Extracellular vesicles from adipose-derived stem cells in bone regeneration: Mechanisms and therapeutic advances

Table 1 Preclinical strategies of adipose-derived stem cell-derived extracellular vesicles in bone defect

Pretreated cells/modified EVs	Strategy	In vivo model	Delivery route	In vivo effects	Ref.
Osteogenically induced ADSC-EVs	PLGA/PDA scaffold for sustained release	Mouse (4 mm defect)	Scaffold implantation	↑Bone volume, collagen, RUNX2/OCN expression; ↑BMSC osteogenesis	[21]
ADSC-EVs enriched with miR-375 (genetically modified ADSCs)	MiR-375 overexpression targeting IGFBP3	Rat (5 mm defect)	Hydrogel implantation	↑BV/TV, BMD, new bone	[26]
CREKA-modified rat ADSC-EVs	CREKA peptide for fibrin targeting	Rat femoral condyle (2.8 mm × 3 mm)	Local injection (40 μL)	↑BV/TV, Tb.Th, OCN, CD31; ↑M2 macrophages; ↓inflammation	[28]
Biotinylated ADSC-EVs	Avidin-biotin complex system on Bio-Ppy-Ti surface	Subcutaneous ectopic model	Immobilization on Ti (not injected)	↑ALP, COL I, OCN; ↑osseointegration	[29]
ADSC-EVs (unmodified)	PDA-coated gelatin sponge scaffold	Rat femoral condyle (3 mm defect)	Scaffold implantation	↑New bone, BMD, BV/TV, osteogenic markers; ↓Tb.Sp	[30]
ADSC-EVs (unmodified)	3D-bioprinted bilayer dECM hydrogel	Rat knee joint (4 mm defect)	Bilayer hydrogel implantation	↑Cartilage/subchondral bone repair, biomechanics; ↓IL-1β	[31]
ADSC-EVs (unmodified)	Injectable GNP hydrogel via miR-451a/MIF	Rat (5 mm defect)	Hydrogel injection	↑Bone healing, BV/TV, Tb.N/Th; ↑M2 polarization	[32]
ADSC-EVs (unmodified)	PLGA/Mg-GA MOF scaffold	Rat (6.5 mm defect)	Scaffold implantation	↑BV/TV, BMD, angiogenesis, osteogenesis; ↓inflammation	[33]
ADSC-EVs (unmodified)	None	STZ-induced T2DM rat femoral fracture	Local injection (600 μL, 200 μg/mL, every 3 days)	↑Mineralization, callus formation, BV/TV, and fracture healing	[40]

EVs: Extracellular vesicles; ADSC-EVs: Adipose-derived stem cell-derived extracellular vesicles; PLGA: Poly(lactic-co-glycolic acid); PDA: Polydopamine; RUNX2: Runt-related transcription factor 2; OCN: Osteocalcin; BMSC: Bone marrow mesenchymal stem cells; miR-375: MicroRNA-375; ADSC: Adipose-derived stem cell; IGFBP3: Insulin-like growth factor binding protein 3; BV/TV: Bone volume/total volume; BMD: Bone mineral density; CREKA: Cys-Arg-Glu-Lys-Ala; Tb.Th: Trabecular thickness; CD31: Cluster of differentiation 31; ALP: Alkaline phosphatase; COL I: Collagen type I; Ppy: Polypyrrole; Ti: Titanium; Tb.Sp: Trabecular separation; dECM: Decellularized extracellular matrix; IL-1β: Interleukin-1β; GNP: Gelatin-nanoparticle; miR-451a: MicroRNA-451a; MIF: Migration inhibitory factor; Tb.N: Trabecular number; Mg-GA MOF: Magnesium-gallic acid metal-organic framework; STZ: Streptozotocin; T2DM: Type 2 diabetes mellitus.