Hypoxia‐Sensitive Smart Hydrogel Biosensor for Distinct Mechanical and Electrical Signals with Muscle Ischemia Regeneration

Abstract A hypoxia‐specific diselenide‐crosslinked polymer dot (PD) nanoparticles‐based pyrogallol‐modified hydrogel (HS‐PD hydrogel) is developed for the facile monitoring of muscle ischemia recovery through multifaceted mechanical, electrical, and optical modulation. The ischemia environment‐sensitive conductive hydrogel exploits the specific cleavage of diselenide bonds induced by overexpressed reactive oxygen species (ROS), regulating fluorescence “on/off” activation, and subsequently modifies the microstructural morphology of the matrix. The HS‐PD hydrogel utilizes the oxidizing properties of pyrogallol to modulate its electroconductivity (ΔR decreased by ≈78.1%) and mechanophysical properties under normoxic conditions while enabling naked‐eye detection via visible color changes. Moreover, in vitro mechanophysical and electrical changes are evidenced by an increase in stretchability and compression modulus, alongside reduced electrical resistivity under normoxic conditions, as confirmed using C2C12 and 3T3‐L1 cell models. Additionally, in vitro gene expression analysis shows significant downregulation of SOD2 , Hif‐1α , and MuRF‐1 genes associated with muscle degradation, indicating enhanced ROS scavenging and potential oxygen normalization in ischemic regions. In vivo studies using a murine model of femoral artery ligation show a reduced inflammatory response, muscle fiber hypertrophy, and increased regenerative capacity in ischemic tissues. These findings highlight the potential of hydrogels in muscle regeneration and therapeutic applications.