Xiao Pengcheng, Liu Junyan, Du Chengcheng, Cheng Shengwen, Liu Senrui, Liu Jiacheng, Zhan Jingdi, Chen Zhuolin, Yang Yaji, Lei Yiting, Huang Wei, Zhao Chen
Department of Orthopaedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, PR China; Chongqing Municipal Health Commission Key Laboratory of Musculoskeletal Regeneration and Translational Medicine, 400016 Chongqing, PR China; Orthopaedic Research Laboratory of Chongqing Medical University, Chongqing 400016, PR China.
Department of Orthopaedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, PR China; Chongqing Municipal Health Commission Key Laboratory of Musculoskeletal Regeneration and Translational Medicine, 400016 Chongqing, PR China; Orthopaedic Research Laboratory of Chongqing Medical University, Chongqing 400016, PR China; Department of Biomedical Engineering, The Chinese University of Hong Kong, NT 999077, Hong Kong Special Administrative Region.
J Control Release. 2025 Apr 10;380:240-255. doi: 10.1016/j.jconrel.2025.02.002. Epub 2025 Feb 6.
The disruption and limited reconstruction capacity of the osteocyte network are pivotal factors underlying impaired bone regeneration. This study developed an injectable mineralized hydrogel microsphere that provides a mineral-rich environment and optimal matrix stiffness for osteocyte network restoration. Furthermore, it spatially activates Notch signaling through osteocyte-derived vesicles with high Jagged1 expression, promoting osteocyte differentiation and enhancing angiogenic regulatory function. Specifically, hydrogel microspheres combining gelatin methacrylate (GelMA), alginate methacrylate (AlgMA), and osteocyte membrane vesicles (OMVs) were fabricated via gas-shear microfluidics and photopolymerization, followed by in situ pre-mineralization to produce mineralized microspheres. Findings indicate that mineralized hydrogel microspheres exhibit significantly increased compressive modulus and in situ formation of amorphous calcium phosphate particles within the gel matrix. In vitro, the mineralized microspheres effectively facilitated osteogenic differentiation in bone marrow-derived mesenchymal stem cells (BMSCs), with adherent cells displaying accelerated osteocyte marker expression. Co-culture experiments further revealed enhanced vascular formation potential. Ectopic bone regeneration studies demonstrated that mineralized hydrogel microspheres promote rapid formation of mature osteocyte networks in vivo. Moreover, in a femoral critical bone defect model, these microspheres accelerated defect healing. Collectively, mineralized hydrogel microspheres expedite osteocyte network reconstruction, supporting intelligent bone regeneration, and present a promising approach for critical-sized bone defect repair.
骨细胞网络的破坏和有限的重建能力是骨再生受损的关键因素。本研究开发了一种可注射的矿化水凝胶微球，它为骨细胞网络的恢复提供了富含矿物质的环境和最佳的基质硬度。此外，它通过具有高Jagged1表达的骨细胞衍生囊泡在空间上激活Notch信号，促进骨细胞分化并增强血管生成调节功能。具体而言，通过气剪微流控和光聚合制备了结合甲基丙烯酸明胶（GelMA）、甲基丙烯酸藻酸盐（AlgMA）和骨细胞膜囊泡（OMV）的水凝胶微球，然后进行原位预矿化以产生矿化微球。研究结果表明，矿化水凝胶微球的压缩模量显著增加，并且在凝胶基质中形成了无定形磷酸钙颗粒。在体外，矿化微球有效地促进了骨髓间充质干细胞（BMSC）的成骨分化，贴壁细胞显示出加速的骨细胞标志物表达。共培养实验进一步揭示了增强的血管形成潜力。异位骨再生研究表明，矿化水凝胶微球在体内促进成熟骨细胞网络的快速形成。此外，在股骨临界骨缺损模型中，这些微球加速了缺损愈合。总之，矿化水凝胶微球加速了骨细胞网络重建，支持智能骨再生，并为临界尺寸骨缺损修复提供了一种有前景的方法。
