Scientists have developed a 3D-printing method capable of producing highly uniform blocks of embryonic stem cells. These cells are capable of generating all cell types in the body and could be used as the ‘Lego bricks’ to build tissue constructs, larger structures of tissues, and potentially even micro-organs. They could also be used for stem cell regulation and expansion, regenerative medicine, drug screening studies, and potentially even for the construction of micro-organs.
“It was really exciting to see that we could grow embryoid body in such a controlled manner,” explains Wei Sun, a lead author on the paper. “The grown embryoid body is uniform and homogenous, and serves as much better starting point for further tissue growth.”
The study, carried out by researchers at Tsinghua University in Beijing and Drexel University in Philidelphia, represents the first time ESCs have been 3D printed into a 3D cell-laden hydrogel construct, producing uniform, pluripotent (able to generate almost any cell in the body), high-throughput and size-controllable embryoid bodies, with a 90% survival rate. They used extrusion-based 3D printing to produce a grid-like 3D structure to grow embryoid body that demonstrated cell viability and rapid self-renewal for seven days while maintaining high pluripotentcy.
“Two other common methods of printing these cells are either two-dimensional (in a petri dish) or via the suspension method (where a ‘stalagmite’ of cells is built up by material being dropped via gravity),” continues Wei Sun. “However, these don’t show the same cell uniformity and homogenous proliferation. “I think that we’ve produced a 3D microenvironment which is much more like that found in vivo for growing embryoid body, which explains the higher levels of cell proliferation.” The researchers hope that this technique can be developed to produce embryoid body at a high throughput, providing the basic building blocks for other researchers to perform experiments on tissue regeneration and/or for drug screening studies.
“Our next step is to find out more about how we can vary the size of the embryoid body by changing the printing and structural parameters, and how varying the embryoid body size leads to manufacture of different cell types,” adds Rui Yao, another author on the paper. “In the longer term, we’d like to produce controlled heterogeneous embryonic bodies,” says Wei Sun. “This would promote different cell types developing next to each other, which would lead the way for growing micro-organs from scratch within the lab.”
In the paper, the researchers explain that because of their capacity for self-renewal and differentiation into nearly all cell types, ESCs hold great promise as an in vitro model system for studies in early embryonic development, and are also an important source for applications in diagnostics, therapeutics, and drug screening. However, previous methods for printing these cells, either via 2D creation in a petri-dish, or via a ‘suspension’ method, resulted in non-uniform ESCs. They found that reconstructing a 3D cell micro-environment, much like that found in vivo, would be critical to directing stem cell fate and generating uniform cell sources with high levels of proliferation for tissue engineering and other biomedical applications
Luckily, recent advances in bioprinting technologies allowed them to control the precise deposition of ESCs in a reproducible manner. They used a temperature-sensitive extrusion-based 3D bioprinter, previously developed in their lab for bioprinting hepatocytes and other complex cells, to produce a grid-like 3D structure that could grow embryoid bodies. These bodies could successfully self-renew for seven days while maintaining high pluripotency. Furthermore, about 90% of the bioprinted ESCs remained alive. The researchers believe that their 3D bioprinting technique could be used to develop embryoid bodies at a high throughput. They could then be used to by researchers to perform experiments on tissue regeneration and for drug screening studies.
“Our next step is to find out more about how we can vary the size of the embryoid body by changing the printing and structural parameters, and how varying the embryoid body size leads to ‘manufacture’ of different cell types” said Rui Yao, another author on the paper. “In the longer term, we’d like to produce controlled heterogeneous embryonic bodies” said Wei Sun. “This would promote different cell types developing next to each other – which would lead the way for growing micro-organs from scratch within the lab.”
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