Colorectal cancer organoids: Construction, applications, and hydrogel microsphere-based engineering strategies
Colorectal cancer (CRC) is one of the most prevalent malignancies globally, characterized by high incidence and mortality rates. Its marked heterogeneity and complex tumor microenvironment (TME) pose considerable challenges to traditional preclinical models. Patient-derived organoids (PDOs) have emerged as pivotal tools for elucidating disease mechanisms, enabling personalized drug screening, and advancing precision medicine, as they faithfully preserve the histological structure, molecular features, and genetic heterogeneity of primary tumors in vitro. However, conventional matrix gel-based culture systems suffer from inherent limitations, including ill-defined composition, significant batch-to-batch variation, and a lack of precise control over mechanical properties, which impede their ability to faithfully recapitulate dynamic intercellular crosstalk and spatiotemporal TME heterogeneity. Recent advances in biomaterials and tissue engineering have provided new opportunities to innovate organoid technologies. This review systematically summarizes the establishment strategies, major applications, and core challenges of CRC organoids, highlighting the potential of modular and programmable biomaterials, particularly hydrogel microspheres, for developing novel construction systems. We propose that hydrogel microspheres, with well-defined chemical composition, tunable mechanical properties, and function as basic building blocks, can be integrated with modular or controllable assembly strategies to construct next-generation CRC organoid models with enhanced biomimetic properties, greater structural complexity, and improved reproducibility. In summary, this review outlines core challenges and future directions, emphasizing that deep integration of engineered culture systems with organoid technology is a critical approach to advancing CRC research toward improved biomimetic recapitulation and greater clinical translational relevance.
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