Dynamic hydrogel mechanics in organoid engineering: From matrix design to translational paradigms

Abstract

The extracellular matrix (ECM) serves as a dynamic biomechanical regulator of cellular behavior, yet conventional 3D culture systems, such as Matrigel, lack the spatiotemporal control required to dissect mechanotransductive mechanisms in organoids. This review systematically explores the synthesis of mechanically tunable hydrogels—spanning stiffness and viscoelasticity—and their transformative applications in organoid research. By integrating natural, synthetic, and hybrid polymers, these hydrogels enable precise recapitulation of tissue-specific ECM mechanics, overcoming limitations of batch variability and static properties. We categorize hydrogel design strategies, emphasizing crosslinking paradigms (physical vs. chemical) and dynamic bond engineering, which permit real-time modulation of mechanical cues. Applications across developmental organoids (intestinal, hepatic, renal, neural) reveal stiffness-dependent morphogenesis, where optimal mechanical niches enhance maturation via YAP/Notch signaling. Tumor organoid models (breast, pancreatic, colorectal) further demonstrate how matrix stiffening drives malignancy through mechanosensitive pathways, such as epithelial-mesenchymal transition and drug resistance. Emerging viscoelastic hydrogels, tailored via alginate molecular weight or decellularized ECM, replicate dynamic tissue mechanics, advancing cartilage and cerebellar organoid models. Critically, this review highlights innovations in programmable hydrogels that bridge 2D reductionist models and in vivo complexity, offering unprecedented insights into ECM-driven organogenesis and disease progression. Future directions include integrating bioprinting and organ-on-a-chip technologies to achieve vascularized, patient-specific organoids. By synthesizing design principles and mechanobiological mechanisms, this work establishes a roadmap for next-generation biomaterials, accelerating translational applications in drug screening, regenerative medicine, and personalized oncology.