Injectable hydrogel microspheres promoting inflammation modulation and nucleus pulposus-like differentiation for intervertebral disc regeneration.

Local inflammation modulation and stem cell therapy have attracted much attention in the treatment of intervertebral disc degeneration (IDD). However, severe oxidative stress and limited nucleus pulposus (NP)-like differentiation of stem cells largely impair biomaterial implantation's therapeutic efficacy. Due to their excellent performance in injectability and flowability, and minor compression to NP tissue, hydrogel microspheres have become an attractive carrier for IDD treatment. Herein, an injectable hydrogel microsphere consisting of Wnt5a-mimetic peptide Foxy5- and the antioxidative peptide-grafted gelatin methacryloyl matrix (GFA), was developed as a stem cell delivery system for IDD therapy. Being fabricated and encapsulating bone marrow-derived mesenchymal stem cells (BMSCs) using the microfluidic technology, GFA hydrogel microspheres ameliorate IDD by promoting inflammation inhibition, NP-like differentiation and extracellular matrix regeneration. They efficiently eliminated reactive oxygen species, and downregulated the inflammation level through the inhibition of interleukin-17B/nuclear factor-κB signaling pathway. Moreover, the NP-like differentiation of BMSCs was effectively stimulated by Foxy5 via the calcium/calmodulin dependent protein kinase kinase 2/protein kinase A/sex determining region Y box protein 9 signaling pathway, thereby leading to a rebalance between the generation and degradation of NP matrix. In vivo rat IDD model demonstrated that BMSC-loaded GFA hydrogel microspheres mitigated local inflammation, preserved disc height, and promoted intervertebral disc regeneration. In conclusion, this study introduces an BMSC-loaded injectable hydrogel microspheres as a promising therapy for regulating the microenvironment and alleviating the progression of IDD.