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New Technique Measures Flows Down to Nanoliters per Minute

Accurate low-flow measurements are critical for drug delivery and biotech studies.

Scientists and engineers at the National Institute of Standards and Technology (NIST) have devised an optical device that measures the flow of extraordinarily small amounts of liquids, as little as 10 billionths of a liter (nanoliters) per minute. At that rate, it would take a liter-bottle of water about 190 years to drain (a single drop of water contains 50,000 nanoliters).

Precisely measuring and controlling minuscule flow rates has become critically important in the growing field of microfluidics, which includes delivering small amounts of drugs, preparing tiny amounts of liquids, forming microdroplets, and conducting biotechnology studies that monitor nutrients flowing to cells. In treating cancer and other diseases, drug-delivery pumps dispense as little as tens of nanoliters (nL) per minute into the bloodstream. That flow must be precise so that the total dosage patients receive is exactly what physicians prescribed. Low flow rates are also important for separating mixtures into their chemical constituents based on how slowly they travel through a gel or other medium.

The new method from NIST relies on a laser that shines on light-sensitive molecules in a liquid flowing through a microchannel about the diameter of a human hair. How the laser interacts with the molecules depends on the liquid’s flow rate.

If the fluid flows relatively rapidly through the microchannel, the laser simply makes light-sensitive molecules shine or fluoresce. But if the liquid flows slowly, they are exposed to the laser light for a longer time, the molecules eventually burn out and no longer fluoresce. Thus, the slower the flow, the greater the number of light-sensitive molecules that are extinguished and the dimmer the fluorescence.

For a video illustrating the NIST scientists' efforts, click here.

The team calibrated their measurements by comparing them with measurements of much higher rates of flow recorded by established flow meters, which do not require a laser.

A key advantage of the new method is that the flow measurements are independent of the size and shape of the channel carrying the fluid. The new method is an offshoot of a previous device developed by NIST. But it required knowledge of the channel’s geometry and laser intensity, adding considerable uncertainties to the measurements.

The new method is sensitive enough to determine the slowest rate of flow that can be measured for a given experimental setup. Below this rate, the random motion of particles in all directions (aka diffusion) confounds measurements of particle flow.

The lowest rate of flow that could be distinguished from diffusion was 0.2 nL, or 200 trillionths of a liter per minute. Precise determination of this limit, known as zero flow, lets researchers control flow rates more precisely than they can be measured. The NIST team is now experimenting with larger molecules, which diffuse more slowly, and narrower channels, to enhance the ability to discriminate ordinary flow from random diffusion.

The team also reported that it could control a rate of flow as small as 2 nL per minute, with an uncertainty of just 5%.

The measurement method provides several opportunities for spinoff technologies and may help manufacturers of microfluidic devices develop the next generation of flow sensors. The team has submitted a patent application on the technique.

The new method of measuring low flow rates is related to one of NIST’s key programs, NIST on a Chip. This program aims to develop a suite of accurate, quantum-based measurement technologies intended to be deployed nearly anywhere and anytime, without a manufacturer having to halt production while a sensor or other device is shipped to NIST for calibration.

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