Mesenchymal stem cell-derived exosomes: The dawn of diabetic wound healing

Table 1 Mesenchymal stem cell-derived exosomes application of diabetic full-thickness acute/chronic cutaneous wounds model

No.	Ref.	Institution(Nation)	Exosomes source	Intervention, administration, dose and time		Control	Model species	Wound diameter	Therapeutic effect	Molecular mechanism
1	Yang et al[140], 2020	The Third Affiliated Hospital of Southern Medical University(China)	Human umbilical cord		1 HUCMSC-Exos + PF-127 hydrogel; injected topically; 100 µg in 100 µL PF-127 (24%); at Day 0	PBS (100 µL)	Rats (Sprague-Dawley)	10 mm × 2 (1.5 cm apart)	1 Accelerated wound closure rate	—
									2 New hair follicle formation, fibroblasts proliferation, sufficient and order collagen deposition
					2 HUCMSC-Exos + PF-127 hydrogel; injected topically; 100 µg in 100 µL PBS; at Day 0
									3 Reduced inflammatory cell infiltration
									4 Higher microvessel densities and higher number of blood vessels (CD31, MVD)
					3 PF-127 hydrogel; injected topically; 100 µL PF-127 (24%); at Day 0
									5 Promoted cell proliferation (Ki67) and enhanced regeneration of granulation tissue
									6 Upregulated expression of VEGF and TGF-β
									7 Hydrogel supported exosome survival and biological activity
2	Wang et al[141], 2019	The Affiliated Hospital of Wenzhou Medical University; Xi'an Jiaotong University(China)	Mouse adipose tissue		1 AMSC-Exos + F127/OHA-EPL hydrogel; covered the wound; 10 μg; at Day 0	Saline	Mice (ICR)	8 mm × 2 mm	1 Accelerated wound closure rates	—
									2 Promoted cell proliferation and abundant granulation tissue in early stage of healing; reduced proliferative activities during the late repair stage to prohibit tissue hyperplasia
					2 AMSC-Exos; covered the wound; 10 μg; at Day 0
									3 Abundant and well-organized collagen fibers, more collagen deposition (Col I, Col III)
					3 F127/OHA-EPL hydrogel; covered the wound; 10 μg; at Day 0
									4 Faster re-epithelization (cytokeratin) and epithelial cell differentiation
									5 Promoted angiogenesis (α-SMA) and blood vessels formation
									6 Complete skin regeneration: skin appendages and less scar tissue appeared
3	Liu et al[121], 2020	Second Military Medical University; Shanghai Sixth People’s Hospital affiliated to Shanghai Jiao Tong University(China)	Human bone marrow		1 Melatonin-pretreated BMSC-Exos (MT-Exo); injected subcutaneously at least six sites per wound; dose not mentioned; at Day 0	PBS	Rats (Sprague-Dawley)	20 mm	1 Accelerated diabetic wound healing	PTEN/AKT signaling pathway
									2 Anti-inflammatory effect on macrophages by promoting M2 and inhibiting M1 polarization
									3 Enhanced re-epithelialization (increased neoepithelium length)
									4 Improved angiogenesis (α-SMA, CD31, Microfli perfusion) and collagen synthesis (Col I and III)
									5 Activated the PTEN/AKT signaling pathway
					2 BMSC-Exos; injected subcutaneously at least six sites per wound; dose not mentioned; at Day 0
4	Pomatto et al[104], 2021	University of Turin(Italy)	Human bone marrow		BMSC-EVs + carboxymethylcellulose; applied on the wound; 1 × 109 in 25 µL of vehicle; at Day 0, 3, 7 and 10	carboxymethylcellulose high viscosity 10 mg/mL (25 µL)	Mice (NSG)	6 mm × 8 mm	Not effective and did not reduce the wound closure rate	—
			Human adipose tissue		AMSC-EVs + carboxymethylcellulose; applied on the wound; 1 × 109 in 25 µL of vehicle; at Day 0, 3, 7, 10 and 14				1 Accelerated cutaneous wound healing
