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Studying the human brain using 3D printing technology

Printed brain models could help fight neurodegenerative diseases

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Each month the Elsevier Atlas Award recognizes research that could significantly impact people's lives around the world.

February 2016 winner (free access)

3D printing of layered brain-like structures using peptide modified gellan gum substrates
Rodrigo Lozano, Leo Stevens, Brianna C. Thompson, Kerry J. Gilmore, Robert Gorkin III, Elise M. Stewart, Marc in het Panhuis, Mario Romero-Ortega, Gordon G. Wallace
Biomaterials, Volume 67, October 2015, Pages 264–273

Read the story about the award-winning research

Our brains are amazing: they control our movements, thoughts and memories, regulate our body temperature and influence our emotions. But they’re also the source of neurological disorders, cognitive disabilities and psychological problems. Understanding the brain is helping scientists build a clearer picture of neurodegenerative diseases like Alzheimer’s disease, but that picture has been in two dimensions – until now.

Researchers at the University of Wollongong in Australia and the University of Texas at Dallas in the US have figured out how to make more accurate models of the brain – using 3D printing. Their Elsevier Atlas award-winning article was published recently in Biomaterials.

At two percent of our body weight, and made up of 100 billion nerve cells, the brain is a hugely complex organ. Scientists can study the brain using animal models, but in recent years much work has gone into seeking alternatives, with the support of organizations like the National Centre for the Replacement, Refinement & Reduction of Animals in Research (NC3Rs).

One such alternative is creating models of brains in the lab: growing brain cells in a structural material that lets scientists observe what happens in the tissue. Until now, it has only been possible to do this in two dimensions, producing sheets of cells.

Professor Gordon Wallace and his colleagues have come up with a way of creating layered 3D structures that mimic the brain more closely, using 3D printing.

“The advent of 3D printing in recent years and the ability to create structures containing materials, and even living cells, gives us that ability to start to probe some very fundamental questions,” said Prof. Wallace. “It lets us build structures that have more real-world applications, for example you can create a 3D structure that can facilitate the reconnection of nerves.”

The team used gellan gum to create the structures. Gellan gum is a substance made by the bacterium Sphingomonas elodea, which is often used as a gelling agent in microbiology labs. They created a bio-ink using the gellan gum, which they combined with brain cells. They found that the gellan gum helped the brain cells grow well and function as a network – much like in a real brain.

Having a 3D model will help give scientists a much more accurate image of what’s really going on in our brains, and Prof. Wallace believes this will help propel research into diseases like Alzheimer’s and Parkinson’s disease.

“I think the ability to study biological systems in three dimensions reveals new knowledge every day,” he said. “The brain is enormously complex and so are neurodegenerative diseases. Looking at what’s going on in 3D – in a similar structure to the real human brain – will give us a much better idea of the biology behind these diseases, and help researchers working on ways to treat them.”

The new model has potentially huge benefits, and the collaboration that went into the research has made it even more useful. Prof. Wallace concluded:

“It’s really important to build collaborative, interdisciplinary teams to address challenges like this. This paper wouldn’t have been possible without the input of clinicians, biologists, materials scientists and chemists. Bringing those sorts of teams together is critical to address these clinical challenges.”

Commentary from Prof. Kam W. Leong, Editor-in-Chief of Biomaterials

Inaccessibility to the human brain renders molecular studies challenging, if not impossible. A brain-like structure constructed of human cells would be invaluable for applications ranging from pathway analysis to disease modeling and drug discovery. Although cerebral organoids can be formed by a bottom-up process of cellular self-assembly, a top-down fabrication technique such as 3D bioprinting offers advantages of spatial control of cellular distribution, robustness and scale-up possibility. Neuronal cells are delicate. This work innovates with the use of a peptide-functionalized gellan gum hydrogel and a printing technique that can maintain the viability and functions of the printed cortical neurons from mice. This excellent proof-of-concept study suggests the possibility of fabricating a human brain-like structure in the future using bioprinting.

A conversation with Gordon Wallace

We talked to author Professor Gordon Wallace to find out why it’s so important to study the brain in three dimensions, and how a new 3D printing technique could help tackle neurodegenerative diseases.

Listen to the interview
In this podcast Professor Gordon Wallace talks about a new 3D printing technique that could help tackle neurodegenerative diseases.

