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. 2023 Feb 22;31(2):755–772. doi: 10.1007/s10787-023-01157-5

The wound healing effect of botanicals and pure natural substances used in in vivo models

S A El-Sherbeni 1, W A Negm 1,✉
PMCID: PMC10140094  PMID: 36811778

Abstract

Repairing the wound is a multistep process that includes the spatial and temporal synchronization of a different range of cell types to increase the speed of wound contraction, the proliferation of epithelial cells, and collagen formation. The need for proper management of acute wounds to be cured and not turned into chronic wounds is a significant clinical challenge. The traditional practice of medicinal plants in many regions of the world has been used in wound healing since ancient times. Recent scientific research introduced evidence of the efficacy of medicinal plants, their phyto-components, and the mechanisms underlying their wound-repairing activity. This review aims to briefly highlight the wound-curing effect of different plant extracts and purely natural substances in excision, incision, and burn experimental animal models with or without infection of mice, rats (diabetic and nondiabetic), and rabbits in the last 5 years. The in vivo studies represented reliable evidence of how powerful natural products are in healing wounds properly. They have good scavenging activity against Reactive oxygen species (ROS) and anti-inflammatory and antimicrobial effects that help in the process of wound healing. It is evident that incorporating bioactive natural products into wound dressings of bio- or synthetic polymers in nanofiber, hydrogel, film, scaffold, and sponge forms showed promising results in different phases of the wound-curing process of haemostasis, inflammation, growth, re-epithelialization, and remodelling.

Keywords: Animal models, Burns, Inflammation, Natural products, Wound healing, Wound dressings

Introduction

The human body includes different organs. One of them is the skin which occupies a large body area. It represents the outermost defensive covering of the body and an immunological barrier that regularly faces different external factors. It fortifies against mechanical pressure, microbial contagion, and septicity and maintains normal body temperature. It is responsible for the sensation of touch, heat, and cold (Richmond and Harris 2014; Kwiecien et al. 2019; Kumar P and Kothari 2021).

The antimicrobial protective role of different skin layers was evidenced through different previous studies. An external layer displays the composition of human skin outside the epidermis called microbiota, epidermis, dermis, adipose tissue, glands (sweat and sebaceous), and hair follicles (Kwiecien et al. 2019).

Epidermis is composed of keratinocytes, melanocytes, Langerhans’ cells, and Merkel cells. Keratinocytes are a significant type of cells that has a role in vitamin D formation and produce keratin and lipids to form a water barrier. Keratinocytes could act against chemical and biochemical toxins by creating pro-inflammatory cytokines, e.g., interleukins: IL-1α, IL-1β, IL-3, and IL-6, interferons-alpha and beta, transforming growth factors, tumour necrosis factors, and others (Blume-Peytavi et al. 2016). Melanocytes are responsible for skin pigmentation. The first line of protectors of the skin is represented by Langerhans cells. They transport antigens in the skin to the lymph node. The membranes of Merkel cells interact with free nerve endings in the skin, so they have a sensory function. The dermis layer includes the sweat glands, blood vessels, muscles, and sensory neurons (Yousef et al. 2017). Symbiotic microorganisms of bacteria and fungi are recognized as skin colonies with harmless and vital effects in protecting the skin. They are inside hair follicles, sweat and sebaceous glands to protect the skin against invasive and microbial pathogens. Among them, species of Staphylococcus, Malassezia, Demodex folliculorum, and Demodex brevis were the most important (Grice and Segre 2011; Ibrahim et al. 2020).

Wounds have happened due to the loss of histological composition of the skin tissue due to internal or external factors or sequential loss of function in any layer of the skin, which leads to tissue disturbance (Herman and Bordoni 2020). The existence of wounds permits the entrance of different microbial agents as bacteria and viruses or any foreign elements, into the body. Inflammation of skin wounds is happened because of local microbial infections. Also, a generalized systemic infection (septicemia) could be found, a life-threatening condition (Percival 2002). Consequently, more research should be done to find out simple and effective ways of taking care of skin wounds to heal properly. The main goals are to stop bleeding, get rid of microbial infection of wounds, and help wounds to heal effectively without any complications or deformities (Sarabahi et al. 2012; Jones 2015).

Once any damage has occurred to the skin tissue, multiple cellular and extracellular pathways act in a harmonized way, and their functions must be performed in the appropriate order at a suitable time to achieve repair, growth, and tissue regeneration (Richmond and Harris 2014).

Bleeding due to damaged blood vessels must be stopped, which is considered the initial reaction in the process of wound repair, besides platelet stimulation to compose a fibrin clot. Immediately after that, the disturbed tissues discharge growth factors and pro-inflammatory cytokines. Upon controlling the bleeding, many inflammatory cells such as monocytes, macrophages, and neutrophils are gathered at the wound site to provoke the inflammatory response (inflammatory phase). Moreover, the different self and exogenous antigens trigger the immune system to fight against them (Rodrigues et al. 2019; Alotaibi et al. 2021).

Angiogenesis is the following phase, which is parallel to the inflammation phase. The formation of a new blood vessel characterizes this phase. It is then followed by the growth and proliferative phases, which are predominate by fibroblast relocation and propagation, production of the matrix proteins, keratinocyte proliferation, differentiation, and restoration of hair follicles, etc. lastly, the wound healing process is finished with the remodelling of the extracellular matrix (ECM), besides the reordering of granulation tissue to scar tissue. Collagen synthesis and cross-linking afford stability to the healing tissue (Rodrigues et al. 2019). Figure 1 demonstrates the different phases of wound healing, while Table 1 summarizes herbal extracts studied using in vivo wound healing models. Structures of purely natural substances that were investigated using wound healing in vivo models showed in Fig. 2 and Table 2.

