Oxime Cross-Linked Alginate Hydrogels with Tunable Stress Relaxation

Abstract

Stress relaxation is an important design parameter of biomaterials that can provide an artificial microenvironment mimicking natural extracellular matrix (ECM). Here, we report a novel hydrogel platform based on sodium alginate (NaAlg) with tunable stress relaxation. We first developed a new synthesis route to introduce alkoxyamine functional groups into the alginate polymer backbone. By mixing the resulting polymer (NaAlg-AA) with aldehydecontaining oxidized alginate (NaAlg-Ald), oxime cross-linked alginate hydrogels were prepared. We demonstrate that highly tunable stress relaxation and mechanical properties can be achieved by systematically varying the composition (concentration, polymer mixing ratios, degree of oxidation of NaAlg-Ald) or environmental factors (pH, temperature, and use of catalyst). Combined with the natural capability of the alginate to be cross-linked by divalent cations, the developed hydrogel formations possess the unique capability of dual cross-linking mechanisms with different gelation kinetics. We demonstrated that this dual cross-linking capability can (i) be utilized for the creation of hydrogels in microbead or microthread geometries and (ii) be useful for biomedical applications that require both the fast encapsulation of cells in hydrogels (fast calcium cross-linking) and the provision of controlled viscoelastic environments to cultured cells for an extended period (durable oxime cross-linking). With biocompatibility confirmed by the culture of a B-cell line encapsulated within the developed hydrogel, this novel hydrogel platform provides a good prospect in various applications where stress relaxation plays a key role in cell−matrix interactions.

Covalently Crosslinked Hydrogels via Step‐Growth Reactions: Crosslinking Chemistries, Polymers, and Clinical Impact

“…[ 90 ] It is of particular interest to combine chemical crosslinking with ionic crosslinking methods to fabricate alginate hydrogels with dual crosslinking mechanisms. [ 105 ] Such dual crosslinked hydrogels with tunable stress relaxation on a local and global scale are suitable for various applications, such as cell encapsulation.…”

Viscoelastic Cell Microenvironment: Hydrogel‐Based Strategy for Recapitulating Dynamic ECM Mechanics

“…Besides physically crosslinked hydrogels, the hydrogels containing dynamic covalent chemistries, such as thioester, [ 47,175–177 ] allyl sulfide, [ 178 ] disulfide, [ 158 ] hydrazone, [ 48,179,180 ] boronate, [ 49,50,181 ] oxime, [ 182–184 ] Schiff base, [ 185–187 ] and Diel–Alder [ 188–190 ] that create covalent adaptable networks can also possess viscoelasticity. Thioester‐containing hydrogels were fabricated via thiol‐ene click chemistry to yield adaptable networks ( Figure A).…”

“…Data are collected from previous reports. [ 25,32,35,42,44,184 ]…”

Designing Hydrogels for 3D Cell Culture Using Dynamic Covalent Crosslinking

“…[ 200 ] The stress relaxation of an alginate oxime hydrogel can be tuned from slow to fast by varying the ratio of oxyamine to aldehyde and fast relaxing gels were useful for the 3D growth and migration of murine B lymphoma cells. [ 43 ]…”

“…Dynamic covalent bonds are reversible chemical bonds which can break and reform on time scales relevant for cell‐based matrix remodeling, an important feature for 3D culture. [ 17 ] Specific examples of DCC which have been tailored to be compatible with 3D cell culture include boronate ester, [ 18–23 ] hydrazone, [ 24–30 ] Diels‐Alder, [ 31–37 ] oxime, [ 38–43 ] thiol–disulfide exchange, [ 44–46 ] and imine crosslinking. [ 17,47,48 ] These crosslinking methods can be performed at physiological pH and temperature, are fast reacting, and their reaction kinetics can be tailored to achieve a wide range of viscoelastic properties.…”