Table 2.

Malaysian medicinal plants with potential wound healing activity

Medicinal plant	Active	Study	Model/method used	Mechanism of action	Reference
	ingredient
Aloe barbadensis Miller	50 µg/mL processed aloe gel + 25 µg/mL or 100 µg/mL aloe vera flower extract	In vitro	Cell migration assay, BrdU cell proliferation assay, scratch wound healing assay, qRT-PCR, western blotting, ELISA, MFAP 4 specific siRNA knockdown	Increases cell migration rate	[27]
				Increases proliferation of NHDF cells
				Increases the expression of VEGF and TGF-β
				Reduces inflammatory cytokines (IL-6 and IL-1β)
				Upregulates the expression of MFAP4, COL 1A, α-SMA, fibrillin and elastin
	Nanofibers containing 3% aloe vera	In vitro	MTS assay	Promotes the synthesis of hyaluronic acid and dermatan sulfate	[28]
	50, 100 and 150 µg/mL aloe vera gel	In vitro	Mouse embryonic fibroblasts, RT-PCR, ELISA	Increases the expression of bFGF and TGF-β1	[29]
	Nanofibers containing 10% aloe vera powder	In vitro	NIH-3T3 cell viability, SEM technique	Increases cell proliferation and adhesion	[32]
			Agar disc diffusion assay	Antibacterial effects against S. aureus and E. coli
	Nanofibers containing aloe vera extract	In vitro	Agar disc diffusion assay	Antibacterial effects against S. aureus and S. epidermidis	[33]
			BalbC/3T3 A31 fibroblast bioactivity assay	Increase in cell proliferation
		In vivo	Full-thickness wound healing assay in male db/db mice	Significant improvement in wound closure and reepithelization
	Wound dressing containing aloe vera gel	In vivo	Full-thickness excisional wound model in male Wistar rats	Improves the wound closure	[34]
				Anti-inflammation
	Nanofibers containing 5% or 10% aloe vera powder	In vitro	Disc diffusion, broth dilution method	Antibacterial activity against S. aureus and E. coli	[35]
			Cell-scaffold interaction, FE-SEM	Increases the cell growth of NIH-3T3 fibroblast cells
			Colorimetric MTT assay	Increases cell proliferation
	30 mg lyophilized aloe vera powder dissolved in 1.5 mL purified water	In vivo	Full-thickness skin wound excision in Goto-Kakizaki rats	Speeds up the recovery of diabetic wounds	[36]
				Increases inflammatory cell infiltration, angiogenesis, epithelialization and extracellular matrix deposition
				Increases TGF-β1 and VEGF
	Acemannan	In vitro	Human gingival fibroblasts, [3H]-thymidine incorporation assay	Stimulates DNA synthesis	[37]
				Increases gingival fibroblast proliferation
			ELISA	Increase the expression of KGF-1, VEGF and COL 1A
	Carbopol® containing 0.5%, 1% and 2% acemannan	In vivo	Punch biopsy wounds from the hard palate of male Sprague Dawley rats	Reduces oral wound areas
				Increase re-epithelialization
	Acemannan	In vitro, in vivo	35S-methionine incorporation assay, phosphorylation of AKT in acemannan-stimulated fibroblast cells, m7 GTP pull-down assay, full-thickness skin excisional wound model in male BALB/c mice, in vivo block of mTOR signaling by rapamycin	Promotes wound healing through AKT/mTOR signal pathway	[41]
				Upregulates cyclin D1
	Glucomannan	In vitro	FE-SEM	Binds to β2-integrins (LFA-01 and Mac-1) on fibroblast	[42]
	Gibberellins	In vitro	MTS assay	Stimulates fibroblast proliferation and protein synthesis
	β-sitosterol	In vitro	Chorioallantoic membrane assay	Enhances angiogenesis	[43]
	Aloesin	In vitro	Western blotting, ELISA	Activation of the Smad 2, Smad 3 and MAPK signaling pathways. Increases the expression of TGF-β1	[44]
			Scratch wound healing assay	Promotes keratinocyte migration
			Masson’s trichrome staining	Promotes collagen synthesis
			Endothelial cell tube formation assay	Promotes angiogenesis
	0.1% and 0.5% aloesin solution	In vivo	Full-thickness wounds in SKH-1 hairless mice	Promotes the formation of neoepithelium
				Increases the rate of granulation tissue formation, epidermal regeneration and dermal regeneration
Carica papaya Linn.	Methanolic leaf extract	In vitro	Scratch assay	Promotes cell proliferation	[56]
