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This study focuses on the core issue of the difficulty in achieving temporal and spatial coupling of angiogenesis and bone differentiation during bone defect repair. It explores the regulatory role of proprotein convertase subtilisin/kexin type 9 (PCSK9) in bone metabolism and constructs a composite hydrogel system loaded with PCSK9 and vascular endothelial growth factor (VEGF). This system utilizes the sustained release characteristics of the material to simulate the natural bone healing process and can achieve coordinated regulation of early angiogenesis and late bone differentiation. In vitro and in vivo experiments have confirmed that this composite hydrogel can enhance the effect of PCSK9, efficiently mediate vascularized bone regeneration, and clarify the molecular signaling pathways by which PCSK9 promotes osteogenic differentiation of bone marrow mesenchymal stem cells. This provides a new target and innovative research strategy for basic repair studies of bone defects.
01 Research Background
Bone defects are a common condition in the field of orthopedics. Achieving early vascularization and synchronous completion of late bone differentiation during the repair process is the key to effective bone repair. Growth factor delivery is a widely used technical strategy in current bone tissue regeneration research. However, how to achieve temporal and spatial coupling regulation of vascularized bone regeneration remains an important problem to be solved in this field. PCSK9, a proprotein convertase subtilisin/kexin type 9, plays a key regulatory role in bone metabolism. Previous studies have found that the expression level of PCSK9 increases during bone regeneration, and exogenous supplementation of PCSK9 can enhance the osteogenic differentiation ability of bone marrow mesenchymal stem cells, providing a new research entry point for bone regeneration repair studies.
02 Main Content
This study first clarifies the expression characteristics and osteogenic differentiation-promoting effect of PCSK9 in the bone regeneration process, and then designs a composite hydrogel construction plan: PCSK9 is adsorbed onto the extracellular matrix derived from blood vessels, and VEGF is incorporated into gelatin methacryloyl (GelMA). A multifunctional composite hydrogel is prepared. Using the sustained release characteristics of this biomaterial, it simulates the physiological sequence of natural bone healing and achieves coupled regulation of early angiogenesis and late bone differentiation. Through in vitro cell experiments and in vivo model experiments, it is verified that the composite hydrogel enhances the therapeutic effect of PCSK9, efficiently mediates vascularized bone regeneration, and explores the molecular signaling pathways by which PCSK9 promotes osteogenic differentiation of bone marrow mesenchymal stem cells, clarifying the intrinsic mechanism of this system mediating vascularized bone regeneration.
03 Research Design
This study designs the experimental scheme based on the core requirement of temporal and spatial coupling regulation of bone regeneration. Firstly, based on the previous basic findings, PCSK9 is established as the key factor for bone regeneration regulation; then, a biocomposite strategy is adopted to load PCSK9 onto the extracellular matrix derived from blood vessels and integrate VEGF into GelMA hydrogel, constructing a dual-factor temporal delivery composite hydrogel system. Utilizing the sustained release performance of the material, it matches the sequence of vascularization and differentiation during bone healing. Separate in vitro cell-level experiments and in vivo animal model experiments are conducted to systematically verify the promoting effect of this hydrogel system on vascularization and osteogenic differentiation; finally, through molecular mechanism research, the core signaling pathway regulated by PCSK9 for osteogenic differentiation of bone marrow mesenchymal stem cells is clarified.
04 Results
The results of in vitro and in vivo experiments indicate that the composite hydrogel constructed in this study can further enhance the regulatory effect of PCSK9 and successfully achieve efficient vascularized bone regeneration. Mechanism research results show that PCSK9 can promote osteogenic differentiation of bone marrow mesenchymal stem cells by activating the ERK signaling pathway. Overall, the composite hydrogel loaded with PCSK9 and VEGF exhibits excellent promoting effects on vascularization and osteogenic coupling regulation, effectively promoting the bone regeneration process.
05 Extension of Thoughts This study clarified the core regulatory role of PCSK9 in the bone regeneration process and the corresponding molecular regulatory pathways, providing a new target for bone tissue regeneration research. Based on the design concept of dual biological factor temporal delivery of composite hydrogels, it can provide a reference for the development of multi-factor temporal regulation systems in bone tissue engineering. Combining the composite strategy of natural extracellular matrix and synthetic hydrogels also further expands the application direction of biomaterials in constructing biomimetic bone regeneration microenvironments, providing new ideas for the deepening of basic research related to bone regeneration.
