Modulation of Properties through Covalent Bond Induced Formation of Strong Ion Pairing between Polyelectrolytes in Injectable Conetwork Hydrogels.

In situ simultaneous formation of both covalent linkages and ion pair is challenging yet necessary to control the biological properties of a hydrogel. We report that the generation of covalent linkages (N-C) facilitates the simultaneous formation of ion pairs between polyelectrolytes (PEs) in a hydrogel network. Co-injection of tertiary amine functional macromolecules and reactive poly(ethylene glycol) (PEG) containing negatively charged PE leads to the formation of hydrogel conetworks consisting of covalent junctions and ion pairs. Our design is based on the gradual appearance of N-C junctions followed by formation of ion pairs. This strategy provides an easy access to hydrogel networks bearing a predetermined proportion of ion pair and covalent cross-linking junction. The proportion of ion pair could be varied by introducing a precalculated proportion of mono- and difunctional reactive PEG in the hydrogel system. The topology of the prepolymer and the hydrogel could be modulated (graft) during hydrogel formation. This approach is applicable to obtain covalent/ionic, covalent bond induced purely ionic, and purely covalent hydrogels of several macromolecular entities. The effect of ion pairing in the hydrogels is strongly reflected in the modulus, strain bearing, degradation, free volume, swelling, and drug release properties. The hydrogels exhibit microscopic recovery of modulus after application of high amplitude strain depending on the prepolymer concentration (chain entanglement) and nature of hydrogel network. The hydrogels are hemocompatible, and the covalent/ionic hydrogels show a slower release of methotrexate than that of the purely covalent hydrogel. This work provides an understanding for the in situ construction and manipulation of biological properties of hydrogels through the covalent bond induced formation of a strong ion pair.