Why is it challenging to model the brain in vitro?
There’s lots of complexity in the brain – lots of different layers and types of neurons. So the idea to try to recreate that structure is challenging. To date we haven’t had the fabrication tools to enable us to have a go at doing that.

What led you to this area of research?
We’ve had an interest in developing new materials that could help with communicating with neurons, right back to our early work with Professor Graham Clark, the inventor of the cochlear implant. And then building on that to see how we could build three-dimensional structures that might be able to recreate some of the neuronal situations in terms of treating clinical diseases or understanding those diseases. It started from the ability just to stimulate neurons that led us into this area, and stimulate them with new materials.

Why did you use gellan gum for printing?
We’ve investigated quite a number of materials to see their compatibility with neurons. Certain polysaccharides have the right chemical composition but also when they’re formed into a material structure they have the right mechanical properties to facilitate the development of neurons and gellan gum is one of those particular materials, but there are a range of naturally occurring polysaccharides that do that and we are constantly expanding the materials inventory to develop these 3D structures for developing neuronal communication systems.

How does your method work?
We’ve moved from developing new materials that are known to be highly effective in communicating with neurons in two dimensions into what is really the challenge for all biological systems, and that is how do you emulate what is happening in three dimensions. Now the advent of 3D printing in recent years and the ability to create structures containing materials and even containing living cells gives us that ability to start to probe some very fundamental questions about how neuronal connections might occur, what sort of environmental circumstances influences the occurrence of those connections, but also that build structures that perhaps have more real applications, for example for nerve regeneration that you can create a 3D structure that can facilitate the reconnection of nerves.

Did anything surprise you during this study?
We get surprised every day. We have started to print structures where we can locate particular cells in a certain special arrangement and surround them with particular growth factors and introduce electrical stimulation into the structure would have been – we didn’t really think five years ago we could do that. But the advent of 3D bioprinting has allowed us to do it. I think the ability to study biological systems in three dimensions reveals new knowledge every day.

What needs to be done to make this widely used? Are there any limitations?
This is the first step towards creating the “brain on a bench”. We need to understand how we can get better resolution in the 3D printing so we can start to place the neurons where we want them in the spatial arrangement that’s much more appropriate, and also to place other bioactive molecules where we want them. There are still challenges in terms of the whole resolution of the printing techniques that are available to us at the moment. But there’s lots of advances going on in parallel here. We and others are developing new printing technologies – as we start to understand the actual consequences of being able to develop new printers on fundamental and applied biological environment, there’s a great drive to do that.

You say your approach will help people studying neurodegenerative diseases, among other things. How will this work?
There are two fronts: one is in understanding how those diseases develop through the use of stem cells from patients, and the other is being able – at least at a preliminary level – to test therapies on the bench as well.

Is there anything you’d like to add?
It’s really important to build collaborative, interdisciplinary teams to address challenges like this. This paper wouldn’t have been possible without the input of clinicians, biologists, materials scientists and chemists. Bringing those sorts of teams together is critical to address these clinical challenges. That’s a non-technical that’s sometimes overlooked. It’s a challenging issue, but one that needs to be addressed by all of us.


About Biomaterials

Biomaterials is an international journal covering the science and clinical applications of biomaterials. Biomaterials are substances that have been engineered as components of living systems, and can be used in therapeutics and diagnostics. The journal publishes articles about all aspects of biomaterials, from synthesizing polymers to designing drugs and analysing the way the body responds to biomaterials.


Further reading

A new approach to printing soft tissue containing stem cells, which could be used in reconstructive and plastic surgery.

An analysis of the complete process of inkjet printing, which could help improve the structure of 3D printed materials.

Bioprinting a 3D gel that neural cells can be added to, without the need for toxic solvents.

A review of inkjet, microextrusion, and laser bioprinting techniques to create tumors for use in cancer research.

How 3D bioprinting of virtual human organs and tissues is becoming a new information technology.

A new methodology to recreate and investigate the remarkable nanostructures in biomineralized organisms.

An overview of the use of bioprinting in engineering heart valves.

Using a gelatin hydrogel to grow hematopoietic stem cells (HSCs) outside of the body.

A review of the surgical applications of 3D printing, including converting anatomical images into solid objects.

Improving the functionality of 3D-printed scaffolds for bone regeneration with cells to mimic a bony environment.

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