			Sircol collagen assay	Promotes collagen synthesis
	25%, 50% and 75% fruit extract	In vivo	Incised wound in Mus musculus	Promotes epithelization and fibrillation of the wound	[57]
				Reduces the length of the incised oral wound in mice
	Ethanolic aqueous leaf extract	In vitro	Disc diffusion, broth dilution method	Antibacterial effects against C. bacillus, S. epidermidis, S. viridans and E. coli	[58]
	Ethanolic leaf extract	In vivo	Oral ulcers in Wistar rats	Regulates the activity of macrophages, angiogenesis and re-epithelization	[59]
	Papaya paste	Clinical study	Deep burn wound	Promote the growth of healthy granulation tissue	[61]
				Enzymatic proteolytic debridement
	Unripe pawpaw dressing	Case report	Sacral radiation ulcer	Promotes the growth of healthy granulation tissue	[62]
	Hydrogel containing 0.4%, 1%, 2% and 4% papain	In vitro	NIH/3T3 fibroblasts activity	Regulates fibroblasts proliferation	[63]
	Hydrogel containing 4% papain	In vivo	H&E staining	Inhibits the formation of hypertrophic scar
			Masson staining	Regulates collagen deposition
	Unripe crushed papaya dressing	Case study	Non-healing chronic ulcer	Enzymatic debridement effect	[64]
	Papain, chymopapain, vitamin C	Clinical study	Second-degree and third-degree burns	Promotes the growth of healthy granulation tissue	[65]
				Loosens eschar for easy removal
				Stimulates collagen synthesis
Centella asiatica Linn.	Nanofibers containing asiaticoside	In vitro	Agar well disc diffusion method, time kill assay	Antibacterial activity against S. aureus and P. aeruginosa	[74]
			In vitro scratch assay	Promotes wound re-epithelialization
		In vivo	Single circular full thickness wound in albino Wistar male rats	Increases fibroblast proliferation
				Reduces inflammatory cells
				Stimulates epithelialization and collagen synthesis
	Gel containing 8% C. asiatica total glycosides	In vivo	Diabetic cutaneous ulcers in Sprague Dawley rats	Promotes epidermal epithelialization	[75]
				Promotes collagen synthesis
				Stimulates fibroblast proliferation
	Fabric coated C. asiatica extract	In vitro	Fabric diffusion method	Antibacterial activity against E. coli, S. aureus, B. subtilis and K. pneumonia	[84]
		In vivo	Wound on dorsal side of male albino Wistar rats	Significant wound healing effects
	Dressing containing 0.012% asiaticoside	In vitro	Cytotoxicity study	Enhance the proliferation of NHDF and NHEK	[87]
			Chick-chorioallantoic membrane assay	Promotes angiogenesis
	Asiaticoside	In vitro, in vivo	H&E staining	Reduces the number of inflammatory cells	[77]
				Increases fibroblast distribution
				Enhance angiogenesis
			Masson staining	Increases collagen deposition
			CCK8 assay, transwell assay, flow cytometry	Stimulates cell migration and proliferation
			Diabetic rats with full-thickness wounds, western blotting	Increases the expression of Wnt/β-catenin signaling cascade-linked proteins (Wnt1 and Wnt 4), c-myc, total β-catenin and nuclear β-catenin
				Increases GSK3β phosphorylation level
	10% hexane, ethyl acetate, methanol and aqueous extract	In vivo	Male Sprague Dawley rats with incision and burn wound	Increases the healing rate of incision and burn wounds	[79]
				Increases in tensile strength by collagen synthesis
				Complete epithelialization and keratinization
	β-sitosterol	In vitro	Chick embryo chorioallantoic membrane assay	Promotes angiogenesis	[81]
	Asiatic acid	In vitro	cDNA microarrays, RT-PCR	Induces the expression of TNFAIP6	[80]
	Asiaticoside	In vitro	Smad immunoprecipitation and blotting, western blotting	Upregulates the synthesis of COL 1A via TGF-β receptor I kinase-independent Smad signaling pathway	[82]
	Asiaticoside	In vitro, in vivo	RT-PCR, ELISA, western blotting, full-thickness burn injury in male ICR mice	Increases the mRNA levels of type I and type II collagen	[83]
				Increase in procollagen type I and type III levels
