APPLYING DISSOCIATIVE CHEMISTRY TO OBTAIN GRADIENT HYDROGELS

Abstract

Gradients in the extracellular matrix (ECM) play an important role in tissue development and disease progression. In Pancreatic ductal adenocarcinoma (PDAC), the ECM’s mechanical properties correlate with the staging of the disease. Studying PDAC in vitro requires models that mimic its ECM's mechanical anisotropy. We present an innovative approach to create hydrogels with tunable stiffness gradients using dissociative bioorthogonal chemistry. Our method uses cross-linkers that can be selectively cleaved by a diffusing chemical agent as the external trigger. Controlling the spatial distribution of this cleavage agent allows the formation of continuous stiffness gradients in hydrogels. PEG-based hydrogels were selected as versatile, biocompatible model systems. In-depth characterization relates the hydrogels’ mechanical properties (obtained via compression testing) to their molecular structure (studied via NMR spectroscopy or derived from gel characteristics) and the reaction kinetics of the studied dissociative chemistry. This contribution showcases a novel application of dissociative bioorthogonal chemistry. The resulting materials are expected to better emulate the complex tumor microenvironment and may provide a powerful platform for fundamental cancer research by enabling precise studies of how mechanical cues influence tumor development, cellular behavior, and disease progression.