Microfabricated devices and methods

Details Microfabricated devices and methods Microfabricated devices and methods

2000-11-01

2002-09-24

Drodge, Joseph W. (Department: 1723)

Liquid purification or separation

Processes

Liquid/liquid solvent or colloidal extraction or diffusing...

C210S243000, C210S511000, C210S748080, C073S061710, C204S600000, C209S001000, C209S155000, C422S105000, C436S177000

Reexamination Certificate

active

06454945

ABSTRACT:

FIELD OF THE INVENTION
This invention relates generally to microfabricated extraction systems and methods for separating analytes from streams containing other constituents by differential transport principles such as diffusion and applied fields. The invention is useful, for example, for processing blood to separate a stream containing smaller particles such as albumin molecules from a stream containing cells. In another aspect this invention relates generally to microsensors and methods for analyzing the presence and concentration of small particles in streams containing both these small particles and larger particles by diffusion principles, and is useful, for example, for analyzing blood to detect the presence of small particles such as hydrogen, sodium or calcium ions in a stream containing cells.
BACKGROUND OF THE INVENTION
In Maxwell's famous gedanken (thought) experiment, a demon operates a door between two boxes of gas at the same temperature. The demon sorts the molecules, keeping the faster molecules in one box and the slower in the other, violating the basic laws of thermodynamics. This paradox has since been resolved in many different ways. Leff, H. S. and Rex, A. F. (1990), “Resource letter md-1: Maxwell's demon,” Am. J. Physics 58:201-209.
A similar arrangement can be used to separate particles. Consider a mixture of particles of two different sizes suspended in water in one box and pure water in the other. If the demon opens and closes the door between the boxes quickly enough so that none of the larger particles have time to diffuse through the doorway, but long enough so that some of the smaller particles have enough time to diffuse into the other box, some separation will be achieved.
Recently two experiments have been done where a spatially asymmetric potential is periodically applied in the presence of a number of Brownian particles. Faucheux, L. S., et al. (1995), “Optical thermal ratchet,” Physical Rev. Letters 74:1504-1507; Rousselet, J., et al. (1994), “Directional motion of Brownian particles induced by a periodic asymmetric potential,” Nature 370:446-448. This has been shown to lead to a directed motion of the particles at a rate depending on the diffusion coefficient. One experiment (Rousselet, J., et al. (1994), “Directional motion of Brownian particles induced by a periodic asymmetric potential,” Nature 370:446-448) used microfabricated electrodes on a microscope slide to apply an electric field for the potential. This idea is also the subject of European Patent Publication 645169 of Mar. 29, 1995, for “Separation of particles in a fluid using a saw-tooth electrode and an intermittent excitation field,” Adjari, A., et al. The other experiment (Faucheux, L. S., et al. (1995), “Optical thermal ratchet,” Physical Rev. Letters 74:1504-1507) used a modulated optical tweezer arrangement.
Chemical analysis of biological samples is constrained by sample size. Withdrawing a few milliliters of blood from an adult may have little effect, but repeating this procedure every hour or even withdrawing this amount once from an infant can significantly alter the health of the subject. For these reasons, a miniaturized blood analysis system would be useful. Furthermore, while many sophisticated tests that have great importance for critical care can be performed in major hospital laboratories, a substantial impact could be made on the practice of emergency medicine if some key tests could be performed on the patient at the site of injury. For some assays it is vital to make measurements in the absence of red blood cells, so some form of separation of cells from plasma is required.
Diffusion is a process which can easily be neglected at large scales, but rapidly becomes important at the microscale. The average time t for a molecule to diffuse across a distance d is 2t=d
