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Clear Brain – The Core Technology is ‘Tissue Elasticizing’

Clearing of biological tissues is of great interest in biomedical research, because the technology can turn the tissues transparent, allowing for high-resolution observation of cell structures and molecules inside organs. The issue involved in tissue clearing is that the lipids in the tissue, which scatter light, should be removed to view tissues clearly. However, once lipids are removed, the tissues lose their original shape and become mushy. Large tissue samples, such as human tissues, may collapse because they cannot withstand their own weight, being incapable of enduring routine experimental procedures, such as dipping into an aqueous solution or placing on a microscope slide. The tissues may harden through chemical treatment, but a hard sample is useless because substances of large molecular size, such as dyes, may not permeate into the sample.

Professor Taeyun Ku’s group has addressed the difficult choice between robustness and molecular permeability of tissue samples by transforming the tissue into an elastic material. An elasticized tissue sample was found to show good molecular permeability and was soft, but it was not damaged by most mechanical stresses. Prof. Ku’s group demonstrated that the elasticized human tissue was not damaged but immediately recovered its original shape even after it was stretched to double the original length or compressed to one tenth of the original thickness. The research group successfully cleared a huge tissue sample of human brain size by using elasticized tissue.

Elasticizing in biology - Elastic gel that can be hybridized with tissue samples

Changing the physical properties of a biological tissue was not an easy task. Prof. Ku’s group decided to make such a drastic change by using an external material. First, the group explored an elastic gel that is compatible with biological tissues. The existing elastic gels required a too-complicated synthesis
method or had a molecular weight that was too large to permeate into tissues. Therefore, the group invented a simple elastic gel that can be formed by self-growing in a tissue. The mechanism is similar to that of a skein of entangled thread that may be moved freely but is not easily unraveled. Surprisingly, the tissue sample that was naturally hybridized with the internally growing elastic gel showed the same properties as the elastic gel.

Such an elastic material was unfamiliar in the field of biology, but the applicability was better than expected. Although the tissue sample was converted into a material having totally different physical properties, various proteins or nucleic acids remained in their original positions. Thanks to the excellent
molecular permeability of the elastic material, the biomolecules could be stained by large molecular dyes, such as antibody probes, to be observed with microscopy. The easy clearing of the sample allowed for three-dimensional observation of the deep regions.

“Problem-solving with a convergent idea” ··· Exploring hidden principles of life

The most outstanding and fresh attempt in the present study was the ultrafast staining technology. Staining is always a prerequisite of tissue sample observation. The time required for staining tissues exponentially increases with increases of tissue thickness. This was the most difficult problem in the field of tissue clearing, which is aimed at the observation of thick tissues.

Prof. Ku said, “I thought that if a tissue sample can be stretched thinly, a dye can permeate rapidly, just as we unfold a wet cloth to dry it quickly. The same was possible with the elasticized tissue. We stretched an elastic tissue in all directions to make it thin, and the staining speed became 100 times faster. Of course, when the tension is released, the tissue recovers its original shape, as if nothing happened, and thus can be observed microscopically.” He added, “These good results were obtained by applying various new ideas to the study.” The present study is considered an ideal convergent study in which a biological breakthrough was found by borrowing principles from other fields such as material sciences and chemical engineering.

The research group mentioned that the significance of the results is that the technology allows for detailed threedimensional observation of large human tissues. The tissue clearing technology is expected to make great contributions to the investigation of biological structures and functions of the human body and to the development of diagnostic methods. The results of the present study were published in the June 2020 issue of Nature Methods, and the researchers applied for an US patent.

Prof. Taeyun Ku
2020 KI Annual Report

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