									2 Reduced size of the scar
									3 Increased epithelial thickness and re-epithelization
									4 Promoted angiogenesis (the number of vessels)
5	Shi et al[139], 2020	Affiliated Hospital of Nantong university(China)	Human adipose tissue		1 mmu_circ_0000250-modified AMSC-Exos;injected subcutaneously at four sites around the wound;200 μg in 100 μL PBS;at Day 0	PBS (100 μL)	Mice (C57BL)	4 mm	1 Accelerated cutaneous wound healing	mmu_circ_0000250/miR-128-3p/SIRT1-mediated autophagy
									2 Reduced scar areas
									3 Enhanced angiogenesis (CD31, vessel density)
									4 Suppressed apoptosis of skin tissue
									5 Suppressed expression of miR-128-3p but promoted SIRT1 expression
					2 AMSC-Exos; injected subcutaneously at four sites around the wound; 200 μg in 100 μL PBS; at Day 0
									6 Increased expression of autophagy-related gene (LC3)
6	Hu et al[138], 2021	Union Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology(China)	Rat bone marrow		1 Pioglitazone-treated BMSC-Exos (PGZ-Exos); injected subcutaneously(at least six sites per wound); 100 μg in 100 μL PBS; at Day 0	PBS (100 μL)	Rats (Sprague-Dawley)	15 mm	1 Accelerated cutaneous wound healing	PTEN/PI3K/AKT/eNOS pathway
									2 Enhanced re-epithelization
									3 Promoted collagen synthesis (Col I, Col III) and collagen deposition, indicating more superior ECM remodeling ability
									4 Enhanced angiogenesis (VEGF, CD31) and blood flow of the wound
					2 BMSC-Exos; injected subcutaneously (at least six sites per wound); 100 μg in 100 μL PBS; at Day 0
7	Yu et al[137], 2020	Shanghai Sixth People’s Hospital affiliated to Shanghai Jiao Tong University; Second Military Medical University(China)	Human bone marrow		1 Atorvastatin-pretreated BMSC-Exos (ATV-Exos); injected subcutaneously (six points); dose not mentioned; at Day 0	PBS	Rats (Sprague-Dawley)	20 mm	1 Accelerated cutaneous wound healing	miR-221-3p /PTEN/AKT/eNOS pathway
									2 Increased re-epithelization (more epithelial structures and longer neuroepithelium)
					2 BMSC-Exos; injected subcutaneously (six points); dose not mentioned; at Day 0
									3 Promoted collagen synthesis and deposition, indicating more superior ECM remodeling ability (thicker wavy collagen fibers and more extensive collagen deposition arranged neatly)
									4 Superior biosafety of the therapy of exosomes
									5 Enhanced angiogenesis (CD31, α-SMA and Microfil perfusion)
8	Zhao et al[123], 2021	Tongji University(China)	Human adipose tissue		1. AMSC-Exos; smeared at the wound; 200 μg in 200 μL PBS; 3 times/day, 2 wk	PBS;Untreated	Mice (db/db)	15 mm	1 Accelerated cutaneous wound healing	—
									2 Exosomes entered the dermis of wounds after smearing
					2 Recombinant human epidermal growth factor (rhEGF); smeared at the wound;3 times/day, 2 wk
									3 Mild hyperkeratosis and typical fibrous structures with new glands and hair follicles, implying enhanced tissue remodeling
					3 AMSC-CM; smeared at the wound; 3 times/day, 2 wk
									4 Enhanced collagen synthesis (Col I, Col III), deposition and remodeling (large amounts, large area, regular arrangement and dense distribution of new collagen)
									5 Enhanced cell proliferation and inhibited apoptosis
									6 Increased blood vessel intensity and promoted angiogenesis (CD31, VEGF)
