New bioprinting technology enables complex micro-tissues

A typical 3D printer deposits molten plastic in layers and gradually builds a solid shape as those layers cure. Bioprinters work in a similar way, except that they use living cells that grow into rudimentary tissues, similar to what happens in an organism.

Bioprinting is currently used to create model tissues for research and has potential applications in regenerative medicine. Existing bioprinting techniques rely on pressure cells embedded in hydrogels, resulting in low cell density constructs well below what is required for functional tissues to grow. Maneuvering different types of cells into position to replicate the complex composition of an organ, especially at organ-like cell densities, is still beyond their means.

The researchers' new technology makes it possible to pick up cell clumps and place them in a self-healing hydrogel that holds them in complex spatial arrangements as they grow together. Once the tissue model is formed, the hydrogel is washed away. Photo credit: University of Pennsylvania

Now researchers from the University of Pennsylvania's School of Engineering and Applied Science have demonstrated a new bioprinting technique that enables the bioprinting of spatially complex tissues with high cell density.

Using a self-healing hydrogel capable of picking up dense clusters of cells and placing them in a three-dimensional suspension, the researchers constructed a model of heart tissue that contained a mixture of cells that mimicked the results of a heart attack.

The study was led by Jason Burdick, Robert D. Bent Professor in the Department of Bioengineering, and Andrew C. Daly, a postdoctoral fellow in his laboratory. Matthew Davidson, a postdoc at the Burdick Laboratory, also contributed to the study, which was published in the journal Communication with nature.

Even without a bioprinter, cell groups can clump together to form larger aggregates, so-called spheroids. For Burdick and colleagues, these spheroids represented a potential building block for a better approach to bioprinting.

"Spheroids are often useful for studying biological issues based on the cells' 3-D microenvironments or for building new tissues," says Burdick. "However, we want to produce even higher levels of organization by" printing "different types of spheroids in specific arrangements and fusing them into structurally complex micro-tissues."

There are several current techniques for fabricating such complex structures from spheroids, but they either damage the spheroids during processing or involve a number of tedious and tedious steps.

Here, the research team's progress depended on the use of a self-healing hydrogel, which acts as a scaffold for spheroids when they are picked up with a micropipette and brought into the desired 3D arrangement within the hydrogel.

"Because the hydrogel reforms itself when new spheroids are pulled into position, sophisticated structures can be built in three dimensions as if their components were suspended in the air," says Daly. "Also, the hydrogel can be washed away after the spheroids have melted into the micro-tissue."

Burdick's group is particularly interested in modeling heart tissue that has become scarred as a result of a heart attack. After a seizure, stiffer scar tissue prevents healthy heart cells from beating, which affects the overall function of the organ. With this new bioprinting technique, spheroids with the properties of healthy and scarred heart tissue can be precisely arranged in realistic 3D geometries.

The researchers tested their technique by building rings of heart tissue that mimicked the heart chambers with different arrangements of healthy and scarred regions that might occur after a heart attack. These regions are a primary target for drugs that may have the potential to regenerate healthy cells. Developing tissue models that capture such features would therefore lead to better testing.

Because their bioprinting technique allows for spatial control, the researchers were able to create tissue models with scarred regions in different parts of the ring. Photo credit: University of Pennsylvania

"The heterogeneity of tissues is important in assessing biological issues or drug screening because it would better mimic the actual response of the tissue," says Burdick. “In our experiments, we used microRNA therapeutics to regenerate cardiomyocytes, important cells that are lost after a heart attack, in the scarred regions. Testing functional results such as electrical conductivity across the scar would not be possible with previous approaches to bioprinting. "

Future research on the new bioprinting system will include options for automating, scaling and accelerating the printing process.

Source: University of Pennsylvania

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