Ultrafast water-responsive shape-adaptive magnesium-loaded silk fibroin-based scaffold modulates macrophage glycolytic reprogramming for endogenous cartilage regeneration

Abstract

Shape-adaptive scaffolds have shown promise in regenerating critical-sized irregular articular cartilage defects. However, limitations on the speed and degree of adaptation, mechanical robustness, host integration, and targeted biological functionality have greatly restricted their clinical application. In this study, an ultrafast (0.29 s) water-responsive shape-adaptive Mg-containing silk fibroin-gelatin methacryloyl scaffold was fabricated using a simple photo-crosslinking combined with water vapor annealing. We demonstrated that the reversible weak hydrogen bonding interactions between water molecules and silk fibroin (SF) chains enabled the compressed scaffold to rapidly regain its original shape upon bodily fluid exposure, adapting to the cartilage defect geometry while establishing seamless integration with host tissues. During the early inflammation phase, the controllable and on-demand release of Mg²⁺ could promote M2-like macrophage polarization, which is associated with PI3K/AKT/mTOR activation and glycolytic remodeling; thereby remodeling a favorable immune microenvironment that enhanced the chondrogenic differentiation of endogenous bone marrow stem cells (BMSCs). In vivo rabbit critical-size osteochondral defect models confirmed that this scaffold facilitated robust hyaline cartilage formation enriched in chondrocytes and type II collagen with seamless marginal integration at 12 weeks post-implantation. Collectively, this ultrafast shape-adaptive silk scaffold represents a cell-free therapeutic platform for irregular full-thickness cartilage defects.

Statement of significance

This study presents an ultrafast water-responsive (0.29 s) shape-adaptive Mg-containing silk fibroin-based scaffold to facilitate cartilage regeneration. The water vapor annealing treatment provides gentle and uniform stimulation, enabling the quasi-linear and controllable regulation of the performance of silk fibroin (SF) porous scaffolds. The compressed scaffold can rapidly adapt to irregular geometry. The controllable and on-demand release of Mg²⁺ create a favorable immune microenvironment for enhancing in-situ cartilage regeneration, and transcriptomic anlysis revealed the key immunomodulatory mechanisms. These findings provide a promising strategy for treating critical-size irregular cartilage defects.