Abstract
Epithelial, stem‐cell derived organoids are ideal building blocks for tissue engineering, however, scalable and shape‐controlled bio‐assembly of epithelial organoids into larger and anatomical structures is yet to be achieved. Here, a robust organoid engineering approach, Multi‐Organoid Patterning and Fusion (MOrPF), is presented to assemble individual airway organoids of different sizes into upscaled, scaffold‐free airway tubes with predefined shapes. Multi‐Organoid Aggregates (MOAs) undergo accelerated fusion in a matrix‐depleted, free‐floating environment, possess a continuous lumen, and maintain prescribed shapes without an exogenous scaffold interface. MOAs in the floating culture exhibit a well‐defined three‐stage process of inter‐organoid surface integration, luminal material clearance, and lumina connection. The observed shape stability of patterned MOAs is confirmed by theoretical modelling based on organoid morphology and the physical forces involved in organoid fusion. Immunofluorescent characterization shows that fused MOA tubes possess an unstratified epithelium consisting mainly of tracheal basal stem cells. By generating large, shape‐controllable organ tubes, MOrPF enables upscaled organoid engineering towards integrated organoid devices and structurally complex organ tubes.
Highlights
Engineered fusion of multicellular materials, such as spheroids and organoids, represents a biomimetic cell assembly process fundamental to the fields of biofabrication, tissue engineering and in vitro tissue modelling,[1,2,3] Organization and fusion of cell aggregates to achieve prescribed shapes depends on the selection of initial multicellular building blocks
Starting with individual airway organoids derived from adult mouse tracheal epithelial cells, we established a robust organoid fusion platform, for the upscaled engineering of size-relevant epithelial organ tubes (Figure 1a)
Day-12 organoids were dissociated from Matrigel drops and transferred in a 3Ddesigned polydimethylsiloxane (PDMS) mold to form shapepatterned multiorganoid aggregates (MOAs)
Summary
Engineered fusion of multicellular materials, such as spheroids and organoids, represents a biomimetic cell assembly process fundamental to the fields of biofabrication, tissue engineering and in vitro tissue modelling,[1,2,3] Organization and fusion of cell aggregates to achieve prescribed shapes (and functions) depends on the selection of initial multicellular building blocks. Coalescence of solid-core spheroids can readily occur via so-called “tissue liquidity”,[4] in small aggregates of epithelial cells,[1] fibroblasts,[5] mesenchymal stem cells,[6] and in hybrid spheroids consisting multiple cell types.[7,8] Guided-assembly through micro-fabricated molds or 3D-printing can further define the three-dimensional (3D) architecture of engineered tissues.[9] due to the diffusion limit, fused tissue constructs from solid-core spheroids are hardly upscaled to viable thick tissues.
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