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Bone defects are one of the most common clinical conditions in orthopedic diseases. The key to successful treatment lies in achieving early vascularization and subsequent late bone differentiation. Growth factor delivery is one of the most widely adopted strategies in bone tissue regeneration. However, the spatiotemporal coupling regulation for achieving vascularized bone regeneration remains a major challenge. Preprotein converting enzyme subtilisin/kexin type 9 (PCSK9) plays a crucial role in bone metabolism. Our preliminary findings indicate that PCSK9 expression is upregulated during bone regeneration, and the supplementation of exogenous PCSK9 can enhance the osteogenic differentiation of bone marrow mesenchymal stem cells (BMMSCs). Based on these findings, we attached PCSK9 to extracellular matrix (ECM) derived from blood vessels and incorporated vascular endothelial growth factor (VEGF) into gel methacrylate (GelMA) to prepare a composite hydrogel. Utilizing the unique sustained release characteristics of these biomaterials, this hydrogel system was designed to reproduce the natural healing process of bone defects, thereby promoting the coupling regulation of accelerated early vascularization and enhanced late bone differentiation. Both in vitro and in vivo experimental results have confirmed that the constructed composite hydrogel can further enhance the therapeutic effect of PCSK9 and achieve efficient vascularized bone regeneration. From a mechanistic perspective, our findings indicate that PCSK9 promotes the osteogenic differentiation of BMMSCs by activating the ERK signaling pathway. The composite hydrogel loaded with PCSK9 and VEGF shows promising pre-angiogenic and pre-boneogenic coupling capabilities, promoting bone regeneration and providing new therapeutic targets and innovative strategies for clinical bone defect management. This study was published in Bioactive Materials under the title "A composite hydrogel enables the spatiotemporal delivery of distinct cytokines to drive native vascularized bone regeneration".
Reference Information:
DOI: 10.1016/j.bioactmat.2026.02.048
