Biomimetic double network hydrogels: Combining dynamic and static crosslinks to enable biofabrication and control cell‐matrix interactions

Abstract

Hydrogels are promising candidates for recapitulation of the native extracellular matrix (ECM), yet recreating molecular and spatiotemporal complexity within a single network remains a challenge. Double network (DN) hydrogels are a promising step towards recapitulating the multicomponent ECM and have enhanced mechanical properties. Here, we investigate DNs based on dynamic covalent and covalent bonds to mimic the dynamicity of the ECM and enable biofabrication. We also investigate the spatiotemporal molecular attachment of a bioactive adhesive peptide within the networks. Using oxidized alginate (dynamic network, Schiff base) and polyethylene glycol diacrylate (static network, acrylate polymerization) we find an optimized procedure, where the dynamic network is formed first, followed by the static network. This initial dynamically cross-linked hydrogel imparts self-healing, injectability, and 3D printability, while the subsequent DN hydrogel improves the stability of the 3D gels and imparts toughness. Rheology and compression testing show that the toughening is due to the combination of energy dissipation (dynamic network) and elasticity (static network). Furthermore, where we place adhesive sites in the network matters; we find distinct differences when an adhesive peptide, Arg-Gly-Asp (RGD), is attached to the different networks. This DN strategy bring us closer to understanding and recreating the complex multicomponent ECM-pushing us past a materials view of cell adhesionwhile enabling injectabiltiy and printing of tough hydrogels.

Drinkable, liquidin situ-forming and tough hydrogels for gastrointestinal therapeutics

“…While we and others have developed orally administrable tough hydrogels 55, 58, 59 , these require templated radical polymerization of toxic acrylamide monomer that cannot be safely performed in vivo and are dosed as a solid 60 . Other hydrogel systems have been designed that require UV light to facilitate polymer crosslinking 61, 62 , utilize polyacrylamide as a polymer network 37 , require a specific construction of hydrogel components 59 , or are enzymatically polymerized 63, 64 . While these hydrogels are mechanically tough, they either require a pre-solidified dosage format or are challenging and unsafe to crosslink and gel in situ .…”

Dynamic protein and polypeptide hydrogels based on Schiff base co-assembly for biomedicine

“…68,69 A growing number of studies have shown that the use of both dynamic covalent and non-covalent interactions to form hybrid crosslinked hydrogels overcomes important limitations of purely dynamic covalent or noncovalent hydrogels. [70][71][72] For example, single hydrogen bonds between hydroxyl, carboxyl and amino groups are not strong enough to form hydrogels by themselves, and hydrophobically crosslinked hydrogels generally exhibit poor mechanical strength. Moreover, Schiff base bonds are mechanically weak and highly sensitive to hydrolysis with pH shifts.…”

Recent developments of polysaccharide‐based double‐network hydrogels

“…For example, oxidized Alg (OA) was used to form a dynamic first network by Schiff-base reaction, while the polyethylene glycol diacrylate (PEGDA) acted as the second covalent network (Figure 6B). 90 The synergetic effect of both networks provides the hydrogel with self-healing ability and injectability as well as excellent stability. Similarly, Chen et al 91 prepared dopamine (DA)-grafted OA to interact with PAAm chains via Schiff cross-linking.…”

“…Reproduced with permission. 90 Copyright Wiley 2021 engineering, and strain sensors. 103 The DN hydrogel based on poly (acrylic acid-co-acrylamide) (PAA-co-PAAm) and HA showed an excellent sensory to strain, temperature, and humidity.…”