Injectable Interpenetrating Network Hydrogels via Kinetically Orthogonal Reactive Mixing of Functionalized Polymeric Precursors

The enhanced mechanics, unique chemistries, and potential for domain formation in interpenetrating network (IPN) hydrogels have attracted significant interest in the context of biomedical applications. However, conventional IPNs are not directly injectable in a biological context, limiting their potential utility in such applications. Herein, we report a fully injectable and thermoresponsive interpenetrating polymer network formed by simultaneous reactive mixing of hydrazone cross-linked poly­(<i>N</i>-isopropylacrylamide) (PNIPAM), and thiosuccinimide cross-linked poly­(<i>N</i>-vinylpyrrolidone) (PVP). The resulting IPN gels rapidly (<1 min) after injection without the need for heat, UV irradiation, or small-molecule cross-linkers. The IPNs, cross-linked by kinetically orthogonal mechanisms, showed a significant synergistic enhancement in shear storage modulus compared to the individual component networks as well as distinctive pore morphology, degradation kinetics, and thermal swelling; in particular, significantly lower hysteresis was observed over the thermal phase transition relative to single-network PNIPAM hydrogels

Nanostructure of Fully Injectable Hydrazone–Thiosuccinimide Interpenetrating Polymer Network Hydrogels Assessed by Small-Angle Neutron Scattering and dSTORM Single-Molecule Fluorescence Microscopy

Herein, we comprehensively investigate the internal morphology of fully injectable interpenetrating networks (IPNs) prepared via coextrusion of functionalized precursor polymer solutions based on thermoresponsive poly­(<i>N</i>-isopropylacrylamide) (PNIPAM) and nonthermoresponsive poly­(vinyl pyrrolidone) (PVP) by reactive mixing using kinetically orthogonal hydrazone and thiosuccinimide cross-linking mechanisms. Small-angle neutron scattering, probing both the full IPN as well as the individual constituent networks of the IPN using index-matching, suggests a partially mixed internal structure characterized by PNIPAM-rich domains entrapped in a clustered PVP-rich phase. This interpretation is supported by super-resolution fluorescence microscopy (direct stochastic optical reconstruction microscopy) measurements on the same gels on a different length scale, which show both the overall phase segregation typical of an IPN as well as moderate mixing of PNIPAM into the PVP-rich phase. Such a morphology is consistent with the kinetics of both gelation and phase separation in this in situ gelling system, in which gelation effectively traps a fraction of the PNIPAM in the PVP phase prior to full phase separation; by contrast, such interphase mixing is not observed in semi-IPN control hydrogels. This knowledge has significant potential for the design of an injectable hydrogel with internal morphologies optimized for particular biomedical applications