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ORNL's Mike Ramsey, a pioneer of the "lab on a chip," has moved from microfluidics to nanofluidics in pursuit of an artificial cell for rapidly sensing chemicals and sequencing DNA.
When ORNL Corporate Fellow Mike Ramsey proposed the "lab on a chip," he helped start the field of microfluidics, which now has its own annual international conference. He co-founded Caliper Technologies, Inc., a California company that in 2002 sold $30 million worth of lab-on-a-chip technology. Caliper's devices promise to spur the pharmaceutical industry's development of more effective therapeutic drugs at lower cost. When Ramsey learned that DOE's Office of Nonproliferation and National Security was seeking small devices to detect trace amounts of materials related to weapons of mass destruction, he combined two ideas. "I had seen a miniature gas chromatograph fabricated on a silicon wafer using the same tools that make semiconductor chips possible," says Ramsey. "A contemporary from graduate school at Indiana University had invented the technique of capillary electrophoresis. So my idea was to microfabricate a network of channels in a glass chip to do fluid experiments, rather than gas-phase experiments, and to use electric fields to move fluids and the ions and molecules contained within them." Ions of various types migrate at different rates when driven electrokinetically, allowing their physical separation. Ramsey pitched the idea of a miniature device for separating molecules and measuring chemical reaction rates using very small liquid samples. Compared with conventional chemical separation technologies, a microfluidics device, he argued, would use smaller samples, separate chemicals much faster, produce less waste, and cost much less. Eventually, the concept won DOE funding. Ramsey fabricated the first microfluidic chip in 1991 and performed the first viable experiments in 1992-93. In 1994 the chip concept was patented and described in a scientific journal. The chip's applications include process and environmental monitoring, clinical diagnostics, combinatorial discovery, and high-throughput experimentation. The first lab-on-a-chip device available for sale was the Agilent 2100 Bioanalyzer, the only desktop device that can analyze DNA, RNA, proteins, and cells. For example, the device can determine the molecular weight of proteins and help identify chemical compounds that might be useful therapeutic drugs. Biotechnology researchers using the device simply load multiple microliter-sized samples on the chip, press a button, and minutes later view the resulting data on a laptop computer. Other lab-on-a-chip devices marketed by Caliper are the ASME 90, a high-throughput version of the Agilent 2100 Bioanalyzer, and the HTS 250, a high-throughput machine that helps determine which of the pharmaceutical industry's millions of synthesized compounds might make effective drugs, based on molecular or cellular reactions. Each test compound is reacted with a disease-related enzyme or cell on the chip; results, typically from fluorescence assays, indicate the potential therapeutic effectiveness of the compound. "The advantage of Caliper machines over conventional assay methods is that they make very precise measurements," Ramsey says. "Ten of the Caliper 250 HTS systems can perform approximately one million assays a day while consuming a mere microgram of protein." By shrinking down the widths and depths of the fluid paths etched into glass chips, Ramsey's group has moved into nanofluidics. "We have found a number of interesting effects not observed at the microscale, such as anomalously high electrical conductivity of fluid in nanochannels compared with in the bulk," Ramsey says. With funding from the Defense Advanced Research Projects Agency, Ramsey's group is building a chemical sensor based upon nanofluidic components. The device, an artificial cell made of layers of silicon and silicon oxide, has an array of ion channels and nanopores drilled by a focused ion beam system. The nanopores, coated with target attractors, are crossed by electrical currents. The current signature changes if target molecules stick inside a nanopore. How long or how much the current is reduced is correlated with the characteristics of the nanochannel and the target molecule, allowing chemical identification. By moving from lab chips to nanofluidics and artificial cells, Ramsey is becoming a nanoscience pioneer.
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