An all-UC San Diego research team reports using stem cells to rapidly create ‘bioprinted” miniature sections of human liver tissue, using cells arrayed in a lobule pattern that more closely resembles natural liver tissue than previous attempts.
This bioprinted liver tissue is derived from induced pluripotent stem cells, which are arrayed in a small hexagonal shape like that found in natural liver tissue. Besides liver cells, they include fat-derived stem cells and umbilical vein endothelial cells. These three cell types combine to form units that could potentially be placed in larger groups to build liver tissue that could serve as “disease in a dish” models.
Farther off is the Holy Grail of all such bioprinting efforts — creation of a functional human liver that could be transplanted into patients.
The study was published Monday in the Proceedings of the National Academy of Sciences. Its co-senior authors are UCSD’s Shaochen Chen, a nanoengineering professor at the Jacobs School of Engineering, and Shu Chien, director of the Institute of Engineering in Medicine. First author was Xuanyi Ma, in the Department of Bioengineering.
Each bioprinted tissue sample measures 3 x 3 millimeters, with a thickness of 0.2 millimeter. The hexagonal units it contains measure 0.9 millimeters. The unit’ interiors contain liver cells, separated by spaces between the hexagons. The spaces contain the endothelial and fat-derived mesenchymal supporting cells.
Sheets of cells in 2D arrays or thin 3D slices such as the new bioprinted tissue samples can get nutrients by diffusion. But for supporting thicker samples, some sort of blood vessel network is needed.
By including endothelial umbilical vein cells, the UCSD team provides the means to create such a network of vessels. This work is being attempted now, said Chen said. And even in the existing tissue samples, the endothelial cells support the functioning of the liver cells.
In another innovation, the team used a rapid bioprinting process developed at UCSD to lay down each tissue sample in “several seconds.”
Chen developed the rapid bioprinting process, which uses UV light to form the hexagonal structures out of hydrogels in which the cells are embedded, a variant of photolithography. The UV light is applied in a low amount, which is enough to congeal the hydrogel into the desired shape.
The combination of bioprinting and IPS cells to form human liver tissue apparently hasn’t been performed elsewhere, Chen said. In 2013, Japanese researchers reported growing miniature “liver buds,” which are not bioprinted but self-organize.
Bioprinted liver tissue is already being produced by researchers and biotech companies, such as San Diego’s Organovo. That company offers testing services using its exVive3D liver tissue, which remains functional for more than 40 days. Last month, Organovo launched a subsidiary company, Saṃsāra Sciences, that sells human liver cells for research use.
For exVive3D, Organovo gets its liver cells from whole human livers and other sources, but not including IPS cells. The UCSD team can make the liver cells on the spot from IPS cells, which provide greater versatility, assuming the technology is validated by other researchers.
Because IPS cells can be derived from any person just by getting a sample of skin cells, the tissue can be genetically matched to any patient. This enables its use for personalized drug screening to meet the needs of individual patients.
The UCSD researchers have filed for patents on the liver tissue model. The work was funded by the National Institutes of Health.