Mike Ramsey has a dream: one day you’ll be able to walk into a pharmacy and pick up a microchip for the blood test you need. You’ll take the chip home, insert it into an analyzer, and place your finger on it to extract a tiny sample of blood. Instant results.

How close is he to his dream?

Ramsey is a chemist and a pioneer in the field of microfluidics. In the mid-80s, Ramsey started thinking about how he could use tiny fluidic circuits—microplumbing, if you will—to shrink lab tests.

Ramsey’s idea was to take a chip about the size of the one that runs your computer and etch on it a series of interconnected channels. These channels would bring chemicals together and, under the control of a computer, mix them in a reactor—a reactor one million times smaller than a teardrop.

But getting the work funded wasn’t easy, and in the early days there were skeptics. Jim Jorgenson, also a professor of chemistry at Carolina and a graduate school classmate of Ramsey’s, says, “It’s not uncommon, particularly with really good ideas, to have trouble getting funded. The routine, mundane things are very easy to propose and very easy to get supporting data for, but really good ideas are hard to support because they actually are novel.”

Jorgenson, it turns out, was part of the inspiration for Ramsey early on. Jorgenson perfected reducing the size of DNA separation techniques. And the advantages of that—quicker, faster, cheaper—were not lost on Ramsey. “I knew we’d get automation at a scale that’s too small to be manipulated manually, typically six orders of magnitude below conventional technology,” he says. “That leads to a saving in reagents and a speed advantage.” As devices get smaller the distances that molecules have to travel get shorter. “We’d be able to do a chemical separation a lot faster,” he says.

But Ramsey’s graduate training and early career were in spectroscopy, a technique he was using to identify single molecules. So his switch to microfluidics was a pretty hard sell to funding agencies, “because I basically had no expertise in this area,” he says.

He looked at many different sponsors and their needs, adapting his ideas to fit the particular funding agencies. Early sponsors were interested in doing chemistry in very small packages out in the field. Among other things, they wanted to monitor the potential production of weapons of mass destruction. As in the U.N.? “Actually,” Ramsey says with a smile, “the applications were situations of cooperative and ‘noncooperative’ monitoring, to put it politely.”

With work ongoing for the Department of Defense and other government agencies, Ramsey’s vision broadened and he got to thinking about biotechnology. “Biotechnology problems are, in general, easier than searching for a small molecule out in the environment,” Ramsey says. There are typically higher concentrations of the substances you are testing or looking for and the ways to measure them tend to be less difficult.

Ramsey decided to work on restriction fragment analysis, more commonly referred to as DNA fingerprinting. “That’s when you take a chunk of DNA, chop it up into little pieces, and separate the pieces based on their size,” Ramsey says. As we all have slightly different DNA, the resulting fragments are unique for every individual: a DNA “fingerprint.”

Since it was developed twenty years ago, DNA fingerprinting has been routinely used to match crime-scene DNA with a suspect and to establish paternity. But the technique is time-consuming and expensive.

So Ramsey went back to his chips. “We mixed the reagents and DNA fragments together in a tiny reactor. Then, using a computer, we automatically injected those fragments into a separation device,” Ramsey says. They managed a DNA fingerprint in five minutes and published their results in the journal Analytical Chemistry in 1996. It’s an article that other scientists have cited more than two hundred times.

With this success, Ramsey turned his attention to biotechnology applications. He reasoned that, with vast libraries of potential drugs to screen, the pharmaceutical industry would be a natural user of microfluidics technology.

Screening potential molecules to determine which ones might eventually become drugs means carrying out lots of repetitive tests. By shrinking those tests down onto microfluidic chips, Ramsey has allowed machines to take over and screen more drugs at once.

“The chips are manufactured by photolithography, which is a technique that allows you to make many of the same thing side by side with very small incremental costs and with very good reproducibility,” Ramsey says. And with machines capable of running twelve simultaneous channels of samples, this parallelism increases the number of tests. “In the best-case scenario a company can run about fifty thousand samples in an eight-hour day,” Ramsey says.

These improvements in volume and speed potentially allow drug companies to test millions of possible new drugs against every protein that is known and then to refine them based on the results. “If you want to inhibit one particular protein, then you look at your results and see which drugs work best, and that tells us how to design a better drug,” Ramsey says.

In 1994, to push microfluidic technology into the marketplace, Ramsey cofounded Caliper Technologies, which formed a joint development agreement with Agilent Technologies. Their first product, a toaster-sized bioanalyzer, appeared in 1999. “It’s a Nintendo for scientists,” Ramsey says, as the different chips for proteins, DNA, and cell-based assays all fit into the same bioanalyzer.