									7 Repaired skin barrier functions (elevated expression levels Filaggrin, Loricrin, and AQP3)
									8 Suppressed expression of inflammatory cytokines (IL-6, TNF-α, CD14, CD19 and CD68)
									9 Negatively regulated MMP1 and MMP3 expression in promoting collagen synthesis
9	Tao et al[150], 2017	Shanghai Jiao Tong University Affiliated Sixth People’s Hospital(China)	Human synovial membrane		1 miR-126-3p overexpressed SMSC-Exos + chitosan wound dressings; placed on the wound bed with pressure dressing; at Day 0	Untreated	Rats (Sprague-Dawley)	18 mm	1 Accelerated cutaneous wound healing	PI3K/AKT and MAPK/ERK signaling pathways
									2 Enhanced angiogenesis (microcomputed tomography, CD31, α-SMA)
									3 Promoted re-epithelialization, granulation tissue formation, collagen alignment and deposition, implying enhanced ECM remodeling
					2 Chitosan wound dressings; placed on the wound bed with pressure dressing; at Day 0
									4 Accelerated development of hair follicles and sebaceous glands
10	Ti et al[126], 2015	Chinese PLA General Hospital(China)	Human umbilical cord		1 LPS-pretreated HUCMSC-Exos; injected dispersively into the wound edge; 60 μg in 0.5 mL PBS; at Day 0	Untreated	Rats	10 mm	1 Accelerated cutaneous wound healing	let-7b/TLR4/NF-κB/STAT3/AKT pathway
									2 Decreased inflammatory cell infiltration
									3 Regulate macrophage polarization to M2 macrophages
					2 HUCMSC-Exos; injected dispersively into the wound edge; 60 μg in 0.5 mL PBS; at Day 0
									4 Promoted the appearance of new small capillaries
11	Li et al[136], 2020	The Fourth Affiliated Hospital of Harbin Medical University(China)	Mouse bone marrow		1 lncRNA H19 overexpressed BMSC-Exos; injected into the skin around the wound; at Day 0	Untreated	Mice (C57BL/6)	10 mm	1 Accelerated cutaneous wound healing.	lncRNA H19/miR-152-3p/PTEN/ PI3K/AKT signaling pathway
									2 Ameliorated inflammation of the wound (IL-10 ↑, IL-1β↓, TNF-α↓ and fewer inflammatory cells around the wound)
					2 BMSC-Exos; injected into the skin around the wound; at Day 0
									3 Promoted granulation tissue formation
									4 Enhanced angiogenesis (Increased expression of VEGF, TGF-β1, α-SMA, and Col I)
									5 Suppressed cell apoptosis
									6 Interacted with miR-152-3p via PTEN-mediated PI3K/AKT signaling pathway (diminished miR-152-3p expression, elevated PTEN expression and decreased expression of PI3K, AKT and p-AKT)
12	Shi et al.(2017)[142]	Chinese PLA General Hospital(China)	Human gingival tissue		1 GMSC-Exos+ chitosan/silk hydrogel sponge; covered the wound with restraining bandage; 150 μg in 100 μl PBS; at Day 0, changed every 3 d	1. PBS (100 μL);2. gauze (13 mm× 13 mm) covered the wound	Rats (Sprague-Dawley)	10 mm	1 Accelerated cutaneous wound healing	—
									2 Promoted re-epithelialization, deposition and remodeling of ECM (more collagen deposition and thick wavy collagen fibers, the collagen fibers arranged in an orderly fashion similar to that of normal skin)
					2 Chitosan/silk hydrogel sponge; covered the wound with restraining bandage; in 100 μL PBS; at Day 0, changed every 3 d
									3 Enhanced angiogenesis (CD34, microvessel density)
									4 Enhanced neuronal ingrowth (nerve fiber density)
13	Xiao et al[151], 2021	Nan Fang Hospital of Southern Medical University(China)	Human adipose tissue		1 AMSC-Exos + human acellular amniotic membrane (hAAM) scaffold; covered on the wound; 100 μg in 100 μL PBS; at Day 0, every other day, 3 times in total	PBS (100 μL)	Mice (BALB/c)	10 mm	1 Accelerated cutaneous wound healing	—
