A team of scientists led by Masaya Hagiwara of RIKEN in Japan has developed an ingenious device that uses multilayer hydrogels in a cubic structure to allow researchers to construct complex three-dimensional organisms without using complex techniques. The team also recently demonstrated the ability to use the device to build an organism that faithfully reproduces asymmetric gene expression during the organism's actual development.
The device has the potential to revolutionize the way we test drugs, give us insight into how tissues develop, and lead to better techniques for the growth of artificial organs.
Scientists have long struggled to create organoids — organ-like tissue grown in a lab — to replicate actual biological development. Making organoids that function similarly to real tissues is critical to developing drugs, as it is necessary to understand how drugs move through various tissues. Organ tissue also helps us gain insight into the developmental process itself and is a stepping stone to developing complete organs that can help patients.
One of the cubes used in the experiment. Source: Institute of Physical Chemistry
However, it turns out that it is not easy to create lifelike organ tissue. In nature, tissue development takes place through an elaborate dance that includes chemical gradients and physical scaffolds that guide cells to specific three-dimensional patterns. In contrast, lab-grown organoids are typically formed by letting cells grow under uniform conditions – creating simple spheres of similar cells – or by using three-dimensional printing or microfluidics, both of which require sophisticated equipment and technical skills.
A schematic diagram showing the cube system and purpose. Source: Institute of Physical Chemistry
But now, in a paper published in Advanced Materials Technologies, the pioneering research team at RIC announces that they have developed a new and innovative technique that spatially controls the environment around a cube-based population of cells using just a pipette.
This method is to close multiple layers of hydrogels (substances mainly composed of water) with different physical and chemical properties within a cube culture vessel. In this study, different hydrogels were inserted into the holder using a pipette and held in place according to the surface tension. Cells can either be inserted into a single hydrogel in a cube or moved into different layers in the form of particles, making it possible to create a range of tissue types.
Controls the position of an organism in a cube system. Source: Institute of Physical Chemistry
In a second paper, published in Communications Biology, the team also demonstrated the ability to reproduce so-called body axis patterning. Essentially, vertebrates develop patterns of cell differentiation in the head/back/abdomen during development. Although this is important for creating organisms that faithfully reproduce the situation in real organisms, it is difficult to achieve in the laboratory.
In this work, the team reproduced this patterning using a cube-based system, using a mold cap to precisely seed a set of induced pluripotent stem cells (iPSCs) in the cube and then expose the cells to a gradient of two different growth factors. They even "recruited" a lab assistant and a junior high school student to successfully complete the work, suggesting that cell seeding does not require a high level of expertise. The team also demonstrated that the resulting tissue can be sliced and imaged and still maintain information in the direction of the gradient.
Cell seeding control in the cube system. Source: Institute of Physical Chemistry
"We are very excited about these achievements, as the new system will allow researchers to quickly and unobstructedly recreate organoids that are closer to the way organs of actual organisms develop," Hagiwara said. We hope that researchers can use our methods to create a variety of new organ tissues and contribute to the study of different organ systems. Ultimately, we hope it will also help us understand how we can build truly artificial organs to help patients. "
Differentiation, sectioning, and analysis of organisms. Source: Institute of Physical Chemistry