				Activation of TGF-β/Smad pathway
				Accelerates wound healing
	Madecassoside	In vitro, in vivo	RT-PCR, ELISA, western blotting, full-thickness burn injury in male ICR mice	Increases the mRNA levels of type I and type II collagen
				Increase in procollagen type I and type III levels
				Activation of TGF-β/Smad pathway
				Accelerates wound healing
	Madecassic acid	In silico	Glide module, grid-based docking protocol, glide extra precision (XP) docking protocol, Qik-Prop, Prime/MM-GBSA module	Strongly bound to TNF-α	[85]
				Inhibits the degradation of antioxidants and collagen
	Madecassoside	In silico	Glide module, grid-based docking protocol, glide extra precision (XP) docking protocol, Qik-Prop, Prime/MM-GBSA module	Strongly bound to TNF-α
	Asiatic acid	In silico	Glide module, grid-based docking protocol, glide extra precision (XP) docking protocol, Qik-Prop, Prime/MM-GBSA module	Strongly bound to TNF-α
				Inhibits proinflammatory cytokines
	Asiaticoside	In silico	Glide module, grid-based docking protocol, glide extra precision (XP) docking protocol, Qik-Prop, Prime/MM-GBSA module	Good binding affinity against Nrf2-Keap1
				Promotes collagen synthesis
	Madecassoside, terminoloside, isomadecassoside	In vitro	Colorimetric nitrite assay	Inhibits lipopolysaccharide-induced nitrite production	[86]
Cymbopogon nardus Linn.	Ethanolic extract of leaves and stem	In vitro	Disc diffusion method, macro dilution test	Antibacterial effects against S. aureus and E. coli	[97]
	Antiseptic gel containing 1% citronella grass extract	In vitro	Disc diffusion method, macro dilution test	Antibacterial effects against S. aureus and E. coli
	Essential oil	In vitro	Agar well diffusion method, broth macro dilution method	Inhibits the growth of C. albicans, C. glabrata and C. tropicalis	[93]
	25 µg essential oil in 100 mL olive oil	In vivo	Fungal infected diabetic wound in Swiss albino mice	Effectively eradicates C. albicans colonization and accelerates wound closure
				Reduces the levels of inflammatory markers (TNF-α and IL-1β)
	Essential oil	In vitro	Broth microdilution method	Antibacterial effects against S. aureus, S. epidermidis, A. baumannii, P. aeruginosa and S. pyogenes	[98]
	Essential oil	In vitro	Disc diffusion method, broth microdilution method	Bactericidal against S. aureus	[100]
	Geraniol	In vitro	Disc diffusion method, broth microdilution method	Bactericidal against S. aureus
	0.25%, 0.5% and 1% citronellal ointment	In vivo	Burn wound in Mus musculus	Promotes the healing of burn wounds	[96]
	Citronellal	In vitro	Disc diffusion method, serial dilution method	Antibacterial and antifungal effects	[99]
Ficus benghalensis Linn.	Aqueous bark extract	In vitro	Cell scratch assay	Promotes cell migration at wound site	[104]
			Kirby-Bauer disk diffusion method	Antibacterial effects
	Ointment containing 4% petroleum ether, ethanolic and aqueous leaf extract	In vivo	Excision wound healing model in male adult albino rats	Promotes wound healing and wound closure	[105]
	Ethanolic extract	In vitro	Disc diffusion method	Antibacterial effects against S. aureus, E. coli, P. protobacteria and B. cereus	[106]
	Methanolic bark extract	In vitro	Nitroblue tetrazolium assay, nitric oxide assay, lipid peroxidation assay	Anti-inflammatory action	[108]
			PCR	Downregulates the expression of TNF-α expression and upregulates the expression of IL-10
	10% aqueous leaf extract ointment	In vivo	Excision wound model in albino Wistar rats	Greatest wound healing effects among the Ficus species	[109]
				Comparable percentage of wound closure with Betadine
	Ethanolic and hydroalcoholic extract	In vitro	Red blood cells membrane stabilization	Inhibits hemolysis	[110]
	Gel containing 10% ethanolic/ hydroalcoholic extract	In vivo	Excision wound model in rats	Complete wound healing after 17–18 days
	Nanoparticles synthesized from extract	In vitro	ELISA	Stimulates the production of TGF-α	[113]
