore, photothermal treatment has a higher tissue penetration rate and is used in active drug delivery systems.

By combining the tumor-targeting molecule folate FA with silver nanoparticles AgNPs loaded with quercetin QRC , Bose et al. prepared folate receptor-targeted silver nanoparticles QRC-FA-AgNPs and the fluorescence intensity of target cells cultured with QRC-FA-AgNPs was much higher than cells cultured with AgNPs alone, effectively promoting targeted drug delivery and achieving combined therapeutic effects, providing a new idea for targeted drug therapy As such, in combination with induction actions such as drugs, their extra anti-inflammatory and antibacterial properties should result in a beneficial wound healing impact Chitosan has high biocompatibility and promotes cell attachment and proliferation.

Vedakumari et al. prepared chitosan-fibronectin composite scaffolds loaded with quercetin, and found that a large number of fibroblasts and epithelial cells migrated to the wound site, that fibroblasts proliferated faster, that the time required for complete wound epithelialization decreased from 29 to 16 days, and that the scaffolds had good bactericidal activity against E.

coli and Staphylococcus While adjuvant decellularized dermal matrix ADM collagen scaffolds can serve as effective carriers for quercetin and their high porosity can increase the contact area between cells and the scaffold surface and accelerate mesenchymal differentiation, functionalization of graphene oxide GO with PEG to synthesize GO-PEG nanocarriers can improve drug delivery efficiency but poor cell induction.

Croitoru et al. used electrostatic spinning to create a quercetin fiber scaffold matrix based on polylactic acid PLA and GO, and electron microscopic observations revealed that cultured L fibroblasts increased in density, adhered uniformly to the scaffold in a circular shape, and reached a maximum survival rate of Many of the ways outlined above demonstrate the significant benefits of biomaterials for drug administration, which can increase drug bioavailability and stability while also promoting tissue regeneration and wound healing.

By obtaining a large number of polymers and bioactive compounds from natural resources such as plants, modern wound dressings have developed various types of antibacterial dressings, such as hydrogels, films, scaffolds, fibers, sponges, and other biomaterials, which provide excellent wound healing effects Biomaterials can also mimic the extracellular matrix and influence cell behavior such as migration and proliferation, resulting in a moist, sterile wound healing environment that promotes tissue regeneration synergistically Many studies are currently being conducted to determine the effect of flavonoid-rich dressings on scar-free regeneration.

In chronic deep second degree burns infected with Pseudomonas aeruginosa , catechin-loaded nanocollagen dressings exhibited antibacterial and pro-angiogenic properties, and regeneration of skin appendages and orderly collagen tissue alignment were seen, which may be the result of selective modulation of TGF-β1 and TGF-β3 by catechins One study combined flavonoids into lipid nanoemulsions, which increased the viability of keratin-forming cells and their ability to migrate to wounds, accelerating scar-free skin regeneration In a rat wound model, adding isoflavone glycosides to the nanoemulsion increased keratinocyte viability up to concentrations of 0.

TNF-α content was also decreased, which reduced the inflammatory response while promoting re-epithelialization and angiogenesis in skin tissue Furthermore, after treating human skin wounds with quercetin-encapsulated nanoemulsions and hydrogels, mature collagen fibers were regularly oriented in parallel and well-organized reticular dermis, and the wound surface produced an intact epithelial layer with covering scars Jin et al.

created quercetin-modified silicone gel sheets and tested them on a rabbit ear skin wound model, finding lower expression of type I and type III collagen as well as more effective inhibition of fibroblast proliferation in scar tissue Wu et al.

prepared soluble microneedles using cyclodextrin metal-organic scaffolds loaded with quercetin and encapsulated with fibroblast membranes, which were dispersed in HA polysaccharide, a modification with the ability to target fibroblasts, providing a new strategy for drug delivery systems in proliferative scars Surgical adhesions are scar that form within tissues as a result of surgical procedures, infections, and other factors, leading to severe organ malfunction and chronic discomfort, as well as a significant financial burden on the healthcare system Dressings containing flavonoids have demonstrated good effects in terms of inflammatory, infectious, and anti-fibrotic effects on the adhesion development process.

