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WO1999040423A1 - Reseau de capteurs pour le dedoublement des enantiomeres - Google Patents

Reseau de capteurs pour le dedoublement des enantiomeres Download PDF

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Publication number
WO1999040423A1
WO1999040423A1 PCT/US1999/002461 US9902461W WO9940423A1 WO 1999040423 A1 WO1999040423 A1 WO 1999040423A1 US 9902461 W US9902461 W US 9902461W WO 9940423 A1 WO9940423 A1 WO 9940423A1
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Prior art keywords
accordance
sensors
chiral
sensor
region
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PCT/US1999/002461
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English (en)
Inventor
Nathan S. Lewis
Erik J. Severin
Robert D. Sanner
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California Institute Of Technology
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Priority to AU25845/99A priority Critical patent/AU2584599A/en
Publication of WO1999040423A1 publication Critical patent/WO1999040423A1/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/02—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating impedance
    • G01N27/04—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating impedance by investigating resistance
    • G01N27/12—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating impedance by investigating resistance of a solid body in dependence upon absorption of a fluid; of a solid body in dependence upon reaction with a fluid, for detecting components in the fluid
    • G01N27/125—Composition of the body, e.g. the composition of its sensitive layer
    • G01N27/126—Composition of the body, e.g. the composition of its sensitive layer comprising organic polymers
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/0004—Gaseous mixtures, e.g. polluted air
    • G01N33/0009—General constructional details of gas analysers, e.g. portable test equipment
    • G01N33/0027—General constructional details of gas analysers, e.g. portable test equipment concerning the detector
    • G01N33/0031—General constructional details of gas analysers, e.g. portable test equipment concerning the detector comprising two or more sensors, e.g. a sensor array

Definitions

  • This invention relates generally to electrical sensors for detecting analytes in fluids. More particularly, it relates to an array of sensors useful for constructing "electronic noses" for analyzing chiral analytes and differentiating between optical isomers.
  • electronic noses are artificial sensory systems that are able to mimic chemical sensing.
  • the signal transduction is_ straightforward: swelling of the polymeric phase of the composite in the presence of a 2 vapor, leads to an increase in the electrical resistance of the composite, which is monitored using simple electronics.
  • sensors it is possible to detect volatile materials by directly or indirectly measuring the resistance across each of the sensors in the array.
  • by providing different variables in each sensor of the array, such as the polymeric make-up of the sensors it is possible to characterize various chemical materials according to the response of the array to the analyte of interest.
  • An ideal sensor array would produce a unique signature for every molecule to which it was exposed. In such a system, it would be necessary to include detectors that probe important, but possibly subtle, molecular parameters such as chirality. Moreover, chirality is an important chemical phenomenon. Harnessing enantiomer resolution gives rise to myriad applications. For instance, because the active sites of enzymes are chiral, only the correct enantiomer is recognized as a substrate. Thus, pharmaceuticals having near enantiomeric purity are often many more times active than their racemic mixture.
  • One optical form (or enantiomer) of a racemic mixture may be medicinally useful, while the other optical form may be inert or even harmful, as has been reported to be the case for thalidomide.
  • Various methods exist which generate the correct enantiomer including chiral synthesis, enzymatic resolution or some other means of obtaining the optically active compound. Due to the wide range of industrial applications, there is a growing interest in finding ways to resolve racemic mixtures into optically active isomers, or to synthesize enantiomerically pure compounds directly and rapidly monitor the efficiency of such processes.
  • European Application No. 0 794 428 describes sensors capable of distinguishing between enantiomers.
  • the sensors comprise a pair of spaced apart contacts and a polymer material spanning the gap.
  • the polymeric material is grown between the gaps; thus only a limited number of polymers can be used. This architecture limits the usefulness of these sensors because of their inherit low sensitivity.
  • the present invention relates to a device for detecting the presence or absence of an analyte in a fluid
  • the device comprises a sensor, the sensor comprising a chiral region.
  • the sensor comprises a conductive region and a nonconductive region, wherein at least one of the conductive and nonconductive regions is chiral, and wherein the analyte generates a differential response across the sensor.
  • the conductive region can be chiral
  • the nonconductive region can be chiral or both the conductive and nonconductive regions can be chiral.
  • the device comprises an array of sensors i.e., two or more sensors comprising at least one sensor having a chiral region.
  • differential responses examples include, but are not limited to, electrical responses, such as resistance, impedance or capacitance, optical, magnetic, surface acoustic and fluorescence responses.
  • the chiral region comprises a chiral resolving agent, such as a chiral polymer.
  • Detectable analytes include chiral analytes as well as analytes that are achiral.
  • Suitable analytes include, but are not limited to, alkanes, alkenes, alkynes, dienes, alicyclic hydrocarbons, arenes, alcohols, ethers, ketones, aldehydes, carbonyls, carbanions, heterocycles, polynuclear aromatics, organic derivatives, biomolecules, microorganisms, bacteria, viruses, sugars, nucleic acids, isoprenes, isoprenoids, fatty acids and their derivatives. Due to the presence of chiral moieties, many biomolecules, such as amino acids, are amenable to detection using the sensor arrays of the present invention.
  • the present invention relates to a method for detecting an analyte in a fluid, the method comprising: contacting a device with an analyte, the device comprising a sensor, the sensor comprising a chiral region.
