Zheng Jiahe, Li Chengrun, Zhang Qingxia, Ou Tao, Li Linlong, Yu Pengfei, Wei Shujuan, Hou Guige, Yan Huanhuan
School of Pharmacy, the Key Laboratory of Prescription Effect and Clinical Evaluation of State Administration of Traditional Chinese Medicine of China, Binzhou Medical University, Yantai, 264003, PR China.
Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun 130022, PR China.
Bioact Mater. 2025 Aug 13;54:103-125. doi: 10.1016/j.bioactmat.2025.08.005. eCollection 2025 Dec.
Critical-sized calvarial defects remain a formidable clinical challenge due to dyssynchronous immunomodulation-osteogenesis coupling and unregulated growth factor release. Here, a bioinspired porous core-shell microsphere system (GCI@HPPS) is developed, integrating hydroxyapatite (HA)-loaded shell, surface-immobilized SDF-1α, and IGF-1-encapsulated cores to immunomodulate osteoimmune microenvironment and osteogenesis promotion. The hierarchical architecture achieved spatiotemporally programmed release: HA degradation-dependent mineralization, SDF-1α-mediated BMSC chemotaxis, and sustained IGF-1 delivery, mimicking natural bone repair cascades. Dual covalent/guest-host crosslinking (GelMA/Ac-β-CD) enhanced compressive strength, while polydopamine functionalization of microspheres conferred electroactivity, hydrophilicity, ROS/RNS scavenging (97.29 % ABTS•+ elimination), antibacterial efficacy (>99.8 %) and hemostasis. , GCI@HPPS mitigates oxidative stress, induces M2 macrophage polarization, and suppresses inflammatory cascades while concomitantly enhancing endogenous BMSC recruitment, proliferation, and osteogenic differentiation. Proteomics revealed a tetradic anti-inflammatory mechanisms of GCI@HPPS: NF-κB/P-JNK suppression, pro-inflammatory cytokines downregulation, mitochondrial oxidative modulation, and STAT6-driven M2 polarization. , GCI@HPPS achieved calvarial defect closure at 8 weeks through porous matrix-guided cellular infiltration, and SDF-1α/IGF-1-mediated chemotaxis, Rho/MAPK signaling pathway activation balancing osteoclast-osteoblast dynamics, stage-specific osteogenic induction and AGE-RAGE/VEGF-coupled angiogenesis-osteogenesis. This work pioneers a spatiotemporal delivery paradigm that coordinates inflammation modulation, stem cell recruitment, osteogenic differentiation, and mineralization phases, offering a promising approach for complex cranial reconstruction.
由于免疫调节 - 骨生成耦合失调和生长因子释放不受调控，临界尺寸的颅骨缺损仍然是一个严峻的临床挑战。在此，开发了一种受生物启发的多孔核壳微球系统（GCI@HPPS），其整合了负载羟基磷灰石（HA）的壳、表面固定的SDF - 1α和封装有IGF - 1的核，以免疫调节骨免疫微环境并促进骨生成。这种分层结构实现了时空编程释放：HA降解依赖性矿化、SDF - 1α介导的骨髓间充质干细胞趋化作用以及IGF - 1的持续递送，模拟了天然骨修复级联反应。双共价/主客体交联（GelMA/Ac - β - CD）提高了抗压强度，而微球的聚多巴胺功能化赋予了电活性、亲水性、ROS/RNS清除能力（97.29% ABTS•+消除率）、抗菌功效（>99.8%）和止血能力。GCI@HPPS减轻氧化应激，诱导M2巨噬细胞极化，并抑制炎症级联反应，同时增强内源性骨髓间充质干细胞的募集、增殖和成骨分化。蛋白质组学揭示了GCI@HPPS的四重抗炎机制：NF - κB/P - JNK抑制、促炎细胞因子下调、线粒体氧化调节和STAT6驱动的M2极化。GCI@HPPS在8周时通过多孔基质引导的细胞浸润以及SDF - 1α/IGF - 1介导的趋化作用、Rho/MAPK信号通路激活平衡破骨细胞 - 成骨细胞动态、阶段特异性成骨诱导以及AGE - RAGE/VEGF耦合的血管生成 - 骨生成实现了颅骨缺损闭合。这项工作开创了一种时空递送模式，协调炎症调节、干细胞募集、成骨分化和矿化阶段，为复杂的颅骨重建提供了一种有前景的方法。
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