Simple yet revolutionary modular organoids created using hydrogels

A team led by Masaya Hagiwara of the RIKEN National Institute of Science in Japan has developed an innovative device that, using layers of hydrogels in a cube-like structure, allows researchers to build complex 3D organoids without using elaborate techniques. The group also recently demonstrated the ability to use the device to construct organelles that faithfully reproduce the asymmetric gene expression that characterizes the actual development of organisms. The device has the potential to revolutionize the way we test drugs, and it could also provide insights into how tissues develop and lead to better techniques for growing artificial organs.

Scientists have long struggled to create organoids — organ-like tissues grown in the laboratory — to replicate actual biological evolution. The formation of organoids that function similarly to real tissues is important for drug development, as it is essential to understand how drugs are transported through different tissues. Organoids also help us gain insight into the process of evolution itself, and are a stepping stone on the path to growing full organs that can help patients.

However, creating life-like organelles has proven difficult. In nature, tissues develop through a complex dance involving chemical gradients and physical scaffolding that guide cells into specific three-dimensional patterns. By contrast, lab-grown organoids develop either by allowing cells to grow in homogeneous conditions — creating simple spheres of like cells — or by using 3D printing or microfluidic techniques, which require sophisticated equipment and technical skills.

But now, in a preliminary research paper published in advanced materials technologiesThe RIKEN Cluster for Pioneering Research has announced the development of an innovative new technology that allows them to spatially control the environment around clusters of cells based on cubes, without using anything more elaborate than a pipette.

The method involves confining layers of hydrogels — materials consisting mostly of water — with different physical and chemical properties inside a cube-shaped culture vessel. In the study, different hydrogels were inserted into the scaffold using a pipette, and held in place based on surface tension. Cells can be introduced into the cubes either within individual hydrogels or as granules that can migrate into the different layers, making it possible to create a range of tissue types.

Credit: RIKEN

In a second paper, published in Communication biologyThe group has also shown the ability to recreate what is known as a body axis pattern. Basically, when vertebrates develop, there is a head/back and back/gastric pattern of cell differentiation. Although important for the formation of organisms that faithfully recreate what happens in living organisms, it has been very difficult to achieve in the laboratory.

In this work, using the cube-based system, the group was able to recreate this pattern, by using a mold lid to precisely seed a batch of induced pluripotent stem cells (iPSCs) inside a cube, and then allow the cells to be exposed. Two different growth factors are included. They even went so far as to “hire” a lab assistant and a high school student to successfully perform the work, showing that cell transplantation would not require a high level of expertise. The team also showed that the resulting tissue can be sliced ​​for imaging while retaining information about the direction of the gradient.

According to Hagiwara, “We are very excited about these achievements, because the new system will allow researchers to quickly, and without difficult technical hurdles, recreate organisms that closely resemble the way organs develop in actual organisms. We hope that a group of researchers will use our method to create Many new organisms and contribute to research on different organ systems. Ultimately, we hope that this will also contribute to understanding how to build actual artificial organs that can help patients.”