Graft copolymers of alginate backbone and N-isopropylacrylamide/N-tert-butylacrylamide random copolymer, P(NIPAM_x-co-NtBAM_y), side chains (stickers) with various NtBAM content were designed and explored in aqueous media. Self-assembling thermoresponsive hydrogels are formed upon heating, in all cases, through the hydrophobic association of the P(NIPAM_x-co-NtBAM_y) sticky pendant chains. The rheological properties of the formulations depend remarkably on the NtBAM hydrophobic content, which regulates the lower critical solution temperature (LCST) and, in turn, the stickers’ thermo-responsiveness. The gelation point, T_gel, was shifted to lower temperatures from 38 to 20 °C by enriching the PNIPAM chains with 20 mol % NtBAM, shifting accordingly to the gelation temperature window. The consequences of the T_gel shift to the hydrogels’ rheological properties are significant at room and body temperature. For instance, at 37 °C, the storage modulus increases about two orders of magnitude and the terminal relaxation time increase about 10 orders of magnitude by enriching the stickers with 20 mol % hydrophobic moieties. Two main thermo-induced behaviors were revealed, characterized by a sol–gel and a weak gel–stiff gel transition for the copolymer with stickers of low (0.6 mol %) and high (14, 20 mol %) NtBAM content, respectively. The first type of hydrogels is easily injectable, while for the second one, the injectability is provided by shear-thinning effects. The influence of the type of media (phosphate buffer (PB), phosphate-buffered saline (PBS), Dulbecco’s modified Eagle’s medium (DMEM)) on the hydrogel properties was also explored and discussed. The 4 wt % NaALG-g-P(NIPAM₈₀-co-NtBAM₂₀)/DMEM formulation showed excellent shear-induced injectability at room temperature and instantaneous thermo-induced gel stiffening at body temperature, rendering it a good candidate for cell transplantation potential applications.

We report the preparation of mesoporous silica nanoparticles covered by layer by layer (LbL) oppositely charged weak polyelectrolytes, comprising poly(allylamine hydrochloride) (PAH) and a sodium alginate, highly grafted by N-isopropylacrylamide/N-tert-butylacrylamide random copolymers, NaALG-g-P(NIPAM₉₀-co-NtBAM₁₀) (NaALG-g). Thanks to the pH dependence of the degree of ionization of the polyelectrolytes and the LCST-type thermosensitivity of the grafting chains of the NaALG-g, the as-prepared hybrid nanoparticles (hNP) exhibit pH/thermo-responsive drug delivery capabilities. The release kinetics of rhodamine B (RB, model drug) can be controlled by the number of PAH/NaALG-g bilayers and more importantly by the environmental conditions, namely, pH and temperature. As observed, the increase of pH and/or temperature accelerates the RB release under sink conditions. The same NaALG-g was used as gelator to fabricate a hNP@NaALG-g hydrogel composite. This formulation forms a viscous solution at room temperature, and it is transformed to a self-assembling hydrogel (sol-gel transition) upon heating at physiological temperature provided that its T_gel was regulated at 30.7 °C, by the NtBAM hydrophobic monomer incorporation in the side chains. It exhibits excellent injectability thanks to its combined thermo- and shear-responsiveness. The hNP@NaALG-g hydrogel composite, encapsulating hNP covered with one bilayer, exhibited pH-responsive sustainable drug delivery. The presented highly tunable drug delivery system (DDS) (hNP and/or composite hydrogel) might be useful for biomedical potential applications.

Polysaccharide-based graft copolymers bearing thermo-responsive grafting chains, exhibiting LCST, have been designed to afford thermo-responsive injectable hydrogels. The good performance of the hydrogel requires control of the critical gelation temperature, T_gel. In the present article, we wish to show an alternative method to tune T_gel using an alginate-based thermo-responsive gelator bearing two kinds of grafting chains (heterograft copolymer topology) of P(NIPAM₈₆-co-NtBAM₁₄) random copolymers and pure PNIPAM, differing in their lower critical solution temperature (LCST) about 10 °C. Interestingly, the T_gel of the heterograft copolymer is controlled from the overall hydrophobic content, NtBAM, of both grafts, implying the formation of blended side chains in the crosslinked nanodomains of the formed network. Rheological investigation of the hydrogel showed excellent responsiveness to temperature and shear. Thus, a combination of shear-thinning and thermo-thickening effects provides the hydrogel with injectability and self-healing properties, making it a good candidate for biomedical applications.

In this work, a sodium alginate-based copolymer grafted by thermoresponsive poly(N-isopropylacrylamide) (PNIPAM) chains was used as gelator (Alg-g-PNIPAM) in combination with methylcellulose (MC). It was found that the mechanical properties of the resulting gel could be enhanced by the addition of MC and calcium ions (Ca²⁺). The proposed network is formed via a dual crosslinking mechanism including ionic interactions among Ca²⁺ and carboxyl groups and secondary hydrophobic associations of PNIPAM chains. MC was found to further reinforce the dynamic moduli of the resulting gels (i.e., a storage modulus of ca. 1500 Pa at physiological body and post-printing temperature), rendering them suitable for 3D printing in biomedical applications. The polymer networks were stable and retained their printed fidelity with minimum erosion as low as 6% for up to seven days. Furthermore, adhered pre-osteoblastic cells on Alg-g-PNIPAM/MC printed scaffolds presented 80% viability compared to tissue culture polystyrene control, and more importantly, they promoted the osteogenic potential, as indicated by the increased alkaline phosphatase activity, calcium, and collagen production relative to the Alg-g-PNIPAM control scaffolds. Specifically, ALP activity and collagen secreted by cells were significantly enhanced in Alg-g-PNIPAM/MC scaffolds compared to the Alg-g-PNIPAM counterparts, demonstrating their potential in bone tissue engineering.

This work is focused on the design and development of biocompatible self-assembling hydrogels, which behave as soft gels at room temperature and strong gels at the physiological temperature, suitable for potential bio-applications. A graft copolymer of sodium-alginate, bearing eight side chains of poly(N-isopropylacrylamide), enriched with the hydrophobic comonomer N-tertiary-butyl-acrylamide (NtBAM), (NaALG-g-P(NIPAM-co-NtBAM)) were used as gelator. In total, 5 wt% aqueous polymer solutions in the presence of Ca²⁺ cations were prepared and evaluated as thermo-responsive hydrogels. Rheological experiments revealed a twostep reversible gelation either upon heating or cooling. The divalent cations operated as a cross-linking agent through ionic interactions, inducing the formation of a network at low temperatures. Upon heating, an additional crosslinking develops through thermo-induced hydrophobic association of the thermo-responsive P(NIPAM-co-NtBAM) side chains above a critical temperature. The combination of thermo- and shear-responsiveness provides shelf-assembling systems as potential candidates for injectable strategies. For instance, the system under investigation could be used for cell transplantation, which requires a weak gel to protect the cells during injection and a gel strengthening after the injection at a physiological temperature to immobilize the created scaffold in the targeting position of the host tissue.