Low melting point amphiphilic microspheres for delivery of bone morphogenetic protein-6 and transforming growth factor-β3 in a hydrogel matrix

Low melting-point poly(1,3-trimethylene carbonate-co-ε-caprolactone)-b-poly(ethylene glycol)-b-poly(1,3-trimethylene carbonate-co-ε-caprolactone), P(TMC-CL)2-PEG, was employed to fabricate microspheres for sustained growth factor delivery in a photocrosslinked N-methacrylate glycol chitosan hydrogel matrix. The P(TMC-CL)2-PEG had a melting range such that it was solid at 10 °C, yet liquid with a low degree of crystallinity at 37 °C. The in vitro degradation of P(TMC-CL)2-PEG microspheres was slow, regardless of the triblock copolymer molecular weight and so did not influence protein release. The size of protein loaded P(TMC-CL)2-PEG microspheres manufactured using a low-temperature electrospray technique was between 65 and 85 μm. Initial formulation work was done with the model protein lysozyme, co-lyophilized with trehalose and encapsulated as approximately 2 μm particles within P(TMC-CL)2-PEG microspheres. This work indicated a sustained release could be achieved with high trehalose content (90% w/w) in the particles. Under these conditions, the release rate of bone morphogenetic protein-6 was more sustained than that of the excipient bovine serum albumin (BSA) and closely followed that of lysozyme. On the other hand, transforming growth factor-β3 and the stabilizing agent BSA generated similar release profiles. This difference in release was proposed to be linked to the protein isoelectric point, with positively charged proteins possibly being more strongly adsorbed to the P(TMC-CL)2-PEG. Both growth factors were released in highly bioactive form, indicating the potential of the release approach.

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