Well-Defined Synthetic\nCopolymers with Pendant Aldehydes\nForm Biocompatible Strain-Stiffening Hydrogels and Enable Competitive\nLigand Displacement

Dynamic hydrogels are attractive platforms for tissue\nengineering\nand regenerative medicine due to their ability to mimic key extracellular\nmatrix (ECM) mechanical properties like strain-stiffening and stress\nrelaxation while enabling enhanced processing characteristics like\ninjectability, 3D printing, and self-healing. Systems based on imine-type\ndynamic covalent chemistry (DCvC) have become increasingly popular.\nHowever, most reported polymers comprising aldehyde groups are based\non either end-group-modified synthetic or side-chain-modified natural\npolymers; synthetic versions of side-chain-modified polymers are noticeably\nabsent. To facilitate access to new classes of dynamic hydrogels,\nwe report the straightforward synthesis of a water-soluble copolymer\nwith a tunable fraction of pendant aldehyde groups (12–64%)\nusing controlled radical polymerization and their formation into hydrogel\nbiomaterials with dynamic cross-links. We found the polymer synthesis\nto be well-controlled with the determined reactivity ratios consistent\nwith a blocky gradient microarchitecture. Subsequently, we observed\nfast gelation kinetics with imine-type cross-linking. We were able\nto vary hydrogel stiffness from ≈2 to 20 kPa, tune the onset\nof strain-stiffening toward a biologically relevant regime (σ<sub>c</sub> ≈ 10 Pa), and demonstrate cytocompatibility using\nhuman dermal fibroblasts. Moreover, to begin to mimic the dynamic\nbiochemical nature of the native ECM, we highlight the potential for\ntemporal modulation of ligands in our system to demonstrate ligand\ndisplacement along the copolymer backbone via competitive binding.\nThe combination of highly tunable composition, stiffness, and strain-stiffening,\nin conjunction with spatiotemporal control of functionality, positions\nthese cytocompatible copolymers as a powerful platform for the rational\ndesign of next-generation synthetic biomaterials.