| Microfabricated diffusion-based chemical sensor -> Monitor Keywords |
|
|
  Microfabricated diffusion-based chemical sensorUSPTO Application #: 20060073599Title: Microfabricated diffusion-based chemical sensor Abstract: A channel-cell system is provided for detecting the presence and/or measuring the presence of analyte particles in a sample stream comprising: a) a laminar flow channel; b) two inlet means in fluid connection with said laminar flow channel for respectively conducting into said laminar flow channel (1) an indicator stream which may comprise an indicator substance which indicates the presence of said analyte particles by a detectable change in property when contacted with said analyte particles, and (2) said sample stream; c) wherein said laminar flow channel has a depth sufficiently small to allow laminar flow of said streams and a length sufficient to allow particles of said analyte to diffuse into said indicator stream to the substantial exclusion of said larger particles in said sample stream to form a detection area; and d) outlet means for conducting said streams out of said laminar flow channel to form a single mixed stream. (end of abstract) Agent: Seed Intellectual Property Law Group PLLC - Seattle, WA, US Inventors: Bernhard H. Weigl, Paul Yager USPTO Applicaton #: 20060073599 - Class: 436034000 (USPTO) Related Patent Categories: Chemistry: Analytical And Immunological Testing, Rate Of Reaction Determination The Patent Description & Claims data below is from USPTO Patent Application 20060073599. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application is a continuation of U.S. application Ser. No. 09/426,683 filed Oct. 25, 1999, which is a continuation of U.S. application Ser. No. 08/829,679 filed Mar. 31, 1997, now U.S. Pat. No. 5,972,710 issued Oct. 26, 1999, which is a continuation-in-part of U.S. application Ser. No. 08/625,808 filed Mar. 29, 1996, now U.S. Pat. No. 5,716,852 issued Feb. 10, 1998. This application also claims priority to U.S. application Ser. No. 09/703,764 filed Nov. 1, 2000, which is a continuation-in-part of co-pending application Ser. No. 09/500,398, filed Feb. 8, 2000, a continuation of application Ser. No. 09/346,852 filed Jul. 2, 1999, which is a divisional application of application Ser. No. 08/663,916 filed Jun. 14, 1996, now U.S. Pat. No. 5,932,100 issued Aug. 3, 1999, claiming priority to application No. 60/000,261 filed Jun. 16, 1995, all of the foregoing applications being incorporated herein by reference to the extent not inconsistent herewith. FIELD OF THE INVENTION [0003] 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. The invention 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 [0004] 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. [0005] 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. [0006] 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. [0007] 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. [0008] 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 t=d.sup.2/D where D is the diffusion coefficient of the molecule. For a protein or other large molecule, diffusion is relatively slow at the macro-scale (e.g. hemoglobin with D equal to 7.times.10.sup.-7 cm.sup.2/s in water at room temperature takes about 10.sup.6 seconds (ten days) to diffuse across a one centimeter pipe, but about one second to diffuse across a ten micron channel). [0009] 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. [0010] A process called "field-flow fractionation" (FFF) has been used to separate and analyze components of a single input stream in a system not made on the microscale, but having channels small enough to produce laminar flow. Various fields, including concentration gradients, are used to produce a force perpendicular to the direction of flow to cause separation of particles in the input 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. 4,141,651, 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." None of these references disclose the use of a separate input stream to receive particles diffused from a particle-containing input stream. [0011] A related method for particle fractionation is the "Split Flow Thin Cell" (SPLITT) process. See, e.g., Williams, P. S., et al. (1992), "Continuous SPLITT Fractionation Based on a Diffusion Mechanism," Ind. Eng. Chem. Res. 31:2172-2181; and J. C. Giddings U.S. Pat. No. 5,039,426. These publications disclose channel cells with channels small enough to produce laminar flow, but again only provide for one inlet stream. A further U.S. patent to J. C. Giddings, U.S. Pat. No. 4,737,268, discloses a SPLITT flow cell having two inlet streams (FIG. 3); however the second inlet stream is not an indicator stream, but rather a particle-free stream. Giddings U.S. Pat. No. 4,894,146 also discloses a SPLITT flow cell having two input streams, but no indicator stream. All these SPLITT flow methods require the presence of more than one output stream for separating various particle fractions. [0012] None of the foregoing publications describe a channel system capable of analyzing small particles in very small quantities of sample containing larger particles, particularly larger particles capable of affecting the indicator used for the analysis. No devices or methods using indicator streams within the cell system are described. SUMMARY OF THE INVENTION [0013] Microfluidic devices allow one to take advantage of diffusion as a rapid separation mechanism. Flow behavior in microstructures differs significantly from that in the macroscopic world. Due to extremely small inertial forces in such structures, practically all flow in microstructures is laminar. This allows the movement of different layers of fluid and particles next to each other in a channel without any mixing other than diffusion. On the other hand, due to the small lateral distances in such channels, diffusion is a powerful tool to separate molecules and small particles according to their