Photoinduced Dithiolane Crosslinking for Multiresponsive Dynamic Hydrogels

Abstract

While many hydrogels are elastic networks crosslinked by covalent bonds, viscoelastic hydrogels with adaptable crosslinks are increasingly being developed to better recapitulate time and position‐dependent processes found in many tissues. In this work, 1,2‐dithiolanes are presented as dynamic covalent photocrosslinkers of hydrogels, resulting in disulfide bonds throughout the hydrogel that respond to multiple stimuli. Using lipoic acid as a model dithiolane, disulfide crosslinks are formed under physiological conditions, enabling cell encapsulation via an initiator‐free light‐induced dithiolane ring‐opening photopolymerization. The resulting hydrogels allow for multiple photoinduced dynamic responses including stress relaxation, stiffening, softening, and network functionalization using a single chemistry, which can be supplemented by permanent reaction with alkenes to further control network properties and connectivity using irreversible thioether crosslinks. Moreover, complementary photochemical approaches are used to achieve rapid and complete sample degradation via radical scission and post‐gelation network stiffening when irradiated in the presence of reactive gel precursor. The results herein demonstrate the versatility of this material chemistry to study and direct 2D and 3D cell‐material interactions. This work highlights dithiolane‐based hydrogel photocrosslinking as a robust method for generating adaptable hydrogels with a range of biologically relevant mechanical and chemical properties that are varied on demand.

Modular multiwell viscoelastic hydrogel platform for two- and three-dimensional cell culture applications

“…Hyaluronic acid (HA) hydrogels have seen widespread use for cell culture due to their biological relevance and their ability to be highly modified with various functional groups, including a range of crosslinking handle s and bioactive moieties 16 . For example, various modes of HA crosslinking have enabled orthogonal control over mechanical properties 14,17–19 as well as in situ stiffening 20,21 . Further, the independent control of bioactive cues has enabled investigation into the distinct roles of integrin engagement and mechanics on cell behavior 6,22 .…”

Emerging Trends in the Chemistry of End-to-End Depolymerization

“…130,159 Notably, controlled solid-state or solution self-assembly of fully depolymerizable block copolymers could possibly accelerate the fabrication of nanoporous separation membranes and simplify their end-of-life management. 160 In addition, the properties of cross-linked networks or thermosets consisting of depolymerizable chains or cross-links could be easily tuned on demand as advanced biomaterials 161 or dynamic materials. 136,144 Third, programmed end-to-end depolymerization for sequence-defined oligomers has proven to be advantageous to decode information that is encoded in their primary sequences.…”

“…On the basis of emerging depolymerizable backbones and click reactions, complex functional materials can be attainable. , Notably, controlled solid-state or solution self-assembly of fully depolymerizable block copolymers could possibly accelerate the fabrication of nanoporous separation membranes and simplify their end-of-life management . In addition, the properties of cross-linked networks or thermosets consisting of depolymerizable chains or cross-links could be easily tuned on demand as advanced biomaterials or dynamic materials. , …”

Implications of Cellular Mechanical Memory in Bioengineering

“…To further confirm the occurrence of mechanical memory in 3D, more experiments are required in which mechanical stress or substrate stiffness are modulated after cell or organoid encapsulation. Tunable biomaterials allow in situ softening after encapsulation, , and many more novel biomaterials with dynamic control of mechanical properties have recently been developed. , In addition, there are also various methods to either directly apply mechanical stresses (atomic force microscopy, cell stretching) or to alter cell contractility that can be adapted to 3D systems . These toolboxes for control of cell and substrate mechanical properties will be useful in determining if cells in 3D culture are similarly sensitiveto mechanical memory as they are in 2D.…”