Table 3.

Therapeutic applications of stem cell spheroids for tissue repair and regeneration.

Tissue	Stem cell	Formation method	Spheroid size	Seeding density	In vivo model (Functional evaluation)	Paracrine factors	Ref.
Bone	hADSC	Microfibers, centrifugation	1.2 mm2	2 × 104 cells/100 μL	Calvarial bone defect (Bone regeneration: 42.48 ± 10.84%)	VEGF	[169]
	hADSC	Nanofibers, centrifugation	0.425 mm2	4 × 104 cells	Calvarial bone defect(Bone regeneration: 59.97 ± 18.33%)	Non-analysis	[168]
	BMSC	Ultra-Low Attachment plates	530 μm	1 × 104 cells	Calvarial bone defect(Bone regeneration: 77.1 ± 4.1%)	Non-analysis	[170]
	BMSC	Nonadherent microwell plates	300 μm	1 × 104 cells	Segmental bone defect(Bone volume: 58 mm3)	VEGF	[171]
Cartilage	ADMSC	Non-fouling scaffold	80–110 μm	5 × 107 cells/mL	Articular cartilage defect(Collagen type II: 92%GAG: 89%)	Non-analysis	[175]
	hADSC	Porous scaffold	100–200 μm	5 × 107 cells/mL	Articular cartilage defect(Collagen type II: 83%GAGs: 82%)	TGF-β1	[176]
	MSC	Ultra-Low Attachment plates	291.3 μm	1 × 104 cells/well	Osteochondraldefect(Cartilage tissue regeneration: 74.0 ± 5.9%)	Non-analysis	[178]
	ASC	Porous scaffold	80–110 μm	5 × 107 cells/mL	Osteochondraldefect(Collagen type II: 81%,GAGs: 91%)	–	[177]
	ADSC	Membrane	∼90 μm	8 × 104 cells/well	Articular cartilage defect(High GAG expression)	SDF-1	[179]
Nerve	hGMSC	Ultra-Low Attachment plates	∼500 μm	4 × 104 cells/well	Facial nerve(High β-tubulin IIIand S-100 β expression)	Non-analysis	[188]
	ADMSC	Sulfonated chitosan well plate	–	2.8 × 104 cells/cm2	Nerve conduits(90% differentiation into immature Schwann cells; great peak amplitude and nerve conduction velocity)	HGF, NGF, BDNF, GDNF, and SDF-1	[117]
Blood vessel	hAMSC	Porous hydrogel	200–300 μm	5 × 106 cells/mL	Ischemic limb(Promoted angiogenesis, healthy myofiber, and regeneration of myofiber)	VEGF and IGF-1	[192]
	hAMSC	Porous scaffold	220 μm	5 × 107 cells/mL	Subcutaneous vascular ingrowth, and adipose tissue regeneration	VEGF and FGF-2	[190]
Tooth	hDPSC	Agarose microwell	∼300 μm	2.6 × 105 cells/190 μL	Regenerated and vascularized dental pulp-like tissue	Non-analysis	[194]
	hDPSC	Ultra-Low Attachment plates	∼60 μm	3.3 × 105 cells in 3 mL of pellet	Regenerative dentin and neurovascular-like structures that mimicked the native teeth	VEGF and TGF-β	[195]
Skin	hADSC	Hanging drop	200–300 μm	8000−10000 cells/25 μL	Skin wounds(Wound regeneration: 100%epithelium thickness: 150 μmcollagen density: 40%CD31 expression: 35%)	IL-10 and TGF-β1	[200]
	hADSC	Ultra-Low Attachment plates	1.2–1.5 mm	7.5 × 104 cells/cm2	Skin wounds(Rapid wound closure andhigher histological score)	VEGF, FGF, and HGF	[199]
	Human placenta-derived MSCs	Hanging drop	100 μm	5000 cells/droplet	Skin wound(Fast wound reepithelization and closure,enhanced microvessel density, andhigher expression of paracrine factors)	VEGFa, SDF-1, and Ang1	[197]
Heart	hBMSC	Hanging drop	260 μm	3 × 105 cells	Myocardial infarction(Enhanced vascularization, enhanced Cx43 expression, and improved cardiac function	VEGF, FGF, and HGF	[250]
	Human cardiac stem cell	Ultra-Low Attachment plates	95 μm	5 × 105	Myocardial infarction(Enhanced neovascularization, decreased fibrotic area, increased left ventricle thickness, and improved cardiac function)	FGF1, FGF2, FGF4, FGF5, FGF7, FGF16, IGF1, NGFβ, NRG4, ZEP91, ANGPT4, EFNA1, EFNA5, EFNB3, PDGFC, VEGFC, GH1, IFNA1, and IFNE1	[112]
	Human cardiac stem cell	6-well tissue culture plates coated with poly-2-hydroxyethyl methacrylate	75 μm	1052 cells	Myocardial infarction(Improved cardiac function and decreased fibrotic area)	SDF-1α and MCP-1	[201]
Kidney	hMSC	Ultra-Low Attachment plates	241 μm	1500 cells	Hypertensive kidney disease(Reduced proteinuria, improved glomerular permselective function)	VEGFA, HGF, IGF, and SDF-1	[204]
	hADMSC	Hanging drop	200 μm	25,000 cells	Ischemic kidney(Decreased creatinine and BUN levels, reduced tissue apoptosis and damage, and enhanced vascularization)	VEGF, EGF, IGF, bFGF, HGF, and TSG-6	[113]
Liver	hADMSC	Hanging drop	500 μm	1 × 106 cells	Hepatic fibrosis(Reduced hepatic fibrosis, decreased collagen I and collagen III expression, and improved liver function	IGF-1, HGF, and IL-6	[114]
	Human teeth-derived Stem cells	Ultra-Low Attachment plates	–	1 × 105 cells	Hepatic fibrosis(Reduced hepatic fibrosis and reduced bleeding)	TGF-β1	[206]
	human umbilical cord-derived -MSC	Rocker system	111 μm	1 × 106 cells	Acute liver failure(Activated liver regeneration, reduced necrosis, and improved regeneration of hepatocytes	IFN-γ, IL-6, and TNF-α	[251]
Lung	hADMSC	PDMS-based microwell	150 μm	1 × 105 cells	Emphysema(Recovered alveolar damage and enhanced growth factor production)	FGF-2, VEGF, and HGF	[115]