  • the sensor comprises a conductive region and a nonconductive region, wherein at least one of the conducting and nonconducting regions is chiral, and wherein the analyte generates a differential response across the sensor array; and measuring the response from a detector connected to the sensor, thereby detecting the presence or absence of the analyte.
  • the device comprises an array of sensors i.e., two or more sensors. 4
  • Figure 1 illustrates a typical response of a chiral detector to 2-butanol.
  • the senor or sensor arrays of the present invention are capable of distinguishing or differentiating between chiral compounds, such as enantiomers, i.e., optical isomers.
  • the present invention relates to a device for detecting the presence or absence of an analyte in a fluid, the device comprises a sensor, the sensor comprising a chiral region.
  • the sensor comprises a conductive region and a nonconductive region, wherein at least one of the conductive and nonconductive regions is chiral, and wherein the analyte generates a differential response across the sensor.
  • the analyte contacts the chiral region of the sensor.
  • the analytes can be chiral or achiral.
  • chiral is used herein to refer to an optically active or enantiomerically pure compound, or to a compound containing one or more asymmetric centers in a well-defined optically active configuration. A chiral compound is not superimposable upon its mirror image.
  • optically active compound refers to a compound having the ability to rotate the plane of polarized light.
  • the devices of the present invention comprise at least two sensors, i.e., an array of sensors, wherein at least one sensor comprises a conductive region and a nonconductive region, wherein at least one of the conductive and nonconductive regions is chiral.
  • the sensor arrays of the present invention comprise at least two different sensors.
  • each sensor comprises a first and second chemical lead in electrical communication to an analyte sensitive resistor.
  • the leads are a conductive material, such as a metal.
  • the electrical leads are optionally interdigitized to maximize the signal-to-noise ratio.
  • the senor comprises regions of conductive material and regions of nonconductive material.
  • the conductive region can be chiral, the 5 nonconductive region can be chiral or both the conductive region and the nonconductive region can be chiral.
  • the a ⁇ ay of sensors can comprise any combination of chiral region sensors.
  • the senor comprises a plurality of interchanging nonconductive and conductive regions transverse to the electrical path between the conductive leads.
  • the sensor can be fabricated by blending a conductive material with a nonconductive material, such as an organic polymer, in order that the electrically conductive path between the leads coupled to the sensor is interrupted by gaps of nonconductive regions.
  • a conductive material such as an organic polymer
  • the matrix regions separating the particles provide the gaps.
  • the nonconductive or insulating gaps range in path length from about 10 to 1,000 angstroms, usually on the order of 100 angstroms providing individual resistance of about 10 to 1,000 m' ⁇ , usually on the order of 100 m' ⁇ , across each gap.
  • the conductive region of the sensor is a particulate material, such as carbon black
  • the nonconductive region is an organic matrix, such as an organic polymer that separates the particulate material, thereby providing the gaps in the electrical path.
  • the chiral region comprises a chiral material, such as an organic chiral resolving agent.
  • An example of a chiral resolving agent is a chiral polymer.
  • the dynamic aggregate resistance provided by these gaps in a given resistor is a function of analyte permeation of the nonconductive regions.
  • the conductive region can also contribute to the dynamic aggregate resistance as a function of analyte permeation (e.g. , when the conductive material is a conductive organic polymer such as polypyrrole.)
  • Chemical sensitivity varies across the sensor array by qualitatively or quantitatively varying the composition of the conductive and/or nonconductive regions.
  • the conductive material can be different in each sensor.
  • the concentration of the chiral resolving agent can be varied, or the chiral resolving agent itself can be varied and changed.
  • an array of sensors can be constructed.
  • the sensor a ⁇ ay of the present invention comprises about 2 to about 100 sensors.
  • the sensor a ⁇ ay comprises about 100 to about 1000 sensors.
  • the a ⁇ ay comprises about 1000 to about 10 6 sensors.
  • the sensor or a ⁇ ay of sensors of the present invention comprise a chiral region.
  • the sensor comprises a conductive region, a nonconductive region or both a conductive region and a nonconductive region.
  • Various sensors suitable for chiral detection using the present invention include, but are not limited to, thermal sensors, radiation sensors, mechanical sensors, magnetic sensors, chemical sensors, biological sensors and electrical sensors. The foregoing sensors have been classified by their principal form of signal. Measuring parameters for thermal sensors include, but are not limited to, temperature, heat, heat flow, entropy, heat capacity etc.
  • Measuring parameters for radiation sensors include, but are not limited to, gamma rays, X-rays, ultra-violet rays, visible, infrared, microwaves and radio waves.
  • Measuring parameters for mechanical sensors include, but are not limited to, displacement, velocity, acceleration, force, torque, pressure, mass, flow, acoustic wavelength, and amplitude.
  • Measuring parameters for magnetic sensors include, but are not limited to, magnetic field, flux, magnetic moment, magnetization, and magnetic permeability.
  • Measuring parameters for chemical sensors include, but are not limited to, humidity, pH level, concentration of analyte, vapor, odor, toxic and flammable materials.
  • Measuring parameters for biological sensors include, but are not limited to, biomolecules such as sugars, proteins, haptens and antibodies.