									2 Suppressed wound inflammatory responses (fewer inflammatory cells around the wound and higher recruitment of M2 macrophages to the wound sites)
					2 AMSC-Exos; covered on the wound;100 μg in 100 μL PBS; at Day 0, every other day, 3 times in total
									3 Enhanced angiogenesis (CD31)
									4 Enhanced extracellular matrix (ECM) deposition (Col III)
									5 Promoted re-epithelialization (completed epithelial and dermal regenerated)
					3 hAAM patch; covered on the wound; at Day 0, every other day, 3 times in total
									6 Failed regenerated hair follicle and sebaceous glands
14	Yan et al[152], 2022	Union Hospital, Tongji Medical College, Huazhong University of Science and Technology(China)	Human umbilical cord		1 HUCMSC-Exos injected locally to the wound site; 100 μL, 50 μg/ml; at days 0, 3, 5, 7, 9, and 11	PBS (100 μL)	Mice (C57BL/6J)	10 mm	1 Accelerated cutaneous wound healing	—
									2 Reduced oxidative stress (ROS)
									3 Promoted granulation tissue formation
					2 HUCMSC-Exos injected locally to the wound site; 100 μL, 100 μg/mL; at days 0, 3, 5, 7, 9, and 11
									4 Enhanced angiogenesis (CD31, mean perfusion unit ratio)
15	Geng et al[128], 2022	Jinzhou Medical University(China)	Rat bone marrow		1 BMSC-Exos + carboxyethyl chitosan-dialdehyde carboxymethyl cellulose hydrogel; covered the wound; twice a day, two weeks	Untreated	Rats (Sprague-Dawley)	20 mm	1 Accelerated cutaneous wound healing	VEGF-mediated PI3K/AKT signaling pathways
									2 Promoted collagen deposition and remodeling, and fibrin regeneration
					2 Carboxyethyl chitosan-dialdehyde carboxymethyl cellulose hydrogel; covered the wound; twice a day, two weeks				3 Enhanced antibacterial effects by significantly inhibiting bacterial growth
									4 Skew macrophage functional polarity from M1 (iNOS) towards an anti-inflammatory M2 phenotype (CD206)
									5 Decreased inflammatory factors (IL-1β, TNF-α)
									6 Promoted proliferation of blood vessels and angiogenesis (CD31)
16	Gondaliya et al[153], 2022	National Institute of Pharmaceutical Educationand Research(India)	Bone marrow		1 BMSC-Exos loaded with miR-155 inhibitor; injected subcutaneously; 0.1 μg/μL; 1 d after wound induction	Untreated	Mice (C57BL/6)	4 mm	1 Accelerated cutaneous wound healing	—
									2 Declined miR-155 levels with a concomitant increase in FGF-7
					2 BMSC-Exos; injected subcutaneously; 0.1 μg/μL; 1 d after wound induction
									3 Downregulated expression of MMP-2 and MMP-9
									4 Declined expression of pro-inflammatory cytokines (TIMP-2, lymphotactin, sTNF RI, sTNF RII, and LIX); declined regulated upon activation, normal T cell expressed and secreted (RANTES) chemokine; downregulated pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) and TGF-β1
					3 BMSC-Exos loaded with negative control sequences; injected subcutaneously; 0.1 μg/μL; 1 d after wound induction
									5 Promoted re-epithelialization, collagen synthesis and deposition, angiogenesis (α-SMA) and vascularization (CAM)
17	Dalirfardouei et al[125], 2019	Mashhad University of Medical Sciences(Iran)	Human menstrual blood		1 MenSC-Exos; injected intradermally; 10 μg in 100 μL of PBS; at Day 0	PBS (100 μL)	Mice (C57BL/6)	8 mm	1 Accelerated cutaneous wound healing	NF-κB signaling pathway (possible)
