Core–shell microspheres delivering FGF-2 and BMP-2 in different release patterns for bone regeneration

Bone regeneration by applying fibroblast growth factor-2 (FGF-2) plus bone morphogenetic protein-2 (BMP-2) is considered advantageous over a single growth factor (GF) treatment because the spontaneous repair of bone defects is essentially regulated by a series of GFs, including FGF-2 and BMP2. However, the temporal interactions between FGF-2 and BMP-2 remain elusive and how to take full advantage of the interactions is a bottleneck in translating this dual-GF strategy into clinical applications. To compare the long-term effects of different temporal patterns of FGF-2 and BMP-2 on bone regeneration, a novel delivery system is needed. Herein, we report a type of PLLA core-PLGA shell double-walled microsphere. Different release patterns of FGF-2 and BMP-2 in the core and shell, respectively, were achieved due to different distributions of these two GFs. In vivo evaluations of different release patterns of dual GFs using a rat bone graft model suggested that a sequential delivery of FGF-2 and BMP-2 helped bridge and remodel the critical-sized bone grafts more efficiently than the other release patterns. More importantly, core-shell microspheres simultaneously and continuously releasing FGF-2 and BMP-2 resulted in the obvious resorption of grafted bone and bone non-union at 4 weeks. Consistently, the in vitro treatment of bovine bone sections by FGF-2 plus BMP-2 led to enhanced osteoclastogenesis compared to single GF treatments. The temporal organization of FGF-2 and BMP-2 by taking advantage of the core-shell microspheres will enable the development of more efficient devices for bone defects than existing delivery systems.