Tunable Engineering of Heparinized Injectable Hydrogels for Affinity-Based Sustained Delivery of Bioactive Factors

Here, the design of an in situ-forming injectable hydrogel is reported based on pH- and temperature-responsive copolymers finely engineered with heparin for the sustained delivery of bioactive factors. In order to develop such heparinized injectable hydrogels, pH- and temperature-responsive copolymers based on poly(ethylene glycol) and poly(urethane sulfamethazine) (PEG-PUSSM) are synthesized and acrylated, and subsequently coupled with thiolated heparin through Michael-addition reaction. The content of heparin in the bioconjugates (Hep-PUSSM) is finely tuned to control the release of heparin-binding bioactive factors. The free-flowing bioconjugate sols at room temperature transform to stable viscoelastic gel in physiological conditions, indicating that heparin modification does not affect the sol-gel transition. The subcutaneous administration of bioconjugate sols to the dorsal-region of Sprague-Dawley rats forms a hydrogel depot and shows controlled degradation. The bioconjugates effectively bind with bioactive factors (VEGF) through simple mixing, and the release is controlled over a period of 4 weeks without an initial burst. As a result, the implantation of VEGF-loaded bioconjugate gel induces angiogenesis throughout the hydrogel network. The tunable engineering of the injectable hydrogel by heparinization with independent controllable physical properties sustains the release of bioactive factors, indicating that it may be a promising platform for the delivery of bioactive factors.