Injectable fibroblast growth factor-2 coacervate for persistent angiogenesis

Chu, Hunghao; Gao, Jin; Chen, Chien-Wen; Huard, Johnny; Wang, Yadong

Enhancing the maturity of the newly formed blood vessels is critical for the success of therapeutic angiogenesis. The maturationof vasculature relies on active participation of mural cells to stabilize endothelium and a basal level of relevant growthfactors. We set out to design and successfully achieved robust angiogenesis using an injectable polyvalent coacervate of apolycation, heparin, and fibroblast growth factor-2 (FGF2). FGF2 was loaded into the coacervate at nearly 100% efficiency.In vitro assays demonstrated that the matrix protected FGF2 from proteolytic degradations. FGF2 released from the coacervatewas more effective in the differentiation of endothelial cells and chemotaxis of pericytes than free FGF2. One injection of500 ng of FGF2 in the coacervate elicited comprehensive angiogenesis in vivo. The number of endothelial and mural cells increasedsignificantly, and the local tissue contained more and larger blood vessels with increased circulation. Mural cells activelyparticipated during the whole angiogenic process: Within 7 d of the injection, pericytes were recruited to close proximityof the endothelial cells. Mature vasculature stabilized by vascular smooth muscle cells persisted till at least 4 wk. On theother hand, bolus injection of an identical amount of free FGF2 induced weak angiogenic responses. These results demonstratethe potential of polyvalent coacervate as a new controlled delivery platform.