Modular Synthetic Platform to Tailor Therapeutic-Specific Delivery in Injectable Hydrogels

Injectable thermoresponsive hydrogels (thermogels), valued for their conformability and minimal invasiveness, are increasingly used as in situ forming implants for drug delivery and as regenerative scaffolds. These gels exhibit sol-to-gel phase transitions at body temperature. As localized depots and scaffolds, these gels determine the chemical and mechanical environments and could dramatically influence the release kinetics of drugs or the fate of cells. Current synthetic approaches for thermogels, however, often limit the ability to fully exploit interactions between the thermogel matrix and the encapsulated agent. In this study, we introduce a modular synthetic platform for creating a library of functionalized polyurethane thermogels that enables customization of gelation properties and intermolecular interactions. These thermogels can exhibit a wide range of stiffness, offer complementary ionic interactions, and enhance hydrophobic interactions and hydrogen bonding. By leveraging these tunable interactions between the thermogelling scaffold, functional groups, and encapsulated agents, we achieved sustained and controlled release, from days to over 6 months, for both low and high molecular weight drug analogs. Release profiles varied from monophasic to biphasic and triphasic depending on the compatibility between the thermogel properties and the encapsulated agents. The design rules identified here support the development of drug-specific formulations, facilitating precise, sustained, and modulated release tailored to therapeutic needs. Beyond providing an adaptable strategy for customizable injectable drug depots, this synthetic strategy lays the groundwork for future iterations of multi stimuli-responsive thermogels with enhanced bioactivity, advancing the potential for customizable, biointeractive therapeutic systems.