Phase Transitions of P(NIPAM-g-PLA) Copolymers in the Injectable Hydrogel Design

Thermoresponsive polymers have attracted significant attention in the design of injectable hydrogels for biomedical applications. Their gelation is conventionally attributed to the coil-to-globule transition, and other possible gelation mechanisms are frequently overlooked. Here, we present a graft copolymer P(NIPAM-g-PLA), representative of a distinct type of thermoresponsive polymers with gelation and coil-to-globule transition being separate processes. Its temperatures of gelation (T_gel) are consistently lower than the binodal temperatures (T_b); it forms a transparent gel at T_gel < T < T_b, and T_gel significantly depends on the polymer concentration, in contrast to T_b. At T_b, the polymer becomes opaque. Thus, the P(NIPAM-g-PLA)-water system exists in four phases: transparent sol, opaque sol, transparent gel, and opaque gel. P(NIPAM-g-PLA) gelation may be modeled by the formation of physical cross-links between hydrophobic "pearls" in the "pearl-necklace" polymer chains. P(NIPAM-g-PLA) forms viscous solutions at T < T_gel, with the viscosity dramatically depending on the polymer concentration. Its injectability appears restricted by approximately 10 wt %, above which the solutions become too viscous. Upon gelation at T_gel < T_b, transparent gels with stable mechanical properties and storage moduli of up to megapascals are formed. The rheological properties of P(NIPAM-g-PLA) were essentially modified by the presence of a biological buffer (PBS) as compared with pure water. An important finding of the study was the complete loss of the copolymer's ability to form gels due to aging (after a year-long storage). The potential influence of salts in biological buffers and the adverse effects of polymer aging should be considered when creating injectable hydrogels for biomedical applications.