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Cotton Candy Machines May Hold The Answer For Building Artificial Organs

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It’s been said that innovation often happens when you least expect it.

And sometimes, a discovery is staring right at you—but you just have to take a deeper look to appreciate it.

In this case, the machine that makes one of the most popular carnival treats--cotton candy--may hold the key to building and sustaining microfiber networks, the complex network of capillaries that are integral for supplying oxygen and removing waste from vital organs such as the kidney and liver.

Leon Bellan, an assistant professor of mechanical engineering at Vanderbilt, set out to solve the problem of building an artificial framework of blood vessels to support vital organs and in the process figured out that a cotton candy machine was ideal because the threads of the sugary confection provide an ideal thickness that simulates a human capillary.

Building a Viable Blood Supply: The Holy Grail

But constructing such a network of capillaries to nourish the thick tissue of a solid organ (kidney or liver or bone) has been an ongoing challenge, and a major barrier for realizing the coveted rewards of artificial organs. The highly vascular network is akin to a living and breathing organ with a high metabolic requirement that is not unlike supporting a miniature planet.

In fact, 3D printing as an approach to building a capillary network was reported last year using so-called “bioinks” of varying consistency to lay down a matrix in which small blood vessels close to the size of capillaries would be capable of nourishing small tissue beds.

The 3D Advantage

Bellan’s long-term goal has been to produce 3D templates of such microfiber networks that are suitable to support the nutritional and vascular requirements of major organs in the body. Achieving a 2D network is just not sustainable from a physiologic standpoint.

And the reward is far-reaching: If you can reliably produce intricate 3D microfiber networks, then you can sustain artificially constructed or lab-grown organs for long periods of time, bridging the gap before such a transplant is done.

In fact, Bellan and his research team report a remarkable advance—creating a 3D microfluidic network able to maintain living cells viable and healthy for one week outside the body--using this unconventional approach applied from a simple cotton candy machine. This represents a significant advance in longevity over more traditional methods currently under study.

His team’s research was published February 4 in the Advanced Healthcare Materials Journal.

"Some people in the field think this approach is a little crazy," said Bellan, "But now we've shown we can use this simple technique to make microfluidic networks that mimic the three-dimensional capillary system in the human body in a cell-friendly fashion. Generally, it's not that difficult to make two-dimensional networks, but adding the third dimension is much harder; with this approach, we can make our system as three-dimensional as we like.

Water- based gels, known as hydrogels, have been the main focus and approach to tissue engineering as a vascular network to nourish and support 3D organs. Similar to hair gels, they allow the diffusion and movement of molecules in and out of the tiny capillaries, and have properties that are ideal for an extracellular matrix (ECM), the substance of the underlying capillary beds.

While such hydrogels can support diffusion throughout the ECM, it’s quite limited because oxygen, nutrients and other waste products can only travel so far. Having the cells close together, less than the width of a human hair, allows for the diffusion or movement of such compounds and promotes a functional environment.

Keeping engineered tissues and organs alive rests upon the creation of a specialized network of capillaries that can nourish the tissues and remove detrimental waste at the same time.

And, of the two methods available to create artificial capillary networks—so-called “bottom-up” and “top-down”—the top-down approach offers a clear advantage as a result of time savings and overall feasibility.

A bottom-up approach involves allowing cells to grow on a thin slab of gel, often taking weeks for such capillary networks to develop and mature. Its not very practical for maintaining a viable or sustainable program for artificial organ development.

In contrast, using a top-down approach via the cotton candy spinning method, minute channels ranging from 3-55 microns with a mean diameter of 35 microns are possible.

"So far the other top-down approaches have only managed to create networks with microchannels larger than 100 microns, about ten times the size of capillaries," explained Bellan. And according to Bellan, the majority of other top-down techniques currently available are not able to form networks as complex as his cotton candy method.

Bellan’s approach is an offshoot of a process referred to as electrospinning that he developed in graduate school, which involves the production of nanofibers as a result of strong magnetic fields. He was influenced to innovate, he explains, by a professor who advocated the creation of an artificial vascular system that can nourish thick engineered tissue. So via electrospinning he deduced that the capillary networks could be created on the level of microns.

"The analogies everyone uses to describe electrospun fibers are that they look like silly string, or Cheese Whiz, or cotton candy," offered Bellan. "So I decided to give the cotton candy machine a try. I went to Target and bought a cotton candy machine for about $40. It turned out that it formed threads that were about one tenth the diameter of a human hair--roughly the same size as capillaries--so they could be used to make channel structures in other materials."

But actually producing artificial capillaries is not a cut-and-dried process. For example, if the network of fibers is made up of sugar, when you actually pour a hydrogel on it, the sugar dissolves away because the hydrogel is mostly water.

This is a classic example of the challenges involved in creating these structures. "First, the material has to be insoluble in water when you make the mold so it doesn't dissolve when you pour the gel. Then it must dissolve in water to create the microchannels because cells will only grow in aqueous environments," Bellan added.

The chosen material, after much experimentation, was referred to as PNIPAM, Poly(N-isopropylacrylamide), a unlikely polymer, which was actually insoluble at temperatures above 32 degrees Celsius and soluble below that temperature. What was going for the team is that this polymer was already considered bio- and cell-friendly and had been used previously in cultured cells grown in a laboratory setting.

The process works in this fashion: The first step is to spin a network of PNIPAM threads using a “cotton candy” machine. After a solution of gelatin in water is produced, human cells are added in to the gel-like concoction. Transglutaminase, also known as "meat glue," catalyzes the process of permanent gel formation. The heated mixture is poured over the PNIPAM structure and forms a gel when incubated at 37 degrees. Finally, the gel containing cells and fibers is removed from the incubator and allowed to cool to room temperature. Embedded fibers then dissolve, revealing a residual network of micoscale channels. Pumps are added to the network bathe them in specialized culture media containing critical nutrients, and oxygen.

"Our experiments show that, after seven days, 90% of the cells in a scaffold with perfused microchannels remained alive and functional compared to only 60% to 70% in scaffolds that were not perfused or did not have microchannels," Belan described.

With proof of concept, the team will be planning to match specific tissues—kidney or liver or bone--with the properties of the small vessel networks, to assure compatibility.

"Our goal is to create a basic 'toolbox' that will allow other researchers to use this simple, low-cost approach to create the artificial vasculature needed to sustain artificial livers, kidneys, bone and other organs," added Bellan.