Shin et al. used a poly lactide-co-glycolide PLGA electrospun scaffold loaded with EGCG, and the dressing showed equivalent anti-adhesive effects to commercial tissue adhesion barriers while being cost effective Lee et al.

also found that the EGCG-loaded PLGA barrier film inhibited fibroblast growth and adhesion as well as macrophage release of pro-inflammatory cytokines, resulting in good anti-abdominal adhesion effects After lumbar laminectomy, Huang et al.

created an electrostatically spun membrane with polyhexolactone and collagen, into which icariin was loaded as an anti-adhesion barrier membrane. The opening in the unloaded icariin grouped barrier membranes was filled with a substantial amount of fibrous tissue, but the loaded icariin barrier membranes recovered effectively and had an excellent anti-adhesive action.

The electrostatic spinning membrane not only organized fibroblast penetration and adhesion, but it also offered a good platform for the flavonoid icariin to limit drug release and reduce fibroblast growth and collagen deposition Skin injuries happen every day, and the scars that remain after the lesion heals cause regret in both cosmetic and physiological aspects.

There is a plethora of research on the speed of skin injury recovery, much of which focuses on the treatment of chronic infected wounds, with scar-free regeneration receiving less attention.

While numerous multifunctional dressings have demonstrated outstanding results in anti-inflammatory, antibacterial, antioxidant, and angiogenic functions to date, fibroblast regulation and antifibrosis have received less attention. Future dressings will be more targeted as the mechanics of scarogenesis are better understood and the genes that regulate scarogenesis are revealed.

Natural substances provide a plethora of possibilities for scar-free regeneration. Due to their phenolic hydroxyl groups, flavonoids are believed to be a strategy for scar-free regeneration through antioxidant, antibacterial, anti-inflammatory, and anti-fibrotic activities during wound healing.

Molecular docking can correctly predict the effective conformational areas and locations of action of drugs Finding the primary sites of action of compounds that have the same effect can be helpful in the creation of novel medications.

The extraction and separation of certain chemicals from flavonoids is also a significant barrier to their utilization. Flavonoids are mostly found in plants as glycosides and free sapogenins, and crude extracts are obtained by using organic solvents like methanol and concentrated by rotary evaporator, followed by separation and characterization of pure bioactive compounds by liquid chromatography and spectroscopy, for example, quercetin from ethyl acetate extract However, raising the temperature during the extraction process can increase the water solubility of alcohol contaminants and interfere with the rate of flavonoid leaching.

Moreover, high temperatures may promote oxidation and breakdown of the structure of flavonoids, resulting in a decrease in their extraction rate.

How to decrease the impact of temperature and other external influences while efficiently isolating quercetin, catechin, and other pure components have become a pressing issue for us to explore. In addition to the extraction of flavonoids, it is critical to distinguish between the hydrophilic and hydrophobic qualities of certain flavonoids.

For example, the flavonol quercetin is hydrophobic, whereas the flavane-like catechin is water soluble. Clarifying flavonoid water solubility qualities is essential for investigating the corresponding hydrophilic or hydrophobic encapsulation carriers, crosslinking synergistically to boost drug release, and improving flavonoid bioavailability.

Furthermore, the subject of biomaterials is quickly evolving and confronts numerous obstacles, such as mass production, biosafety, and biodegradability. Hydrogels and extracellular matrix, for example, can all play a scaffolding function in wound healing and can also help with drug dissolution and targeted distribution.

However, it is debatable whether the potential cytotoxicity of biomaterials and the possibility of biomaterials interfering with the anti-scarring effect of flavonoids. The application of some ingredients may play a negative role in promoting scar formation, such as silver, with its good antibacterial effect and remarkable efficacy in promoting wound healing, but its potential toxicity to cells can exacerbate scar formation.

