Multi-Responsive Polymers with Degradable Side-Chain Functionality for Controlled Hydrolysis and Tunable Thermal Transition

Abstract

Stimuli-responsive polymers that integrate environmental sensitivity with controlled degradation offer powerful opportunities for next-generation biomedical materials. Here, we introduce a new class of multi-responsive terpolymers synthesized via reversible addition-fragmentation chain-transfer (RAFT) polymerization, incorporating comonomers with hydrolytically labile lactone (LMA) or cyclic carbonate (C2MA) side chains into thermoresponsive oligo(ethylene glycol)-based systems. By systematically tuning monomer composition, we achieved controlled modulation of cloud point temperature (Tcp), viscosity, and degradation kinetics within the physiologically relevant window (25–37 °C). Cyclic carbonate-containing terpolymers exhibited lower viscosity, lower glass transition temperatures, and faster hydrolysis than lactone analogues, enabling facile injectability and time-dependent solubility transitions. Density functional theory (DFT) calculations revealed distinct transition state geometries and energetics for lactone versus carbonate ring-opening, with cyclic carbonate hydrolysis kinetically favored. Hydrolysis-driven shifts in Tcp linked side-chain chemistry to temporal control of thermal phase behavior. Notably, radiofrequency (RF)-induced heating triggered a rapid, localized temperature increase for lactone and cyclic carbonate terpolymers, demonstrating the potential for remote, on-demand actuation. Injectability tests in tissue-mimicking matrices revealed qualitatively sustained, localized release profiles governed by polymer viscosity and degradation rates. Consistent with these observations, dialysis-based dye release studies demonstrated composition-dependent release kinetics, where cyclic carbonate terpolymers exhibited faster payload release relative to lactone analogues. Collectively, this work establishes a versatile platform of hydrolytically and thermally programmable polymers, uniquely integrating physiological responsiveness with potential external triggering mechanisms for applications in injectable therapeutics, tissue adhesives, and smart biomedical interfaces.