In 1996, this “lab-on-a-chip” technology won Discover magazine’s Technology Award, a NOVA Award from Lockheed Martin Corporation, and an R&D 100 Award.

But Ramsey had come to a realization. He knew that Caliper and Agilent could invest more time and money in the technology than his research lab could, and he knew he wouldn’t be able to compete with them on the same technology-development programs. “We needed to think farther out,” Ramsey says.

So they shrank the size even more by moving into the realm of nanofluidics. Instead of one-millionth of a drop, think one-millionth of one-millionth of a drop.

At this scale, it’s possible to make a hole that’s smaller than a single strand of DNA. “The DNA has to contort to get through the hole,” Ramsey says, and this has opened up the possibility of a new method of sequencing DNA strands.

Since scientists finished sequencing the human genome in 2001, there have been all sorts of predictions about the future of medicine. But in reality, it still costs about ten million dollars and takes several weeks to sequence a genome. So if you and I are ever going to benefit from personalized medicine, DNA sequencing is going to have to be cheaper and faster.

That’s one area in which nanofluidics may be able to help.

DNA is a relatively simple structure, made up of four different molecules—called bases—that connect to each other to form a long chain. The order of these four bases determines our genes—much as the order of letters determines this sentence. Ultimately, genes make proteins that account for everything from our eye color to whether we have a disease such as cystic fibrosis. Sequencing DNA involves learning the order in which those four bases appear along the length of a gene.

A nanofluidic sequencer would force single DNA strands through an electrically charged nanopore. As DNA moved through the pore, it would interrupt the electrical current and cause the current to fluctuate. Ramsey’s hope is that each base will produce a unique and measurable current change, allowing the base to be identified.

That’s the theory. “But, it’s still conjecture whether that can actually be done,” Ramsey says. “If it can, then we’re talking about kilohertz DNA sequencing rates.”

To put that into context, nanofluidics technology would allow the sequencing of a complete human genome in fifty minutes. “The goal,” Ramsey says, with his tongue firmly in cheek, “is to have screening portals at the airport. We blow some air over a person, collect a few skin cells, and sequence their genome as they walk through.”

Whether or not that particular goal is ever achieved, Ramsey says, “it’s pretty clear that the next generation of sequencing machines will be microfluidics-based.”

So how close is Ramsey to his dream? Microfluidics technology is now routinely used both in research and drug discovery. And nanofluidics? “Who knows?” Ramsey says. “Maybe in ten years?”

better, faster, smaller.

We’ve all been there. Your yearly physical and the doctor suggests a cholesterol test. So a technician fills a tube with your blood. But then you have to wait at least a week for the results.

Debashis Dutta, a postdoctoral researcher in the department of chemistry, is trying to turn that week into a few hours. He’s been working to miniaturize a lab test called high pressure liquid chromatography (HPLC). If he’s successful, many types of blood tests will be done faster, will cost less, and will require only a drop of blood.

HPLC is a technique that chemists have been using for the past forty years to separate the components of a liquid. Its uses include drug testing and checking vitamin levels.

In the old method, a chemist used pressure to force your blood sample through a tube packed with a mesh. The mesh is coated with a chemical or antibody to the drug or protein of interest. When the blood sample runs through the mesh, the drug or protein sticks. Then, using a chemical solution, the chemist can collect and quantify the drug or protein. This whole process is time-consuming, needs a large sample, and can only be performed by a skilled chemist.

Dutta’s miniature version of HPLC takes place on a chip, one by two inches, with wells the size of the period at the end of this sentence, joined by channels thinner than your hair. A drop of your blood is placed in the well and pressure forces it along a channel. Now, it’s the channel walls that are coated with antibody and the drug or protein sticks to the side of the channel. Dutta can then collect and measure the drug by chemically washing it out of the channel.

This process is very quick, and because it’s performed by a computer, errors are much less likely. And it’s cheap, because hardly any chemicals are required.

Dutta’s HPLC—and other lab tests being miniaturized by his colleagues—are still in the development stages. “But we’ve done the proof-of-principle experiments,” Dutta says, “and shown that it can be done.”

So in the next five years, if Dutta and his colleagues have their way, when we head to the doctor’s office, we may only need to give a tiny drop of blood and we’ll have our results back within the day.

J. Michael Ramsey is the Minnie N. Goldby Distinguished Professor of Chemistry. He was one of several Carolina faculty members to establish the Carolina Center of Cancer Nanotechnology Excellence, funded by a National Cancer Institute grant. The Office of Technology Development is the only UNC-Chapel Hill office authorized to execute license agreements with companies. For more information, contact OTD at (919) 966-3929 or visit research.unc.edu/otd/.