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

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.