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

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 (mu-fibers) first and subsequently crosslinking the mu-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.