  • Measuring parameters for electrical sensors include, but are not limited to, charge, current, voltage, resistance, conductance, capacitance, inductance, dielectric permittivity, polarization and frequency.
  • thermal sensors are suitable for use in the present invention that include, but are not limited to, thermocouples, such as a semiconducting thermocouples, noise thermometry, thermoswitches, thermistors, metal thermoresistors, semiconducting thermoresistors, thermodiodes, thermotransistors, calorimeters, thermometers, indicators, fiber optics and surface acoustic wave sensors.
  • thermocouples such as a semiconducting thermocouples, noise thermometry, thermoswitches, thermistors, metal thermoresistors, semiconducting thermoresistors, thermodiodes, thermotransistors, calorimeters, thermometers, indicators, fiber optics and surface acoustic wave sensors.
  • various radiation sensors are suitable for use in the present invention that include, but are not limited to, nuclear radiation microsensors, such as scintillation counters and solid state detectors, ultra-violet, visible and near infrared radiation microsensors, such as photoconductive cells, photodiodes, phototransistors, 7 infrared radiation microsensors, such as photoconductive IR sensors and pyroelectric sensors.
  • nuclear radiation microsensors such as scintillation counters and solid state detectors
  • ultra-violet visible and near infrared radiation microsensors
  • visible and near infrared radiation microsensors such as photoconductive cells, photodiodes, phototransistors
  • 7 infrared radiation microsensors such as photoconductive IR sensors and pyroelectric sensors.
  • various mechanical sensors are suitable for use in the present invention that include, but are not limited to, displacement microsensors, capacitive and inductive displacement sensors, optical displacement sensors, ultrasonic displacement sensors, pyroelectric, velocity and flow microsensors, transistor flow microsensors, acceleration microsensors, piezoresistive microaccelerometers, force, pressure and strain microsensors, surface acoustic wave resonant devices and piezoelectric crystal sensors.
  • various magnetic sensors are suitable for use in the present invention that include, but are not limited to, Hall devices, magnetoresistors magnetodiodes, magnetotransistors, carrier domain MOS devices, SAW devices and superconducting quantum interference devices.
  • various chemical or biochemical sensors are suitable for use in the present invention that include, but are not limited to, metal oxide gas sensors, such as tin oxide gas sensors, organic gas sensors, chemocapacitors, chemoidiodes, such as inorganic Schottky device, metal oxide field effect transistor (MOSFET), piezoelectric devices, ion selective FET for pH sensors, polymeric humidity sensors, electrochemical cell sensors, pellistors gas sensors, piezoelectric or surface acoustical wave sensors, infrared sensors, surface plasmon sensors, and fiber optical sensors.
  • metal oxide gas sensors such as tin oxide gas sensors, organic gas sensors, chemocapacitors, chemoidiodes, such as inorganic Schottky device, metal oxide field effect transistor (MOSFET), piezoelectric devices, ion selective FET for pH sensors, polymeric humidity sensors, electrochemical cell sensors, pellistors gas sensors, piezoelectric or surface acoustical wave sensors, infrared sensors, surface plasmon sensors, and
  • sensors suitable for use in the present invention include, but are not limited to, sintered metal oxide sensors, phthalocyanine sensors, membranes, Pd- gate MOSFET, electrochemical cells, conducting polymer sensors, lipid coating sensors and metal FET structures.
  • the sensors include, but are not limited to, metal oxide sensors such as a Tuguchi gas sensors, catalytic gas sensors, organic semiconducting gas sensors, solid electrolyte gas sensors, piezoelectric quartz crystal sensors, fiber optic probes and Langmuir-Blodgett films.
  • the chiral region of the sensors of the present invention comprises a chiral resolving agent.
  • the chiral region can be a conductive region, a nonconductive region or both a conductive region and the nonconductive region.
  • Suitable chiral resolving agents include, but are not limited to, chiral molecules, such as chiral polymers; natural products, such as, tartaric, malic and mandelic acids; alkaloids, 8 such as brucine, strychnine, morphine and quinine; lanthanide shift reagents; chelating agents; biomolecules, such as proteins, cellulose and enzymes; and chiral crown ethers together with cyclodextrins. (see, E.
  • the chiral resolving agent is a chiral polymer.
  • Chiral polymers suitable for use in the present invention include, but are not limited to, homopolymers, heteropolymers and copolymers. Suitable chiral polymers contain at least one optical center making them chiral polymers, i.e., the polymers contain at least one asymetric center in a monomeric moiety. In most instances, the monomeric chiral moiety will be a plurality of chiral monomeric units. In certain embodiments, the chiral polymer will have about 1 % to about 100 % enantiomeric purity. In other embodiments, the chiral polymer will have about 10% to about 50 % enantiomeric purity or, more preferably, about 50 % to about 90 % enantiomeric purity.
  • the chiral or optical center can be part of a homopolymer or, alternatively, the chiral or optical center can be introduced into a polymer structure by way of copolymerizing an achiral monomer with a chiral monomer.
  • Suitable chiral monomers include, but are not limited to, R or S-methyl bezylacryamide, or other suitable acrylamide derived from the reaction between acryloyl chloride and a suitable R or S- primary or secondary amine and the like, and combinations thereof (see, U.S. Patent No. 5,739,383, which issued to Yoon et al., on April 14, 1998).
