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. 

https://doi.org/10.1016/j.mtbio.2022.100522

Extracellular vesicle-loaded hydrogels for tissue repair and regeneration

Hydrogels, which are hydrophilic polymer networks, have attracted great attention, and significant advances in their biological and biomedical applications, such as for drug delivery, tissue engineering, and models for medical studies, have been made. Due to their similarity in physiological structure, hydrogels are highly compatible with extracellular matrices and biological tissues and can be used as both carriers and matrices to encapsulate cellular secretions. As small extracellular vesicles secreted by nearly all mammalian cells to mediate cell–cell interactions, exosomes play very important roles in therapeutic approaches and disease diagnosis. To maintain their biological activity and achieve controlled release, a strategy that embeds exosomes in hydrogels as a composite system has been focused on in recent studies. Therefore, this review aims to provide a thorough overview of the use of composite hydrogels for embedding exosomes in medical applications, including the resources for making hydrogels and the properties of hydrogels, and strategies for their combination with exosomes.

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Hydrogels for Exosome Delivery in Biomedical Applications

The efficacy of neural repair and regeneration strategies for traumatic brain injury (TBI) treatment is greatly hampered by the harsh brain lesion microenvironment including oxidative stress and hyper-inflammatory response. Functionalized hydrogel with the capability of oxidative stress suppression and neuroinflammation inhibition will greatly contribute to the repairment of TBI. Herein, antioxidant gallic acid-grafted hyaluronic acid (HGA) was combined with hyaluronic acid-tyramine (HT) polymer to develop an injectable hydrogel by dual-enzymatically crosslinking method. The resulting HT/HGA hydrogel is biocompatible and possesses effective scavenging activity against DPPH and hydroxyl radicals. Meanwhile, this hydrogel improved cell viability and reduced intracellular reactive oxygen species (ROS) production under H2O2 insult. The in vivo study showed that in situ injection of HT/HGA hydrogel significantly reduced malondialdehyde (MDA) production and increased glutathione (GSH) expression in lesion area after treatment for 3 or 21 days, which might be associated with the activation of Nrf2/HO-1 pathway. Furthermore, this hydrogel promoted the microglia polarization to M2 (Arg1) phenotype, it also decreased the level of proinflammatory factors including TNF-α and IL-6 and increased anti-inflammatory factor expression of IL-4. Finally, blood-brain barrier (BBB) was protected, neurogenesis in hippocampus was promoted, and the motor, learning and memory ability was enhanced. Therefore, this injectable, biocompatible, and antioxidant hydrogel exhibits a huge potential for treating TBI and allows us to recognize the great value of this novel biomaterial for remodeling brain structure and function. 

https://doi.org/10.1016/j.mtbio.2022.100278

In situ forming and biocompatible hyaluronic acid hydrogel with reactive oxygen species-scavenging activity to improve traumatic brain injury repair by suppressing oxidative stress and neuroinflammation

Denghui Xie

Papers

Exosome-loaded extracellular matrix-mimic hydrogel with anti-inflammatory property Facilitates/promotes growth plate injury repair