UCSF Uses 3D Cell Patterning Technology to Fold Living Tissue Into Complex Shapes

The concept behind the ancient, well-known paper folding art known as origami can also be applied to an organism’s development process – as an egg turns into an embryo, and later a mature, fully-formed being, the body wrinkles, stretches, and folds, just like a piece of origami art. We’ve seen 3D printing and origami combined before in scientific research projects to create self-folding objects, and a team of bioengineers from UC San Francisco (UCSF) recently demonstrated that many of the folded, complex shapes that make up internal tissue structures and the bodies of mammals are able to be re-created with simple instructions.

The research team discovered that mesenchymal cells actually help fold some tissue during the development process by pulling on a network of extracellular matrix (ECM) fibers, which cells secrete naturally to surround themselves with structural support.

Zev Gartner, PhD

“Development is starting to become a canvas for engineering, and by breaking the complexity of development down into simpler engineering principles, scientists are beginning to better understand, and ultimately control, the fundamental biology,” said Zev Gartner, PhD, an associate professor of pharmaceutical chemistry in the UCSF School of Pharmacy and co-director of the UCSF Center for Cellular Construction. “In this case, the intrinsic ability of mechanically active cells to promote changes in tissue shape is a fantastic chassis for building complex and functional synthetic tissues.”

The work, recently published in a paper titled “Engineered Tissue Folding by Mechanical Compaction of the Mesenchyme” in the Developmental Cell journal, could result in applications such as soft biological robots and lab-grown organs in the future.

According to the paper’s summary, “We use embryonic tissue explants, finite element modeling, and 3D cell-patterning techniques to show that mechanical compaction of the extracellular matrix during mesenchymal condensation is sufficient to drive tissue folding along programmed trajectories.”

In addition to senior author Gartner, other co-authors of the paper include:

• Alex J. Hughes
• Hikaru Miyazaki
• Maxwell C. Coyle
• Jesse Zhang
• Matthew T. Laurie
• Daniel Chu
• Zuzana Vavrušová
• Richard A. Schneider
• Ophir D. Klein

When the specialized mesenchymal cells in different parts of a human tissue pull in tandem on the network of ECM fibers, they create forces inside the tissue that bend and fold into different shapes, some of which you may recognize – villi, which resemble fingers and line the human gut, and the buds which form animal hair and feathers. The researchers were able to re-create this folding in laboratory tissue samples by applying the same natural development processes: the researchers laid down certain patterns of mesenchymal cells from humans and mice, which caused the living tissue to fold itself into various shapes, like ripples, coils, bowls, and even cubes, which are not normally seen in nature.

While many laboratories working with tissue engineering create 3D shapes through the use of micro-molding and 3D printing technologies, many of these shapes don’t include, as UCSF puts it, “key structural features of tissues” which grow in normal developmental processes. The UCSF bioengineers got around this by using DNA-programmed assembly of cells (DPAC), a 3D cell-patterning technology that can fabricate the initial tissue template that folds itself up.

Gartner said, “Our sense is that you can’t print a final living structure directly with a bioprinter. You need to print a template that will evolve over time through a kind of artificial development, or what you might call 4-D bioprinting.”

The team wants to determine if they can combine this developmental tissue-folding program with other tissue patterning programs. One of their goals is to improve the ability to create tissue organioids, which are often used in precision medicine these days.

First author Alex Hughes, PhD, a postdoctoral scholar in Gartner’s lab, said, “We’re beginning to see that it’s possible to break down natural developmental processes into engineering principles that we can then repurpose to build and understand tissues. It’s a totally new angle in tissue engineering.”

Gartner hopes that in the future, the team’s principles could be used to develop better techniques for designing soft robots from living materials, as well as growing transplantable human organs in the lab.

“It was astonishing to me about how well this idea worked and how simply the cells behave. This idea showed us that when we reveal robust developmental design principles, what we can do with them from an engineering perspective is only limited by our imagination,” Gartner said.

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[Source/Images: UCSF]