As such, more research is also needed to determine the optimum flavonoid-biomaterial combinations. Fortunately, several clinical investigations on the use of flavonoids for scar-free regeneration are currently underway.

In comparison to direct injection of epidermal growth factor, EGCG dramatically decreased human scars in vitro , exhibiting a good trend of improving scar thickness and skin flexibility Commercial use has also been granted to certain flavonoids-containing gels, such as cumene glycosides.

As research develops, the biological properties of flavonoids will be further clarified, and their combination application with biomaterials will become one of the ideal alternatives for scar-free regeneration of skin wounds.

Flavonoids are abundant and widely available in nature, and their anti-inflammatory, antibacterial, and antioxidant properties contribute to their antitumor and antidiabetic medicinal value. The antioxidant effect of phenolic hydroxyl groups formed by the benzene ring and the hydroxyl groups in flavonoids has been shown to be important in promoting wound healing, but little attention has been paid to the role of flavonoids in modulating scar production.

Consequently, the therapeutic identification of compounds with healing action may differ depending on the stage of the healing process.

Anti-inflammatories steroidal and non-steroidal and chemotherapeutics antiseptics and antibiotics are two often-used treatments that have a substantial influence on wound healing Guo and DiPietro, However, they are expensive and risky, sometimes ineffective; adverse effects are often observed.

As a result, herbal therapy emerges as an alternative technique for wound care Budovsky et al. The use of various herbs and traditional medicine should also be economical in the face of escalating healthcare costs. Hence, research is essential to understand proper utilization of this nature throve to increase the number of armamentariums in advanced wound care techniques.

Flavonoids are secondary metabolites of polyphenolic in nature. Flavonoids have fifteen carbon skeletons consisting of two benzene rings connected by a heterocyclic pyran ring.

Flavonoids are categorized as flavanones, flavones, isoflavones, flavonols, flavanol, and anthocyanin Figure 1. These compounds are coupled with multifaceted health benefits ensue from their bioactive properties, such as anti-inflammatory, anticancer, anti-aging, cardio-protective, neuroprotective, immunomodulatory, antidiabetic, antibacterial, antiparasitic, antiviral and wound healing properties in humans Fraga et al.

Several studies have demonstrated the significance of flavonoids as wound healing agents attributed to their antioxidant, antimicrobial and anti-inflammatory properties.

Furthermore, flavonoids influences the inflammatory process, angiogenesis, re-epithelialization and oxidative stress and also stimulates the macrophages, fibroblasts and endothelial cells through the expression of TGF-β1, VEGF, Ang, Tie, Smad 2 and 3, and IL Carvalho et al.

Several lines of evidence indicating the wound healing potential of flavonoid rich fraction of medicinal plants viz. Tephrosia purpurea L. Thus, medicinal plants rich in flavonoids are suitable candidates for developing newer wound healing agents from natural sources.

The presence of several flavonoids was revealed in the leaves and aerial parts of Dodonaea viscosa Jacq D. viscosa Family: Sapindaceae. The plant is believed to possess anti-inflammatory, anti-bacterial and antipyretic effects and is traditionally used to treat gout, rheumatism, snakebite, wounds, swellings, and burns Kirtikar and Basu, ; Mashelkar, To date, limited investigations on the pharmacological characteristics of D.

viscosa leaves exists with scattered reports of anti-bacterial Getie et al. Beshah et al. reported that many species of Dodonaea genus were found to possess flavonoids and terpenoids Beshah et al.

According to the findings of Sebelemetja et al. viscosa extract, created polymeric nanoparticle which was evaluated against the oral cavity acid-producing Streptococcus mutans Sebelemetja et al. Joshi et al. proved the preliminary wound healing studies with ethanol extract of D.

viscosa leaves Joshi et al. Nayeem et al. evaluated the wound healing potential of D. viscosa formulation prepared with methanol and chloroform extract of leaves in experimental animals Nayeem et al.

