Thermo/Shear-Responsive Injectable Hydrogels from an Alginate/PNIPAM-Based Graft Copolymer: Effect of Divalent Cations Ca²⁺

This work is focused on the design and development of biocompatible self-assembling hydrogels which behave as soft gels at room temperature and as strong ones at the physiological temperature, suitable for potential bio-applications. A graft copolymer of sodium-alginate bearing 8 side chains of poly(N-isopropylacrylamide), enriched with the hydrophobic comonomer N-tertiary-butyl-acrylamide (NtBAM), [ALG-g-P(NIPAM-co-NtBAM)] were used as gelator. 5 wt % aqueous polymer solutions in the presence of various concentrations of Ca²⁺ cations were prepared and evaluated as thermoresponsive hydrogels. Rheological experiments revealed a twostep reversible gelation either upon heating or upon cooling .

The divalent cations operate as cross-linking agent through ionic interactions inducing the formation of a network at low temperatures. Upon heating, an additional crosslinking develops through thermo-generated hydrophobic association of the thermo-responsive P(NIPAM-co-NtBAM) side chains above a critical temperature.

The storage modulus, G’, increases with the cation concentration below and above the critical temperature. More importantly, the difference of G’ between 20 ^oC and 50 ^oC (ΔG’) increases linearly with the cation concentration, revealing a cooperative effect between the two-association mechanism, i.e. ionic and hydrophobic. In other words, the thermo-induced hydrogel elasticity is enhanced in the presence of the ionic bonds.

Furthermore, the combination of thermo- and shear-responsiveness provides shelf-assembling systems as potential candidates for injectable strategies. Especially, the systems with lower cation concentration could be used for drug delivery, while the gelators with higher cation concentration could be used for cell transplantation, which require a weak gel to protect the cells during injection and an instantaneous gelation at physiological temperature after the injection to immobilize the created scaffold in the targeting position of the host tissue.