Next-Generation Hydrogels for Biliary Organoid Engineering

The biliary tree is a fundamental structural and functional component of the liver, lined with cholangiocytes which control bile flow and regulate bile homeostasis. In addition to their physiological roles, cholangiocytes are involved in pathological processes known as cholangiopathies. These biliary disorders significantly impair liver function, and their effects are often irreversible, making liver transplantation the only curative option. This substantial clinical burden highlights the need for innovative bioengineered strategies to study disease mechanisms and to restore or replace biliary tissue. In this framework, biliary organoids offer a robust platform to model liver diseases in vitro with physiological accuracy. Compared with traditional 2D or explant-based systems, organoids provide higher physiological relevance, patient specificity, and scalability, although challenges remain in standardization and clinical translation. Organoids are traditionally cultured within basement membrane extract (BME) matrices, which are commercially available under various names. While BME-based matrices support organoid growth and function, their undefined composition, variability, and animal origin limit reproducibility and clinical translation. These drawbacks have driven the development of alternative matrices based on engineered hydrogels. Hydrogels, whether of natural or synthetic origin, provide chemically defined and tunable environments that allow independent modulation of their biochemical and biophysical properties. Acting at the interface between materials science and biology, they enable the creation of microenvironments with precisely controlled cues. In this review, we summarize advances in biliary organoid bioengineering and discuss how hydrogel-based systems are shaping next-generation platforms for organoid growth, differentiation, and disease modeling toward more translationally relevant biliary models.