Origami Techniques Deliver Advances in Tissue Engineering

Northeastern University's Micropower and Nanoengineering Laboratory's new technique in origami folding to build 3D liver tissue constructs from flat sheets could mimic human organs and reduce time, expense, and testing needed to commercialize new pharmaceuticals.

by Poornima Apte
March 26, 2018

A new technique that uses origami folding to build 3D liver tissue constructs from flat sheets could mimic human organs and reduce the time, expense, and testing needed to commercialize new pharmaceuticals.

"If you have a tissue model that actually responds the way a human would, then you could get so much more accurate information much earlier in the process than is possible now," says Carol Livermore, an associate professor of mechanical and industrial engineering at Northeastern University's Micropower and Nanoengineering Laboratory. "It could cut down on time, expense, and potentially connect patients with the right medications earlier."

Pharmaceutical companies typically filter bioactive molecules by testing them on cell cultures. Only the most promising candidates move into animal and eventually human testing.

Cell cultures, however, are not very good predictors of a drug's effects on a human being. This is because they do not mimic the complex interactions among multiple types of cells and the structures they form in 3D tissues. 3D constructs could act like canaries in a coal mine, showing damage if a drug is potentially dangerous.

This is why many researchers like Livermore focus on liver tissue. The liver is an important predictor of the toxicity of medicines. Some drugs can show liver toxicity but, even if they don't, the liver can metabolize them into other compounds that might prove toxic. Medicines that make it through the liver and do their work have the most promise.

The problem with liver tissue is that its structure and behavior are among the hardest to reproduce using tissue engineering methods. "Its three-dimensionality and fine structure are absolutely critical to replicate to have cells function the right way," Livermore says.

It is this 3D aspect of liver tissue that Livermore is modeling with origami techniques, along with her collaborators Sangeeta Bhatia at the Massachusetts Institute of Technology, origami artist and physicist Robert Lang, and origami mathematician Roger Alperin and mechanical engineering professor Martin Culpepper, both at MIT.

Existing microtechnology can produce 2D structures on substrates following the established principles of PDMS microfluidics fabrication, where fluidic channels are molded into a layer of polydimethylsiloxane (PDMS). But such 2D structures do a poor job of modeling 3D tissue behavior.

The solution, Livermore said, is to create a 2D set of structures and pull them together into a 3D model using folding techniques.

"You can do fine-scale features in 2D easily," she says. "Since you want three-dimensionality, you leverage existing technology to make a sheet that's bigger than what you need and that has a whole bunch of 2D features. Then, when you fold it up so that the features line up properly, you have a 3D structure that has these 2D features, such as flow pathways, integrated into it."

Models that mimic how the liver functions need to replicate the liver's spatial features.

"There are a lot of functions that need to be carried out in the tissue. There are places where blood needs to flow, but there are also regions where the nutrients from the blood need to be able to diffuse into the nearby hepatocytes," Livermore says, referring to the cells that make up most of the liver's mass.

Standard PDMS microfluidics make places for fluid flow but don’t provide flow and diffusion, which is needed to replicate liver functionality. To enable those functions, Livermore and her team pattern channels into the tape and fold it together with nanoporous membranes. They then populate the surface with liver cells to create the tissue. 

Livermore's lab decided on this origami approach after successfully developing the ability to organize cells by size into whatever arrangement they wanted on a flat surface.

"We came to origami by asking ourselves, 'If we could get this accurate level of organization on a two-dimensional surface, then how can we convert that into 3D?'" she says.

Traditionally, if you wanted to make a 3D device, you would have to create, align, and stack up multiple layers of flow channels. The benefit of folding is that it is faster and easier to produce a 2D surface once and fold it into shape than to create repetitive layers, Livermore says.

The National Science Foundation and the Air Force Office of Scientific Research (AFOSR) have funded the research. Livermore and her team have also launched ApreX Biotech, a startup that hopes to bring the most compelling applications of the technology, such as its use in drug testing, to market.

Livermore and her team are now working to balance manufacturability with tissue function, and making sure the cells wind up where needed consistently in the folded structures.

"You can create the folded structure and then put the cells inside, which gives you somewhat less control than placing the cells first and then folding it up, but the first method is arguably more resistant to contamination," she says.

The origami approach to creating 3D structures has far-reaching implications.

"It is fair to say that you could potentially extend this kind of origami-based technology to make other engineered organ models, and even couple organ models together to mimic more of what happens in your body," she says.

Explore more tissue engineering stories from AABME.org.