Osteoinductive IL-8/tDM/PLGA scaffolds based on autologous BMSC recruitment and endogenous growth factor regulation

The in vitro expanded seed cells and the supraphysiological doses of exogenous growth factors both pose huge safety risks in bone regeneration. In this study, a novel IL-8/tDM/PLGA composite scaffold was developed, where chemokine interleukin-8 (IL-8) and transferable decellularized matrix (tDM) were uniformly overlaid on exterior and interior surfaces of poly(lactic-co-glycolic acid) (PLGA) porous substrates. The in vitro experiments confirmed that the synergy of tDM and IL-8 achieved the obvious promotion of osteogenesis and angiogenesis via enhancing chemotaxis, adhesion, spreading, osteogenic differentiation and mineralization of bone marrow mesenchymal stem cells (BMSCs). IL-8 mediated the in situ recruitment of BMSCs and macrophages via binding with C-X-C motif chemokine receptor 2 (CXCR2), while maintaining cellular viability without inducing macrophage polarization. Moreover, tDM improved BMSC adhesion and spreading via the recognition and binding of the affinitive ligand existing in tDM by the cell adhesion molecules (CAMs) on the BMSC cytomembrane. Furthermore, tDM promoted the osteogenic differentiation and mineralization of BMSCs, benefiting from the retained growth factors. In a rat femoral defect model, the IL-8/tDM/PLGA scaffold significantly accelerated new bone mineralization and maturation through synergistic regulations of cell recruitment, matrix adhesion, and osteogenic signaling pathways. After 8 weeks post-implantation of the IL-8/tDM/PLGA scaffolds, the bone volume fraction of the newly formed bone, trabecular number, and trabecular separation at the defect site were 47%, 1.21 mm^-2, and 0.50 mm, respectively, which presented significantly better bone repair effects than those in other groups. These results demonstrated that the innovative bone regeneration strategy combining chemokine-driven recruitment and endogenous tDM regulation offered a potential solution for clinical repair of large-sized bone defects.