ABSTRACT Reactive oxygen species (ROS)‐responsive biomaterials have drawn increasing interest in regenerative medicine, drug delivery systems, and biodegradable implants. These materials are especially promising as local ROS levels are increased in healing tissues and during inflammation. Various ROS‐responsive polymers containing thioketals (TK) have been developed and show notable effectiveness because of their ease of synthesis and selective oxidative biodegradation. However, conventional TK bonds are relatively hydrophobic and have limited responsiveness to physiological doses of water‐borne ROS. Here, a library of TK linkers was synthesized to evaluate the relationship between linker hydrophilicity and ROS‐mediated degradation. NMR studies demonstrated that hydrophilic TK constructs degraded more rapidly at lower ROS concentrations compared to standard TK bonds. Crosslinked hydrogels made with more hydrophilic TKs showed greater polymer network degradation when exposed to ROS than traditional TK formulations. When these TK linkers were incorporated into scaffolds, the more hydrophilic varieties experienced nearly doubled mass loss upon oxidation. This structure‐function relationship was also confirmed in vivo as porous scaffolds constructed from more hydrophilic TKs underwent significantly more bioresorption and improved tissue in‐growth when implanted subcutaneously in rats. This work presents a simple yet powerful method for enhancing the responsiveness and functionality of TK materials across regenerative medicine applications.
Bruce et al. (2026) studied this question.