Protein release from poly(lactide-co-glycolide) implants prepared by hot-melt extrusion: Thioester formation as a reason for incomplete release
The aim of this study was to characterize the protein release from PLGA-based implants prepared by hot-melt extrusion with special emphasis on identifying reasons for incomplete release. Biodegradable PLGA-implants loaded with BSA were prepared with a syringe-die extrusion device. A burst-free release was achieved up to 25% BSA loading by milling the protein prior to extrusion. The release was incomplete at 70% at loadings below the percolation threshold of the protein; higher protein loadings increased the release to 97%. However, an insoluble implant mass remained for over 180 days, which was attributed to the acylation of BSA by PLGA oligomers via a thioester bond. The incomplete protein release due to the formation of this covalent bond was overcome when increasing the porosity of the implant, which effectively reduced the contact between BSA and PLGA oligomers. Accordingly, melt-extrusion facilitated incorporating high loadings of BSA into burst-free biodegradable implants. Additionally, it enhanced complete protein release by a process- or formulation controlled increase of the implant porosity.