TABLE 2.
The examples of engineered EVs for wound healing.
| EV origin | Model | Disease | Route | Engineering methodology | Effector molecules; pathways | Effects | Ref |
|---|---|---|---|---|---|---|---|
| Human BMSCs | In vitro In vivo (Rat) | Diabetic skin wound | Subcutaneous injection | Preconditioning donor cells with melatonin | IL-1β, TNF-α iNOS, IL-10, and Arg-1; PTEN/AKT pathway | In vitro: ↓pro-inflammatory factors ↑anti-inflammatory factors ↑ratio of M2 polarization to M1 polarization In vivo: ↓inflammation ↑collagen synthesis ↑angiogenesis | Liu et al. (2020) |
| BMSCs | In vitro In vivo (Rat) | Diabetic skin wound | Subcutaneous injection | Preconditioning donor cells with pioglitazone | VEGF and CD31; PI3K/AKT/eNOS pathway | In vitro: ↑HUVECs migration and proliferation ↑HUVECs tube formation ↑VEGF expression In vivo: ↑collagen deposition and ECM remodeling ↑VEGF and CD31 expression ↑angiogenesis | Hu et al. (2021) |
| Human ADSCs | In vitro In vivo (Mouse) | Diabetic skin wound | Subcutaneous injection | Preconditioning donor cells with hypoxia conditions | COLI, COLIII, TGF-β, EGF, bFGF, IL-6 and CD31; PI3K/AKT pathway | In vitro: ↑fibroblasts proliferation and migration ↑the secretion of extracellular matrix and growth factors ↑ratio of M2 polarization to M1 polarization In vivo: ↓inflammatory cytokines ↑re-epithelialization ↑angiogenesis | Wang et al. (2021) |
| Human BMSCs | In vitro In vivo (Rat) | Full-thickness skin wound | Subcutaneous injection | Preconditioning donor cells with MNPs and SMF | MiR-21-5p, and SPRY2; PI3K/AKT and ERK1/2 pathways | In vitro: ↑migration and proliferation of HUVECs and HSFs ↑HUVECs tube formation ↑VEGF expression In vivo: ↑wound closure ↓scar widths ↑angiogenesis | Wu et al. (2020) |
| Human ADSCs | In vitro In vivo (Mouse) | Full-thickness skin wound | Subcutaneous injection | Overexpressing miR-21 | MiR-21, TGF-βI, MMP-2 and TIMP-1; PI3K/AKT signal pathway | In vitro: ↑HaCaTs migration and proliferation ↓TGF-βI expression ↑VEGF expression ↑the MMP-9 and TIMP-2 protein expression In vivo: ↑wound healing velocity | Yang et al. (2020b) |
| HEK293 | In vitro In vivo (Rat) | Diabetic skin wound | Subcutaneous injection | Overexpressing miR-31-5p | MiR-31-5p, HIF-1, EMP-1; HIF pathway | In vitro: ↑HaCaTs migration and proliferation ↑ECs migration and proliferation ↑HFF-1 cells migration and proliferation In vivo: ↑angiogenesis ↑fibrogenesis ↑re-epithelization | Huang et al. (2021) |
| BMSCs | In vitro In vivo (Mouse) | Diabetic skin wound | Subcutaneous injection | Overexpressing HOTAIR | HOTAIR and VEGF; not studied | In vitro: ↑VEGF expression ↑HUVECs and HDMECs proliferation and migration In vivo: ↑wound closure ↑new blood vessels | Born et al. (2022) |
| ASCs | In vitro In vivo (Mouse) | Diabetic skin wound | Apply on the wound bed (covered with Tegaderm Film and gaze) | Combined with FEP hydrogel (F127-PEI and APu) | MiR-126, miR-130a, miR-132, miR-let7b and miR-let7c; not studied | In vitro: ↑ECs migration and proliferation ↑ECs tube formation In vivo: ↑angiogenesis ↑cell proliferation and granulation tissue formation ↑collagen deposition and remodeling ↑re-epithelization ↓scar tissue formation ↑skin appendage regeneration. Other effects of hydrogel: antibacterial activity; fast hemostatic ability; self-healing behavior; tissue-adhesive and good UV-shielding performance | Wang et al. (2019) |
| Human BMSCs | In vitro In vivo (Rat and Rabbit) | Full-thickness skin wound | Apply to the wound surface (covered with a sterile gaze) | Combined with BSSPD hydrogel | MiR-29b-3p; PI3K/Akt, Erk1/2, and Smad3/TGFβ1 pathways | In vitro: ↑ECs migration and proliferation ↑fibroblasts migration and proliferation ↑angiogenesis and collagen deposition ↓excessive capillary proliferation and collagen deposition In vivo: ↑uniform vascular structure distribution ↑regular collagen arrangement ↓volume of hyperplastic scar tissue ↑skin appendage regeneration | Shen et al. (2021) |
| M2-Mφs | In vitro In vivo (Mouse) | Full-thickness skin wound | Subcutaneous injection (covered with Tegaderm Film) | Combined with PEG hydrogel | MiR-301b-3p, miR-149-5p, miR-125b-5p, miR-26a-5p, and miR-15a-5p; TLR4/NF-κB pathway | In vitro: ↑induction of M2-Mφ polarization In vivo: ↓acute inflammation ↑induction of M2-Mφ polarizationm ↑efficiency and quality of wound care ↑dermal adipogenesis and hair follicle regeneration | Kwak et al. (2022) |
| M2-Mφs | In vitro In vivo (Mouse) | Diabetic skin wound | Subcutaneous injection (covered with Tegader TM Film) | Overexpressing miRNA-223 and combined with HA@MnO2/FGF-2/Exos hydrogel | MiR-223 FGF-2; not studied | In vitro: ↓ROS damage ↑HSFs and HUVECs proliferation ↑HUVECs angiogenesis In vivo: ↓inflammation ↑angiogenesis ↑cell proliferation ↑granulation tissue formation ↑re-epithelization ↓ROS damage ↑supply of oxygen Other effects of hydrogel: antibacterial activity; hemostatic ability; self-healing ability; adhesive ability | Xiong et al. (2022) |
| SMSCs | In vitro In vivo (Rat) | Diabetic skin wound | Apply on the wound bed (covered with Tegaderm film) | Overexpressing miR-126-3p and combined with CS hydrogel | MiR-126-3p; AKT and ERK1/2 pathway | In vitro: HMEC-1 migration and tube formation In vivo: ↑wound closure ↑new blood vessels formation and maturation ↑re-epithelialization ↑mature granulation tissue ↑collagen alignment and deposition ↑the development of hair follicles and sebaceous gland | Tao et al. (2017) |
VEGF, vascular endothelial growth factor; MNPs, magnetic nanoparticles; SMF, static magnetic field; HSFs, human skin fibroblasts; HaCaT, human keratinocyte cells; MPP, matrix metalloprotein; TIMP, tissue inhibitor of metalloproteinases; HOTAIR, long non-coding RNA HOX transcript antisense RNA; HDMECs, human dermal microvascular endothelial cells; ASCs, adipose stromal cell; APu, Aldehyde pullulan; F127-PEI , Pluronic F127 grafting polyethylenimine; BSSPD, bilayered thiolated alginate/PEG diacrylate; M2-Mφs, M2 macrophages; PEG, poly (ethylene glycol); ROS, reactive oxygen species; SMSCs, synovium mesenchymal stem cells; CS, chitosan.