diffusion coefficients, which is usually a function of their size. [0014] This invention provides a channel cell system for detecting the presence of analyte particles in a sample stream also comprising larger particles comprising: [0015] a) a laminar flow channel; [0016] b) at least two inlet means in fluid connection with said laminar flow channel for respectively conducting into said laminar flow channel (1) indicator stream, said indicator stream preferably comprising an indicator substance, for example, a pH-sensitive dye, which indicates the presence of said analyte particles by a detectable change in property when contacted with said analyte particles, and (2) said sample stream; [0017] c) wherein said laminar flow channel has a depth sufficiently small to allow laminar flow of said streams adjacent to each other and a length sufficient to allow analyte particles to diffuse into said indicator stream to the substantial exclusion of said larger particles in said sample stream to form a detection area; [0018] d) outlet means for conducting said streams out of said laminar flow channel to form a single mixed stream. [0019] In the simplest embodiment of this invention, a single indicator stream and a single sample stream are used; however, the methods and devices of this invention may also use multiple sample and/or indicator streams, and reference or calibration streams, all in laminar flow with each other. [0020] The preferred embodiments of this invention utilize liquid streams, although the methods and devices are also suitable for use with gaseous streams. The term "fluid connection" means that fluid flows between the two or more elements which are in fluid connection with each other. [0021] The term "detection" as used herein means determination that a particular substance is present. Typically, the concentration of a particular substance is determined. The methods and apparatuses of this invention can be used to determine the concentration of a substance in a sample stream. [0022] The channel cell system of this invention may comprise external detecting means for detecting changes in an indicator substance carried within the indicator stream as a result of contact with analyte particles. Detection and analysis is done by any means known to the art, including optical means, such as optical spectroscopy, and other means such as absorption spectroscopy or fluorescence, by chemical indicators which change color or other properties when exposed to the analyte, by immunological means, electrical means, e.g. electrodes inserted into the device, electrochemical means, radioactive means, or virtually any microanalytical technique known to the art including magnetic resonance techniques, or other means known to the art to detect the presence of an analyte such as an ion, molecule, polymer, virus, DNA sequence, antigen, microorganism or other factor. Preferably optical or fluorescent means are used, and antibodies, DNA sequences and the like are attached to fluorescent markers. [0023] The term "particles" refers to any particulate material including molecules, cells, suspended and dissolved particles, ions and atoms. [0024] The input stream may be any stream containing particles of the same or different size, for example blood or other body fluid, contaminated drinking water, contaminated organic solvents, urine, biotechnological process samples, e.g. fermentation broths, and the like. The analyte may be any smaller particle in the input stream which is capable of diffusing into the indicator stream in the device, e.g. hydrogen, calcium or sodium ions, proteins, e.g. albumin, organic molecules, drugs, pesticides, and other particles. In the preferred embodiment when the sample stream is whole blood, small ions such as hydrogen and sodium diffuse rapidly across the channel, whereas larger particles such as those of large proteins, blood cells, etc. diffuse slowly. Preferably the analyte particles are no larger than about 3 micrometers, more preferably no larger than about 0.5 micrometers, or are no larger than about 1,000,000 MW, and more preferably no larger than about 50,000 MW. [0025] The system may also include an indicator stream introduced into one of the inlet means comprising a liquid carrier containing substrate particles such as polymers or beads having an indicator substance immobilized thereon. The system may also include an analyte stream comprising substrate particles such as polymer beads, antibodies and the like on which an indicator substance is immobilized. The liquid carrier can be any fluid capable of accepting particles diffusing from the feed stream and containing an indicator substance. Preferred indicator streams comprise water and isotonic solutions such as salt water with a salt concentration of about 10 mM NaCl, KCl or MgCl, or organic solvents like acetone, isopropyl alcohol, ethanol, or any other liquid convenient which does not interfere with the effect of the analyte on the indicator substance or detection means. Continue reading... Full patent description for Microfabricated diffusion-based chemical sensor Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Microfabricated diffusion-based chemical sensor patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. Start now! - Receive info on patent apps like Microfabricated diffusion-based chemical sensor or other areas of interest. ### Previous Patent Application: Particle complex and method for producing the same Next Patent Application: Temperature control method for liquid components in analyzing instrument, the analyzing instrument and analyzing apparatus Industry Class: Chemistry: analytical and immunological testing ### FreshPatents.com Support Thank you for viewing the Microfabricated diffusion-based chemical sensor patent info. IP-related news and info Results in 2.71344 seconds Other interesting Feshpatents.com categories: Novartis , Pfizer , Philips , Polaroid , Procter & Gamble , |
||
