A biosilica nanocage-based injectable hydrogel to trap endogenous TGF-β1 for in-situ hyaline cartilage regeneration

Regeneration of hyaline cartilage remains a major clinical challenge. Current first-line treatments for focal articular cartilage defects, typically induce fibrocartilage instead of hyaline cartilage, resulting in inferior mechanical and biological outcomes. Here we report a biomimetic strategy inspired by the biosilicification process of diatoms, for the de novo synthesis of biosilica nanocages exhibiting effective binding to the hyaline chondrogenic cytokine transforming growth factor β1 (TGF-β1). To enhance clinical applicability, an injectable biosilica nanocage-based hydrogel (Si-aGel hydrogel) was further engineered to conformally fill cartilage defects of diverse geometries while exhibiting excellent mechanical performance. Si-aGel hydrogel preserves long-term hyaline chondrogenic commitment of rat primary bone marrow-derived mesenchymal stem/stromal cells (BMSCs) in vitro. Moreover, when injected into the full-thickness cartilage defects, Si-aGel hydrogel effectively sustained stable TGF-β1-activated chondral differentiation of BMSCs and promoted complete hyaline cartilage repair with a type II collagen- and aggrecan-rich hyaline matrix deposition without any exogenous supplements. In contrast, those without intervention or treated with hydrogel lacking biosilica nanocages developed fibrocartilaginous and hypertrophic repair tissue, marked by a disorganized matrix with abundant type I and type X collagen. Together, our study suggested the biosilica nanocage-based therapy has the great potential for hyaline cartilage regeneration.