Heparin-based temperature-sensitive injectable hydrogels for protein delivery

Stimuli-sensitive injectable hydrogels, composed of biodegradable copolymers, have emerged as prominent candidate materials for the sustained delivery of therapeutic drugs. In this study, we developed a biodegradable and temperature-sensitive injectable hydrogel system based on heparin-bearing poly(ε-caprolactone-co-lactide)-b-poly(ethylene glycol)-b-poly(ε-caprolactone-co-lactide) (Hep-PCLA) as the carrier system for lysozyme. Hep-PCLA conjugates are capable of undergoing temperature-induced sol-to-gel transitions in an aqueous solution. The gelation rate, mechanical strength, and viscosity of Hep-PCLA conjugates are controllably tunable by varying the graft density of PCLA copolymers to heparin. The gel window in which Hep-PCLA forms a gel covers the physiological conditions (37 °C), i.e., free flowing Hep-PCLA in aqueous solutions (25 °C) could form a hydrogel at body temperature. Using an in vitro cytotoxicity test, Hep-PCLA conjugates were found to be non-toxic to fibroblast cells, even at high concentrations. Lysozyme, chosen as a model protein, was effectively loaded into Hep-PCLA conjugates using ionic and hydrophobic interactions. The lysozyme-loaded conjugates readily formed a hydrogel when implanted in the back of Sprague-Dawley rats, and retarded the initial burst of lysozyme release, exhibiting sustained release. Our results show that biodegradable, temperature-sensitive injectable Hep-PCLA hydrogels can be used as sustained protein carriers.