Selenoprotein‐Regulated Hydrogel for Ultrasound‐Controlled Microenvironment Remodeling to Promote Bone Defect Repair

Abstract Abnormal levels of reactive oxygen species (ROS) and the hypoxic microenvironment within bone defects are important factors that impede bone repair processes. Herein, an innovative ultrasound‐modulatable hydrogel platform with selenoprotein‐mediated antioxidant effects to promote bone injury repair is presented. This hydrogel platform encapsulates oxygen‐enriched selene‐incorporated thin‐shell silicon within methacrylate gelatin (O₂‐PSSG). The resultant construct orchestrates the modulation of the bone‐defect microenvironment, thereby expediting the course of bone regeneration. Ultrasound (US) is used to regulate the pore size of the hydrogel to release selenium‐containing nanoparticles and promote the in situ synthesis of efficient intracellular selenoproteins and hydrogen peroxide consumption. As expected, O₂‐PSSG rapidly releases selenocystine ([Sec]₂) under US control to scavenge reactive oxygen species and maintain the homeostasis of bone marrow mesenchymal stem cells (BMSCs). Over time, the action of the system by selenoprotein increases the activation of Wnt/β‐catenin pathways and promotes the differentiation of BMSCs. Consequently, O₂‐PSSG potentiates the antioxidant proficiency of BMSCs both in vitro and in vivo, alleviates hypoxic environments, promotes osteogenic differentiation, and expedites cranial bone repair in rat models. In summary, this study suggests that the designed and constructed US‐responsive antioxidant hydrogel is a promising prospective strategy for addressing bone defects and fostering bone regeneration.