Microwave‐Assisted Aqueous Synthesis of Gelatin‐Norbornene for Hydrogel Crosslinking and Bioprinting

Abstract Gelatin‐norbornene (GelNB) is a bioactive macromer increasingly used to create hydrogels via rapid and modular step‐growth thiol‐norbornene photopolymerization. GelNB hydrogels demonstrate high cytocompatibility for stem cell differentiation, disease modeling, drug delivery, and 3D biofabrication. However, current GelNB synthesis lacks stringent control over the degree of modification. Herein, rapid and reproducible GelNB synthesis is reported using a microwave reactor, where the reaction time is drastically reduced to minutes and the degree of norbornene conjugation is readily controlled between ≈60–90%. Microwave‐synthesized GelNB (i.e., mGelNB) preserves highly tunable step‐growth hydrogel crosslinking, with shear moduli (G′) tuned between 60 and 15 000 Pa. Moreover, microwave heating lowers the upper‐critical solution temperature (UCST), thereby increasing the water solubility of GelNB at room temperature. This greatly facilitates its use in digital light processing (DLP) three dimensional (3D) bioprinting of hydrogels without heating up the samples to above physiological temperature. Finally, mGelNB hydrogels are highly cytocompatible for in situ encapsulation of human umbilical endothelial cells (HUVEC). In comparison to conventionally synthesized GelNB (cGelNB), mGelNB hydrogels support higher vascular junction density and vessel length density. The new microwave heating technique not only simplifies the synthesis of GelNB but also enhances its utility as a photo‐clickable macromer for various biomedical applications.