Fig. 1.

Fig. 1

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Different phases of skin wound healing

Table 1.

Botanical extracts investigated by wound healing in vivo models (animal models)

No. Plant name and part used Family Wound model and treatment Animal Outcome References
1 Aloe megalacantha Baker (Leaf latex) Xanthorrhoeaceae Leaf latex was loaded to an ointment base (5% and 10% w/w) Using for incision Swiss albino mice and excision Sprague Dawley rats' models Both wound models showed a significant increase in the speed of wound contraction, epithelial cell proliferation, and increased tensile strength Gebremeskel et al. 2018
2 Phyllanthus muellerianus (water extract of aerial part and pure compound geraniin) Euphorbiaceae Aqueous creams of the plant (0.25, 0.5, and 1% w/w) and geraniin (0.1, 0.2, and 0.4% w/w) Male Sprague–Dawley rats were used with induced excision and incision wounds A Remarkable elevation in fibroblasts, cross-linking, and collagen content in P. muellerianus and geraniin-treated wound tissues were shown. Also, notable levels of TGF-β1 were recorded Boakye et al. 2018
3 The biofunctionalized silver nanoparticle was produced from cloves extract Myrtaceae AgNP was loaded into a cream with concentrations of 3% and 5% Excision and incision male and female albino rats wound models The wound-repairing impact was notable in animals treated with 5% silver nanoparticles. Collagen Parveen et al. 2018
4 Euphorbia characias subsp. Wulfenii Euphorbiaceae 1% ointment of methanol n-hexane, and ethyl acetate extracts E. characias subsp. It was investigated in the linear incision and circular excision wounds in male Sprague Dawley rats E. characias subsp. wulfenii displayed significant wound-curing activity Özbilgin et al. 2018
5 Lafoensia pacari A. St.-Hil Lythraceae The hydroethanolic leaves extract was tested at 10, 30, or 100 mg/g of gel Excision and incision-rat (Rattus norvegicus, Wistar strain model) Increased rates of wound contraction, moderate re-epithelialization, neovascularization, proliferation, and acceleration of the remodeling phase Pereira et al. 2018
6 Alkanna strigose Boraginaceae (Hexane extract of roots) Rattus norvgecis model Excision and incision Albino Wistar rats The beneficial effect of A. strigosa extract was confirmed Aburjai et al. 2019
7 Vitis labrusca (Hydroalcoholic extract of leaves) Vitaceae Oral administration of the extract at 100, 200, and 300 mg/kg Excision wounds male Wistar rats Histological evidence showed that the extract could be a potential oral medicine for healing purposes Santos et al. 2021
8 Coccinia grandis (Polyphenol- rich fraction was obtained from the methanol extract of leaves) Cucurbitaceae The hydrogel of Coccinia grandis (1.5 mg/ g) was tested Excision wounds in male albino rats which was infected by B. cereus Polyphenolic compounds of Coccinia grandis could be utilized as a natural wound-repairing drug Al-Madhagy et al. 2019
9 Jacaranda decurrens (Hydroalcoholic extract of leaves.) Bignoniaceae 15 mg/g of extract in the ointment base was tested Mice-excision wound model The extract increases rate of wound curing by modulating the action of pro-inflammatory cytokines Serra et al. 2020
10 Phlomis russeliana (n-hexane fraction of methanol extract of the aerial part.) Lamiaceae 5% of the extract in carbopol- hydroxypropyl gel excisional wound model in Swiss mice (Mus musculus) Phlomis russeliana has a wound-healing effect following the ethnobotanical application Okur et al. 2020
11 Plumeria obtusa (Ethanolic extract of leaves) Apocynaceae 2.5, 5, and 10% spray of the plant extract Excision wound Swiss albino Wistar rats model The formula with 10% P. rutic extract spray showed the best wound healing effect Bihani and Mhaske 2020
12 Boerhavia diffusa (Methanol and chloroform extracts of the leaves) Nyctaginaceae Ointment (10% w/v) of methanol or chloroform extracts Excision wound assays in a Albino Wistar rat model The methanol extract of B. diffusa have a significant wound-healing effect Juneja et al. 2020
13 Ephedra ciliata (methanol extract and quercetin) Ephedraceae 5, 10, 20% cream of Ephedra ciliata methanol extract and 20% quercetin Albino male and female rat model with excision and burn wounds was used The extract rich with quercetin (methanol extract) of Ephedra ciliata promoted natural wound healing. The healing effects of the 20% methanol extract were comparable to the 20% quercetin (Yaseen et al. 2020)
14 Moringa oliefera (Hexane extract of seeds Moringaceae 5% and 10% hydrogel of n-hexane extracts of Moringa oleifera seeds Excision and incision Male Swiss albino mice wound healing model The hydrogel containing n-hexane extract of Moringa oleifera seeds could act as a wound-healing agent Ali et al. 2021
15 Moringa oleifera leaves Moringaceae Moringa leaves extract gel Incision wound male Wister rat (Rattus norvegicus) model Moringa oleifera leaves extract gel exerted wound healing effect by speeding epithelialization Ayu et al. 2020
16 Curatella americana Linn. (Hydroethanolic extract of leaves) (HECA) Dilleniaceae lyophilized extract of C. americana 0.5 and 1% loaded to a gel Excision Adult Swiss albino mice wound model treatment with 1% of the extract displayed the highest wound-repairing effect Fujishima et al. 2020
17 Nigella sativa oil Ranunculaceae Mats of polyurethane electrospun nanofibrous loaded with Nigella sativa oil were tested as wound healing dressing The full-thickness excisional wound in female Sprague Dawley rats The mat of N. sativa-loaded Polyurethane nanofibrous, significantly provoked the wound-healing process Aras et al. 2021 Nordin et al. 2019
18 Dodonaea viscosa (Leaves methanol and chloroform extracts) Sapindaceae 10% w/w herbal. Ointment of the extracts Incision and excision Sprague Dawley rats wound models Methanolic extract significantly accelerated the epithelization of the excision wound. The extracts exerted a notable elevation in the tensile strength regarding the incision model Nayeem et al. 2021
19 Roylea elegans (Aqueous leaves extract) Lamiaceae The cream contained 5 or 10% of the aqueous extract of leaves Burn Wistar albino rats model Roylea elegans caused wound-healing acceleration Upadhyay et al. 2021
