Applying dissociative chemistry to obtain gradient hydrogels

Abstract

Gradients in the extracellular matrix (ECM) are critical regulators of tissue development, physiological function, and disease progression. In pancreatic ductal adenocarcinoma (PDAC), progressive changes in ECM mechanics correlate with disease stage. Studying PDAC in vitro requires models that mimic the mechanical anisotropy of the native tumor microenvironment. Here, we present an innovative approach to fabricate hydrogels with tunable stiffness gradients using tetrazine–isonitrile click-to-release chemistry. Tetrazine moieties serve as degradable crosslinkers, which are selectively cleaved by the isonitrile cleaving solution. Diffusion of the cleaving solution through the hydrogels results in spatially controlled reductions in crosslink density. This dissociative bioorthogonal strategy enables the generation of mechanical gradients in hydrogels that mimic key features of the PDAC tumor ECM.