Fabrication of Hypoxia-Mimicking Supramolecular Hydrogels for Cartilage Repair

Despite advancements in chronic arthritis treatment, there remains a significant demand for advanced nanotechnologies capable of efficiently delivering a wide range of therapeutic agents to provide symptomatic relief and facilitate the healing of inflamed cartilage tissue. Considering the significant impact of hypoxia on the development and maintenance of chondral tissue, replicating its effects on stem cells could be a potential approach for the treatment of osteoarthritis (OA). Cobalt is a prominent hypoxia-inducing agent, owing to its ability to activate the hypoxia-inducible factor (HIF) pathway regardless of cellular oxygen levels. The intra-articular (IA) injection of dexamethasone (Dex) is often used to alleviate inflammation and pain associated with OA. Nevertheless, several obstacles impede the drug's efficacy, including its short duration of action and rapid elimination from the joint space. Considering these research problems, the study brings an advanced strategy for the development of a three-dimensional (3D) bioprintable hypoxia-mimicking supramolecular hydrogel (HMSG) through the self-assembly of Dex-loaded poly(ethylene glycol) diacrylate (PEGDA) guest polymers with acryloyl β-cyclodextrin (AβCD) host monomers, in combination with cobalt nanowires (Co NWs). Through the process of photo-cross-linking, HMSG can generate multivalent host-guest nanoclusters, making it an excellent candidate for 3D bioprinting, showcasing remarkable mechanical properties. By effectively delivering Dex and Co²⁺ in a sustained manner, the HMSG affords a suitable microenvironment for the encapsulated umbilical cord-derived mesenchymal stem cells (UMSCs), thereby promoting the synthesis of matrix components and decreasing the release of catabolic factors. Moreover, the HMSG ameliorates OA severity by increasing the M2 macrophage polarization, which can ultimately contribute to immunomodulatory effects. In conclusion, the results propose potential approaches for utilizing HMSG as efficient carriers to transport various therapeutic molecules to the injury site, thereby assimilating into nearby tissues and promoting successful tissue repair without the need for external growth factors.