Functional Liver Organoids Created by 3D Bioprinting Liver Spheroids

Functional Liver Organoids Created by 3D Bioprinting Liver Spheroids

A team of scientists in Brazil have used 3D bioprinting to create functional liver organoids in the lab. The mini-livers can perform all of the essential functions of human livers, including the synthesis of essential proteins and vitamin storage, amongst others.

To create the liver organoids the researchers first had to make a bioink that was capable of surviving the 3D bioprinting process. A blood sample was taken from a patient and cells were converted to induced pluripotent stem cells (IPSCs) using a technique first developed by the Japanese scientist Shinya Yamanaka. In the lab, the researchers induced differentiation of the IPSCs into liver cells – a combination of hepatocytes, vascular, and mesenchymal cells.

Other research teams have used 3D bioprinting to create liver organoids by printing individualized cells. The Brazilian researchers used a different technique and printed clusters of cells that they formed during the differentiation process.

These cell clusters, which the researchers call spheroids, were combined with a hydrogel and were 3D bioprinted. Cells were printed along three different axes, with the tissue crosslinked to improve rigidity. The resultant tissue could be manipulated and even sutured. It took around 18 days for the structures to mature, and the whole process from taking blood samples, converting cells to IPSCs and differentiating them, and maturing the printed cells took 90 days.

The researchers report that their liver organoids survived for longer than liver organoids created by other teams of researchers, which they attribute to their new printing technique. Current techniques for 3D bioprinting tissues involves immersion and cell dispersion in hydrogel, but the process disrupts cell contact and there tends to be loss of cell functionality as a result. The researchers found no loss of function after the printing process and maturation. The mini-livers were capable of secreting albumin and had the ability to clear toxins from the blood and store vitamins.

“Our spheroids worked much better than those obtained from single-cell dispersion. As expected, during maturation, the markers of hepatic function were not reduced,” said first author of the study, Ernesto Goulart.

The liver organoids cannot really be classed as a tissue as the cells are still quite dispersed, but the organoids did have the main functions of liver cells. There are further stages to be completed before it is possible to 3D bioprint a fully functional, complete liver but the researchers say their technique is scalable and with further funding they are confident that they will be able to create transplantable liver tissue and even complete organs. Further, since the cells would be harvested from the patient requiring the transplant, the issue of rejection would not arise.

The study – 3D bioprinting of liver spheroids derived from human induced pluripotent stem cells sustain liver function and viability in vitro -has been published in in the journal Biofabrication. DOI: 10.1088/1758-5090/ab4a30

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