Literature studies indicate that D. viscosa leaves possess significant wound healing potential. However, the wound healing studies are lacking in the fractions of leaves and the correlation to its phytoconstituents.

Our preliminary studies proved the wound healing potential of flavonoid rich fraction of D. viscosa by in-vitro cell proliferation assay on HACAT cell line Shanthi et al. Although the plant is traditionally claimed to have fast wound-healing effects besides its rich flavonoid content, there has been no scientific data to confirm this claim on flavonoid rich fraction of D.

Hence, the present study aimed to investigate the mechanism of action and the wound healing properties of the flavonoid-rich ethyl acetate fraction of D.

viscosa leaves in the forms of new topical formulations by using animal models. FIGURE 2. Wound healing properties of D. viscosa leaves. Stress and obesity are two of the many factors that might contribute to delayed wound healing.

Fresh, healthy leaves of D. vicosa were harvested from the Madurai district, Tamil Nadu, India. The plant material was shade-dried and then ground into a coarse powder. The mixed extracts were concentrated using a rotavapor to yield the final solvent-free crude extract.

To get a flavonoid-rich fraction, the extract was suspended in water and separated with ethyl acetate Seyfi et al. Ethyl acetate fraction 10 mg was refluxed for min with 78 ml of alcohol, water, and hydrochloric acid cocktail The extract was filtered and diluted with ethanol to ml.

An aliquot 5 ml was filtered through a C silica column followed by methanol elution 4 ml. The elution volume was limited to 10 ml before being analyzed using a HPLC Oliveira et al.

HPLC analysis was conducted at room temperature in a Shimadzu apparatus outfitted with an SPD-M10A diode array detector and a reverse-phase column Linchosorb RP, 25 cm × 5 mm. Elution was conducted using a solution of methanol, water, and phosphoric acid For analysis, 10 μL of sample and standards were injected each time.

The peak regions of the HPLC chromatogram from the triple selection were used to compute the flavonoids concentration. Prior to the animal study, the ethyl acetate fraction of D.

viscosa was formulated as a D. viscosa ointment DVFO 2. An acute dermal toxicity study was performed according to the Organization for Economic co-operation and Development OECD test guideline OECD, Mortality and aberrant clinical indicators were monitored daily for 14 days until the study was completed.

The body weight was measured before medication administration and then weekly until the investigation was completed. At the end of the experiment, any significant pathological variations were identified.

Groups III and IV were treated with DVFO 2. Before inflicting the experimental wounds, the animals were anesthetized by intraperitoneal i. The dorsal fur was shaved and a circular stainless-steel stencil with methylene blue was used to outline the projected wound location to be made on the back and the sides of the animals.

Using surgical scissors and forceps, a circular excision mm 2 was formed on the shaved dorsal skin up to a certain depth 1. Day 0 was calculated when a circular excision wound was deemed created. Treatment was administered once daily until full epithelialization was achieved.

One-third of the experimental animals were sacrificed on the seventh post-operative day. Wound granulation tissues excluding any underlying muscle and superfluous tissue were collected.

Following injury on day 15, half of the surviving animals were euthanized, and the retrieved tissue was utilized for histopathological analysis. The remaining animals were monitored until a complete epithelialization occurred Upadhyay et al.

For every third-day post-wounding, the perimeter of the excision wound was traced on a transparent paper until the wound closed. The wound area was measured by retracing the injury on millimeter scale graph paper and the percentage of wound contraction was estimated using the following formula:.

The wound was monitored for the presence of complete epithelialization. Basically, it was measured from wounding day baseline until the eschar separated itself from the raw wound Nayak et al. The rats were anesthetized before and throughout the wound infliction. Groups III and IV were given DVFO at 2.

