Geometric interface-guided self-formation of hollow multicellular spheroids in engineered composite structured hyaluronic acid (HA) hydrogels: Experiment and modeling.

Authors

Xiaolu Zhu, Fengliang He, Qiang Yin, Fang Teng

Published in

International journal of biological macromolecules. Pages 154360. Sep 06, 2026. Epub Sep 06, 2026.

Abstract

The extracellular matrix (ECM) is a noncellular structure component that provides mechanical support and mediates chemical and physical guidance for cellular behaviors. Hydrogels are typical ECM-mimicking materials, which are intricately associated with cellular self-organization. This study pioneers a composite hyaluronic acid (HA) hydrogel system with micropatterned interfaces that directs mesenchymal cells to self-organize into 3D hollow spheroids-unachievable in conventional homogeneous hydrogels. By designing rectangular groove interfaces between stiffness-differentiated hydrogel domains (cell-laden soft gel within grooves of cell-free stiff gel), we establish a spatiotemporally regulated niche for multicellular morphogenesis. The experimental findings reveal that 3D hollow multicellular spheroids with large internal cavities (100-250 μm in diameter) preferentially form adjacent to the engineered groove interfaces. Computational simulations reveal that the self-formation of hollow spheroids is mediated by the designed geometry of the hydrogel interface separating the sub-domains with differing stiffness. Hydrogel sub-domains with distinct mechanical properties and tailored sizes exhibit differential biomolecular diffusion and cell migration kinetics, thereby establishing a complex spatiotemporal regulation of the reaction and diffusion processes of biomolecules and cells. Experimental data align with our activator-inhibitor-substrate (AIS) model, demonstrating that interfacial geometry controls reaction-diffusion dynamics to induce cavity formation. This platform enables the on-demand fabrication of 3D tissue analogues with luminal structures, laying a foundation for advancing organoid engineering and pathological modeling.

PMID:
42702314
Bibliographic data and abstract were imported from PubMed on 07 Sep 2026.

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