Coiled Coil Crosslinked Alginate Hydrogels Dampen Macrophage-Driven Inflammation

Abstract

Alginate hydrogels are widely used for tissue engineering and regenerative medicine due to their excellent biocompatibility. A facile and commonly used strategy to crosslink alginate is the addition of Ca2+ that leads to hydrogelation. However, extracellular Ca2+ is a secondary messenger in activating inflammasome pathways following physical injury or pathogenic insult, which carries the risk of persistent inflammation and scaffold rejection. Here, we present graft copolymers of charge complementary heterodimeric coiled coil (CC) peptides and alginate that undergo supramolecular self-assembly to form Ca2+ free alginate hydrogels. The formation of heterodimeric CCs was confirmed using circular dichroism spectroscopy, and scanning electron microscopy revealed a significant difference in crosslink density and homogeneity between Ca2+ and CC crosslinked gels. The resulting hydrogels were self-supporting and display shear-thinning and shear-recovery properties. In response to lipopolysaccharide (LPS) stimulation, peritoneal macrophages and bone marrow-derived dendritic cells cultured in the CC crosslinked gels exhibited a 10-fold reduction in secretion of the proinflammatory cytokine IL-1β compared to Ca2+ crosslinked gels. A similar response was also observed in vivo upon peritoneal delivery of Ca2+ or CC crosslinked gels. Analysis of peritoneal lavage showed that macrophages in mice injected with Ca2+ crosslinked gels display a more inflammatory phenotype compared to macrophages from mice injected with CC crosslinked gels. These results suggest that CC peptides by virtue of their tunable sequence–structure–function relationship and mild gelation conditions are promising alternative crosslinkers for alginate and other biopolymer scaffolds used in tissue engineering.

Gold nanocluster decorated fibrous substrate for photo-modulated cellular growth

“…The slight background leakage of protein may result from ion exchange in the PBS. 14 Correspondingly, the 520 nm emission of the irradiated area in fibrous-Au/protein-GG was significantly decreased (Fig. 6f), while there was a slight decrease in the emission for fibrous-Au/protein-GG without irradiation.…”

“…12 The metal-coordination bonds can be easily introduced to increase the extent of crosslinking, which has potential for improving the architectural strength. [13][14][15] Self-assembled fibrous substrates with tunable mechanical properties enable the mimicry of structural features of the extracellular matrix to provide mechanical cues.…”

A review on the synthesis and development of alginate hydrogels for wound therapy

“…The hydrogel formed by this composite polymer skeleton can have a variety of special structures and functions at the same time. After the introduction of other macromolecules into the sodium alginate hydrogel, 111 due to the entanglement between molecular chains, crosslinking can indirectly act on sodium alginate molecules. Such sodium alginate hydrogel usually has a variety of physical and chemical effects.…”

“…In order to alleviate the inflammatory reaction in advance, active factors such as anthocyanin can be loaded in sodium alginate hydrogel to alleviate the pain of the wounded. 111,196,197…”

Potential effects of biomaterials on macrophage function and their signalling pathways

“…Clapacs et al investigated the effects of coiled-coil (CC)- and Ca 2+ -crosslinked alginate hydrogels on macrophages in vitro and in vivo . 65 Following LPS stimulation, murine peritoneal macrophages were encapsulated in hydrogels crosslinked with CC or Ca 2+ and subsequently characterized for IL-1β release and macrophage phenotype. Cells encapsulated in CC-crosslinked gels released significantly less IL-1β compared with those encapsulated in Ca 2+ -crosslinked gels.…”