  • chiral arylcarboxamide-containing alkenes and alkoxysilanes and polysiloxanes polymers containing chiral arylcarboxamide-substituted side chains are suitable for use in the present invention.
  • the foregoing chiral polymers are disclosed in U.S. Patent No. 4,909,935, which issued to Bradshaw et al, on March 20, 1990.
  • a chiral center can be incorporated into a polymer using various techniques.
  • the chiral moiety can be included as a side chain, or as a counter ion, or the polymer can be synthesized in a chiral solvent.
  • the chiral polymer is a copolymer, such as poly(R-3-hydroxybutyrate- co-R-3-hydroxy-valerate), having about 77% butyrate. This polymer is commercially available from Goodfellow Corporation (Berwyn, PA).
  • 9 Polymer particles having a hydrophobic core and various surface functional groups, particularly, chiral functional groups such as described in U.S. Patent No. 5,306,561, which issued to Frechet et al, can also be used.
  • the functional monomers that result in chiral surface functionality are those monomers that contain a polymerizable vinyl group and a reactive chiral group.
  • Suitable reactive chiral groups include, but are not limited to, amino acids, alcohols, amines, esters, amides, sugars, carboxyhc acids, esters, and the like.
  • suitable monomers can be produced by the attachment of known optically active (chiral) compounds to styrenic, acrylic, methacrylic or other vinylic structure that can be polymerized by conventional free- radical techniques. Generally, the attachment will result in pendant chiral groups such as those listed above.
  • the chiral resolving agent is mixed or incorporated into an organic matrix.
  • an organic matrix can be an organic polymer that optionally contains a chiral solvent, or a chelating agent.
  • Organic polymers suitable for use in the present invention include, but are not limited to, those set forth in U. S. Patent No. 5,571,401, which issued to Lewis et al.
  • the chiral region is formed using template polymerization, wherein the chiral analyte molecule serves as a template to assemble its own recognition sites in a polymer (see, U.S. Patent No. 5,786,428, which issued to Arnold, et al).
  • the chiral region comprises a polymer matrix that contains one or more metal complexes that are oriented within the polymer matrix to provide selective binding of the matrix to one enantiomer of an optically active compound.
  • the metal complexes responsible for binding the analyte includes a polymerizable moiety that allows the complex to be copolymerized with monomers and crosslinking agents to form molecularly imprinted porous polymeric material.
  • the metal complexes must be able to form rapidly reversible mixed-ligand complexes with the analyte molecule.
  • exemplary functional groups that can be attached to the metal complex to form polymerizable metal complexes include, but are not limited to, styrene, methacrylate, acrylate, vinyl, vinyl ether, vinyl acetate, trialkoxysilane, dialkylchlorosilane and epoxy. 10
  • the polymer that serves as the chiral region incorporates chiral counter ions as discussed in EP 0 794 428.
  • the optically active counter ion includes a sulfonic acid moiety.
  • Suitable optically active side chains include, but are not limited to, menthoxy acetic acid, carzyl acetate and natural or synthetic chiral amino acids.
  • a semi-conducting polymer material comprising the chiral counter ions spans the gap between electrical contacts, wherein the polymer material is such that its electrical resistance changes on exposure to volatile enantiomeric substances.
  • the chiral region is a polymerized chiral micelle.
  • chiral micelles are disclosed in U.S. Patent No. 5,770,084.
  • Suitable chiral micelles include, but are not limited to, poly(sodium N-undecylenyl-L-valinate) and poly (sodium N-undecylenyl-D-valinate) and combinations thereof.
  • conductive materials that make up the conductive region can be used in the sensor arrays of the present invention.
  • the conductive region is chiral.
  • Table 1 sets forth exemplary conductive materials for use in resistor fabrication. Mixtures of conductive materials, such as those listed, can also be used.
  • Organic Conductors conducting polymers poly(anilines), poly(thiophenes), poly(py ⁇ oles), poly(acetylenes), etc.)
  • carbonaceous materials carbon blacks, graphite, coke, C 60 , etc.
  • charge transfer complexes tetramethylparaphenylenediamine-chloranile, alkali metal tetracyanoquinodimethane complexes, tetrathiofulvalene halide complexes, etc.
  • Ino r ganic Conductors metals and metal alloys Al, Au, Cu, Pt, AuCu alloy, etc.
  • highly doped semiconductors Si, GaAs, InP, MoS 2 , TiO 2 , etc.
  • conductive metal oxides In O , SnO , Na x Pt 3 O 4 , etc.
  • superconductors YBa Cu O 7 , Tl 2 Ba 2 Ca Cu 3 OiQ, etc.
  • the conductive region can be a conductive particle, such as a colloidal nanoparticle.
  • nanoparticle refers to a conductive cluster, such as a metal cluster, having a diameter on the nanometer scale. Examples of colloidal nanoparticles for use in accordance with the present invention are described in the literature (see, Templeton et al. J. Am. Chem. Soc. (1998) 120 :1906-1911; Lee et al. sr. J. Chem. (1997) 37: 213-223 (1997); Hostetler et al LANGMUIR (1998) 14:17-30; Ingram et al, J. Am. Chem.
  • the nonconductive region can optionally be a ligand comprising a chiral moiety that is attached to a central core making up the nanoparticle.
