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Thermo/Shear-Responsive Injectable Hydrogels from an Alginate/PNIPAM-Based Graft Copolymer: Effect of Divalent Cations Ca2+
Sofia - Falia Saravanou * , Fotoula Kounelaki, Constantinos Tsitsilianis
1  Department of Chemical Engineering, University of Patras, 26500 Patras, Greece


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.

Keywords: Alginate; P(Nisopropylacrylamide-co-N-tert-butylacrylamide); Thermo/Shear-responsive graft copolymer; Divalent Cations; Injectability
Comments on this paper
Ana Maria Diez-Pascual
Comment on 10.3390/CGPM2020-07196
Thanks for the interesting paper. I am a bit concerned about the potential toxicity of poly(N-isopropylacrylamide)
Thank you very much for your reasonable question. Poly(N-isopropylacrylamide) (PNIPAM) is a well-studied material, however there is not much information about its biocompatibility. Surely, to use a material as cell scaffold in tissue engineering and in other biomedical applications it is crucial to determine if the material is toxic in contact with cells. It is known that the monomer NIPAM is toxic to all cell types. Anyhow, the biocompatibility of the PNIPAM alters depending on the cell type. Based on previous works PNIPAM was tested in various cell types and it is shown that is non-toxic even in long-term experiments. Additionally, I cite three interesting studies which evaluate the cell viability and offer various potential bioapplications using PNIPAM.

Ana Maria Diez-Pascual
Thank you very much for your reply. I will read the studies.