									2 Promoted re-epithelialization
					2 MenSCs; injected intradermally; 1 × 106 cells in 100 μL of PBS; at Day 0
									3 Induced macrophage polarization from M1 (iNOS) to M2 (Arg) phenotype
									4 Enhanced angiogenesis (VEGF, microvessel density)
									5 Improved collagen deposition (upregulated Col I/Col III ratio at Day 7, downregulated at Day 14)
									6 Decreased size of scar tissues
									7 Decreased cellularity in the granulation tissue
									8 Decreased Rela gene expression at Day 4, enhanced at Day 7.
18	Wang et al[124], 2022	Affiliated Hospital of Nantong University(China)	Rat bone marrow		1 BMSC-Exos + 50 mg/kg intraperitoneal tertbutylhydroquinone (tBHQ); injected subcutaneously of 4 sites at the base and edge of the wound; 100 μg/mL, 200 μL; at Day 0 and 7	PBS	Rats (Sprague-Dawley)	15 mm	1 Accelerated cutaneous wound healing	—
									2 Promoted re-epithelialization and collagen deposition
									3 Enhanced angiogenesis (CD31)
									4 Reduced inflammation (decreased inflammatory cytokines TNF-α, IL-1β and increased anti-inflammatory cytokines IL-4, IL-10).
					2 BMSC-Exos + 200 μL intravenous Lenti-sh-NC; injected subcutaneously of 4 sites at the base and edge of the wound; 100 μg/mL, 200 μL; at Day 0 and 7
					3 BMSC-Exos; injected subcutaneously of 4 sites at the base and edge of the wound; 100 μg/mL, 200 μL; at Day 0 and 7
					4 BMSC-Exos + 200 μL intravenous Lenti-sh-Nrf2; injected subcutaneously of 4 sites at the base and edge of the wound; 100 μg/mL, 200 μL; at Day 0 and 7
19	Sun et al[127], 2022	Nanjing Normal University; Nanjing University; Nanjing medical University; Nanjing Tech University(China)	Human umbilical vein		1 Engineering TNF-α/hypoxia-pretreated HUVMSC-Exos +PCOF; each subsequent day later, total 21 d	PBS	Mice (C57BL/6)	15 mm (S.aureus-infected chronic wounds)	1 Accelerated cutaneous wound healing	miR-126/ SPRED1/RAS/ERK pathway (possible)
									2 Reduced bacterial burden and suppressed bacterial colonization in the wound sites
					2 Engineering TNF-α/hypoxia-pretreated HUVMSC-Exos; each subsequent day later, total 21 d
									3 Reduced the inflammatory response (immune cells counting); decreased proinflammatory cytokines (TNF-α, IL-1β, IL-6); induced M2 (CD206) macrophages polarization
					3 Vancomycin; each subsequent day later, total 21 d
					4 PCOF; each subsequent day later, total 21 d
									4 Promoted collagen deposition and remodeling, granulation formation, re-epithelialization and enhanced proliferation of fibroblasts
									5 Enhanced cell proliferation (Ki67)
									6 Suppressed oxidative stress induced by bacteria and peroxide substrates (reduced the content of oxidative biomarkers and (MDA) increased the antioxidant mediators (GSH-Px, SOD)
									7 Promoted angiogenesis (upregulated miR-126, HIF-1α, VEGF, CD31 and α-SMA; increased neovascularization)
									8 In vivo biosafety (blood system, heart, liver, kidney and other organs)
20	Li et al[147], 2016	Shanghai Normal University; Shanghai Jiao Tong University Affiliated Sixth People's Hospital(China)	Human synovial tissue		1 miR-126-3p overexpressed SMSC-Exos + hydroxyapatite/chitosan composite hydrogel; placed on the wound bed with pressure dressing	Untreated	Rats (Sprague-Dawley)	18 mm	1 Accelerated cutaneous wound healing	Activated MAPK/ERK and PI3K/AKT pathways
