Extracellular vesicles loaded dual-network bioactive sealant via immunoregulation and annulus fibrosus repair for intervertebral disc herniation

Intervertebral disc herniation (IVDH) is a common manifestation of intervertebral disc degeneration (IVDD) characterized by inflammation that results in the rupture of the annulus fibrosus (AF) and herniation of the nucleus pulposus (NP). While current clinical research primarily focuses on regulating the degenerative NP, the crucial role of the AF in maintaining the mechanical stability and metabolic balance of the intervertebral disc (IVD) has been overlooked. Resolving immunoregulation and AF repair is imperative to effectively prevent recurrent herniation. Therefore, this study introduces a bioactive sealant (OD/GM/QCS-sEVs), which combines gelatin methacryloyl (GM) and oxidized dextran (OD) with quaternized chitosan (QCS) and incorporates small extracellular vesicles (sEVs). The developed sealant possesses injectability, self-healing capabilities, tissue adhesiveness, and mechanical stability, with an average adhesive strength of 109.63 kPa. In vitro experiments demonstrate that OD/GM/QCS-sEVs effectively seal AF defects while preserving mechanical properties comparable to those of a normal IVD. Additionally, the sealant releases sEVs through a pH-responsive mechanism, thereby modulating macrophage polarization to the M2 phenotype via the NF-κB signaling pathway. This mechanism facilitates immunoregulation and anti-inflammatory effects, and promotes stem cell differentiation into fibrocartilage. Animal experiments confirm the ability of OD/GM/QCS-sEVs to seal defects, prevent proteoglycan loss, inhibit IVDD development, and promote AF regeneration. Overall, OD/GM/QCS-sEVs hold promise as an innovative bioactive sealant for recurrent herniation by resolving immunoregulation and AF regeneration.