Sulfated polysaccharide reprograms arterialized angiogenesis of endochondral ossification to rescue defective osteonecrosis therapy

Abstract

Excessive administration of glucocorticoids leads to arterial involvement and induces osteonecrosis. Conventional biomaterial-based strategies aimed at direct vascularization have shown limited therapeutic efficacy, primarily due to pronounced heterogeneity of neovasculature and vascular mispatterning. Here, we report a semisynthetic sulfated chitosan (SCS) that, when combined with bone morphogenetic protein-2 (BMP-2), rapidly reconstructs arterialized vasculature (type H vessels and arterioles) within the deteriorated bone, thereby coupling active osteoprogenitor cells. SCS positively regulates BMP-2-induced hypertrophic chondrocytes, which in turn secrete endogenous vascular endothelial growth factor to mediate arterial neovascularization. Instead of directly enhancing the Smad1/5/8 signaling pathway, SCS mitigates the intrinsic chronic inflammatory process of bone deterioration, preventing inflammatory factors from disrupting cartilage-to-bone transformation. In an osteonecrosis model, the synergistic effect of SCS and BMP-2 sustainably improved the femoral head’s internal circulation system, rather than merely delaying disease progression. Therefore, this bioactive polysaccharide combined with an osteogenic factor enables arterialized vascularization during endochondral ossification, representing a promising therapeutic strategy for the treatment of ischemia-associated bone homeostasis disruption.