									2 Enhanced angiogenesis (μCT), formation and maturation of new vessels (CD31, α-SMA)
									3 Promoted re-epithelialization, granulation tissue maturation, collagen alignment and deposition that indicated improved ECM remodeling
					2 Hydroxyapatite/chitosan composite hydrogel; placed on the wound bed with pressure dressing
									4 Accelerated growth of follicles and sebaceous glands
21	Zhang et al[148], 2021	Jinzhou Medical University(China)	Human umbilical cord		1 HUCMSC-Exos + polyvinyl alcohol (PVA)/alginate (Alg) nanohydrogel; locally transplanted; 300 μL; once a day	Untreated	Rats (Sprague-Dawley)	15 mm × 2 mm	1 Accelerated cutaneous wound healing	ERK1/2 pathway
									2 Enhanced re-epithelialization and hair follicles formation
									3 Promoted collagen deposition and remodeling (increased and orderly arranged collagen fibers)
					2 HUCMSC-Exos; locally transplanted; 300 μL; once a day
					3 PVA/Alg nanohydrogel; locally transplanted; 300 μL; once a day
									4 Promoted angiogenesis (CD31, α-SMA, SR-B1, VEGF)
22	Han et al[154], 2022	The First Affiliated Hospital of Zhengzhou University(China)	Human bone marrow		1 lncRNA KLF3-AS1 overexpressed BMSC-Exos; injected via tail vein; 100 µL; at Day 0	Untreated	Mice (BALB/c)	Not mentioned	1 Accelerated cutaneous wound healing	lncRNA KLF3-AS1/miR-383/VEGFA signaling pathway
									2 Minimized weight loss.
					2 Negative control silenced BMSC-Exos;injected via tail vein;100 µL;at Day 0				3 Reduced inflammation (decreased IL-6 and IL-1β)
									4 Promoted angiogenesis (CD31), collagen deposition and follicle regeneration
					3 Negative control overexpressed BMSC-Exos; injected via tail vein; 100 µL; at Day 0
									5 Decreased expression of miR-383 and increased VEGFA
					4 lncRNA KLF3-AS1 silenced BMSC-Exos; injected via tail vein; 100 µL; at Day 0
23	Ding et al[155], 2019	Shanghai Jiao Tong University Affiliated Sixth People's Hospital(China)	Human bone marrow		1 Deferoxamine-preconditioned BMSC-Exos (DFO-Exos); injected subcutaneously around the wounds at four sites; 100 μg in 100 μL PBS; at Day 0	PBS (100 μL)	Rats (Sprague-Dawley)	20 mm × 2 mm	1 Accelerated cutaneous wound healing	miR-126/PTEN/PI3K/AKT pathway
									2 Enhanced re-epithelialization and lower scar formation
									3 Promoted collagen deposition (increased wavy collagen fibers)
					2 BMSC-Exos; injected subcutaneously around the wounds at four sites; 100μg in 100μL PBS; at Day 0
									4 Promoted angiogenesis (vessel density by micro-CT, CD31, α-SMA)
24	Bian et al[135], 2020	Chinese PLA General Hospital(China)	Human decidua		dMSC-sEVs; injected around the wounds at 4 sites (25 μL per site); 100 μL, 5.22 × 1011 particles/mL; at Day 7, 14, 21and 28	PBS (100 μL)	Mice (BKS-db)	16 mm	1 Accelerated cutaneous wound healing	RAGE/RAS; Smad pathways
									2 Reduced scar width
									3 Accelerated collagen deposition (larger and better-organized collagen deposition)
									4 Enhanced fibroblast proliferation (PCNA), migration (CXCR4), and differentiation abilities of fibroblast
									5 Promoted angiogenesis (α-SMA)
									6 Improved fibroblast senescent state (p21)