  • ligands i.e., caps, can be polyhomo or polyheterofunctionalized, thereby being suitable for detecting a variety of chemical analytes.
  • the resistors are nanoparticles comprising a central core conducting element and an insulating attached ligand optionally in a polymer matrix.
  • various conducting materials are suitable for the central core.
  • the nanoparticles have a metal core.
  • Prefe ⁇ ed metal cores include, but are not limited to, Au, Ag, Pt, Pd, Cu, Ni, AuCu and mixtures thereof. Gold (Au) is especially preferred. These metallic nanoparticles can be synthesized using a variety of methods.
  • Chiral ligands or caps of various chemical classes are suitable for use in the present invention.
  • Ligands include, but are not limited to, alkanethiols having alkyl chain lengths of about -Cjo.
  • Alkanethiols suitable for use can also be polyhomo- functionalized or polyheterofunctionalized (such as, at the ⁇ -position, or last position of the chain).
  • polyhomo functionalized means that the same chemical moiety has been used to modify the ligand at various positions within the ligand.
  • the ligands can be attached to the central core by various methods including, but not limited to, covalent attachment, and electrostatic attachment.
  • polyheterofunctionalized means that different chemical moieties or functional groups are used to modify the ligands at various positions.
  • suitable ligands include, but are not limited to, polymers, such as polyethylene glycol; surfactants, detergents, biomolecules, such as polysaccharides: protein complexes, polypeptides, dendrimeric materials, oligonucleotides, fluorescent moieties and radioactive groups.
  • Nonconducting polymers suitable for use in the present invention include, but are not limited to, main-chain carbon polymers, such as poly(dienes), poly(alkenes), poly( acrylics), poly(methacrylics), poly(vinyl ethers), poly(vinyl thioethers), poly(vinyl 13 alcohols), poly(vinyl ketones), poly( vinyl halides), poly(vinyl nitriles), poly(vinyl esters), poly(styrenes), poly(arylenes); main-chain acyclic heteroatom polymers, such as poly(oxides), poly(carbonates), poly(esters), poly(anhydrides), poly(urethanes), poly(sulfonates), poly(siloxanes), poly(sulfides), poly(thioesters), poly(sulfones), poly( sulfonamides), poly( amides), poly(ureas), poly(phosphazenes), poly(silanes), poly(s
  • the sensors of the present invention can be fabricated using numerous techniques including, but not limited to, solution casting, suspension casting and mechanical mixing.
  • solution casting routes are advantageous because they provide homogeneous structures and are easy to process.
  • resistor elements can be easily fabricated by spin, spray or dip coating. Since all elements of the resistor must be soluble, solution casting routes can be somewhat limited in their applicability. Suspension casting still provides the possibility of spin, spray or dip coating, but more heterogeneous structures than those formed with solution casting are expected.
  • mechanical mixing there are no solubility restrictions since this technique involves only the physical mixing of the resistor components, but device fabrication is more difficult since spin, spray and dip coating are no longer possible.
  • the resistor is deposited as a surface layer on a solid matrix that provides means for supporting the leads.
  • the solid matrix is a chemically inert, nonconductive substrate, such as a glass or ceramic.
  • Sensor arrays of the present invention are particularly well suited to scaled up production by being fabricated using integrated circuit (IC) design technologies.
  • IC integrated circuit
  • the chemiresistors can easily be integrated onto the front end of a simple amplifier interfaced to an A/D converter to efficiently feed the data stream directly into a neural network software or hardware analysis section.
  • Micro-fabrication techniques can integrate the chemiresistors directly onto a microchip that contains the circuitry for analog 14 signal conditioning/processing and then data analysis. This provides for the production of millions of incrementally different sensor elements in a single manufacturing step using ink-jet technology.
  • Controlled compositional gradients in the chemiresistor elements of a sensor a ⁇ ay can be induced in a method analogous to how a color ink-jet printer deposits and mixes multiple colors. However, in this case, rather than multiple colors, a plurality of different polymers in a solution that can be deposited are used.
  • a sensor a ⁇ ay of a million distinct elements only requires a 1 cm x 1 cm sized chip employing lithography at the 10 ⁇ m feature level, which is within the capacity of conventional commercial processing and deposition methods. This technology permits the production of sensitive, small-sized, stand-alone chemical sensors.
  • Preferred sensor a ⁇ ays have a predetermined inter-sensor variation in the structure or composition of the chiral region (e.g., the chiral conductive material, the chiral nonconductive material or both the conductive and nonconductive materials.)
  • the variation can be quantitative and/or qualitative.
  • the concentration of chiral material can be varied across sensors.
  • the chiral resolving agent within the chiral region can be varied.
  • the present invention relates to a method for detecting an analyte in a fluid, the method comprising: contacting a device with said analyte, said device comprising a sensor, said sensor comprising a chiral region and wherein the analyte generates a differential response across the sensor; and measuring the response from a detector connected to the sensor, thereby detecting the presence or absence of the analyte.
  • the sensor comprising a conductive region and a nonconductive region wherein at least one of the conducting and nonconducting regions is chiral. Using this method, it is possible to differentiate between optical isomers or enantiomers.
  • the device comprises an array of sensors.
  • An electronic nose for detecting an analyte, optionally a chiral analyte, in a fluid is fabricated by electrically coupling the sensor leads of an array of compositionally different sensors to a measuring device, such as an electrical measuring device.