20 Cupressus macrocarpa (Diethyl ether extract of leaves) (DEEL) Cupressaceae DEEL in 20% DMSO in normal saline was applied to wounded and infected rats by methicillin-resistant Staphylococcus aureus clinical isolates Full-thickness excision wounds male albino rats DEEL showed epidermis regeneration, granulation tissue maturation, and a decrease in inflammatory cell infiltration Attallah NGM et al. 2021
21 Zehneria scabra (80% Methanol Leaf Extract) Cucurbitaceae 5% and 10% (w/w) of 80% methanol extract in an ointment base Incision and excision wounds in adult albino mice Z. scabra exerted significant wound-repairing activity Tekleyes et al. 2021
22 Bersama abyssinica (Hydro-methanol, chloroform, hexane, and water fractions of leaves) Francoaceae 5% and 10% w/w ointment of the hydro-methanolic extract was investigated Excision, incision, and burn wounds in adult Swiss albino mice Both 5% and 10% w/w of hydro-methanolic extract and solvent fractions of the plant have wound-curing effects Taddese et al. 2021
23 Semecarpus anacardium L., Argemone mexicana L., Cocculus hirsutus L., and Woodfordia fruticose K Anacardiaceae Papaveraceaei Menispermaceae Lythraceae The polyherbalBhallatakadi Ghrita (BG) formulation is composed of this mixture Incision and excision Wistar rats model Quercetin, gallic acid, and fatty acids increased the healing rate by the ghrita formulation Wayal and Gurav 2021
24 Elaeis guineensis Jacq (Leaves) Arecaceae Leave extracts Sprague Dawley rats were used for making excision wounds with microbial infection E. guineensis promote the healing of wounds even though they were infected, confirming its traditional use in wound curing Rajoo et al. 2021
25 Vernonia auriculifera Hiern (methanol extract of leaves and its fractions Asteraceae Ointment preparations of 5% and 10% w/w of methanol and other fractions Excision, incision, and burn wound models in Swiss albino mice and female Wistar rats The plant’s different extracts (methanol, aqueous, and ethyl acetate) showed Lambebo et al. 2021
26 Brucea antidysentrica Rhamnus prinoides Dodonaea angustifolia Simaroubaceae Brucea antidysentrica (extract of roots bark), Rhamnus prinoides (leaves), and Dodonaea angustifolia (80% methanol extract) Types of induced wounds in Swiss albino mice were excision and incision wounds The traditional use of these plants in repairing wounds was confirmed. This plants increase wound contraction rate and tensile strength and decrease the time needed for efficient epithelialization Tessema and Molla 2021
27 Jatropha Neopauciflora Pax Latex Euphorbiaceae latex (50%, 75%, and 100%) Incisions were made in normal and diabetic male mice (Mus musculus) mice neopauciflora could be beneficial for wound management in diabetes mellitus and speeds up and stimulates the wound-healing process Hernandez-Hernandez et al. 2021
28 Sanguisorba officinalis Roots (the isolated Rhoifolin-Rich Fraction RRF) Rosoideae 2% carbopol and hydroxypropyl cellulose gel of RRF Full-thickness excision wound white albino rat model RRF enhanced re-epithelization, angiogenesis, and shoed anti-bacterial, immunomodulatory, and anti-inflammatory activities Negm et al. 2022
29 Platycodon grandifloras (Water extract of the dried tuberous roots) Campanulaceae The concentrated water extract was mixed with medical vaseline to make an ointment. 10% P. grandiflorus mixed emulsifiable paste was tested Scald model males specific-pathogen-free (SPF) Sprague–Dawley rat P. grandiflorus showed a significant healing effect on cutaneous scald lesions. A well-repaired epidermis was observed in rats treated with P. grandifloras Wang et al. 2022
30 Pistacia vera (Italian and Algerian oleoresins) Anacardiaceae Oleoresins mixed with vaseline (5% w/w) Circular wound excision ew Zealand albino rabbits model Both oleoresins had very high wound-healing activity agents Boudjelal et al. 2022
31 Moringa oleifera (Hydroethanolic extract of seeds) Moringaceae 5% and 10% of the extract of Moringa oleifera seeds is added to the hydrogel Excision and incision wound Male Swiss albino mice models Hydr-ethanolic extract of M. oleifera could be utilized in wound management as an alternative plan Ali et al. 2022
32 Calendula officinalis L. (Flower extract) Asteraceae The wound dressing of collagen film containing flower extract Excision wound male Sprague–Dawley rat model The tested dressing for wound repair contained the calendula extract. It was loaded with collagen film and showed safe, stable, and effective effects Rathod et al. 2022
33 Curcuma longa (Aqueous, 70% methanolic, and ethanolic extracts) Zingiberaceae Different extracts of C. longa encapsulated in Ethosome were tested to heal wounds.(0.25, 0.5, and 1 g/cm2) Full-thickness skin wounds in adult Wistar rats Encapsulation of C. longa led to a better shape of wound, and maturation of granulation tissue, with an accelerated rate of healing, compared to crude extract Kumar S et al. 2022
34 Globularia arabica (Leaf methanol extract) Plantaginaceae The study used variable concentrations of G. arabica extract (1%, 5%, and 10%) in ointment base Excision diabetic and nondiabetic male Wistar rat model G. arabica could be useful in healing wounds by provoking collagen and hydroxyproline formation when added externally on the wounded skin Alsarayreh et al. 2022
35 Premna integrifolia (Standardized extract) Lamiaceae 5% (w/w) ointment of the standardized extract Excision wound model in male and female Wistar albino rats Premna integrifolia had a wound-healing impact and could contribute to curing the wounds as a source of bioactive constituents with wound-healing characteristics Alsareii et al. 2022
36 Zizyphus mauritiana Rhamnaceae (Fruit extract) Full-thickness excisional wounds in adult male New Zealand Dutch strain albino rabbits ZFE might act as a potential alternative drug to speed wound repair due to its antioxidant and anti-inflammatory effects Shady et al. 2022
37 Parkia clappertoniana Keay (Fruit husk extract) Fabaceae Ointment of fruit extract (0.3, 1, and 3%) Excision wound model in male Sprague–Dawley rats P.clappertoniana exerted wound-healing and antimicrobial effects Kuma et al. 2022
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Fig. 2.