25	Zhang et al[156], 2022	Xijing Hospital of Fourth Military Medical University(China)	Human adipose tissue		AMSC-Exos; injected subcutaneously; 200 μg; 3 d after wound induction, for three consecutive days	PBS (100 μL)	Mice (db/db)	10 mm	1 Accelerated cutaneous wound healing	SIRT3/SOD2 pathway
									2 Enhanced re-epithelialization
									3 Promoted angiogenesis (CD34, VEGF)
									4 Improved oxidative stress (MDA, T-AOC, SOD)
									5 Reduced inflammatory cytokines (IL-1β, IL-6, TNF-α, MCP-1)
26	Born et al[157], 2021	University of Maryland; Johns Hopkins University School of Medicine(USA)	Human bone marrow		1 HOX transcript antisense RNA (HOTAIR) overexpressed BMSC-EVs; injected around the wound in a cross pattern of four sites; 50 μg in 50 μL PBS; at Day 3, four times	PBS (50 μL)	Mice (db/db)	8 mm	1 Accelerated cutaneous wound healing	—
									2 Promoted angiogenesis (CD31, VEGFA)
					2 BMSC-EVs; injected around the wound in a cross pattern of four sites; 50 μg in 50 μL PBS; at Day 3, four times
27	Teng et al[158], 2022	Jiangnan University (China)	Human umbilical cord		HUCMSC-Exos; injected subcutaneously around the wounds at four sites; 100 μL (100 μg/mL); at Day 0	PBS (100 μL)	Rats (Sprague-Dawley)	10 mm	1 Accelerated cutaneous wound healing	—
									2 Inhibited chronic inflammation: (decreased number of inflammatory cells); inhibited pro-inflammatory cytokines (TNF-α); induced M2 (CD206) macrophages polarization
									3 Enhanced re-epithelialization
									4 Promoted angiogenesis (increased new blood vessels, CD31, VEGF)
									5 Promoted collagen synthesis and skin regeneration

HUCMSC-Exos: Human umbilical cord mesenchymal stem cell derived exosomes; PF-127: Pluronic F-127; PBS: Phosphate buffered saline; MVD: Microvascular density; Ki67: Nucleus related antigen; TGF-β: Transforming growth factor-β; VEGF: Vascular endothelial growth factor; F127: Pluronic F127; OHA: Oxidative hyaluronic acid; EPL: Poly-ε-L-lysine; Col I: Collagen I; Col III: Collagen III; α-SMA: Alpha smooth muscle actin; BMSC-Exos: Bone marrow mesenchymal stem cell derived exosomes; PTEN: Phosphatase and tensin homolog; BMSC-EVs: Bone marrow mesenchymal stem cell derived extracellular vesicles; AMSC-EVs: Adipose tissue mesenchymal stem cell derived extracellular vesicles; AMSC-Exos: Adipose tissue mesenchymal stem cell derived exosomes; SIRT1: Silent mating type information regulation 2 homolog-1; LG3: Light chain 3; ECM: Extracellular matrix; PI3K: Phophatidylinositol3-kinase; eNOS: Endothelial nitric oxide synthase; AMSC-CM: Adipose tissue stem cell conditioned medium; AQP3: Recombinant aquaporin 3; IL-6: Interleukin 6; TNF-α: Tumor necrosis factor alpha; SMSC-Exos: Synovial membrane mesenchymal stem cell derived exosomes; MAPK: Mitogen-activated protein; ERK: Extracellular signal regulated kinase; let-7b: MicroRNA let-7b; TLR4: Toll like receptor 4; NF-κB: Nuclear factor kappa-B; STAT3: Signal transducer and activator of transcription 3; Il-10: Interleukin 10; IL-1β: Interleukin 1β; GMSC-Exos: Gingival tissue mesenchymal stem cell derived exosomes; iNOS: Inducible nitric oxide synthase; sTNF RI: Soluble tumor necrosis factor receptor I; sTNF RII: Soluble tumor necrosis factor receptor II; FGF-7: Fibroblast growth factor 7; LIX: Lipopolysaccharide-induced CXC chemokine; CAM: Chick chorioallantois membrane; MenSC-Exos: Menstrual blood mesenchymal stem cell derived exosomes; MenSCs: