Programmable in vivo degradation of PEG hydrogel microspheres through tailored crosslinker chemistry

The controlled degradation of biomaterials is a key requirement for the design of injectable medical devices with defined in vivo lifetimes. In this study, we developed a series of degradable poly(ethylene glycol) microspheres (PEG-MS) crosslinked with hydrolyzable PEG-polyester triblock copolymers containing varying proportions of ε-caprolactone, lactide, and PEG. Five formulations of PEG-MS (∼90 µm diameter) were synthesized by suspension polymerization and evaluated for their degradation behavior both in vitro and in vivo following intradermal injection in rabbits, with histological assessment conducted over a 12-month period. The degradation rate of PEG-MS was tuned by modulating the crosslinker composition, ranging from 2 weeks to over 2 years in vitro and from 1 to 6 months in vivo. Increasing the caprolactone content and reducing PEG chain length slowed degradation, establishing relationships between crosslinker structure and degradation behavior. Although the ranking of formulations was preserved, degradation proceeded substantially faster in vivo than in vitro, suggesting that biological processes contribute to microsphere degradation in addition to hydrolysis. Histological analyses showed that PEG-MS elicited a mild foreign body response characterized mainly by macrophages and giant cells, with no evidence of necrosis or fibrotic encapsulation, followed by progressive restoration of normal dermal architecture. Compared to clinically established fillers, PEG-MS exhibited a tissue response more pronounced than crosslinked hyaluronic acid hydrogels but substantially less persistent than polyester-based collagen stimulators. In addition, PEG-MS could be loaded with buprenorphine and provided sustained drug release for up to 3 weeks in vitro, highlighting the versatility of this platform. Overall, this study identifies degradable crosslinker composition as a key design parameter governing PEG-MS degradation and demonstrates that the persistence of PEG hydrogel microspheres can be modulated over a broad time range while preserving their manufacturing process, sterilization stability and favorable tissue compatibility. These findings establish a framework for the rational design of degradable PEG hydrogel microspheres with tailored degradation profiles for biomedical applications.