Regulation of macrophage subtype via injectable micro/nano-structured porous microsphere for reprogramming osteoimmune microenvironment

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.