Bone fracture microenvironment responsive hydrogel for timing sequential release of cargoes

Regulating biological events by releasing bioactive molecules in accordance with the natural repair process is recognized to enable to promote the repair process. To this end, a novel hydrogel delivery system that can respond to the bone fracture microenvironment signal to timingly and sequentially release bioactive molecules was designed for the first time. The hydrogel system was synthesized by Michael addition reaction via maleimide-end-capped eight-armed poly (ethylene glycol) (8-arm-PEG-Mal) and matrix metalloproteinases-7 (MMP7) sensitive peptides. Nanoparticles developed previously by us were employed here to encapsulate the cargoes and release them once taken by cells. One type of cargo-loaded nanoparticles was embedded into the hydrogel through physical embedding, while the other was modified by MMP7 sensitive peptides followed by covalently bonding into the hydrogel. The results showed that 80% of physically embedded nanoparticles could be released in the first three days. Once MMP7 appeared after three days according to the natural regeneration process, the chemically bonded nanoparticles were released sharply along with hydrogel degradation, and the cumulative release could reach 100%. In addition, the hydrogel system was applied to release microRNA (miRNA)-loaded nanoparticles to identify its timing sequential release effect. It was also confirmed that the nanoparticles discharged could be taken by macrophages to further regulate their behaviors in the future. Overall, this release system realized the delivery of different cargoes in an accurate and timing sequential way according to the natural principle of bone reconstruction, providing a new design strategy of drug delivery system for accelerating bone tissue repair.