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.