Fig. 2

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Structures of natural pure substances were investigated using wound healing in vivo models (animal models)

Table 2.

Natural pure substances investigated using wound healing in vivo models (animal models)

No. Natural products derived substances Wound model and treatment Animal Outcome References
1 Quercetin This combination is prepared by taking 15% carbopol and varying the gelatin ratio Excision albino rat wound model.Multiple phases hydrogel system combined with quercetin loaded to liposomes The rate of wound repair is raised, with a prominent decrease in wound closure time compared to the drug's dosage form Jangde et al. 2018
2 Quercetin Two ischemia–reperfusion (I/R) cycles were utilized in each animal to induce ulcer formation. Topical treatment was performed with 1 μmol/L quercetin in DMSO The animal pressure ulcer mice model was established with two cycles The treatment by quercetin caused a significant acceleration of wound closure, a reduction in immune cell infiltration, and pro-inflammatory cytokines formation Yin et al. 2018
3 Quercetin Different treatments of quercetin (0.3%) and quercetin-loaded chitosan nanoparticles (0.03%, 0.1%, 0.3%) in pluronic F-127 gel (20% w/v) Excision male Wistar rat wound model Quercetin nanoparticles at 0.03% showed significant hastening wound healing by affecting cytokines and growth factors in inflammatory and proliferative phases Choudhary et al. 2020
4 Quercetin Quercetin of 0.03, 0.1, and 0.3% in DMSO was tested Excision wound adult male Wistar rat model Modulation of growth factors, antioxidant parameters, and different cells of the wound healing process was confirmed by 0.3% quercetin Kant et al. 2020a, b
5 Quercetin quercetin at 10, 20, and 40 mg/mL concentrations in 10% DMSO Diabetic Sprague Dawley rats, excision wounds, Conversion from M1 to M2 phenotype by modulation of macrophage polarization led to inhibition of inflammation process by quercetin Fu et al. 2020
6 Quercetin Quercetin as well as the photo-stimulatory impact of low energy 632.8 nm laser irradiation, were tested. Quercetin was taken by oral gavage at 25 mg/kg b. w. in 5 ml of 1% carboxymethylcellulose (CMC) with or without low-level laser treatment The wound type was an excisional wound used in nondiabetic and diabetic male albino rats The quercetin combined with low-level laser treatment improves the wound-curing process more than the utilization of only one of them Ahmed et al. 2018
7 Quercetin Three different solvents were used to contain 0.3% of quercetin: corn oil, 10% DMSO, and ointment base Excisional wounded adult male Wistar rats The most efficient wound healing impact with an accelerated healing rate Kant, Kumar, et al. 2020
8 Quercetin incorporated in a new scaffold:Polyethylene glycol (PEG)ylated graphene oxide/quercetin (GO-PEG/Que) and artificial acellular dermal matrix/quercetin (ADM-GO-PEG/Que) 1-Polyethylene glycol (PEG)ylated graphene oxide (GO-PEG) /quercetin. 2-Artificial acellular dermal matrix -GO-PEG/quercetin (0.1 mg/mL) Excision wound model in diabetic male albino mice Helps in collagen deposition and angiogenesis. ADM-GO-PEG/Que represents a new material for tissue engineering scaffold Chu et al. 2018
9 Quercetin Secondary intention wound healing model in Wistar rats. 0.2 ml of gel contained 5% quercetin, 5% benzocaine, and glycerin Palatal wounds of 5 mm diameter in Wistar rats A reduction in inflammatory cells and an elevation in fibroblast cells were observed Taskan et al. 2019
10 Quercetin (QCN)- and oxygen-carrying 1-bromoperfluorooctane (PFOB)-loaded nano emulsions (QCN-NE and OXY-PFOBNE) The hydrogel is containing LMWP-GFs/QCN-NE/OXY-PFOB-NE. Low-molecular-weight protamine (LMWP) /skin-permeable growth factors (GFs) The type of wound was excisional in diabetic C57BL/6 mice (females) The hydrogel elevated the wound repairing rate in the diabetic mice and downregulated wound size relative to the vehicle and LMWP-GFs. Nano-emulsion was produced to ameliorate the external delivery of quercetin and oxygen Jee et al. 2019
11 Quercetin and ciprofloxacin PCL-bases nanofiber loaded with ciprofloxacin hydrochloride and quercetin A full-thickness excisional wound in male Wistar rats The topical delivery of ciprofloxacin hydrochloride and quercetin functionalized nanofiber. Both drugs could act as a bioactive wound dressing substance Ajmal et al. 2019a, b
12 Quercitrin and myricitrin were isolated from Pistacia lentiscus leaves Pistacia lentiscus leaves methanol extract 5, 20 mg/mL. Quercitrin and myricitrin 1 mg/mL Excisional wounds in male Wistar rats PDL, quercitrin, and myricitrin efficiently impact the healing of skin wounds Elloumi et al. 2022
13 Hesperidin Alginate/chitosan containing different concentrations of hesperidin Full-thickness excision in male Wistar rats Hesperidin loaded to alginate/chitosan hydrogels can be utilized to treat skin wounds in humans Bagher et al. 2020
14 Quercetin in nanofiber scaffold Four treatments were tested:1-gauze, 2-Poly ε-caprolactone-gelatin, 3-Poly ε-caprolactone-gelatin-ciprofloxacin hydrochloride, and 4-Poly ε-caprolactone-gelatin-ciprofloxacin hydrochloride-quercetin nanofibers Excision wounds in male Wistar rats A new scaffold showed full repair of wounds, and it could be used as a dressing material for healing wounds Ajmal et al. 2019a, b
15 Quercetin 20% quercetin Excision wound albino rat model Animal treated with quercetin and heparin sodium exhibited significant healing effects in comparison to the control group Yaseen et al. 2020
16 Quercetin Quercetin was loaded to polycaprolactone/gelatin electrospun nanofiber Excision wound male Wistar rat model Quercetin nanofibers treated wounds exhibited a significant wound contraction with upregulation of angiogenesis and collagen formation. These nanofibers provided good integrity and hydrophilicity for wound dressing applications Karuppannan et al. 2022
17 A homogeneous polysaccharide (ZWP) from Curcuma zedoaria Chitosan/silk hydrogel sponge loaded with platelet-rich plasma exosomes (PRP-Exos), ZWP, or PRP-Exos/ZWP Excision wounds in diabetic emale Sprague Dawley rats Wound contraction was recognized in the separate or combined treatments, as represented by a reduction in ulcer and an elevation in the thickness of epidermis. PRP-Exos/ZWP combined treatment gave better results in wound closure Xu et al. 2018
