Table 2.

Extra cellular vehicles (EVs) delivered via biomaterial scaffolds for tissue repair in representative examples in various injury models.

Disease	Study Done	EV Details	Cargo and Dosage	ROA	BA	Hydrogel Details	Hydrogel Loading	Outcomes	References
Bone Defects	In-vitro; in-vivo	HGMSCs; PEI EVs	N/A	DA	6 wks	Poly Lactide	Seeded on the hydrogel	↑ osteogenic commitment; bone healing	[41]
Skeletal Regeneration	In-vivo	hPDLSCs-EVs; PEI EVs	N/A	trichotomy	6 wks	Collagen membrane [Evo]	seeded on the collagen membrane	↑ mineralization process, ↑ vascular network formation; osseointegration	[88]
Wound Healing	In-vitro	Royal jelly	2.5 × 109/mL	N/A	7 days	Type I Collagen	Gelation	↑ Wound closure; antibacterial properties	[76]
Chronic Liver Failure	In-vivo	Human ES-MSCs	350 μg	IP	1 month	clickable PEG	Gelation	Enhanced antifibrotic effects vs. conventional bolus injection	[95]
Cartilage Defects	In-vivo	hUC-MSCs	miR-23a-3p; 10 × 108 particles/mL	DA	N/A	Gelma/nano- clay	Gelation	↑ cartilage regeneration by activating PTEN/AKT signalling pathway	[90]
Acute Kidney injury	In-vivo	hP-MSCs	miRNA let-7a- 5p; 100 μg/mL	IR	7 days	RGD-biotin (biotin-GFFYGRGD)	Gelation	↑ renal function; proliferation, antifibrosis, antiapoptosis; proautophagy ↓ tubular injury	[97]
Acute Kidney injury	In-vivo	hPMSC	100 μg in 100 μL of gel	IR	6 days	Collagen Matrix	Gelation	↑ proliferation, anti-apoptosis, and angiogenesis	[96]
Vascularization	In-vitro	PMSC	5 × 106 EVs	seeded on scaffolds	N/A	Electrospun scaffolds (PLLA+PCL)	Immobilization of LLP2A	↑ EC angiogenesis and prevented EC apoptosis	[42]
Diabetic skin wounds	In-vivo	hGMSC	150 µ g EVs/wound	DA	2 wks	chitosan/silk	Injected into the hydrogel	↑ re-epithelialization, deposition and remodelling of ECM, angiogenesis and neuronal ingrowth	[40]
Skin wounds	In-vitro; in-vivo	hUCMSC	miR-21, miR-23a, miR-125b; miR-145; 100 µg EVs	DA	N/A	Hydro Matrix	Gelation	↑ anti-scarring effect around each wound prevents α-SMA expression and scar formation.	[81]
Articular Cartilage Lesions	In-vitro; in-vivo	hiPSC-MSC	1 × 1011/mL	IA	N/A	PIC	Gelation	↑ Articular cartilage regeneration	[35]
Wound Healing	In-vivo	ADSCs	22 µg	IP	N/A	Alginate	Gelation	↑ wound closure, reepithelization, collagen deposition, angiogenesis	[82]
Vascular dysfunction	In-vivo	UMSCs	miR-675 11 mg/mL	Femoral artery	N/A	Silk fibroin	Sonication; Gelation	↑ blood perfusion, stability & retention of EVs	[91]
Bone regeneration	In-vitro; In-vivo	hucMSC	50 μg/μL	DA	N/A	CHA/SF/GCS/DF-PEG	Gelation	↑ bone healing; BMP2 deposition, bone collagen deposition; maturation and angiogenesis	[89]
Endometrial Regeneration	In-vivo	UCMSCs	3 × 1011 EVs/mL	DA	15 days	Collagen	dropwise on the scaffold for infiltration	↑ endometrium regeneration, collagen re- modelling, expressions of Erα & PR in the regenerated endometrium	[98]
Cardiac Repair	In-vitro; In-vivo	iPSC-Pg	Trehalose; 4.5 × 1010 EVs/mL	implanted on the polymers	N/A	PSA	Light activated cross linking	↓ degradation of EVs from without inducing an inflammatory response	[93]
Myocardial Infarction	In-vivo	MSCs	80 μg of EVs	IM	14 days	Sodium Alginate	Gelation	↑ angiogenesis and scar thickness ↓ cardiac apoptosis and fibrosis	[94]

Abbreviations: ROA—Route of Administration; BA—Bioavailability; DA—Direct Application; N/A—Not Applicable; Wks—weeks; HGMSCs—human gingival Mesenchymal Stromal Cells; hPMSCs—human placenta—derived MSCs; IR—Intra Renal; PLLA—PolyLactic Acid; PCL—Polycaprolactone; EC—Endothelial Cell; α-SMA—α-smooth muscle actin; hiPSC-MSC—human induced Pluripotent stem cell derived MSCs; IA—Intra articular; PIC—photoinduced imine crosslinking; ADSCs—Adipose derived stromal cells; iPSC-Pg—Human induced pluripotent cardiac progenitors; PSA—Polyglycerol sebacate acrylate; PEI—Polyethyleneimine; hPDLSCs—Human Periodontal-ligament stem cells; Evo—Evolution; ES-MSCs—Embryonic Stem cell derived MSCs; hUC-MSCs—Human Umbilical Cord derived Mesenchymal stromal cells; IP—Intra Peritoneal; PEG—polyethylene Glycol.