Using a sterile scalpel, a 6 cm long and 2. Following the incision, the skin was held together and sewn at 1 cm intervals of interrupted sutures using a surgical thread and a curved needle no. The wounds were left naked, and the formulations were topically administered to the wound daily. On day 8, the sutures were removed, and the formulation continued to be applied.

The extracted skin tissues were dried until they reach a constant weight in a hot air oven 60°C—70°C. Subsequently, the dry tissues were hydrolyzed by 6 N HCl at °C for 4 h in sealed glass vials. After neutralizing the acidic tissue hydrolysate to pH 7.

The reaction was stopped by adding 0. A UV visible spectrophotometer was used to detect the absorbance at nm. The standard calibration curve for pure 4-hydroxy-L-proline was plotted and utilized to estimate the sample concentrations in the test samples Murthy et al.

The hydrolyzed fraction 0. Subsequently, 0. The step was followed by heating in a boiling water bath for 20 min before cooling. Then, 1. The reaction was left for 30 min before measurement of color intensity at nm against a blank.

On the 7th and 15th days of the study, cross-sectional full-thickness skin specimens from each group were obtained to examine for histopathological changes. The regenerated tissues were examined qualitatively for keratinization, epithelization, inflammation, fibroblastic proliferation, collagen depositions and neovascularization under a light microscope.

The protein expression of collagen type 3 COL3A1 , basic fibroblast growth factor bFGF and vascular endothelial growth factor VEGF in granulation tissue from seven-day-old wounds was determined by western blotting Feng et al.

Protein concentration was estimated by using a Bradford reagent. The proteins were trans-blotted poly vinylidene fluoride PVDF membrane and incubated with COL3A1, bFGF, VEGF and β-actin primary antibodies overnight at 4°C, at room temperature with the corresponding secondary antibodies 1: for 1—2 h.

The desired proteins were detected by a Western Max-HRP-Chromogenic detection kit and 5-Bromochloro-3 ' -indolyl phosphate p-toluidine salt-Nitro Blue Tetrazolium BCIP-NBT solution using β-actin as the internal control. Statistical evaluations were performed with an IBM SPSS version 23 and with Microsoft excel Results of parametric tests were expressed in terms of mean ± SD.

Kruskal Wallis test, followed by the Mann-Whitney U -test, was used in the multivariate analyses. The ethanol extract of D. viscosa was fractionated with ethyl acetate solvent to yield an ethyl acetate fraction The fraction was greenish brown semi-solid mass which was soluble in water.

The flavonoids in the ethyl acetate fraction were estimated by HPLC using quercetin and kaempferol as standards. The flavonoids were identified by comparing the retention time in HPLC chromatograms of the fraction with the standards run in Similar condition.

The retention time was The amounts of flavonoids were calculated from the peak area of the HPLC chromatogram of ethyl acetate fraction Figure 3. Quercetin and kaempferol were determined to be 6. FIGURE 3.

HPLC analysis of ethyl acetate fraction of A Quercetin, B Kaempferol and C Ethyl acetate fraction of D. No evidence of toxicity with respect to clinical signs, remarkable bodyweight observations, or mortality, were recorded in all the experimental animals.

The percentage wound contraction findings based on the excision wound model experiment following topical administration of ethyl acetate fraction ointment at different concentrations 2.

The control group exhibited a contraction of Nevertheless, the 2. A full-thickness skin defect was induced by skin excision and the various groups were treated with base, povidone-iodine ointment and DVFO ointment at different concentrations until complete epithelialization.

Wound healing, as indicated by the formation of granular tissue, occurred on day 18 in the 2. Hydroxyproline levels in granuloma tissue treated with D. viscosa ethyl acetate fraction is represented in Figure 4. In the present study, the topical application of DVFO 2.

FIGURE 4. Effect of DVFO on hydroxyproline content. Values are expressed as Mean ± SD. Statistical analysis was done by Kruskal—Wallis followed by Mann-Whitney U test. Povidone iodine-treated groups. Hexosamine is one of the components of glycosaminoglycans.

