Microenvironment-responsive hydrogels for spatiotemporal delivery of epigallocatechin gallate and BMP-2 to promote osteoporotic bone defect repair.

Regenerating osteoporotic bone defects is still a major challenge. Conventional bone tissue engineering materials often fail to achieve on-demand drug delivery. At the same time, the therapeutic logic of osteoporotic bone defects requires spatiotemporal drug delivery to eliminate excess inflammation and high reactive oxygen species (ROS) at an early stage. When inflammation subsides, appropriate drugs are needed to match osteoblast differentiation and bone regeneration. Therefore, we designed a ROS-responsive Polyvinyl alcohol-4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylphenylboronic acid (PVA-TSPBA) hydrogel loaded with epigallocatechin gallate (EGCG) and bone morphogenetic protein-2 (BMP-2). On the one hand, the ROS-responsive properties of composite hydrogels enable controlled delivery of EGCG in the high ROS microenvironment at an early stage of osteoporotic bone defects. On the other hand, BMP-2 is anchored within tannic acid-loaded zeolitic imidazolate framework-8 (TA-ZIF-8), which allows a sustained release and matches late osteoblast differentiation and bone repair. The metal-organic frameworks (MOFs)-enhanced composite hydrogel has good mechanical properties and can provide good support for bone defects. Furthermore, the EGCG + BMP-2@TA-ZIF-8+PVA-TSPBA hydrogel (abbreviated as E + B@TZ + Gel) exhibited excellent biocompatibility. Bioinformatics analysis showed that the composite hydrogel enhanced bone repair by promoting osteogenesis via the PI3K/AKT/mTOR pathway. Thus, the hydrogel system with therapeutic logic and microenvironment regulation offers a promising strategy for the regeneration of osteoporotic bone defects.