	Nanoparticles containing aqueous leaf extract	In vitro	Microdilution method	Bactericidal activity against E. coli	[107]
	Lupenyl acetate, lanosterol	In silico	Discovery Studio software	Inhibits TNF-α and VEGFR	[112]
Hibiscus rosa sinensis Linn.	Ethanolic leaves extract	In vitro	DPPH, nitric oxide, superoxide radical scavenging activity	Free radical scavenging activity	[120]
	10% ethanolic leaves extract ointment	In vivo	Excision wound model in Swiss albino mice	Significantly increase the percentage of excision wound closure
			Incision wound model in Swiss albino mice	Increases wound breaking strength in incision wounds by increasing collagen synthesis
			Burn wound model in Swiss albino mice	Stimulates the growth of keratinocytes and fibroblasts
	200 mg/kg ethanolic leaves extract		Dead space wound model in Swiss albino mice	Increases granulation tissue weight and hydroxyproline content of dead space wound
			In vivo antioxidant assay	Increase in antioxidant enzymes (SOD, CAT) in granulation tissue
	120 mg/kg ethanolic flower extract	In vivo	Masson’s trichrome staining	Stimulates the synthesis of collagen and fibroblast	[121]
				Reduces the number of inflammatory cells in granulation tissue
			Excision wound model in Sprague Dawley rats	Significantly enhance excision wound healing effects
				Increases the rate of epithelialization in excision wound
			Incision wound model in Sprague Dawley rats	Increases the tensile strength in incision wound
			Dead space wound model in Sprague Dawley rats	Significantly increase the granulation tissue weight and hydroxyproline concentration in dead space wounds
	Aqueous and ethanolic extract	In vivo	Incision wound model in Sprague Dawley rats	Promotes re-epithelialization and remodeling of granulation tissues in incision wounds	[122]
				Increases the tensile strength in wounded skin
	80, 160 and 320 mg/mL N-butyl alcohol flower extract	In vivo	Excision wound model in Sprague Dawley rats, H&E staining, Masson’s trichrome staining, immunohistochemistry	Increases the collagen deposition, collagen maturity and fibroblast distribution	[123]
				Promotes epidermal epithelialization of wounds
				Upregulates the expression of VEGF and TGF-β1
				Anti-inflammatory effects
	Ethanolic flower extract	In vivo	Chicken egg chorioallantoic membrane assay	Promotes angiogenesis	[124]
	Aqueous, ethanol and methanol extract	In vitro	Agar diffusion assay, micro-dilution method	Antibacterial activity against S. aureus, B. cereus, C. perfringens, L. monocytogenes, E. coli, S. typhi and P. aeruginosa	[125]
	Nanocomposite containing leaves extract	In vitro	Agar well diffusion method	Antibacterial effects against S. aureus and E. coli	[126]
	Silver nanoparticles synthesized using flowers, leaves and bark extract	In vitro	Not specified	Antibacterial activity against S. aureus, B. subtilis, P. aeruginosa and E. coli	[127]
	Ointment containing 5% and 10% ethanolic flower extract	In vivo	Excision wound model in Wistar albino rats	Significantly improves excision wound contraction	[128]
				Complete wound healing at 18 days (5% ointment) and 16 days (10% ointment)
			Incision wound model in Wistar albino rats	Increase in tensile strength of incision wounds
			Dead space wound model in Wistar albino rats	Significantly increases wet granuloma weight, dry granuloma weight and tensile strength of dead space wound
				Increases DNA, protein, collagen, hexosamine and uronic acid content of wet granulation tissue
	Nanofibers synthesized from 1% leaves mucilage	In vivo	Incision wound model in Swiss albino mice	Promotes collagen and fibroblast growth	[129]
			Excision wound model in Swiss albino mice	Faster wound healing and wound contraction
			Hemo-compatibility analysis	Non-hemolytic
	Ointment containing ethanolic flower extract	In vivo	Excision wound model in Sprague Dawley rats	Anti-inflammatory and antioxidant effects	[130]