18 Curcumin conjugated with hyaluronic acid HA Wounds of mice treated with 20 ml of 210 mg/ml of hyaluronic (HA) or 20 ml of the 25 mM of curcumin or hyaluronic-curcumin (HA–cur) Diabetic Swiss male albino mice Excision wounds Curcumin topical effect enhanced wound healing compared to treatment with HA-free curcumin and HA alone Sharma et al. 2018
19 Cinnamaldehyde Male diabetic (BSK.Cg-m + / + Leprdb; db/db) and WT mice (C57BL/6 J), and male Kunming mice. Doses of intraperitoneal injection of cinnamaldehyde (25, 50, and 100 mg/kg) Mice were injured with excisional skin wounds. Normal and diabetic mice were used in the study Cinnamaldehyde-induced angiogenesis and led to an increased rate of wound repair Yuan et al. 2018
20 Bromelain pineapple (Ananas comosus) Bromelain was given intraperitoneally in doses of 25 mg/kg or 45 mg/kg Full thickness incision and diabetic Male Wistar rats wound model Bromelain significantly enhanced wound contraction and strength, reduced granulation tissue formation, and increased angiogenesis Fathi et al. 2020
21 Bromelain pineapple (Ananas comosus) Chitosan nanofibers loaded with bromelain were investigated in burn wound repair Induced burn wounds in rats The safety significantly improved, good impact on re-epithelialization, reduction of necrosis, and good wound closure were observed Kalalinia et al. 2021
22 Luteolin Intraperitoneal administration of luteolin 100 mg/kg body weight Excision wounds diabetic male Wistar rat model Wounded and diabetic rats experienced wound restoration via improving inflammatory and oxidative stress through the administration of luteolin Chen et al. 2021
23 Luteolin An ointment of luteolin of different concentrations (0.5% and 1% w/w) was applied topically on wounds Excision and incision diabetic and nondiabetic male Wistar rate models Luteolin ointments ameliorated wounds and enhanced skin tissue's healing process in both nondiabetic and diabetic wounds Özay et al. 2018
24 Luteolin Medical vaseline ointment of 10% luteolin Skin wound of scald model males specific-pathogen-free Sprague Dawley rats Inflammation of scalded rats was efficiently reduced with the promotion of proper wounds in luteolin treated group Wang et al. 2022
25 Thymoquinone 0.5% w/w of thymoquinone nano-emulgel incorporated with Carbopol 940 (TMQ-NEG) Excision wounds Wistar rats The examined nano emulgel showed a faster and better wound-healing effect compared to the ordinary hydrogel form of thymoquinone Algahtani et al. 2021
26 Thymoquinone Thymoquinone loaded chitosan-lecithin micelles An investigation was done using 20 mg/mL of thymoquinone loaded to micelles formulation and with the 2% w/ w thymoquinone loaded to polymeric micelle-hydrogel Excision wound model of old Balb/c mice The hydrogel showed a remarkable wound-curing impact on the original thymoquinone and silver sulphadiazine Negi et al. 2020
27 Thymoquinone The polyvinyl pyrrolidone (PVP) matrix-type films containing 20% w/w of TQ were tested (hydrogel formulation) Full-thickness excisional wound infection model in male mice (BALB/c) TQ-containing films exhibited significant activity against Staphylococcus aureus infection Haq et al. 2020
28 Gentiopicroside and Thymoquinone Mats of co-blended polyvinyl pyrrolidine (PVP) and methyl ether Polyethylene glycol (m-PEG) were loaded with gentiopicroside and thymoquinone White albino male rats were used The polymeric mats are loaded with gentiopicroside and thymoquinone, so it could be considered suitable wound dressing Almukainzi M. et al. 2022
29 Vicenin-2 (VCN-2) VCN-2 in the form of hydrocolloid film Wounds were inflicted in diabetic male adult Sprague Dawley rats VCN-2 may have a wound-healing impact as wound treatment with VCN-2 hydrocolloid films could efficiently enhance wound repair in hyperglycemic cases Tan et al. 2019
30 Kaempferol (KM) The KM ointments 1% w/w were used Diabetic excisional and nondiabetic incisional male Wistar rats' models Kaempferol was an efficient wound-healing drug in treating both nondiabetic and diabetic wounds Özay et al. 2019
31 Glycyrrhizin micelle as a genistein nanocarrier Dipotassium glycyrrhizinate-based micelle ophthalmic solution encapsulating genistein (DG-Gen) 1:15 Diabetic corneal and nerve-wounded C57BL/6 J male mice Application of the DG-Gen significantly prompted corneal re-epithelialization and nerve regeneration in wounded diabetic mice Hou et al. 2021
32 Quinoline A hydrogel loaded with Cu (II) Schiff base 8-hydroxy quinoline complex (CuSQ) solid lipid nanoparticles (SLN) excision wound healing model in male Wistar albino rats CuSQ would have a good impact as a drug for cutaneous wound curing through the control of growth factors and different cytokines El-ezz et al. 2022
33 Micro-channeled alkylated chitosan sponge (MACS) Liver perforation in male Wistar rats and Bama miniature male pigs was performed in this study Pigs The Micro-channeled alkylated chitosan sponge introduces higher pro-coagulant and hemostatic effects in lethal conditions of either normal or heparinized animal models. Generally, the MACS displayed promising clinical translational ability in managing fatal noncompressible hemorrhage and improving wound healing Du et al. 2021
34 Green tea catechin (–)-Epigallocatechin-3-O-gallate (EGCG) EGCG-grafted water-soluble silk fibroin hydrogels (SFEGCG). SFEGCG conjugate was co-crosslinked with tyramine-substituted SF (SF-T) via horseradish peroxidase (HRP)/H2O2 mediated enzymatic reaction to form SF-T/SF-EGCG hydrogels Male Sprague Dawley rat model of full-thickness skin defect SF-T70/SF-EGCG30 hydrogels exerted a remarkable wound-healing effect over SF-T hydrogels and a commercial DuoDERM® gel dressing Lee et al. 2022
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Botanical extracts have been extensively utilized in managing wounds in traditional medicine. Therefore, in vitro and in vivo studies have assessed different extracts for their wound-curing characteristics. Their phytochemical content is the purpose of their remedial features in wound repair. Other phytochemicals and plant-derived substances were investigated for their wound-healing activity as flavonols, flavanones, isoflavones, flavanols, flavonolignans, proanthocyanidins (Carvalho et al. 2021), β-glucans (Majtan and Jesenak 2018), bromelain (Fathi et al. 2020), curcumin (Akbik et al. 2014). It was disclosed that different botanicals and medicinal plants are widely used as a topical treatment for wound repairing, such as aloe vera, banana leaves (Sivamani et al. 2012), turmeric, Centella asiatica, Rosmarinus officinalis, Calendula officinalis (Artem Ataide et al. 2018).