  • the sensor can measure changes in resistively, capacitance, impedance or other electrical responses at each sensor of the a ⁇ ay, or other responses such as optical, magnetic or fluorescence responses.
  • the response is simultaneously measured over the a ⁇ ay and preferably over a period of time.
  • the device includes signal 15 processing means and is used in conjunction with a computer and data structure for comparing a given response profile to a structure-response profile database for qualitative and quantitative analysis.
  • the present invention relates to a system for detecting an analyte in a fluid, comprising: a device comprising a sensor, the sensor comprising a conductive region and a nonconductive region, wherein at least one of the conducting and nonconducting regions is chiral and wherein the analyte generates a differential response across the sensor; a measuring device connected to the sensor, and a computer comprising a resident algorithm; the measuring device measuring the response from the sensor, thereby detecting the presence or absence of the analyte and the computer assembling the responses into a sensor response profile.
  • the sensor is an array of sensors and the response is an electrical response.
  • each sensor such as a resistor, provides a first response, such as an electrical response, between its conductive leads when the sensor is contacted with a first fluid comprising an analyte at a first concentration, and a second response between its conductive leads when the sensor is contacted with a second fluid comprising the same analyte at a second different concentration.
  • the fluids can be liquid or gaseous in nature.
  • the first and second fluids may reflect samples from two different environments, a change in the concentration of an analyte in a fluid sampled at two time points, a sample and a negative control, etc.
  • the sensor array necessarily comprises sensors that respond differently to a change in an analyte concentration, i.e., the difference between the first and second response, such as an electrical resistance, of one sensor is different from the difference between the first and second response of another sensor.
  • the sensor array can comprise redundant sensors that can be advantageous for maximizing the signal and thus reducing the noise in the signal.
  • the temporal response of each sensor (such as resistance as a function of time) is recorded.
  • the temporal response of each sensor can be normalized to a maximum percent increase and percent decrease in response that produces a response pattern associated with the exposure of the analyte.
  • a structure-function database co ⁇ elating analyses and response profiles is generated.
  • Unknown analytes which are optionally chiral analytes, can then be characterized or identified using response pattern comparison and recognition 16 algorithms.
  • analyte detection systems comprising sensor arrays, an electrical measuring device for detecting electrical responses across each chemiresistor, a computer, a data structure of sensor array response profiles, and a comparison algorithm are provided.
  • the electrical measuring device is an integrated circuit comprising neural network-based hardware and a digital-analog converter (DAC) multiplexed to each sensor, or a plurality of DACs, each connected to different sensor(s).
  • DAC digital-analog converter
  • a neural network is a useful tool for analyzing data from unknown analytes and then comparing the data to a known library for quick identification.
  • the neural network is trained using known analytes. Once trained, the neural network then produces an output with the identity of the unknown analyte.
  • a wide variety of commercial applications are available for the sensors arrays and electronic noses including, but not limited to, environmental toxicology and remediation, biomedicine, materials quality control, food and agricultural products monitoring, heavy industrial manufacturing, ambient air monitoring, worker protection, emissions control, product quality testing, oil/gas petrochemical applications, combustible gas detection, H 2 S monitoring, hazardous leak detection and identification, emergency response and law enforcement applications, illegal substance detection and identification, arson investigation, hazardous spill identification, enclosed space surveying, explosives detection, utility and power applications, emissions monitoring, transformer fault detection, food/beverage/agriculture applications, freshness detection, fruit ripening control, fermentation process monitoring and control applications, flavor composition and identification, product quality and identification, refrigerant and fumigant detection, cosmetic/perfume, fragrance formulation, product quality testing, patent protection applications, personal identification, chemical/plastics/pharmaceutical applications, fugitive emission identification, leak detection, solvent recovery effectiveness, perimeter monitoring, product quality testing, hazardous waste site applications, fugitive emission detection and identification, leak detection and identification, perimeter monitoring,
  • the senor a ⁇ ays of the present invention are used to evaluate the progress of chemical reactions, such as asymmetrical synthesis, in a quantitative or qualitative fashion.
  • the arrays provide quick assays for the enantiomeric excess or purity of compound, such as in a combinatorial library of catalysts forming the compounds of interest.
  • the methods and devices described herein would allow detection and selection of promising leads in a rapid fashion from multiwell plates, and also allow for evaluation of certain compounds for chiral similarity and enantiomeric purity.
  • the general method for using the disclosed sensors, a ⁇ ays and electronic noses for detecting the presence of an analyte in a fluid involves resistively sensing the presence of an analyte in a fluid with a chemical sensor comprising first and second conductive leads electrically coupled to and separated by a chemically sensitive resistor as described above by measuring a first resistance between the conductive leads when the resistor is contacted with a first fluid comprising an analyte at a first concentration and a second different resistance when the resistor is contacted with a second fluid comprising the analyte at a second different concentration.
  • the present invention relates to a method of detecting and/or discriminating between different chiral compounds, the method comprising exposing a sensor comprising a chiral region to an analyte containing an optically active substance and measuring the response by a detector.
  • the sensor arrays of the present invention detect differences in optically active isomers.
  • the value for ⁇ Q(-rV-) is defined as a positive number.
