Table 3 Summary synthesis methods of EVs combined with hydrogels for wound healing

Combining EVs after crosslink

PRP

Chitosan/silk hydrogel

EVs absorbed by cross-linked hydrogels

Promote diabetic wound healing, enhance collagen deposition and accelerate angiogenesis

[59]

GMSC

Chitosan/silk hydrogel

EVs absorbed by cross-linked hydrogels

Promote diabetic wound healing, enhance collagen deposition, accelerate angiogenesis and nerve regeneration

[54]

Periosteum cells

NAGA/GelMA/Laponite/glycerol hydrogel

EVs absorbed by cross-linked hydrogels

Promote FB and HUVEC viability, proliferation, migration, tube formation and the expression of FGF-1; promote diabetic wound healing, enhance collagen deposition, accelerate angiogenesis

[112]

Crosslink by agents after combining EVs

HUVEC

GelMA

The mixture of GelMA, photoinitiator 2959 and HUVEC-EVs crosslinked under UV light

Promote FB and HaCaT viability, proliferation and migration; promote wound healing, enhance collagen deposition, accelerate angiogenesis

[50]

ADSC

alginate hydrogel

The mixture of alginate and ADSC-EVs crosslinked by adding calcium chloride (CaCL2) solution

Promote HUVEC viability, proliferation and migration; promote wound healing, enhance collagen deposition, accelerate angiogenesis

[66]

ESC

GelMA

The mixture of GelMA, LAP photoinitiator and ESC-EVs crosslinked under UV light

Promote HUVEC viability, proliferation, migration and tube formation; promote diabetic wound healing, enhance collagen deposition, accelerate angiogenesis

[55]

Crosslink without agents after combining EVs

human endometrial stem cell (hEnSCs)

chitosan/glycerol hydrogel

The stable hydrogel construct was obtained through electrostatic interaction between positive NH2 charges of Ch and negative OH charge of glycerol as well as hydrogen-bonding interactions between the Ch chains.

Promote FB viability, proliferation and migration; promote wound healing, enhance collagen deposition, accelerate angiogenesis

[113]

Synovium-derived stem cells

Chitosan hydrogel

The hydrogel mixture with SMSC-EVs was placed at -20 °C for 2 h, and then NaOH solution was added and the mixture was kept at 4 °C for 4 h

Promote FB and HMEC-1 viability, proliferation, migration and tube formation; promote diabetic wound healing, enhance collagen deposition, accelerate angiogenesis

[57]

royal jelly

Type I collagen hydrogel

The hydrogel was mixed with royal jelly derived EVs at 4 °C and polymerized at 37 °C

Promote FB viability, proliferation and migration; form antibacterial biomembrane

[60]

Crosslink in situ through shear thinning

ADSC

FHE hydrogel (F127/OHA-EPL)

The hydrogel was injected into wounds after the solid-liquid transition under injection pressure and quickly gelated in situ

Promote HUVEC viability, proliferation, migration and tube formation; promote diabetic wound healing, enhance collagen deposition, accelerate angiogenesis

[37]

ADSC

FEP scaffold (F127-PEI/APu)

The hydrogel was injected into wounds after the solid-liquid transition under injection pressure and quickly gelated in situ

Promote HUVEC viability, proliferation, migration and tube formation; promote diabetic wound healing, enhance collagen deposition, accelerate angiogenesis and cell proliferation in wounds

[114]

PMSCs

methylcellulose-chitosan hydrogel

The hydrogel was injected into wounds after the solid-liquid transition under injection pressure and quickly gelated in situ

Promote diabetic wound healing, enhance collagen deposition, accelerate angiogenesis and regulate the expression of Bcl-2, Bax and VEGF

[115]

Crosslink in situ through temperature control

hUCMSC

PF-127 hydrogel

The hydrogel mixture stored at 4 °C and the gel transition happened at 37 ℃ on wounds

Promote HUVEC viability, proliferation and migration; promote diabetic wound healing, enhance collagen deposition, accelerate angiogenesis and cell proliferation in wounds, and regulate the expression of VEGF and tgf-β

[73]

ADSC

PF-127 hydrogel

The hydrogel mixture stored at 4 °C and the gel transition happened at 37 ℃ on wounds

Promote wound healing, enhance collagen deposition, accelerate angiogenesis and cell proliferation in wounds, and regulate wound inflammation

[116]

M2 macrophage

HAh and Haaq hydrogel

Both hydrogel precursors were injected in situ on the wounds and the gel transition happened by an efficient Schiff base reaction between the hydrazide moieties of HAh and the aldehyde moieties of HAaq

Promote FB and HUVEC viability, proliferation and tube formation; promote diabetic wound healing, enhance collagen deposition, accelerate angiogenesis and reduce wound ROS level

[45]

3D bioprinting

THP-1-derived activated macrophages (MΦ)

LVG-RGD/gelatin hydrogel

3D bioprinting was performed using the freeform reversible embedding of suspended hydrogel (FRESH) approach

Promoted NRCM viability, metabolic activity, and reduced their apoptosis

[117]

Lyosecretome

SA-SF hydrogel

Printability and shape fidelity of the SA-SF hydrogel were assessed using CELLINK INKREDIBLE+, an extrusion-based 3D bioprinter

Realize controllable EV-release kinetics with better EV-controlled-release effect

[118]

Lyosecretome

PCL/alginate hydrogel

PCL scaffolds were 3D-printed with the Cellink INKREDIBLE+, a pneumatic extrusion-based 3D bioprinter

Realize controllable EV-release kinetics with better EV-controlled-release effect

[72]