Hepatic Spheroid Formation on Carbohydrate-Functionalized Supramolecular Hydrogels

Abstract

Two synthetic supramolecular hydrogels, formed from bis-urea amphiphiles containing lactobionic acid (LBA) and maltobionic acid (MBA) bioactive ligands, are applied as cell culture matrices in vitro. Their fibrillary and dynamic nature mimics essential features of the extracellular matrix (ECM). The carbohydrate amphiphiles self-assemble into long supramolecular fibers in water, and hydrogels are formed by physical entanglement of fibers through bundling. Gels of both amphiphiles exhibit good self-healing behavior, but remarkably different stiffnesses. They display excellent bioactive properties in hepatic cell cultures. Both carbohydrate ligands used are proposed to bind to asialoglycoprotein receptors (ASGPRs) in hepatic cells, thus inducing spheroid formation when seeding hepatic HepG2 cells on both supramolecular hydrogels. Ligand nature, ligand density, and hydrogel stiffness influence cell migration and spheroid size and number. The results illustrate the potential of self-assembled, carbohydrate-functionalized hydrogels as matrices for liver tissue engineering.

Toward reproducible tumor organoid culture: focusing on primary liver cancer

“…Furthermore, the rate of proliferation was influenced by stiffness, where organoid growth was most favorable at lower stiffness levels. In another study, Liu and colleagues ( 130 ) designed synthetic supramolecular hydrogels using bis-urea amphiphiles containing lactobionic acid (LBA) and maltobionic acid (MBA) ligands. These hydrogels closely resemble the ECM due to their dynamic and fibrillary structure.…”

Synthetic approaches of carbohydrate based self-assembling systems

“…Scheme 23 shows the synthesis of two bisurea amphiphiles of sugar derivatives 156 and 157 . 81 These compounds were synthesized from either lactobionic acid 153 or maltobionic acid. The reaction of intermediate lactobiono-δ-lactone 154 with a diamine afforded the monoamine derivative 155 , which was further reacted with a diisocyanate to afford the corresponding bisurea 156 .…”

Bisurea‐Based Supramolecular Polymers for Tunable Biomaterials

“…[30,31] The group of Sijbesma investigated the use of this motif to create water-compatible bolaamphiphiles for the design of supramolecular fibers, which showed strain-stiffening properties and bioactivity. [32][33][34] The group of Brendel has made use of this stronger interaction to drive the assembly of benzene trisureas into cylinder like objects in water, guided by strong hydrogen bonds rather than the hydrophobic/hydrophilic balance of the monomer. [30,31] Another synthetically readily accessible urea motif based on 2,4-toluene diisocyanate (TDI) was developed by the group of Bouteiller.…”

“…Compared to amides, ureas form stronger interactions due to multiple and cooperative hydrogen bonds [30,31] . The group of Sijbesma investigated the use of this motif to create water‐compatible bolaamphiphiles for the design of supramolecular fibers, which showed strain‐stiffening properties and bioactivity [32–34] . The group of Brendel has made use of this stronger interaction to drive the assembly of benzene trisureas into cylinder like objects in water, guided by strong hydrogen bonds rather than the hydrophobic/hydrophilic balance of the monomer [30,31] .…”