Smart µ‐Fiber Hydrogels with Macro‐Porous Structure for Sequentially Promoting Multiple Phases of Articular Cartilage Regeneration

Abstract Hydrogels are widely utilized for articular cartilage regeneration. However, traditional hydrogels with nano‐sized pores lead to poor cell and tissue infiltration. Furthermore, hydrogels that can stimulate each phase of cartilage regeneration to enhance cartilage repair are highly demanded. Herein, a macro‐porous hydrogel is fabricated by crosslinking mixed sodium alginate (SA) and hyaluronic acid (HA) solution into SA/HA micro‐fibers (µ‐fibers) first and subsequently crosslinking the µ‐fibers into hydrogel blocks. Besides, exosomes derived from NR8383 cells activated by lipopolysaccharides (LPS) and stimulated with bioglass (BG) ion extracts (LPS/BG‐exo) are incorporated into the hydrogel as they exhibit a strong ability to regulate inflammation homeostasis and recruit bone marrow mesenchymal stem cells (BMMSCs). Meanwhile, poly (lactic‐co‐glycolic acid) (PLGA) microspheres containing kartogenin (KGN) (PLGA_KGN) are encapsulated within the hydrogel for inducing the chondrogenic differentiation of recruited BMMSCs when KGN is released after the LPS/BG‐exo. Thus, the obtained macro‐porous SA/HA_exo‐PLGA_KGN hydrogel can not only significantly improve the infiltration of tissues into the hydrogel but also sequentially deliver LPS/BG‐exo and KGN to enhance the cartilage regeneration in a rat cartilage defect model. Prospectively speaking, the SA/HA_exo‐PLGA_KGN hydrogel is a potential candidate for other tissue regeneration as the bioactive substances can be adjusted according to different purposes.