Abstract

Periodontal bone defects serve as a significant clinical challenge. They typically fail to heal spontaneously through the body's innate repair mechanisms. Physiological levels of reactive oxygen species (ROS) play a crucial role in antimicrobial defense. However, excessive ROS in periodontal bone defects can severely accelerate disease progression. Precise regulation of the oxidative microenvironment is essential for effective bone repair. This study developed an ROS-responsive double network hydrogel (HA/MeFu-mal/PBA@MET) for the controlled-release of metformin to alleviate oxidative stress and promote osteogenesis in periodontitis. The first network comprises a Diels-Alder reaction between methylfuran and maleimide to enhance the mechanical properties of the hydrogel. The second network forms reversible borate bonds between phenylboronic acid and polyvinyl alcohol (PVA) o-hydroxy groups, enabling micro-environment response to ROS. The double-network hydrogel is loaded with metformin-a drug possessing antioxidant, anti-inflammatory, and pro-osteogenic properties. Under the oxidative stress conditions of periodontitis, the HA/MeFu-mal/PBA@MET hydrogel effectively scavenges excess free radicals and triggers targeted metformin release. It was further validated that the hydrogel system significantly enhances osteogenesis via the AMPK/mTOR signaling pathway. As a microenvironment-regulating hydrogel capable of mitigating local oxidative stress, HA/MeFu-mal/PBA@MET can adapt to complex defect shapes, provide structural support, efficiently eliminate ROS, and release drugs on demand, thereby synergistically reprogramming the periodontal microenvironment to facilitate alveolar bone regeneration. This work offers a novel strategy for the development of micro-environment responsive biomaterials aimed at treating inflammatory bone loss.