As biochemical analyses become more critical to the understanding and treatment of disease, the need for rapid and inexpensive measurement techniques continues to grow. Miniaturization promises to deliver both for small-volume samples, but significant issues must be addressed to ensure accuracy. A new method based on backscatter interferometry may enable researchers to analyze samples in picoliter-scale volumes. Lines in fused silica Professor Darryl Bornhop and his colleagues at Texas Tech University have developed a refractive index measurement device that routes the analyte through a 50-µm half-capillary channel in a fused silica plate. Laser-drilled exit and entrance ports let the analyte reach the channel. Part of the channel is illuminated with unfocused light from a HeNe or 633-nm intensity-stabilized diode laser. The multiply scattered light generates an interference pattern that is measured with a PIN photodiode or a 0.3-mm avalanche photodiode. "It does work like an interferometer," Bornhop said, "and the fringes look like a slice through a set of Newton's rings." Like Newton's rings, he explained, the recombination of the reflected light between the front and back surfaces enhances fringe contrast and thus the sensitivity of the technique. How sensitive is it? The stabilized diode, coupled through an optical fiber, produces a 50-µm-diameter beam. With a 10-µm channel, the detection volume is 1.5 pl and changes in the refractive index can be measured to five parts in 107. Bornhop says that the technique could be useful for all forms of on-chip separation and analysis, including high-performance liquid chromatography, capillary electrophoresis and electrochromatography, and polymerase chain reaction. Simple analysis The team has used the device for solute quantification at the femtomolar level without derivatization, thermometry at millidegree resolution, and flow and velocity sensing. "This system," Bornhop said, "has a wide, almost unbounded, range of applications. Yet talk about simple: an unfocused laser, an unmodified even plastic channel and a transducer."