Dynamic granular hydrogels to assess pancreatic cancer cell fate

Abstract

Granular hydrogels are an emerging biomaterial platform increasingly used in biomedical applications, including therapeutic delivery and tissue regeneration. Assembled from micron-scale hydrogel particles through physical assembly or chemical cross-linking, granular hydrogels possess micro- and macroscopic pores that facilitate molecular transport and cell migration. However, current granular hydrogels are typically fabricated with defined stiffness, porosity, and compositions that do not recapitulate the dynamic nature of native tissues, including the tumor microenvironment. To address this challenge, we have developed dynamic granular hydrogels formed by gelatin-norbornene-carbohydrazide (GelNB-CH) microgels. GelNB-CH microgels were first prepared from a microfluidic droplet generator coupled with the rapid thiol-norbornene photo-click gelation. The collected microgels were annealed via inverse electron-demand Diels–Alder (iEDDA) click reaction to form granular hydrogels, which were dynamically stiffened via hydrazone bonding. Notably, adjusting the concentration of the stiffening reagent (i.e., oxidized dextran, oDex) enabled dynamic stiffening of the granular hydrogels without affecting the void fraction. Pancreatic cancer-associated fibroblasts (CAFs) seeded in the granular hydrogels spread rapidly throughout the scaffold and induced cancer cell migration. This work enhances the design of granular hydrogels, offering a highly adaptable biomaterial platform for in vitro cancer modeling.