Chemically Defined Hydrogels: the Key Biomimetic Matrix for Standardizing and Translating Organoid Technologies
ZHOU Yao#, GAO Yisheng#, FENG Ziling#, ZHANG Kunyu*, BIAN Liming*
Organoids, three-dimensional multicellular mini-tissues derived from stem cells with self-organizing capacity and cellular heterogeneity, have emerged as powerful platforms for developmental biology, disease modeling, drug screening, and regenerative medicine. The successful formation and long-term maintenance of organoids are critically dependent on the surrounding microenvironment, in which three-dimensional scaffold materials play essential roles in supporting structural integrity, regulating cell behavior, and mediating signal transduction. While natural matrices such as Matrigel remain widely used, their undefined composition and significant batch-tobatch variability severely limit the reproducibility, controllability, and clinical translation of organoid-based technologies. In recent years, chemically defined synthetic hydrogels have gained attention as promising alternatives due to their tunable properties, biocompatibility, and functional versatility. This review summarizes representative types of chemically defined hydrogels applied in organoid culture, including synthetic and semi-synthetic systems based on polyethylene glycol, gelatin, and hyaluronic acid. This article discusses key design strategies for modulating mechanical properties, mimicking cell-matrix interactions, and delivering bioactive cues. Furthermore, it highlights the impact of these hydrogels on organoid formation efficiency and phenotype maintenance across various organoid types, including intestinal, brain, and liver models. Finally, it outlines future perspectives on high-throughput fabrication, co-culture of multiple cell types, and the development of stimuli-responsive materials, aiming to provide theoretical and material foundations for the standardization and clinical translation of organoid technologies.
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