Natural products such as plant extracts and other plant-derived products and their phytochemicals assist in managing inflammatory diseases, exert antimicrobial effects, and might aid skin tissue regeneration (Alherz et al. 2022; Attallah NG et al. 2022). They could remove oxidative stress and lower inflammation (Shah and Amini-Nik 2017). The wound-repairing ability of different plant extracts and their actives was confirmed in wound-curing animal models. Such plants improved collagen deposition, the proliferation of epithelial cells, and angiogenesis in diabetic and nondiabetic animal models (Binsuwaidan et al. 2022). Different types of plants are widely used in managing wounds and injuries from previous scientific research (Chingwaru et al. 2019).

The current review demonstrates and focuses on the latest findings in the last 5 years (2018–2022) regarding the in vivo studies of wound repairing effect of different plant extracts, the derived substances from plants, and pure natural substances as a new frontier in treating wounds.

Methods of collecting data

Data collected in the frame of this work were generated by common research engines such as ScienceDirect, Web of Science, PubMed, SciFinder-n, and Scopus, using the references “natural products”, “wound healing” and refining with keywords “animal models”, “burns”, “biological”, “plants” “wound dressings” and “inflammation”. A total of 2194 research items were examined out of which 190 fall into the scope of the review, thus, constituting the baseline of the current survey.

