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Ohio State Researchers Develop 3D, Microfluidic Cell Culture Tech for Drug-Discovery Applications

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Shang-Tian Yang
Professor of chemical and biomolecular engineering
Ohio State University
Name: Shang-Tian Yang
 
Position: Professor of chemical and biomolecular engineering; director, Ohio Bioprocessing Research Consortium, Ohio State University
 
Education: PhD, 1984, and MSE, 1980 – Purdue University
 

 
Researchers from Ohio State University have developed two technologies for assessing drug activity and cytotoxicity in living cells, and are currently seeking commercial partners to bring products to market.
 
The first technology, a device for 3D cell culture, borrows from medical applications such as tissue engineering. It is a fibrous-bed bioreactor made of polyester fibers that allow cells to grow in 3D bundles. The second technology is a microfluidics device that can be used to continuously perfuse cell culture with media or test compounds.
 
Research leader Shang-Tiang Yang, a professor of chemical and biomolecular engineering, and colleagues are hoping to commercialize the two technologies together for use in cell-based fluorescent assays for drug discovery, and presented them for the first time last week at the American Chemical Society fall national meeting in San Francisco.
 
Yang took a few moments from the meeting to discuss the technologies in more detail with CBA News.
 
You are involved in the development of two technologies with commercial potential: the fibrous-bed bioreactor and the microfluidics platform. Did you develop these in tandem? Are they dependent on one another?
 
They are related, but they can be independent technologies. But we’ll be using both for fluorescence cell-based screening. We kind of developed both at the same time and eventually fit them together.
 
Regarding the 3D cell culture scaffolding technology, what are some of the advantages of the fibrous scaffold over other 3D cell culture techniques such as gels?
 
The fibrous scaffold – especially the one we use, polyethylene terephthalate, or PET – is very inexpensive, and is very good for culturing almost every type of mammalian cell. It is also mechanically, chemically, and biologically very stable. These are the main advantages. There are many examples of 3D scaffolding technologies, but most of them are very expensive. 3D scaffolding is not new, because it is a must for tissue engineering. People have been trying to come up with a variety of materials, like foam-type materials; or [have been] using different preparation techniques such as treatment with solvent or microfabrication techniques.
 
There are two types of scaffolding materials: biodegradable or non-biodegradable, depending on the application. In our case, since we are more interested in in vitro-type applications as opposed to implantable devices, we focus on non-biodegradable materials, so it will last longer. So we came up with this PET material, and actually, Dacron, which has been used in surgical repair, has a similar chemistry, and is the same type of fiber. It has proven to be biocompatible. Certainly for our purposes, there are some other optimal characteristics such as pore size and fiber diameter.
 
What are the advantages of using a 3D cell culture for cell-based fluorescence reporter assays?
 
We are using fluorescence techniques to look at cell growth [and] cytotoxicity. You can look at both the positive and negative effects of any compounds with cell culture. The main limitation of conventional 2-D culture is two-fold. One, because the culture is monolayer, the fluorescence intensity is not high enough for most commonly available instruments to detect. Second, there is high background noise, usually because the cell or biological material is autofluorescent.
 
When the cells are grown in a 3D scaffold, there are several advantages. First, there are no limitations on how many cells you can grow. The cells can pile up in another dimension, and then you have a lot more cells, and the fluorescence intensity from the cells is much higher, and therefore easier to detect. The signal from the target is so much higher that the background noise becomes negligible. Another thing we found is that in the 3D scaffold, somehow the fluorescence signal was intensified. Even though you have the same number of cells in a 2-D system, in the 3D scaffold we obtained a three-fold higher intensity.
 
Do you know why?
 
We don’t know the exact mechanism, but we think it has something to do with the 3D environment – some sort of light tunneling, or refraction, or the result of concentrating the light in one area – some physics phenomenon.
 
It sounds like these assays would be measuring bulk fluorescence signals from cells. Have you thought about combining this with some type of imaging approach, to resolve the fluorescence signal from individual cells?
 
Imaging certainly would not be difficult, but it requires more expensive equipment – a high-resolution microscope, image processing software, et cetera. The current fluorescence-based technique can use a fluorimeter, which is a lot cheaper, and much easier to quantify.
 
How do you envision this being used in drug discovery?
 
In drug discovery, there are different assay requirements. You would like to find which drug lead exhibits the biological activity you want. The other aspect is to make sure the drug is not toxic. This particular assay can do both. We can either screen biological compounds to see which ones can stimulate certain growth or affect the expression of a certain protein; or, we can detect whether a compound will inhibit growth or be toxic to a cell.
 
How would you adapt the scaffold to a well-plate format for screening?
 
Basically we just cut the scaffold into small disks and put it into individual wells in a well plate.
 
How does the microfluidics aspect of this fit in?
 
In a multiwell plate, you can only do a basic culture. It’s a very small volume, and you can only make it last for about a week. Sometimes with certain assays – such as cytotoxicity – you want to see the long-term response, to run the assay continuously for several weeks. Also, sometimes you would like to see the interactions between cells among different wells. The microfludics allow us to connect the cell scaffolds, to perfuse the cells, and apply different dosages of drugs to cells. It is important to continuously perfuse the scaffold so you can sustain the culture for a longer time.
 
What types of cells have you tried so far with these technologies?
 
For the fluorescence assays, we have used embryonic stem cells, colon cancer cells, and CHO cells. We have tried a number of other cells, but those three are the ones we have used the most.
 
Have you applied for patents on this?
 
Yes, we have filed a provisional patent. We are in the process of preparing the PCT filing, which would give us protection in multiple countries.
 
Are you and your colleagues at Ohio State looking to commercialize this, or are you seeking partners?
 
The university would like to see the technology be commercialized as soon as possible, because it basically is ready. Most commonly, the university will license the technology to whoever has the capability to commercialize it. The other way would be for us to set up a start-up company, and do it ourselves. That’s the fall-back plan, because we don’t want to wait too long. If nobody comes forward, we may have to move on. We are presenting this for the first time this week at the ACS conference, however, so we are hoping to garner some interest here.

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