Engineered hydrogel microspheres for spheroids and organoids construction

Spheroids and organoids are cellular aggregates formed by multicellular culture under 3D matrix microenvironment in vitro , , capable of recapitulating partial structures, functions and genetic characteristics of tissues, which hold broad application prospects in regenerative medicine and disease therapy. One of the most important challenges in tailoring spheroids and organoids formation is the construction of biomimetic matrix microenvironment. Hydrogel microspheres, as an ideal candidate to alternate Matrigel, not only maintain the good biocompatibility of traditional bulk hydrogels but also exhibit inherent modular characteristics and injectability, have been widely explored for the construction of spheroids and organoids in recent years. Herein, we review the state-of-the-art in engineering preparation of hydrogel microspheres and elucidates the involved functional structures and technologies, intensively discusses the cell-matrix interactions and formation principles in which hydrogel microspheres mimic the extracellular microenvironment to construct spheroids and organoids, and finally outline the current challenges and future perspectives of hydrogel microspheres efforts in the emerging fields of organoids model construction. This review is expected to provide theoretical reference and practical guidance for the construction of spheroids and organoids using hydrogel microspheres, and lay a solid foundation for the clinical application of spheroids and organoids.