Scientists create a functional mini-liver through 3D printing

Scientists create a functional mini-liver through 3D printing

Scientists create a functional mini-liver using 3D printing. (Photo: Daniel Antonio / Agência FAPESP)

Based on human blood cells, Brazilian scientists have managed to obtain liver organoids – also called mini-livers – capable of exercising the typical functions of that organ, such as the production of vital proteins and the secretion and storage of substances. This innovation makes possible the laboratory production of liver tissue in just 90 days, and may in the future become an alternative to organ transplants.

 In this study, conducted at the Research Center on the Human Genome and Stem Cells (CEGH-CEL) – a Research, Innovation and Dissemination Center (CEPID) funded by the Foundation for Scientific Research Support of the State of São Paulo – FAPESP and based at the University of São Paulo (USP) – bioengineering techniques, such as cellular reprogramming and the production of pluripotent stem cells, were combined with 3D bioprinting. This strategy allowed the tissue made in the printer to maintain liver functions for a longer period than was recorded in previous works of other groups.

“There are still stages that must be reached until we can get a complete organ, but we are on a very promising path. In the near future, it is possible that, instead of waiting for an organ transplant, the person’s own cells can be used and reprogrammed to build a new liver in the laboratory. Another important advantage is that, because they are the patient’s own cells, the chances of rejection would be theoretically void, ”said Mayana Zatz, coordinator of CEGH-CEL and co-author of the article published in the journal Biofabrication. The innovation of this study lies in the way to include the cells in the biotint used to form the tissue in the 3D printer. “Instead of printing individualized cells, we developed a way to group them before printing. These ‘clumps’ of cells or spheroids constitute the tissue and maintain their functionality for much longer, ”said Ernesto Goulart, postdoctoral at the USP Institute of Biosciences and first author of the article. 

In this way, a common problem is avoided in most bioprinting techniques of human tissues: the gradual loss of contact between cells and, consequently, that of tissue functionality.

In this study, the formation of spheroids is specified from the differentiation process, when pluripotent cells are transformed into liver tissue cells (hepatocytes, vascular cells and mesenchymal cells). “The differentiation process begins when the cells are grouped. They are grown in agitation and spontaneously form clusters, ”said Goulart. 

According to the researchers, the entire process – from the extraction of the patient’s blood until the functional tissue is obtained – takes approximately 90 days, and can be divided into three stages: differentiation, printing and maturation.

From the outset, the researchers reprogram the blood cells so that they return to a stage of pluripotence characteristic of stem cells (induced pluripotent stem cells or iPS, the technique that rewarded the Nobel Prize in Medicine to Japanese scientist Shinya Yamanaka in 2012). Then they induce their differentiation in liver cells.

The spheroids are then mixed with the biotint, a kind of hydrogel, and printed. The resulting structures go through a period of maturation in cultivation that extends for 18 days.

“The deposition of the spheroids during printing occurs in three axes, something necessary for the material to acquire volume and for the tissue to have support. Subsequently, a crosslinking reaction is carried out so that the impression – which has the consistency of a gel – is enriched to the point that it can be manipulated or even sutured, ”said Goulart.

In most of the methods available for printing living tissues, immersion and cell dispersion are applied within a hydrogel to recapitulate the microenvironment and tissue functionality.

 However, it was found that when dispersing cell by cell, the trend indicates that there is a loss of cell contact and functionality. “It is a somewhat traumatic process for cells, which require some time to get used to the environment and acquire its functionality. At that stage, they are not yet a fabric, because they are scattered; but, as we could see, they already have the ability to detoxify the blood and also to produce and secrete albumin [a protein made exclusively by the liver], for example, ”said Goulart. In the study, the researchers developed.


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