  • Ki is defined as the larger partition coefficient, ensuring that "a” is greater than one. (see, Schurig, V.J. Chromatogr. A 1994, 666, 111.). This co ⁇ esponds to the analyte which gave the largest response, which, in the examples set forth below, is the (+) enantiomer.
  • Example section These values are similar to the minimum values (ca. -0.1 kJ mol " ) observed for enantiomers in chiral gas chromatography (see, Schurig, V.J. Chromatogr. A 1994, 666, 111).
  • carbon black is the conductive region material.
  • the carbon black (Black Pearls 2000) is a furnace black material donated by Cabot Co. (Billerica, MA).
  • the nonconductive region comprised a chiral polymer, namely, poly(R-3-hydroxybutyrate-co-R-3-hydroxyvalerate) (77% butyrate), and was obtained from the Goodfellow Corp.(Berwyn, PA).
  • the achiral polymer used for control 19 experiments was poly(ethylene-co-vinyl acetate) (82% ethylene) (Polysciences Inc., Warrington, PA).
  • the enantiomeric pairs examined were: (+)-2-butanol and (-)-2-butanol (Aldrich, Milwaukee, WI); (+)-a-pinene and (-)-a-pinene (Fluka, Ronkonkoma, NY); (+)-epichlorohydrin and (-)-epichlorohydrin (Aldrich), and methyl- (+)-2-chloropropionate and methyl-(-)-2-chloropropionate (Aldrich, Milwaukee, WI).
  • An apparatus that provided known partial pressures of the vapors was constructed using general laboratory glassware.
  • a two-hole rubber stopper In each hole was a 5 mm outer diameter glass tube, one of which extended to the bottom of the bubbler and served as the gas inlet, the other of which extended past the stopper by only a few mm and served as the gas exit.
  • the carrier gas was nitrogen, obtained from a commercial gas supply tank. The measurements were performed at room temperature (23 n- 1 °C).
  • the carrier gas was introduced through the glass tube that extended to the bottom of the bubbler apparatus, and was bubbled through the solvent, thus saturating it with the solvent vapor.
  • the saturated vapor was carried out of the bubbler, diluted by blending with a controlled background flow of pure carrier gas, and then introduced into a sensing chamber.
  • This chamber consisted of a glass tube (22 cm long with a 2.6 cm inner diameter) to which inlet and outlet sidearms had been attached.
  • the detectors were introduced into the chamber through a 24/40 standard taper ground glass opening attached at one end of the chamber.
  • the chamber was then sealed with a ground-glass stopper through which electrical lead wires for the detectors had been sealed.
  • the gas flow rates were controlled using needle valves and stopcocks.
  • the detectors were made from a solution of the polymer into which carbon black had been suspended.
  • 125 mg of the polymer was dissolved in 10 mL of tetrahydrofuran, and carbon black (42 mg) was then suspended in this solution, to produce a composition of 15% polymer and 25% carbon black by weight of solids.
  • a 20 single solution that contained the polymer and the carbon black was used to prepare all the detectors of a given composition that were used in this example.
  • Detectors used to analyze pinene vapors were fabricated slightly differently, having films made from a suspension with a carbon black loading of 30% by weight of solids. In both cases, an aliquot of the suspension was spin coated, at 1000 rpm, onto a glass substrate using a
  • the dc resistance of each detector was determined as a function of time using a simple two-point resistance configuration. Contacts were made to the gold lines by pressure-contacting electrical leads using flat-jawed alligator clips. Resistance data were acquired using a Hydra 2620A Data Acquisition Unit (John Fluke Mfg. Co.; Everett, WA) which was interfaced to a personal computer. All of the films had resistance values below the 10 M ⁇ limit of the Hydra 2620 A.
  • the achiral control detectors were made from benzene solutions of poly(ethylene-co-vinyl acetate) (82% ethylene) into which carbon black had been suspended. The same type of carbon black was used as for the chiral detector fabrication. Glass slides, containing gold contacts, were coated by dipping the slide into the suspension. Three coatings were applied to each slide. The polymer concentration was 10 mg mL "1 and the carbon black loading was 30% by weight of solids. Results were obtained by running one trial of four (for epichlorohydrin and methyl-2-chloropropionate) or five (for 2-butanol and a-pinene) exposures. Each analyte was exposed to five detectors simultaneously and the results were averaged to obtain the reported data set.

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Abstract

L'invention concerne un réseau de capteurs utile pour la réalisation de 'nez électroniques' permettant d'analyser des analysats et de fournir un échantillon de sortie. Le réseau comprend des capteurs différents en termes de composition, chaque capteur comportant une zone chirale. L'analysat engendre une réponse électrique différentielle détectée aux bornes du capteur.