Botanicals and pure natural substances in the preclinical studies

The present review provided the research work, which included the preclinical studies (in vivo) of plant extracts and pure natural substances on wound healing in the last 5 years. The preclinical investigation by using animal models is important for acute and chronic wounds, in vitro studies could be used, but they do not assess the complexity of the wound healing process (Dunn et al. 2013; Zindle et al. 2021). Acute wounds occur through known sequential steps (Zindle et al. 2021). but chronic wounds exhibited impaired or delayed healing. The acute wound heals within 2–3 weeks, followed by the remodelling phase in normal healthy people. The normal healing sequence could be interrupted by other diseases such as diabetes, wound infection, foreign bodies, chronic inflammation, and ischemia. Microbial infection is the famous reason for wound-related morbidity (Said et al. 2009; Rajendran et al. 2018). This led to a physiological imbalance in the mechanism of healing. It might get stuck in one of the phases, and the wound then falls into the non-healing chronic type (FrykbergRobert 2015; Rajendran et al. 2018). It was reported that a wound is not healed in more than 6–8 weeks defined as a chronic/ non-healing wound (Rajendran et al. 2018). The universal goal of all studies about wound healing is to treat acute wounds perfectly in due time, so we avoid conversion into chronic ones and discover the appropriate therapy if the patient suffers from chronic wounds. Patients with chronic wounds suffer from pain, depression due to isolation from the community, and risk of amputation (Ivanková and Belovičová 2020).

Wound healing potentials of various plant extracts

Different studies of the wound-repairing effect of various plant extracts revealed the diversity of actives responsible for this activity. It was suggested that D-pinitol and caffeic acid, the major constituents of Boerhavia diffusa leaf methanol extract, contributed to the wound-healing effect (Juneja et al. 2020). In another study, the fraction contained a high level of polyphenolic compounds, separated from leaves methanol extract of Coccinia grandis showed a remarkable wound repair effect. This effect was due to (rutin), quercetin-3-O-neohesperidin, nicotiflorin, kaempferol-3-O-glucorhamnoside, and astragalin as well as seco-iridoids of oleuropein and ligstroside (Al-Madhagy et al. 2019). HPLC metabolic profiling of the methanol extract of Ephedra ciliata recognized quercetin as a major compound. The antioxidant and antimicrobial activities of quercetin were related to the wound-closure effect of the extract (Yaseen et al. 2020). Biological guided study of E. characias subsp. wulfenii extracts (methanol, n-hexane, and ethyl acetate) of the aerial parts were tested. It was explored that the methanol extract displayed significant wound-repairing activity in circular excision and linear incision wound models, as well as anti-inflammatory effects. This study explored whether quercetin derivatives (quercitrin, hyperoside, and guaijaverin) were responsible for the wound-repairing effect (Özbilgin et al. 2018). Regarding Jacaranda decurrens Cham., metabolic profiling was done to find out ten compounds in the extract of flavonoidal and triterpenoidal nature. It was concluded that these compounds improved the healing of wounds in this study (Serra et al. 2020). Hydroethanolic extract of leaves of Lafoensia pacari A. St.-Hil. was evaluated in accelerating the contraction of wounds. The plant contained punicalagin, ellagic acid, punicalin, kaempferol, quercetin-3-O-xylopyranoside, and quercitrin, which could be related to re-epithelialization, improved cell proliferation, and enhanced remodeling phase of the wounds (Pereira et al. 2018). The mats composed of polyurethane loaded with Nigella sativa oil were studied to assess the in vivo wound-repairing effect (Aras et al. 2021). The essential oil of Nigella sativa seeds contains thymoquinone, which was reported to have wound-healing activity (Haq et al. 2020). Different studies were performed to obtain an effective wound healing process e. g. loaded thymoquinone chitosan- lecithin micelles which keep thymoquinone at the site of wounds with controlled release of the drug (Negi et al. 2020). Hydro-ethanol extract from Vitis labrusca leaves was found to advance the healing of wounds due to the total phenolic and flavonoid content (Santos et al. 2021). Aqueous ethanol extract of Leaves of Curatella americana Linn. exerted remarkable wound healing properties due to its active constituents. Leaves contain compounds known as wound-healing agents, mainly quercetin, kaempferol, glucosides, catechin, and epicatechin (Fujishima et al. 2020). A homogenous polysaccharide was separated from the rhizomes of Curcuma zedoaria and tested in the process of healing wounds in diabetic rats. It was added with platelet-rich plasma exosomes and loaded to a hydrogel sponge of chitosan and silk. It was found that the previous combination was effective and safe to speed the curing of wounds in the case of diabetes (Xu et al. 2018). Methanol extract of Dodonaea viscosa leaves caused accelerated epithelization of excision wounds and increased tensile strength of incision wounds of rats. HPTLC chromatogram showed 10 constituents of flavonoids, tannins, and saponins, including rutin and kaempferol, with reported healing effects (Nayeem et al. 2021).

bio- and synthetic polymers of bioactive substances from natural products

Wound dressings can be created from a combination of bio- and synthetic polymers. Loading them with bioactive substances from natural products increased the good features of this combination. The combined bio- and synthetic polymers may have little or no anti-bacterial, anti-inflammatory, and antioxidant effects (Alven et al. 2020). Loading the bioactive natural product to either the combined polymers or to only one of them eliminates this problem. Bioactive materials such as curcumin (Lüer et al. 2012; Tejada et al. 2016), quercetin (Choudhary et al. 2020; Karuppannan et al. 2022), rutin (Zhou et al. 2021), bromelain (Kalalinia et al. 2021), thymoquinone, gentiopicroside (Almukainzi M. et al. 2022; Almukainzi May et al. 2022), hesperidin (Carvalho et al. 2021), and others were reported to enhance wound healing by adding them to bio- or synthetic polymers or both.

