The ‘clean-to-repair’ rhythm in the dynamic pathological osteoimmune microenvironment is essential to bone healing but often disturbed by the intense inflammation. Inspired by the native osteoimmune microenvironment, we presented an injectable porous microsphere featured hierarchical micro/nano-structure via an ingenious integration of microfluidic microspheres and self-assembly collagen nanofibers, which could mimic the extracellular matrix and activate the integrin-mediated macrophage (Mφ) polarization, so as to realize a paracrine-transformed microenvironment reprogramming. The integrated hierarchical structure endowed with multiscale fibrous topology and optimized chemical cues well balanced the contradiction between large pores and reduced motifs. In vitro, owing to the modulation of integrin-mediated M2Mφ polarization and its paracrine secretion of endogenous cytokines, such as VEGF, PDGF-BB, TGF-β1, and BMP-2, the microsphere not only supported the tissue repair cell growth, but also promoted angiogenesis and mineralization by 2 and 3 folds, respectively. The capabilities of the osteoimmuno-reprogramming microsphere in progressive vascular sprouting maturation and in situ osteoinduction and osseointegration were further verified in a rat femoral condylar defect model. Hence, the so-produced hierarchical structured microsphere could manipulate the osteoimmune microenvironment by M2Mφ polarization and reconstruct the bone defects.

动态病理性骨免疫微环境中的“从清洁到修复”的节奏对于骨愈合至关重要，但经常受到强烈炎症的干扰。受天然骨免疫微环境的启发，我们通过巧妙整合微流控微球和自组装胶原纳米纤维，提出了一种具有分级微/纳米结构的可注射多孔微球，可以模拟细胞外基质并激活整合素介导的巨噬细胞 (Mφ)极化，从而实现旁分泌转化的微环境重编程。具有多尺度纤维拓扑结构和优化的化学线索的集成层次结构很好地平衡了大孔和减少的基序之间的矛盾。体外, 由于整合素介导的 M2Mφ 极化的调节及其旁分泌内源性细胞因子, 如 VEGF、PDGF-BB、TGF-β1 和 BMP-2, 微球不仅支持组织修复细胞生长, 而且促进血管生成和矿化分别增加了 2 倍和 3 倍。在大鼠股骨髁缺损模型中进一步验证了骨免疫重编程微球在进行性血管萌芽成熟和原位骨诱导和骨整合中的能力。因此，由此产生的分层结构微球可以通过M2Mφ极化操纵骨免疫微环境并重建骨缺损。