In Situ Supply and Anchoring of Glycosaminoglycan by Dual-Modified Hydrogel Loaded with Glycoengineered Stem Cells for Attenuating Disc Degeneration

Stem cells hold great promise for repairing degenerated nucleus pulposus (NP) in intervertebral disc degeneration (IVDD) via differentiating into NP-like cells and replenishing the extracellular matrix (ECM). However, the harsh environment in degenerated NP contributes to poor survival, low differentiation efficiency, and matrix catabolism, hampering stem cells' long-term transplantation and efficacy. Herein, a hyaluronic acid (HA)-based hydrogel (Pep-aGel) functionalized with collagen mimetic peptide and amination is fabricated to deliver glycoengineered stem cells for NP repair. The peptide (GFOGER), which contains the integrin recognition sequence of collagen, is selectively bound to the upregulated integrin-β1 of glycoengineered stem cells, thereby promoting their NP-like differentiation. The amination introduced amino groups in hydrogel and further enhanced the integration of cell-secreted glycosaminoglycans (GAGs) on the HA chains, which mimicked the biosynthesis of Aggrecan, creating an NP-like nanostructure in the hydrogel. Pep-aGel loading with glycoengineered cells showed injectable properties and significantly improved disc height, extracellular matrix content, and GAG deposition in rat degenerated discs. This approach established a self-sufficient system that consists of NP cell replenishment, in situ ECM supply, and GAG anchoring, which may offer a concise, yet synergistic, strategy for the regeneration of IVDD.