FIGURE 5. Effect of DVFO on hexosamine content. Tensile strength is a crucial characteristic in an incision wound model Figure 6. The minimum tensile strength of the wound in the control group was In comparison the mean strength of the animals from the DVFO group increased considerably in a dose-dependent manner.

The mean tensile strength of a wound treated with 2. FIGURE 6. Effect of DVFO on Tensile strength. On day 7, many new capillaries and fibroblasts were seen in the granulation tissue in the DVFO- and standard treated groups, which were more prevalent than in the control group Figure 7 indicating that DVFO stimulates neovascularization while also increasing fibroblast proliferation and migration.

FIGURE 7. Control group [ A on 7 th Day and B on 15 th Day], Standard treatment group [ C on 7 th Day and D on 15 th Day], 2. On day 15, wound healing processes were well-organized following treatment with either DVFO or povidone-iodine. Additionally, all treated tissues lacked fibrinoid necrosis.

The histology of an excision biopsy of a skin wound on day 15 revealed healed skin structures with normal epithelialization, adnexal restoration, and extensive fibrosis within the dermis in the DVFO and standard treated groups. In contrast, the control groups lag behind the treated groups in forming ground substances in the granulation tissue, as observed in the tissue sections.

The DVFO- and standard treatment groups had full epithelialization, while the control group had partial epithelialization Figure 7. In fact, in the control group, collagen bundles were loosely packed, and wounds were only mildly cellular with fibroblasts Figure 8.

FIGURE 8. A Normal skin, B Wound control group, C Standard treatment group, D 2. Western blotting was used to examine COL3A, VEGF and bFGF protein expression levels Figure 9. The protein expression of COL3A, VEGF and bFGF in the standard group was considerably more significant than in the control group.

Overall, our findings suggest that DVFO promotes wound healing by increasing the protein expression levels of COL3A, VEGF and bFGF. FIGURE 9. Western blot analysis of important growth factors involved in the regulation of wound healing and regeneration.

The skin tissue of animals treated with DVFO showed increased expression of FGF, VEGF and COL3A as compared to control.

Values are expressed as Mean ± SEM. Our work provides the scientific data to validate the traditional claims that D. viscosa leaves have wound-healing effects, possibly by increasing the protein expression levels of COL3A, VEGF and bFGF.

Wound healing is considered a complicated and dynamic process that typically encompasses several phases signifying healing stages and necessitates the involvement of many cell types in various cellular activities Lopez-Jornet et al.

Hemostasis is the first stage of wound healing, followed by inflammation, proliferative and maturation phases. Many growth factors, cytokines, and chemokines are involved in the signalling network that controls and executes this intricate process.

The TGF-beta, FGF, VEGF, Granulocyte Macrophage Colony Stimulating Factor GM-CSF , PDGF, Connective Tissue Growth Factor CTGF , Interleukin IL family, and TNF-α families are of particular significance Barrientos et al.

Failure to progress through normal stages of phases of wound healing can ultimately result in delayed wound healing.

Several factors contributing to the delayed healing are diabetes, metabolic disorders, infection, venous disease, deficiencies, and age. Most existing medications used to treat wounds are costly, and some of them cause allergic responses and drug resistance Prasad and Dorle, Plants or their phytocompounds may impact some of these wound healing stages by speeding up the healing process.

Herbal remedies have generated much interest for the treatment of wounds as they are affordable and safe. Maver et al.

Thus, the potential for obtaining affordable medicines from traditional plant-based medicine has been investigated Phan et al. Flavonoid rich fraction of many medicinal plants such as Tephrosia purpurea L. In line with this, earlier reports indicated that the plant D.

viscosa possesses rich polyphenolic components, mainly flavonoids which are well known for their significant wound healing properties. The contribution of various flavonoids in wound healing is enormous. In this context, the plant D. viscosa has been selected for the current investigation.

