Engineering of degradable linkers to improve the oxidative sensitivity of thioketal-based biomaterials

Stimuli-responsive biomaterials have drawn increasing interest in regenerative medicine, particularly drug deliv-ery systems and biodegradable implants. Synthetic polymer systems that respond to reactive oxygen species (ROS) are especially promising as local ROS levels are increased in healing tissues and during infection, inflammation, and disease. Recently, various ROS-responsive polymers have been developed with thioketal (TK)-based biomaterials showing notable effectiveness because of these materials’ 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 from different ketone-containing monomers 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 bond configurations. Similarly, crosslinked hydrogels made with more water-friendly TKs showed greater polymer net-work degradation when exposed to ROS than traditional, more hydrophobic TK formulations. When these TK link-ers were incorporated into tissue engineering scaffolds, all samples exhibited negligible in vitro cytotoxicity while the more hydrophilic varieties experienced nearly a doubling of mass loss upon oxidation. This structure-function relationship was also confirmed in vivo as porous scaffolds constructed from more hydrophilic TKs underwent sig-nificantly 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 to broaden their effectiveness across regenerative medicine applications.