Menstrual blood-derived mesenchymal stem cells; Arg: Arginase; Lenti-sh-Nrf2: Lentiviral shRNA targeting Nrf2; Lenti-sh-NC: Lentiviral control shRNA; HUVMSC-Exos: Human umbilical vein mesenchymal stem cell derived exosomes; PCOF: Polydopamine modified reductive covalent organic frameworks; S.aureus: Staphylococcus aureus; MDA: Malondialdehyde; GSH-Px: Glutathione peroxidase; SOD: Superoxide dismutase; SR-B1: Scavenger receptor class B type I; dMSC-sEVs: Decidua mesenchymal stem cell derived extracellular vesicles; PCNA: Proliferating cell nuclear antigen; CXCR4: CXC-chemokine receptor 4; p21: Cyclin-dependent kinase inhibitor 1A; RAGE: Receptor for advanced glycation end products; RAS: rat sarcoma; T-AOC: Total antioxidant capacity; ,MCP-1: Monocyte chemoattractant protein-1; SIRT3: Silent mating type information regulation 2 homolog 3.

Table 2 Clinical trials of exosomes in treating various wounds

Start year	Institution (Nation)	Type of wounds	Intervention	Autologous/Allogeneic	Administration, frequency	Patients number	Follow-up period	Outcome measures	Phase	Study design	ClinicalTrials.gov identifier	Status
2022	Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University (China)	Full-layer skin wounds	Adipose tissue derived exosomes(200-300 mL of the subject adipose tissue)	Autologous	Applied directly to the wound (mixed with sterile hydrogel), twice a week	5	4 wk	Primary: Percentage of wound healing	Not Applicable	Non-randomized, single group assignment, open label	NCT05475418	Not yet recruiting
2015	Kumamoto University (Japan)	Intractable cutaneous ulcers (e.g., rheumatic disease, peripheral arterial disease, chronic venous insufficiency, decubitus or burns)	Plasma-derived exosomes (Plasma samples will be filtered through 0.45 μm and 0.20 μm filters. The samples will be filtered through 0.02 μm filter to trap exosomes with the filter. Saline solution will be loaded from the other side of the 0.02 μm filter to obtain exosome rich buffer.)	Autologous	Applied to the ulcer, daily	5	28 d	Primary: Ulcer size (length, width, depth)	Early Phase 1	Non-randomized, single group assignment, open label	NCT02565264	Unknown
								Secondary: Pain of cutaneous wounds (VAS)
2023	Aegle Therapeutics (USA)	Dystrophic Epidermolysis Bullosa (DEB); chronic wounds (< 20% closure of wound during observation period); 10-50 cm2	Bone marrow mesenchymal stem cells derived extracellular vesicle (AGLE-102)	Allogeneic	Multiple administrations of 2 ascending dose levels of AGLE-102; (up to 6 administrations); (each administration will occur 14 ± 7 d but no less than 7 d apart); (each administration no more than 3 mo); (wound closes prior to 6 administrations, no additional doses will be given)	10	8 mo; if the wound closes before receiving all 6 doses, for 4 mo after the wound closes	Primary: Dose limiting toxicity	Phase 1/2	Non-randomized, multicenter, ascending dose, single group assignment, open label	NCT04173650	Not yet recruiting
								Secondary: Wound size
2019	Mayapada Hospital (Indonesia)	Chronic wounds	Human Wharton's Jelly mesenchymal stem cells conditioned medium (WJ-MSC-CM)	Allogeneic	Applied to the wound (the conditioned medium gel), every week	38	2 wk	Primary: Success rate of chronic ulcer healing	Phase 1	Non-randomized, single group assignment, open label	NCT04134676	Completed