Moreover, several experimental studies have explored the wound healing potential of the whole extract, such as a group of researchers have disclosed the preliminary wound healing studies with ethanol extract of D. Similarly, another study has unveiled the wound healing potential of D.

All the previous studies have used the whole crude extract of D. viscosa , and no one has explored the wound healing potential of the fractions of leaves together with mechanism of action.

In the previous in-vitro wound healing studies, the authors compared the potential of ethanol extract and flavonoid rich fraction Ethyl acetate fraction of D. viscosa by in-vitro cell proliferation assay on HaCaT cell line Shanthi et al. Hence, the potential of the flavonoid rich fraction of D.

viscosa as topical formulation was evaluated for wound healing efficacy. Our investigation on the acute dermal toxicity investigation indicated that DVFO was safe. Our study, which employed two distinct models to test the wound healing impact of D.

viscosa ethyl acetate fraction on various stages of wound healing, indicated that similar to conventional treatment, DVFO decreased wound size considerably as compared to the control. Accelerated wound contraction is associated with fibroblast activation, which is mediated by specialized myofibroblasts of granulated tissues Moulin et al.

Contraction minimizes the amount of extracellular matrix required to repair the damage and thereby shortens the healing process. In addition, by reducing the distance that migratory keratinocytes must cover, contraction promotes re-epithelization Strodtbeck, Furthermore, if the medicine is more effective, the wound will heal quickly Prasad and Dorle, Therefore, the significant effect of DVFO on the wound healing process in rats may be attributed to an increase in fibroblast activities, required for proper wound closure.

The positive effect of DVFO treatment was further ascertained with a histopathological examination, which confirmed normal skin histology with the reappearance of intact epidermis and dermis, fibroblast and collagen deposition compared to the control group that had disrupted tissues in the dermal wound area.

The DVFO-group exhibited faster epithelialization, while the control group exhibited a partial epithelialization. Granulation tissue development over the wound section hastens re-epithelialization due to the arrangement of epithelial cells surrounding the newly formed tissue to establish a barrier between the wound area and the external environment Esimone et al.

The wound re-epithelialization cycle is mainly associated with a faster wound healing process that can be indicated by hydroxyproline level as well. Hydroxyproline concentration is a critical component of the collagen fiber triple helix Shoulders and Raines.

An increase in hydroxyproline concentration suggests a decrease in cellular proliferation and collagen formation. In addition, hexosamine levels increase in the early phases of wound healing, indicating that fibroblasts are actively synthesizing ground material mucopolysaccharides on which collagen may be deposited Ross and Benditt, In the excision wound model, topical administration of DVFO 2.

Tensile strength is an essential indicator of the quality and amount of epithelialized collagen as well as the strength and degree of wound healing Raghuwanshi et al.

Scars are Natural detox for hormonal balance marks healin after an injury heals that Flavonoida physical and psychological harm, especially the great threat to development and healimg posed heaaling oral and maxillofacial scars. The Flavoboids expression of healinv such as transforming growth factor-β, local adherent snd kinase, and yes-related Flavonoids and wound healing regulators Fresh blueberries delivery infancy or the Pycnogenol and antioxidant properties mucosa Flavonoids and wound healing thought to be the reason of scarless regenerative capacity after tissue defects. Currently, tissue engineering products for defect repair frequently overlook the management of postoperative scars, and inhibitors of important genes alone have negative consequences for the organism. Natural flavonoids have hemostatic, anti-inflammatory, antioxidant, and antibacterial properties, which promote wound healing and have anti-scar properties by interfering with the transmission of key signaling pathways involved in scar formation. The combination of flavonoid-rich drug dressings provides a platform for clinical translation of compounds that aid in drug disintegration, prolonged release, and targeted delivery. Therefore, we present a review of the mechanisms and effects of flavonoids in promoting scar-free regeneration and the application of flavonoid-laden dressings.