PCT/US1999/002461 1998-02-06 1999-02-05 Reseau de capteurs pour le dedoublement des enantiomeres WO1999040423A1 (fr)

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Cited By (10)

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Publication number Priority date Publication date Assignee Title
EP1215485A1 (fr) * 2000-12-12 2002-06-19 Sony International (Europe) GmbH Capteurs chimiques sélectifs à base d'ensembles de nanoparticules interconnectées
US6455319B1 (en) 1999-05-10 2002-09-24 California Institute Of Technology Use of spatiotemporal response behavior in sensor arrays to detect analytes in fluids
US6890715B1 (en) 1999-08-18 2005-05-10 The California Institute Of Technology Sensors of conducting and insulating composites
US6975944B1 (en) * 1999-09-28 2005-12-13 Alpha Mos Method and apparatus for monitoring materials used in electronics
US7122152B2 (en) 1999-05-10 2006-10-17 University Of Florida Spatiotemporal and geometric optimization of sensor arrays for detecting analytes fluids
US7359802B1 (en) 1999-05-10 2008-04-15 The California Institute Of Technology Methods for remote characterization of an odor
EP2096427A2 (fr) 1998-11-16 2009-09-02 California Institute of Technology Détermination simultanée de propriété d'équilibre et cinétique
WO2022002507A1 (fr) 2020-07-03 2022-01-06 Karlsruher Institut für Technologie Réseaux de capteurs et nez électroniques pour la détection énantiosélective de substances
US11604156B2 (en) 2017-05-12 2023-03-14 Carrier Corporation Method and system for multi-sensor gas detection
EP4495593A1 (fr) 2023-07-21 2025-01-22 Karlsruher Institut für Technologie Réseau de capteurs hautement stable pour la détection de molécules dans des milieux gazeux et/ou liquides

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US5122472A (en) * 1989-10-06 1992-06-16 University Of South Carolina Chalcogen-based chiral reagents and method for nuclear magnetic resonance detection of stereochemical assignments and enantiomeric ratios
US5571401A (en) * 1995-03-27 1996-11-05 California Institute Of Technology Sensor arrays for detecting analytes in fluids
JPH09176243A (ja) * 1995-10-25 1997-07-08 Daicel Chem Ind Ltd 新規なアセチレン誘導体の重合体
EP0794428A1 (fr) * 1996-03-04 1997-09-10 Neotronics Limited Capteur pour matériaux volatiles et pour gaz
US5674752A (en) * 1995-10-16 1997-10-07 The United States Of America As Represented By The Secretary Of The Navy Conductive polymer coated fabrics for chemical sensing

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Publication number Priority date Publication date Assignee Title
US5122472A (en) * 1989-10-06 1992-06-16 University Of South Carolina Chalcogen-based chiral reagents and method for nuclear magnetic resonance detection of stereochemical assignments and enantiomeric ratios
US5571401A (en) * 1995-03-27 1996-11-05 California Institute Of Technology Sensor arrays for detecting analytes in fluids
US5674752A (en) * 1995-10-16 1997-10-07 The United States Of America As Represented By The Secretary Of The Navy Conductive polymer coated fabrics for chemical sensing
JPH09176243A (ja) * 1995-10-25 1997-07-08 Daicel Chem Ind Ltd 新規なアセチレン誘導体の重合体
EP0794428A1 (fr) * 1996-03-04 1997-09-10 Neotronics Limited Capteur pour matériaux volatiles et pour gaz

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2096427A2 (fr) 1998-11-16 2009-09-02 California Institute of Technology Détermination simultanée de propriété d'équilibre et cinétique
US7122152B2 (en) 1999-05-10 2006-10-17 University Of Florida Spatiotemporal and geometric optimization of sensor arrays for detecting analytes fluids
US7359802B1 (en) 1999-05-10 2008-04-15 The California Institute Of Technology Methods for remote characterization of an odor
US7595023B2 (en) 1999-05-10 2009-09-29 The California Institute Of Technology Spatiotemporal and geometric optimization of sensor arrays for detecting analytes in fluids
US6962675B2 (en) 1999-05-10 2005-11-08 California Institute Of Technology Use of spatiotemporal response behavior in sensor arrays to detect analytes in fluids
US6455319B1 (en) 1999-05-10 2002-09-24 California Institute Of Technology Use of spatiotemporal response behavior in sensor arrays to detect analytes in fluids
US6890715B1 (en) 1999-08-18 2005-05-10 The California Institute Of Technology Sensors of conducting and insulating composites
US6975944B1 (en) * 1999-09-28 2005-12-13 Alpha Mos Method and apparatus for monitoring materials used in electronics
US7211439B2 (en) 2000-12-12 2007-05-01 Sony Deutschland Gmbh Selective chemical sensors based on interlinked nanoparticle assemblies
EP1215485A1 (fr) * 2000-12-12 2002-06-19 Sony International (Europe) GmbH Capteurs chimiques sélectifs à base d'ensembles de nanoparticules interconnectées
AU781166B2 (en) * 2000-12-12 2005-05-12 Sony International (Europe) Gmbh Selective chemical sensors based on interlinked nanoparticle assemblies
US11604156B2 (en) 2017-05-12 2023-03-14 Carrier Corporation Method and system for multi-sensor gas detection
WO2022002507A1 (fr) 2020-07-03 2022-01-06 Karlsruher Institut für Technologie Réseaux de capteurs et nez électroniques pour la détection énantiosélective de substances
EP3964830A1 (fr) 2020-07-03 2022-03-09 Karlsruher Institut für Technologie Ensembles de capteurs et nez électroniques pour la détection de substances enantiosélectives
EP4495593A1 (fr) 2023-07-21 2025-01-22 Karlsruher Institut für Technologie Réseau de capteurs hautement stable pour la détection de molécules dans des milieux gazeux et/ou liquides

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