Vanillin-based functionalization strategy to construct multifunctional microspheres for treating inflammation and regenerating intervertebral disc

Intervertebral disc degeneration (IVDD) is one of the main causes of low back pain. Although local delivery strategies using biomaterial carriers have shown potential for IVDD treatment, it remains challenging for intervention against multiple adverse contributors by a single delivery platform. In the present work, we propose a new functionalization strategy using vanillin, a natural molecule with anti-inflammatory and antioxidant properties, to develop multifunctional gelatin methacrylate (GelMA) microspheres for local delivery of transforming growth factor β3 (TGFβ3) toward IVDD treatment. In vitro, functionalized microspheres not only improved the release kinetics of TGFβ3 but also effectively inhibited inflammatory responses and promoted the secretion of extracellular matrix (ECM) in lipopolysaccharide-induced nucleus pulposus (NP) cells. In vivo, functionalized platform plays roles in alleviating inflammation and oxidative stress, preserving the water content of NP and disc height, and maintaining intact structure and biomechanical functions, thereby promoting the regeneration of IVD. High-throughput sequencing suggests that inhibition of the phosphatidylinositol 3-kinase (PI3K)-Akt signaling might be associated with their therapeutic effects. In summary, the vanillin-based functionalization strategy provides a novel and simple way for packaging multiple functions into a single delivery platform and holds promise for tissue regeneration beyond the IVD.