Combined and sequential delivery of bioactive VEGF165 and HGF from poly(trimethylene carbonate) based photo-cross-linked elastomers

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The ability of trimethylene carbonate (TMC) based elastomers to release bioactive vascular endothelial growth factor (VEGF165) and hepatocyte growth factor (HGF) separately and in combined and sequential fashions using an osmotic release mechanism was investigated. A TMC-based elastomer was chosen since TMC degrades without producing potentially harmful acidic degradation products, and its mechanical properties can be tailored by copolymerizing with d,l-lactide (DLLA) and ε-caprolactone (ε-CL) and by controlling the cross-link density. The bioactivities of released VEGF165 and HGF were assessed using the proliferation of human aortic endothelial (HAEC) and CCL 208 monkey lung epithelial cell lines. VEGF165 and HGF were lyophilized separately or together with trehalose, rat serum albumin (RSA) and NaCl. No significant elastomer degradation occurred over the initial 8 weeks, during which the bulk of the embedded growth factors were released. The presence of a low concentration of NaCl in the release media did not affect the viability of HAEC and CCL 208 cells. The TMC-based elastomer was able to provide a sustained release of highly bioactive VEGF165 and HGF for more than 10 days. When released in combination from the same device, VEGF165 and HGF were released at similar rates. By preparing a dual-layered cylinder, in which VEGF165 was in the outer layer and HGF in the inner layer, a constant release of VEGF alone was first obtained, followed by overlapping and constant release of the two growth factors after a period of 4 days. This study demonstrates the potential of TMC-based elastomers combined with an osmotic mechanism to release acid-sensitive growth factors in bioactive form alone and in combination, in controlled rates and sequences.Graphical abstract

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