Optimization of release pattern of FGF-2 and BMP-2 for osteogenic differentiation of low-population density hMSCs

In the modern design, most delivery systems for bone regeneration focus on a single growth factor (GF) or a simple mixture of multiple GFs, overlooking the coordination of proliferation and osteogenesis induced by various factors. In this study, core-shell microspheres with poly-l-lactide core-poly(lactic-co-glycolic acid) shell were fabricated, and two GFs, basic fibroblast growth factor 2 (FGF-2) and bone morphogenetic protein 2 (BMP-2) were encapsulated into the core or/and shell. The effects of different release patterns (parallel or sequential manners) of FGF-2 and BMP-2 from these core-shell microspheres on the osteogenic differentiation of low-population density human mesenchymal stem cells (hMSCs) were investigated and the temporal organization of GF release was optimized. In vitro experiments suggested that induction of osteogenic differentiation of low-population density hMSCs by the sequential delivery of FGF-2 followed by BMP-2 from the core-shell microspheres (group S2) was much more efficient than that by the parallel release of the two factors from uniform microspheres (group U). The osteogenic induction by the sequential delivery of BMP-2 followed by FGF-2 from core-shell microspheres (group S1) was even worse than that from microspheres loaded with BMP-2 in both core and shell (group B), although comparable to the cases of parallel delivery of dual GFs (group P). This study showed the advantages of group S2 microspheres in inducing osteogenic differentiation of low-population density hMSCs and the necessity of time sequence studies in tissue engineering while multiple GFs are involved.