2
/D where D is the diffusion coefficient of the molecule. For a protein or other large molecule, diffusion is relatively slow at the macroscale (e.g. hemoglobin with D equal to 7×10
−7
cm
2
/s in water at room temperature takes about 10
6
seconds (ten days) to diffuse across a one centimeter pipe, but about one second to diffuse across a 10 &mgr;m channel).
Using tools developed by the semiconductor industry to miniaturize electronics, it is possible to fabricate intricate fluid systems with channel sizes as small as a micron. These devices can be mass-produced inexpensively and are expected to soon be in widespread use for simple analytical tests. See, e.g., Ramsey, J. M. et al. (1995), “Microfabricated chemical measurement systems,” Nature Medicine 1:1093-1096; and Harrison, D. J. et al (1993), “Micromachining a miniaturized capillary electrophoresis-based chemical analysis system on a chip,” Science 261:895-897.
Miniaturization of analytic instruments is not a simple matter of reducing their size. At small scales different effects become important, rendering some processes inefficient and others useless. It is difficult to replicate smaller versions of some devices because of material or process limitations. For these reasons it is necessary to develop new methods for performing common laboratory tasks on the microscale.
Devices made by micromachining planar substrates have been made and used for chemical separation, analysis, and sensing. See, e.g., Manz, A. et al. (1994), “Electroosmotic pumping and electrophoretic separations for miniaturized chemical analysis system,” J. Micromech. Microeng. 4:257-265.
Field flow fractionation devices involve particle size separation using a single inlet stream. See, e.g. Giddings, J. C., U.S. Pat. No. 3,449,938, Jun. 17, 1969, “Method for Separating and Detecting Fluid Materials”; Giddings, J. C., U.S. Pat. No. 4,147,621, Apr. 3, 1979, “Method and Apparatus for Flow Field-Flow Fractionation”; Giddings, J. C., U.S. Pat. No. 4,214,981, Jul. 29, 1980, “Steric Field-Flow Fractionation”; Giddings, J. C. et al., U.S. Pat. No. 4,250,026, Feb. 10, 1981, “Continuous Steric FFF Device for The Size Separation of Particles”; Giddings, J. C. et al. (1983), “Outlet Stream Splitting for Sample Concentration in Field-Flow Fractionation,” Separation Science and Technology 18:293-306; Giddings, J. C. (1985), “Optimized Field-Flow Fractionation System Based on Dual Stream Splitters,” Anal. Chem. 57:945-947; Giddings, J. C., U.S. Pat. No. 4,830,756, May 16, 1989, “High Speed Separation of Ultra-High Molecular Weight Polymers by Hyperlayer Field-Flow Fractionation”; Giddings, J. C., U.S. Pat. No. 5,141,651, Aug. 25, 1992, “Pinched Channel Inlet System for Reduced Relaxation Effects and Stopless Flow Injection in Field-Flow Fractionation”; Giddings, J. C., U.S. Pat. No. 5,156,039, Oct. 20, 1992, “Procedure for Determining the Size and Size Distribution of Particles Using Sedimentation Field-Flow Fractionation”; Giddings, J. C., U.S. Pat. No. 5,193,688, Mar. 16, 1993, “Method and Apparatus for Hydrodynamic Relaxation and Sample Concentration in Field-Flow Fraction Using Permeable Wall Elements”; Caldwell, K. D. et al., U.S. Pat. No. 5,240,618, Aug. 31, 1993, “Electrical Field-Flow Fractionation Using Redox Couple Added to Carrier Fluid”; Giddings, J. C. (1993), “Field-Flow Fractionation: Analysis of Macromolecular, Colloidal and Particulate Materials,” Science 260:1456-1465; Wada, Y. et al., U.S. Pat. No. 5,465,849, Nov. 14, 1995, “Column and Method for Separating Particles in Accordance with Their Magnetic Susceptibility”; Yue, V. et al. (1994), “Miniature Field-Flow Fractionation Systems for Analysis of Blood Cells,” Clin. Chem. 40:1810-1814; Afromowitz, M. A. and Samaras, J. E. (1989), “Pinch Field Flow Fractionation Using Flow Injection Techniques,” Separation Science and Technology 24(5 and 6):325-339.
Thin-channel split flow fractionation (SPLITT) technology also provides particle separation in a separation cell having a thin channel. A field force is exerted in a direction perpendicular to the flow direction. Particles diffuse or are otherwise transported from a particle-containing stream across a transport stream to a particle-free stream. The

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