Macroporous Granular Hydrogels Functionalized with Aligned Architecture and Small Extracellular Vesicles Stimulate Osteoporotic Tendon‐To‐Bone Healing

Abstract Osteoporotic tendon‐to‐bone healing (TBH) after rotator cuff repair (RCR) is a significant orthopedic challenge. Considering the aligned architecture of the tendon, inflammatory microenvironment at the injury site, and the need for endogenous cell/tissue infiltration, there is an imminent need for an ideal scaffold to promote TBH that has aligned architecture, ability to modulate inflammation, and macroporous structure. Herein, a novel macroporous hydrogel comprising sodium alginate/hyaluronic acid/small extracellular vesicles from adipose‐derived stem cells (sEVs) (MHA‐sEVs) with aligned architecture and immunomodulatory ability is fabricated. When implanted subcutaneously, MHA‐sEVs significantly improve cell infiltration and tissue integration through its macroporous structure. When applied to the osteoporotic RCR model, MHA‐sEVs promote TBH by improving tendon repair through macroporous aligned architecture while enhancing bone regeneration by modulating inflammation. Notably, the biomechanical strength of MHA‐sEVs is approximately two times higher than the control group, indicating great potential in reducing postoperative retear rates. Further cell‐hydrogel interaction studies reveal that the alignment of microfiber gels in MHA‐sEVs induces tenogenic differentiation of tendon‐derived stem cells, while sEVs improve mitochondrial dysfunction in M1 macrophages (Mφ) and inhibit Mφ polarization toward M1 via nuclear factor‐kappaB (NF‐κb) signaling pathway. Taken together, MHA‐sEVs provide a promising strategy for future clinical application in promoting osteoporotic TBH.