Well-defined synthetic copolymers with pendent aldehydes form biocompatible strain-stiffening hydrogels and enable competitive ligand displacement

Dynamic hydrogels are attractive platforms for tissue engineering and regenerative medicine, but there are limited polymer platforms amenable to the formation of these dynamic materials. Most architectures reported are based either on telechelic synthetic polymers or side-chain modified natural polymers; synthetic versions of side-chain modified polymers are noticeably absent. Dynamic hydrogels are key tools for their ability to mimic key extracellular (ECM) mechanical properties like strain stiffening and stress relaxation, while enabling enhanced processing characteristics like injectability, 3D printing, and self-healing. Currently, the limited chemical design space is hindering progress. To facilitate access to new classes of dynamic hydrogels, we report the straightforward synthesis of a water-soluble copolymer with a tunable fraction of pendent aldehyde groups (12–64%) using controlled radical polymerization, and their formation into hydrogel biomaterials with dynamic crosslinks. We found the polymer synthesis to be well-controlled with the determined reactivity ratios consistent with blocky gradient microarchitecture. Subsequently, we observed fast gelation kinetics with imine-type crosslinking. We were able to vary hydrogel stiffness from ≈ 2–20 kPa and tune the onset of strain-stiffening towards a biologically relevant regime (critical stress ≈ 10 Pa). Moreover, we used fluorescence resonance energy transfer (FRET) to demonstrate ligand displacement along the copolymer backbone via competitive binding and highlighted the cytocompatibility of our system using human dermal fibroblasts. The combination of highly tunable composition, stiffness, and strain-stiffening, in conjunction with temporal control over ligand exchange/presentation, positions these cytocompatible copolymers as a powerful synthetic platform for the rational design of next generation synthetic biomaterials.