Cotton Candy Machine Could Lead to the Creation of Artificial Organs

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Source: http://www.biosciencetechnology.com/news/2016/02/c...

Cotton Candy Machine Could Lead to the Creation of Artificial Organs

Wed, 02/10/2016 - 9:35am
Bevin Fletcher, Associate Editor
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Student in the Bellan Lab using a commercial cotton candy machine to spin hydrogel fibers. (Joe Howell / Vanderbilt)

An unlikely tool is behind a new technique that could someday lead to the creation of life-sized artificial livers, kidneys and other essential organs: a cotton candy machine.

Inspiration struck back when Leon Bellan, assistant professor of mechanical engineering at Vanderbilt University, was just a graduate student studying how nanoscale fibers formed using electrospinning, he tells Bioscience Technology. The technique uses a very high voltage to produce a fiber-forming jet that deposits nanofibers in a chaotic mat on a surface.

“When describing this mat, people often use the analogy of silly string, cheese whiz, or cotton candy,” Bellan explained.

He soon went to a seminar on the field of tissue engineering, where the speaker mentioned a major hurdle in the field was trouble building a vasculature, particularly capillaries. Capillaries deliver necessary oxygen and nutrients to cells embedded within thick tissue, and without this “internal plumbing” the cells usually die, Bellan explained.

Bellan began thinking about analogies for electrospinning, noticing that his nanofiber-formed nanochannels looked a bit like capillaries but were far too small, and wondered about approaches to make structures larger than the nanochannels.

“Cotton candy seemed like a promising sacrificial template, and the machine was rather inexpensive and easily obtained,” Bellan said. “Plus how many people get to say they have a cotton candy machine in the lab?”

So Bellan went to the store and scooped up a machine for about $40 dollars and brought it to his lab, where he was able to make channels that looked a lot like capillaries using spun sugar as a sacrificial template.

Three-dimensional slab of gelatin that contains a microvascular network. (Bellan Lab / Vanderbilt)

The new technique, described Feb. 4 in the Advanced Healthcare Materials journal uses a key material known as PNIPAM, Poly(N-isopropylacrylamide), which is a material that has the unique property of being insoluble in water above 32 degrees Celsius and dissolves in water below 32 degrees Celsius.

“Now we have figured out a powerful combination of materials that allows this technique to be applied to biomaterials to keep actual living cells alive,” Bellan said.

The technique produces a three-dimensional artificial capillary system that keeps cells alive and functional for more than a week, which is much longer than other methods.

Important implications for creation of artificial organs

Bellan’s “cotton candy” technique helps overcome two challenges in the quest to make artificial organs a reality. One is that the work is done in 3D. He explained that most cell culture work is done in two dimensions, with cells growing on flat surfaces inside of flasks. However, that does not mimic the 3D environment of the body. Those who have moved to 3D cell culture techniques “are limited to growing cells in very thin 3D structures because oxygen and nutrients cannot diffuse quickly enough through a thick 3D structure.” Artificial blood vessels are necessary so oxygen and nutrients can flow to the cells and keep them viable.

“Because most of the tissues in the body are thicker than a human hair, this is a critical hurdle that must be overcome before we are able to produce full-scale tissues and organs.”

In the paper the team demonstrates two new concepts that may help bring the field closer to full-scale artificial organs with functioning cells.

Bellan said: “First, that we can use the “cotton candy” technique to form capillary-like structures that are able to maintain the viability of cells within very thick artificial tissue (without these structures, the cells end up dying). Second, we demonstrate the use of a thermoresponsive material to form these structures in a ‘cell friendly’ fashion.”

He said that this is the first time PNIPAM has been used to pattern fluidic structures, and noted that because the threshold is between body temperature (37 degrees Celsius) and room temperature (25 degrees Celsius) that the process is exceptionally gentle. Previous work has demonstrated PNIPAM’s compatibility with cells.

“Using the combination of these two concepts, we now have a technique to form complex capillary-like structures in 3D throughout large volumes of artificial organs.”

This fiber-based approach enables the formation of capillary-sized vessels, which are much smaller than what can be produced by more traditional techniques using 3D printers. Bellan explained that while microfabrication techniques could create features that are as small as his method – they could only be made in 2D.

“With the fiber-based approach, we can work in 3D, and at a unique and exciting scale.”

How it works

Bellan described how the capillaries are created using PNIPM, a polymer which has been used in an array of applications: “We spin a fibrous mesh of this material using a machine similar to a cotton candy machine. Larger sticks of material are attached to the fibrous mesh to form inlets to which tubing can be attached. We then mix gelatin, cell culture media, cells, and an enzyme called ‘transglutaminase,’ and pour this mixture over the PNIPAM structure. Everything is then placed in an incubator at 37 degrees Celsius. The enzyme causes bonds to form between the gelatin molecules, and so the gelatin slowly forms an irreversible gel (unlike a typical gelatin dessert mold, which will dissolve again if heated). Once the gel has set, everything is removed from the incubator and allowed to cool to room temperature, at which point the PNIPAM structures dissolve and leave a complex fluidic network behind. This network is within a gelatin gel containing appropriate cells, which are nourished by the vessel system made by the fibers.”

He said that the team hopes by using PNIPAM it will allow them to work with more fragile types of cells in the future.

One area that future work might explore is how to better control the cotton candy technique to optimize the organization of the fibers and resulting channel. As of now scientists do not have exact control over the location of every single channel, but rather the average density and size.

Up next, Bellan’s team will look to expand the types of cells used with the technique to form more complex, functional artificial tissues. “For example, we would like to introduce endothelial cells into the channel network to form a better mimic of a natural capillary.”

Check out this video on http://www.biosciencetechnology.com/news/2016/02/c... to learn more.