Development of an Accurate and Proactive Immunomodulatory Strategy to Improve Bone Substitute Material-Mediated Osteogenesis and Angiogenesis
Development of an Accurate and Proactive Immunomodulatory Strategy to Improve Bone Substitute Material-Mediated Osteogenesis and Angiogenesis
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开发准确且主动的免疫调节策略以改善骨替代材料介导的成骨和血管生成
DOI：
10.7150/thno.28315
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发表时间：
2018-01-01
期刊：
影响因子：
12.4
通讯作者：
Zhang, Zhi-yong
中科院分区：
文献类型：
--
作者：
Zheng, Zhi-wei;Chen, Ya-hong;Zhang, Zhi-yong
背景：大骨缺损的治疗是世界范围内的一个主要临床问题。通常需要合适的骨替代材料来实现成功的骨再生，并且人们花费了大量的精力来优化其化学成分、3D 结构和机械性能。然而，物质-免疫系统的相互作用越来越被认为是影响再生的关键因素。在这里，我们设想了一种准确且主动的免疫调节策略，通过递送 IL-4（巨噬细胞极化的关键调节剂）来促进骨替代材料介导的再生。方法：在脱细胞骨基质（DBM）材料植入术后第3天，将四种不同剂量（0 ng、10 ng、50 ng和100 ng）的IL-4注入大鼠大颅骨缺损中，并仔细评估成骨、血管生成和巨噬细胞极化。结果：Micro-CT分析显示，10 ng IL-4免疫调节在新骨形成（1.23-5.05倍）和血管化（1.29-6.08倍）方面显着优于其他组，在12周时实现了成功的缺损桥接和良好的血管化。第7天和第14天的组织学分析表明，10ng组产生了最理想的M1/M2巨噬细胞极化曲线，产生了IL-10分泌增多、TNF-α分泌减少的促愈合微环境，材料周围组织的凋亡水平降低，间充质干细胞迁移和成骨分化增强。此外，体外研究表明，M1巨噬细胞促进间充质干细胞迁移，而M2巨噬细胞显着增加细胞存活、增殖和成骨分化，解释了体内研究结果。结论：通过 IL4 递送进行精确的免疫调节，通过 M1 和 M2 巨噬细胞的协调参与，显着增强 DBM 介导的成骨和血管生成，揭示了这种准确、主动的免疫调节策略对于开发新型骨替代材料的前景。
Background: Treatment of large bone defects represents a major clinical problem worldwide. Suitable bone substitute materials are commonly required to achieve successful bone regeneration, and much effort has been spent to optimize their chemical compositions, 3D architecture and mechanical properties. However, material-immune system interactions are increasingly being recognized as a crucial factor influencing regeneration. Here, we envisioned an accurate and proactive immunomodulation strategy via delivery of IL-4 (key regulator of macrophage polarization) to promote bone substitute material-mediated regeneration. Methods: Four different IL-4 doses (0 ng, 10 ng, 50 ng and 100 ng) were delivered into rat large cranial bone defects at day 3 post-operation of decellularized bone matrix (DBM) material implantation, and the osteogenesis, angiogenesis and macrophage polarization were meticulously evaluated. Results: Micro-CT analysis showed that immunomodulation with 10 ng IL-4 significantly outperformed the other groups in terms of new bone formation (1.23-5.05 fold) and vascularization (1.29-6.08 fold), achieving successful defect bridging and good vascularization at 12 weeks. Histological analysis at 7 and 14 days showed that the 10 ng group generated the most preferable M1/M2 macrophage polarization profile, resulting in a pro-healing microenvironment with more IL-10 and less TNF-α secretion, a reduced apoptosis level in tissues around the materials, and enhanced mesenchymal stem cell migration and osteogenic differentiation. Moreover, in vitro studies revealed that M1 macrophages facilitated mesenchymal stem cell migration, while M2 macrophages significantly increased cell survival, proliferation and osteogenic differentiation, explaining the in vivo findings. Conclusions: Accurate immunomodulation via IL4 delivery significantly enhanced DBM-mediated osteogenesis and angiogenesis via the coordinated involvement of M1 and M2 macrophages, revealing the promise of this accurate and proactive immunomodulatory strategy for developing new bone substitute materials.