Strain-Stiffening Hydrogels with Dynamic, Secondary Cross-Linking

Abstract

Hydrogels are water-swollen, typically soft networks useful as biomaterials and in other fields of biotechnology. Hydrogel networks capable of sensing and responding to external perturbations, such as light, temperature, pH, or force, are useful across a wide range of applications requiring on-demand cross-linking or dynamic changes. Thus far, although mechanophores have been described as strain-sensitive reactive groups, embedding this type of force-responsiveness into hydrogels is unproven. Here, we synthesized multifunctional polymers that combine a hydrophilic zwitterion with permanently cross-linking alkenes, and dynamically cross-linking disulfides. From these polymers, we created hydrogels that contain irreversible and strong thiol–ene cross-links and reversible disulfide cross-links, and they stiffened in response to strain, increasing hundreds of kPa in modulus under compression. We examined variations in polymer composition and used a constitutive model to determine how to balance the number of thiol–ene vs disulfide cross-links to create maximally force-responsive networks. These strain-stiffening hydrogels represent potential biomaterials that benefit from the mechanoresponsive behavior needed for emerging applications in areas such as tissue engineering.

Embedding Thiols into Choline Phosphate Polymer Zwitterions

“…[1][2][3][5][6][7] More recent synthetic advances have produced new types of polymer zwitterions (e.g., choline phosphates (CP), sulfothetins, and phosphonium sulfonates), many of which embed useful functionality directly within the zwitterionic moieties, including hydrocarbons, fluorocarbons, and reactive functional groups. [4,[8][9][10][11][12][13][14][15][16] These DOI: 10.1002/marc.202300690 novel zwitterionic structures impart unusual properties to the corresponding polymers, [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] including solubility in non-polar organic solvents, [4,12] selfassociation at fluid-fluid interfaces (i.e., affording sticky droplets), [13,17,18,21,23] and the ability to participate in highyielding, versatile chemical reactions such as azide-alkyne cycloaddition. [9,20,22] One impediment to more rapid synthetic progress in functional zwitterions, specific to phosphorylcholine (PC) and CP structures, is associated with complications in the essential phospho...…”

“…[4,[8][9][10][11][12][13][14][15][16] These DOI: 10.1002/marc.202300690 novel zwitterionic structures impart unusual properties to the corresponding polymers, [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] including solubility in non-polar organic solvents, [4,12] selfassociation at fluid-fluid interfaces (i.e., affording sticky droplets), [13,17,18,21,23] and the ability to participate in highyielding, versatile chemical reactions such as azide-alkyne cycloaddition. [9,20,22] One impediment to more rapid synthetic progress in functional zwitterions, specific to phosphorylcholine (PC) and CP structures, is associated with complications in the essential phospholane ring-opening step illustrated in Figure 1a. When nucleophilic attack favors exocyclic bimolecular substitution, the undesired ammonium phosphonate salt forms, whereas the desired endocyclic ringopening pathway produces the zwitterionic product.…”

Modeling the Maturation of the Vocal Fold Lamina Propria Using a Bioorthogonally Tunable Hydrogel Platform

“…Synthetic ECMs with dynamically tunable matrix properties are needed. Various methods have been reported in the literature to afford in situ stiffening, [ 11 ] some relying on the usage of reversible covalent crosslinking [ 12 ] while others employing photochemically triggered bond formation [ 11 ] or temperature‐induced phase transition. [ 13 ]…”

“…Synthetic ECMs with dynamically tunable matrix properties are needed. Various methods have been reported in the literature to afford in situ stiffening, [11] some relying on the usage of reversible covalent crosslinking [12] while others employing photochemically triggered bond formation [11] or temperature-induced phase transition. [13] We have recently reported a bioorthogonally crosslinked hydrogel platform whose matrix property can be dynamically tuned employing tetrazine (Tz) ligation with slow (norbornene, Nb) and fast (trans-cyclooctene, TCO) reacting dienophiles.…”

A Delayed Cross‐Linking Strategy for Evolvable Hydrogels

“…[19,20] Typically, SSHs enhance their mechanical performances through the conformation change of semiflexible filament, [21] finite extensibility of flexible linker, [22] reorientation of nanofiber, [23] construction of dynamically crosslinked networks, [24] and control over the hidden ("'cryptic") binding sites. [25][26][27] However, SSHs change irreversibly at both macroscopic and microscopic levels during strain-stiffening and lose their use value. In comparison, mechanoresponsive selfgrowing hydrogels (SGHs) are much closer to living materials, as they exhibit effective mechanochemical transduction, and thus strengthen themselves when interacting with the environment (repetitive loading and monomer supply).…”