综述与专论:生物材料力学性质调控类器官形成:从微环境感知到生理病理重塑
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1)华中科技大学同济医学院附属武汉中心医院分子诊断湖北省重点实验室,武汉 430014;2)华中科技大学同济医学院药学院,武汉 430030

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武汉英才优秀青年人才项目和国家自然科学基金(82372093)资助。


Review:Organoid Formation Regulating Through Mechanical Properties of Biomaterials: From Microenvironment Sensing to Physiological and Pathological Remodeling
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1)Hubei Key Laboratory of Molecular Diagnosis, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430014, China;2)School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China

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This work was supported by grants from Wuhan Outstanding Young Talents Project and The National Natural Science Foundation of China (82372093).

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    摘要:

    类器官技术已成为生物医学研究中极具潜力的体外模型,但其传统培养依赖动物源基质胶,存在批次变异、成分不明确及机械性能不可控等局限。近年研究证实,基质刚度、黏弹性、拓扑结构及时间力学动态,在干细胞自组织、谱系分化和类器官成熟中发挥与生化信号同等关键的调控作用。本文系统综述细胞外基质力学性质调控类器官形成的研究进展,从力学信号转导机制出发,围绕核心节点YAP/TAZ和核心受体整合素,与生化信号交互作用协同决定细胞命运,阐述刚度、黏弹性及拓扑结构对初始聚集、扩增、分化及功能成熟各阶段的影响,并总结天然及合成水凝胶的工程化策略。天然材料改性可实现力学约束与生化支持的空间分离,合成高分子材料可独立调控刚度和配体密度,动态力学微环境可模拟渐进硬化。未来需解析力学-生化协同规则,发展时空可编程水凝胶,建立组织特异性力学参数库,推进标准化力学筛选平台。本文旨在为理解力学-生物学耦合机制及设计高保真培养平台提供理论参考。

    Abstract:

    Organoid technology has become a highly promising in vitro model in biomedical research, but its traditional culture relies on animal-derived basement membrane matrices, which suffer from batch-to-batch variability, undefined biochemical composition, and poorly controllable mechanical properties. Recent studies have confirmed that matrix stiffness, viscoelasticity, topography, and temporal mechanical dynamics play regulatory roles equally as critical as biochemical signals in stem cell self-organization, lineage specification, and functional maturation of organoids. This review systematically summarizes the progress in understanding how extracellular matrix (ECM) mechanical properties regulate organoid formation. Focusing on the YAP/TAZ factors and the integrin receptors, which engage in crosstalk with biochemical signals to synergistically determine cell fate. We then elaborate how specific mechanical parameters, such as stiffness, viscoelasticity, and topography, influence each distinct stage of organoid development, from initial aggregation and compaction, through proliferative expansion, to lineage-committed differentiation and terminal functional maturation. Appropriate stiffness facilitates efficient aggregation and symmetry breaking, while excessive rigidity impairs proliferation and accelerates cellular senescence. In hepatic organoid expansion where only stiffness matching liver tissue (~6.2 kPa) supported robust growth. Viscoelastic stress relaxation promotes integrin clustering, enhances focal adhesion maturation, and stimulates endogenous ECM deposition, thereby supporting self-organized crypt-villus architecture and basement membrane assembly. Notably, dynamic softening of hydrogels enables optimal crypt budding, whereas rapid stress relaxation permits nephron segment coiling and drives vascular organoid maturation toward arteriole differentiation, highlighting stress relaxation as a key temporal parameter. Topographical cues provide contact guidance that directs polarized outgrowth, lumen formation, and neuronal orientation, all of which are essential for achieving organotypic architecture. The embedded 3D printing of complex neural networks enables precise control over branching geometries, facilitating studies of morphogenesis under spatial constraints. The engineered mechanical microenvironments have been successfully applied to recapitulate disease phenotypes: stiff matrices induce fibrosis and epithelial-mesenchymal transition in liver organoids, promote chemoresistance in cholangiocarcinoma. Furthermore, we summarize engineering strategies for both natural and synthetic hydrogels aimed at creating mechanically defined culture platforms. Natural biomaterial modifications achieve spatial separation of mechanical constraints from biochemical support, enabling self-limited compressive stimulation within a defined time window. Synthetic polymers allow independent tuning of stiffness, ligand density, and viscoelasticity through adjustable crosslinking and dynamic non-covalent interactions, thus providing orthogonal control over multiple mechanical parameters. Dynamic microenvironments that mimic progressive stiffening as observed in development, tumor evolution, or fibrosis can be constructed using composites that undergo spontaneous structural transitions. In the future, critical challenges include deciphering the synergistic rules governing mechanical-biochemical interplay, developing spatiotemporally programmable hydrogels that enable on-demand modulation of local mechanics, establishing comprehensive databases of tissue-specific mechanical parameter windows, and advancing standardized high-throughput screening platforms to accelerate preclinical validation and clinical translation. Moreover, integrating real-time mechanical sensors and non-invasive imaging techniques would allow dynamic monitoring of intracellular forces and tissue-level stress during culture. Ultimately, this review aims to provide a theoretical foundation for deepening our understanding of mechano-biological coupling mechanisms and for rationally designing high-fidelity, physiologically relevant organoid culture platforms that fully harness the regulatory power of mechanical cues.

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汤睿智,刘熙秋.综述与专论:生物材料力学性质调控类器官形成:从微环境感知到生理病理重塑[J].生物化学与生物物理进展,2026,53(9):2253-2268 TANG Rui-Zhi, LIU Xi-Qiu.Review:Organoid Formation Regulating Through Mechanical Properties of Biomaterials: From Microenvironment Sensing to Physiological and Pathological Remodeling[J]. Progress in Biochemistry and Biophysics,2026,53(9):2253-2268

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  • 收稿日期:2026-04-02
  • 最后修改日期:2026-08-22
  • 录用日期:2026-07-15
  • 在线发布日期: 2026-07-15
  • 出版日期: 2026-09-28
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