Injectable and Microporous Microgel Assembly with Sequential Bioactive Factor Release for the Endogenous Repair of Nucleus Pulposus

Harnessing endogenous stem/progenitor cells to enhance extracellular matrix (ECM) deposition in the nucleus pulposus (NP) is considered as a potential treatment for intervertebral disc degeneration (IVDD), but is limited by the lack of suitable scaffolds for cell infiltration and growth, as well as the tailored release of bioactive factors. Herein, an injectable cell-free microgel assembly (MA-TNS) with interconnected microporous structure is developed to recruit stem/progenitor cells and induce the differentiation of the recruited cells by releasing stromal cell-derived factor-1 alpha (SDF-1 alpha) and transforming growth factor-beta 1 (TGF-beta 1) sequentially. TGF-beta 1 is initially loaded by the chondroitin sulfate/gelatin nanoparticles. Together with SDF-1 alpha, these nanoparticles are co-encapsulated into the photo-cross-linked microgels, which are then assembled into a microporous scaffold via dynamic boronate ester bonds. An initial rapid release of SDF-1 alpha followed by a sustained release of TGF-beta 1 lasting over 28 days is achieved. MA-TNS significantly promotes the recruitment, infiltration, and chondrocyte-like differentiation of marrow mesenchymal stem cells in vitro. Furthermore, in vivo experiments on rats and cynomolgus monkeys prove that MA-TNS can inhibit IVDD and recover ECM deposition markedly, thereby enabling long-term NP reconstruction. The resulting efficacy in rats and nonhuman primates supports that MA-TNS is a promising scaffold for intervertebral disc repair and regeneration.