Aqueous Synthesis of Poly(ethylene glycol)‐Amide‐Norbornene‐Carboxylate for Modular Hydrogel Crosslinking

Abstract Poly(ethylene glycol)‐norbornene (e.g., PEGNB) is a versatile macromer amenable to step‐growth thiol‐norbornene photopolymerization and inverse electron demand Diels–Alder (iEDDA) click reaction. The translational potentials of PEGNB‐based hydrogels have been realized in the areas of stem cell differentiation, in vitro disease modeling, implantable therapeutic devices, and controlled release of therapeutics. Even with these advances, prior methods for synthesizing PEGNB all required heavy use of organic solvents that pose significant environmental and personal health burdens. Here, an all‐aqueous synthesis of PEG‐amide‐norbornene‐carboxylate (PEGaNB_CA) is reported via reacting carbic anhydride (CA) with multi‐arm amino‐terminated PEG. Like previously reported ester‐bearing counterparts (i.e., PEGNB and PEGeNB_CA), PEGaNB_CA is readily crosslinked into modular hydrogels by either thiol‐norbornene photopolymerization or tetrazine‐norbornene iEDDA click reaction. Unlike its ester‐bearing counterparts, PEGaNB_CA crosslinked thiol‐norbornene hydrogels provided long‐term hydrolytic stability. However, through blending PEGaNB_CA with hydrolytically labile PEGeNB_CA, hydrogels can be engineered to undergo tunable hydrolytic degradation. The versatility of PEGaNB_CA is further demonstrated via high‐fidelity digital light processing printing and in situ encapsulation and maintenance of human induced pluripotent stem cells (hiPSCs).