Different types of wound dressings have existed as traditional or passive, e.g., plasters and wool dressing which are not favorable nowadays because of the pain and possible re-skin damage. The interactive wound dressing of synthetic or bio-polymers could be represented as hydrogel, foams, sprays, films, and nanofibers, which introduced a moist environment for wound healing and facilitated water vapor transmission but with a limited anti-bacterial effect. Bioactive wound dressings could be represented by the previously mentioned types of interactive wound dressings, which may be composed of synthetic polymers of polyethylene glycol, polyvinyl pyrrolidone polyurethanes, poly-hydroxyethyl methacrylate, polyglycolic acid, polylactide, poly-ε-caprolactone, as well as biopolymers of pectin, chitosan, cellulose, dextran, and alginate, collagen, which are loaded with antibiotics or growth factors or vitamins, and/or bioactive natural products (Zahedi et al. 2010; Aderibigbe and Buyana 2018; Alven et al. 2020).

The merits of combining synthetic and bio-polymer with bioactive natural products in wound dressings for better wound healing were confirmed in many studies e.g., curcumin (Sharma et al. 2018), quercetin, and rutin (Zhou et al. 2021). Curcumin is the active substance of the roots of turmeric or Curcuma longa. It exerts strong antioxidant and anti-inflammatory, anti-bacterial effects but with low water solubility and oral bioavailability. Curcumin was loaded into bio- and synthetic polymers to overcome this problem (Alven et al. 2020). The combination between bio- and synthetic polymers could overcome the problem of poor mechanical support of bio-polymers (Aycan et al. 2019), besides overcoming the problem of lacking biocompatibility, biodegradability, and bad patient compliance of synthetic polymers (Mir et al. 2018). Effective wound dressing for skin burns represents a challenge to the healthcare system due to the probability of skin structure damage leading to an increased risk of infection. Quercetin and rutin are flavonoids with strong antioxidant, antimicrobial and anti-inflammatory effects but have limited water solubility. It was revealed that incorporating quercetin and rutin into polycaprolactone and chitosan oligosaccharides to form a new bioactive electrospun nanofiber membrane, exhibited superior efficacy among all nanofiber membranes for burn injuries (Zhou et al. 2021).

Regarding diabetic wounds, new scaffolds formed of polyethylene glycolylated graphene oxide collagen hybrid for nanoscale drug delivery of quercetin were tested. It was found that it provided a new scaffold with the advantages of being superior, stable, the controllable release of quercetin, biodegradable nanomaterial, and biocompatible, which permitted collagen formation and angiogenesis. Besides, the mesenchymal stem cells' proliferation and differentiation potential were promoted via adhesion to this scaffold. These new scaffolds could help in solving issues of deficient collagen hyperplasia and insufficient blood supply in the case of diabetic wounds (Chu et al. 2018).

Conclusions and future direction

The current review clarifies that nature introduces medicinal plants with remarkable wound-healing effects. Scientific evidence obtained in the last 5 years has allowed us to expand our knowledge about herbal medicines on wound healing and the underlying molecular mechanisms. Plants, with their natural actives, have the ability to cure wounds and to be utilized in skin wound care. Mainly due to their anti-inflammatory, antimicrobial, and antioxidant activities (Pazyar et al. 2014).

Recent literature has proved that different natural substances, such as flavonoids, saponins, phenolic compounds, and polysaccharides, can operate at various phases of the process through diverse mechanisms and are primarily responsible for the activity of herbal remedies active in wound healing. Polyphenolic compounds have been confirmed therapeutical agents in wound healing by regulating and modulating inflammatory responses. Numerous phytochemicals in medicinal plants have been revealed to be important regulators of homeostasis, re-epithelialization, and regeneration by encouraging fibroblast proliferation and/or collagen formation. Scientific research confirmed the powerful impact of medicinal plants and their phytochemicals in wound management through multiple connected mechanisms (Maver et al. 2015; Artem Ataide et al. 2018).

The development of novel wound care techniques that integrate herbal healing agents with modern products and procedures is in line with current trends in wound healing. Nanostructures and nanoformulations have recently shown promise in overcoming the limitations of conventional medications. They control the release of medicines, lower the dosages needed for healing, and enhance the solubility and effectiveness of water-insoluble herbal components in healing wounds. The optimal dressing for wound treatment is made of nanofibers due to their well-controlled porosity and resemblance to skin tissue. The incorporation of natural materials into nanofibrous architectures for wound dressing has been studied. A biocompatible formulation made of natural herbal extracts would give the consumer a “green” option, and almost fewer side effects once put on the skin.

Based on these findings, it is recommended that many therapeutic approaches be employed concurrently in managing wounds, especially chronic wound injuries, to speed up the healing process and prevent complications. Moreover, various problems need to be resolved to improve the efficacy and utilization of natural substances in wound healing. Multidisciplinary efforts are required to confirm the products’ safety, look at their adverse effects, and do double-blind controlled clinical trials. Good production standards and regulatory regulations are equally essential to increase practitioners’ use of phytotherapy and encourage its incorporation into national health systems.

Funding

Open access funding provided by The Science, Technology & Innovation Funding Authority (STDF) in cooperation with The Egyptian Knowledge Bank (EKB). This review received no external funding.

Data availability

The authors confirm that the data supporting this study are available within the article.

Declarations

Conflicts of interest

The authors declare no conflict of interest.

Footnotes

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Contributor Information

S. A. El-Sherbeni, Email: suzy.elsherbini@pharm.tanta.edu.eg

W. A. Negm, Email: walaa.negm@pharm.tanta.edu.eg

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