Extracellular vesicle-loaded hydrogels for tissue repair and regeneration

Abstract

Extracellular vesicles (EVs) are a collective term for nanoscale or microscale vesicles secreted by cells that play important biological roles. Mesenchymal stem cells are a class of cells with the potential for self-healing and multidirectional differentiation. In recent years, numerous studies have shown that EVs, especially those secreted by mesenchymal stem cells, can promote the repair and regeneration of various tissues and, thus, have significant potential in regenerative medicine. However, due to the rapid clearance capacity of the circulatory system, EVs are barely able to act persistently at specific sites for repair of target tissues. Hydrogels have good biocompatibility and loose and porous structural properties that allow them to serve as EV carriers, thereby prolonging the retention in certain specific areas and slowing the release of EVs. When EVs are needed to function at specific sites, the EV-loaded hydrogels can stand as an excellent approach. In this review, we first introduce the sources, roles, and extraction and characterization methods of EVs and describe their current application status. We then review the different types of hydrogels and discuss factors influencing their abilities to carry and release EVs. We summarize several strategies for loading EVs into hydrogels and characterizing EV-loaded hydrogels. Furthermore, we discuss application strategies for EV-loaded hydrogels and review their specific applications in tissue regeneration and repair. This article concludes with a summary of the current state of research on EV-loaded hydrogels and an outlook on future research directions, which we hope will provide promising ideas for researchers.

Keywords: 4-arm-PEG-MAL, four-armed polyethylene glycol (PEG) functionalized with maleimide group; AD/CS/RSF, alginate-dopamine chondroitin sulfate and regenerated silk fibroin; ADSC, Adipose derived mesenchymal stem cells; ADSC-EVs, adipose mesenchymal stem cells derived EVs; ADSC-Exos, adipose mesenchymal stem cells derived exosomes; ATRP, Atom transfer radical polymerization; BCA, bicinchoninic acid; BMSC, Bone marrow mesenchymal stem cells; BMSC-EVs, bone marrow mesenchymal stem cells derived EVs; BMSC-Exos, bone marrow mesenchymal stem cells derived exosomes; CGC, chitosan-gelatin-chondroitin sulfate; CL, chitosan lactate; CNS, central nervous system; CPCs, cardiac progenitor cells; CS-g-PEG, chitosan-g-PEG; DPSC-Exos, dental pulp stem cells derived exosomes; ECM, extracellular matrix; EGF, epidermal growth factor; EVMs, extracellular vesicles mimetics; EVs, Extracellular vesicles; Exos, Exosomes; Exosome; Extracellular vesicle; FEEs, functionally engineered EVs; FGF, fibroblast growth factor; GelMA, Gelatin methacryloyl; HA, Hyaluronic acid; HAMA, Hyaluronic acid methacryloyl; HG, nano-hydroxyapatite-gelatin; HIF-1 α, hypoxia-inducible factor-1 α; HS-HA, hypoxia-sensitive hyaluronic acid; HUVEC, human umbilical vein endothelial cell; Hydrogel; LAP, Lithium Phenyl (2,4,6-trimethylbenzoyl) phosphinate; LSCM, laser scanning confocal microscopy; MC-CHO, Aldehyde methylcellulose; MMP, matrix metalloproteinase; MNs, microneedles; MSC-EVs, mesenchymal stem cells derived EVs; MSC-Exos, mesenchymal stem cells derived exosomes; MSCs, mesenchymal stem cells; NPCs, neural progenitor cells; NTA, nanoparticle tracking analysis; OHA, oxidized hyaluronic acid; OSA, oxidized sodium alginate; PDA, Polydopamine; PDLLA, poly(D l-lactic acid); PDNPs-PELA, Polydopamine nanoparticles incorporated poly (ethylene glycol)-poly(ε-cap-rolactone-co-lactide); PEG, Polyethylene glycol; PF-127, Pluronic F-127; PHEMA, phenoxyethyl methacrylate; PIC, photo-induced imine crosslinking; PKA, protein kinase A system; PLA, Poly lactic acid; PLGA, polylactic acid-hydroxy acetic acid copolymer; PLLA, poly(l-lactic acid); PPy, polypyrrole; PVA, polyvinyl alcohol; RDRP, Reversible deactivation radical polymerization; Regeneration; SCI, spinal cord injury; SEM, Scanning electron microscopy; SF, Silk fibroin; SPT, single-particle tracking; TEM, transmission electron microscopy; Tissue repair; UMSC, umbilical cord mesenchymal stem cells; UMSC-EVs, umbilical cord mesenchymal stem cells derived EVs; UMSC-Exos, umbilical cord mesenchymal stem cells derived exosomes; UV, ultraviolet; VEGF, vascular endothelial growth factor; VEGF-R, vascular endothelial growth factor receptor; WB, western blotting; dECM, decellularized ECM; hiPS-MSC-Exos, human induced pluripotent stem cell-MSC-derived exosomes; iPS-CPCs, pluripotent stem cell-derived cardiac progenitors; nHP, nanohydroxyapatite/poly-ε-caprolactone; sEVs, small extracellular vesicles; β-TCP, β-Tricalcium Phosphate.