Simple but revolutionary modular organoid (with video)

April 07, 2023

(Nanowerk News) A team led by Masaya Hagiwara of the RIKEN National Science Institute in Japan has developed an ingenious device, using hydrogel layers in a cube-like structure, that allows researchers to create complex 3D organoids without resorting to complex techniques. The group also recently demonstrated the ability to use devices to build organoids that faithfully reproduce the asymmetric genetic expressions that characterize true development of organisms. This device has the potential to revolutionize the way we test drugs, and could also provide insight into how tissue develops and lead to better techniques for growing artificial organs.

Scientists have long struggled to create organoids—lab-grown organ-like tissues—to replicate true biological developments. Creating organoids that function similarly to real tissue is important for developing drugs, as it is necessary to understand how drugs move through various tissues. Organoids also help us gain insight into the developmental process itself, and are a springboard for growing whole organs that can help patients.

However, creating life-like organoids proved difficult. In nature, tissues evolve through an intricate dance involving chemical gradients and physical scaffolding that guide cells into specific 3D patterns. In contrast, laboratory-grown organoids are usually grown either by allowing cells to grow under homogeneous conditions — making simple balls of like cells — or by using 3D printing or microfluidic technology, both of which require sophisticated equipment and technical skills.

But now, in a preliminary paper published at Advanced Material Technology (“Localization of Multiple Hydrogels with the MultiCUBE Platform Spatially Guides 3D Tissue Morphogenesis In Vitro”), the group from the RIKEN Cluster for Pioneering Research announced the development of a new and innovative technique that allows them to spatially control the environment around clusters of cells based on a cube, using nothing more complicated than a pipette.


This method involves confined layers of hydrogels – substances consisting mostly of water – with different physical and chemical properties in cuboidal culture vessels. In the study, various hydrogels were introduced into the scaffolds using a pipette, and held together based on surface tension. Cells can be packed into cubes either inside individual hydrogels or as pellets that can migrate to different layers, making it possible to fabricate different types of tissues.

In the second paper, published in Communication Biology (“Gradients to subdivide the CUBE workflow for the generation and imaging of organoids with local differentiation”), the group also demonstrated the ability to recreate what are known as axial body patterns. Basically, as vertebrates develop, there is a head/back and back/abdominal pattern of cell differentiation. While it is important for the manufacture of organoids that are exactly as they occur in real organisms, this is extremely difficult to achieve in the laboratory.

In this work, using a cube-based system, the group was able to recreate this pattern, using a die lid to precisely seed a group of induced pluripotent stem cells (iPSCs) in the cube, and then allowing the cells to be exposed to a gradient of two different growth factors. different. They even went so far as to “recruit” a laboratory assistant and a junior high school student to successfully do the job, demonstrating that cell seeding does not require a high level of expertise. The team also demonstrated that the resulting network could be cropped for imaging and still retain information about the orientation of the gradient.

According to Hagiwara, “We are very excited about this achievement, as the new system will allow researchers to quickly, and without difficult technical hurdles, recreate organoids that more closely resemble the way organs develop in real organisms. We hope that researchers will use our methods to create new organoids and contribute to research on different organ systems. Finally, we hope it will also contribute to understanding how we can build actual artificial organs that can help patients.”

Hagiwara joined RIKEN in 2019 as a RIKEN Hakubi Fellow, a program that encourages talented young researchers to set up their own laboratories. His particular focus is on lung development, but he emphasizes that the technology could be used to manufacture other types of organoids as well.

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