Biomimicking Dual-Responsive Extracellular Matrix Restoring Extracellular Balance through the Na/K-ATPase Pathway

Biomedical implant mimicking the physiological extracellular matrix (ECM) is a new strategy to modulate the cell microenvironment to improve implant integrity and longevity. However, the biomimicking ECM suffers from low sensitivity to pathological change and low efficiency to restore the physiological state in vivo. To overcome these problems, reactive oxygen species (ROS) and K⁺ dual-responsive micro-/nanofibers that encapsulate ascorbic acid-2-glucoside (AA-2G) are fabricated on an elastomer substrate with electrospinning to mimic the ECM. The strategy is based on the fact that ROS and K⁺ dual responsiveness enhance the sensitivity of the ECM to pathological changes and delivery of AA-2G from the ECM to cell membrane promotes reactivating Na/K-ATPase and shifting cellular diseased conditions to the normal state. We demonstrate that the ROS and K⁺-responsive tripolymer of poly(ethylene glycol)diacrylate, 1,2-ethanedithiol, and 4-nitrobenzo-18-crown-6-ether (PEGDA-EDT-BCAm) are synthesized successfully; the ECM composed of acylated poly(caprolactone)/PEGDA-EDT-BCAm/AA-2G micro-/nanofibers is prepared through reactive electrospinning; the ECM is sensitive to ROS and K⁺ concentration in the microenvironment to release AA-2G, which targets the membrane to remove the excessive ROS and reactivate Na/K-ATPase; as a result, the ECM reduces oxidative stress and restores the extracellular physiological state both in vitro and in vivo. This work provides basic principles to design an implant that can adjust the extracellular microenvironment while avoiding pathogenicity to improve implant integrity and longevity in vivo.