Injectable Supramolecular Ureidopyrimidinone Hydrogels Provide Sustained Release of Extracellular Vesicle Therapeutics

Abstract

Extracellular vesicles (EVs) are small vesicles secreted by cells and have gained increasing interest as both drug delivery vehicles or as cell‐free therapeutics for regenerative medicine. To achieve optimal therapeutic effects, strategies are being developed to prolong EV exposure to target organs. One promising approach to achieve this is through EV‐loaded injectable hydrogels. In this study, the use of a hydrogel based on ureido‐pyrimidinone (UPy) units coupled to poly(ethylene glycol) chains (UPy‐hydrogel) is examined as potential delivery platform for EVs. The UPy‐hydrogel undergoes a solution‐to‐gel transition upon switching from a high to neutral pH, allowing immediate gelation upon administration into physiological systems. Here, sustained EV release from the UPy‐hydrogel measured over a period of 4 d is shown. Importantly, EVs retain their functional capacity after release. Upon local administration of fluorescently labeled EVs incorporated in a UPy‐hydrogel in vivo, EVs are still detected in the UPy‐hydrogel after 3 d, whereas in the absence of a hydrogel, EVs are internalized by fat and skin tissue near the injection site. Together, these data demonstrate that UPy‐hydrogels provide sustained EV release over time and enhance local EV retention in vivo, which could contribute to improved therapeutic efficacy upon local delivery and translation toward new applications.

Biomaterials Functionalized with MSC Secreted Extracellular Vesicles and Soluble Factors for Tissue Regeneration

“…[ 208 ] Additionally, injection of MSC‐CM encapsulated in a platelet‐rich plasma hydrogel ameliorated renal healing and function in an acute kidney injury model, [ 209 ] while MSC‐CM delivered in synthetic PLGA nanoparticles coated with red blood cell membranes enhanced liver regeneration. [ 210 ] Several studies have demonstrated the potential of biomaterial‐based delivery of MSC‐EVs [ 211 ] for repair in indications such as peripheral nerve injury, [ 212 ] epidural fibrosis, [ 213 ] and incisional hernia [ 214 ] ( Table 2 ). For example, EV‐functionalized polyethylene glycol hydrogels significantly enhanced hepatic regeneration in a chronic liver failure model compared to bolus EV injections by attenuating inflammation, apoptosis, and fibrosis.…”

Potential Applications of Advanced Nano/Hydrogels in Biomedicine: Static, Dynamic, Multi‐Stage, and Bioinspired

“…As an example, ureido-pyrimidinone (UPy) poly(ethylene glycol) hydrogels were developed for prolonged exosome release at the target site while retaining their function. [131] As mentioned earlier, EVs are involved in tissue repair mechanisms, but when they are used therapeutically, their short lifetime at the site of injury is a limitation. It has been shown that repeated administration of EVs shows superior regenerative effects compared to a single administration of the same total EV concentration.…”

Advances in the Application of Supramolecular Hydrogels for Stem Cell Delivery and Cartilage Tissue Engineering

“…hydrogels (Mol et al, 2019). Multiple hydrogen bonding units simultaneously act as hydrogen bond donors and acceptors.…”

“…During the 1990s, Meijer and his group described quadruple hydrogen bonding in building blocks 2-ureido-4[1H]pyrimidinone (UPy). This has been widely adopted as the force behind the development of supramolecular hydrogels ( Mol et al, 2019 ). Multiple hydrogen bonding units simultaneously act as hydrogen bond donors and acceptors.…”