WO2000078204A2 - Procede de caracterisation a distance d'une odeur - Google Patents

Procede de caracterisation a distance d'une odeur Download PDF

Info

Publication number
WO2000078204A2
WO2000078204A2 PCT/US2000/016770 US0016770W WO0078204A2 WO 2000078204 A2 WO2000078204 A2 WO 2000078204A2 US 0016770 W US0016770 W US 0016770W WO 0078204 A2 WO0078204 A2 WO 0078204A2
Authority
WO
WIPO (PCT)
Prior art keywords
sample
sensor
analyte
data
regions
Prior art date
Application number
PCT/US2000/016770
Other languages
English (en)
Other versions
WO2000078204A3 (fr
Inventor
Nathan S. Lewis
Erik Severin
Original Assignee
California Institute Of Technology
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US09/409,644 external-priority patent/US8394330B1/en
Priority claimed from US09/568,784 external-priority patent/US6455319B1/en
Application filed by California Institute Of Technology filed Critical California Institute Of Technology
Publication of WO2000078204A2 publication Critical patent/WO2000078204A2/fr
Publication of WO2000078204A3 publication Critical patent/WO2000078204A3/fr

Links

Classifications

    • 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

  • the present invention generally relates to remote analysis of analytes and more particularly remote analysis of analytes present in the vapor or odor phase of a sample.
  • Such broadly responsive sensor arrays have exploited heated metal oxide thin film resistors (Gardner et al, Sens. Act. B4: 117-121, 1991; Gardner et al, Sens. Act. B 6:71-75, 1991), polymer sorption layers on the surfaces of acoustic wave resonators(Grate and Abraham, Sens. Act. B 3_:85-l l l, 1991; Grate et al, Anal. Chem. 6_5_: 1868- 1881, 1993), arrays of electrochemical detectors (Stetter et al, Anal. Chem. 58:860-866, 1986; Stetter et al, Sens. Act.
  • Arrays of metal oxide thin film resistors typically based on tin oxide (SnO : ) films that have been coated with various catalysts, yield distinct, diagnostic responses for several vapors (Corcoran et al, Sens. Act. B 15:32-37, 1993).
  • Surface acoustic wave resonators are sensitive to both mass and acoustic impedance changes of the coatings in array elements, but the signal transduction mechanism involves somewhat complicated electronics, requiring frequency measurement to 1 Hz while sustaining a 100 MHZ Rayleigh wave in the crystal. Attempts have also been made to construct arrays of sensors with conducting organic polymer elements that have been grown electrochemically through use of nominally identical polymer films and coatings.
  • Medical symptoms of many types of conditions can be difficult to detect by medical professionals or their detection requires costly, time consuming, and highly invasive procedures often resulting in lost man hours at work, and increased risks of mortality and morbidity.
  • medical diagnostics such as blood pressure readings and glucose readings are taken at doctors' offices or blood laboratories. The readings are then collected manually and depend on the patient's state of health at that particular time. In some cases, individuals take readings at home to assist doctors to better determine medication identification and levels. This data depends on the patient's proficiency and accuracy at taking readings, and is hard for the physician to analyze and is normally communicated only at a doctor's visit.
  • the patient is diagnosed and medicated based on a minimum amount of data and analysis, which furthermore is not presented to the doctor in a format that facilitates diagnosis.
  • Each reading is presented by an individual manually listing out his own readings with the date and time that these readings are taken-often in irregular intervals.
  • Diagnosis of many types of medical conditions can be markedly improved by a system to consolidate the data and present the data in a format which facilitates such diagnosis.
  • remote monitoring of chemical hazard reduces the risk associated with local detection.
  • the present invention provides compositions and systems useful in remote monitoring of chemical hazards, air quality, and medical conditions, for example, robotic systems to search for and detect explosives, mines, and hazardous chemicals.
  • the methods, systems and compositions of the invention provide the ability to mine data from a database containing a plurality of chemical fingerprints.
  • the present invention is used with subjects who may have a medical condition such as, for example, diabetes mellitus to improve diagnosis and treatment of medical disorders more accurately and to assist medical practitioners in determining the proper amount of medication or other treatment to prescribe.
  • a medical condition such as, for example, diabetes mellitus
  • the term "medical practitioner” is intended to include any individual who treats, or prescribes treatment to another individual to improve the latter' s health or well-being.
  • One embodiment of the invention is to gather, organize, and present data which may be collected over a long period of time in a way that best facilitates accurate diagnosis and proper treatment of such medical conditions which can require long-term profiling of medical readings.
  • a method for remote characterization of a gaseous or vapor sample includes contacting at least one sensor with a gaseous or vapor sample, wherein the sample contains at least one analyte, the sensor providing a detectable signal when contacted by the analyte, transmitting data corresponding to the detectable signal to a remote location, analyzing the data received at the remote location, and identifying the analyte present in the gaseous or vapor sample thereby characterizing the sample.
  • the invention provides a sensor array system for remote characterization of a gaseous or vapor sample.
  • the system includes at least one sensor, wherein the sensor provides a detectable signal when contacted by an analyte; a measuring apparatus, in communication with the sensor capable of measuring the detectable signal; a transmitting device, in communication with the measuring apparatus for transmitting information corresponding to the detectable signal to a remote location; and a computer comprising a resident algorithm capable of characterizing the analyte.
  • the invention provides a method for remote characterization of a disease in a subject.
  • the method includes contacting at least one sensor with a gaseous or vapor sample obtained from the subject, wherein the sensor provides a detectable signal when contacted by an analyte present in the sample.
  • the sensor has regions of a conductive material and regions of a material compositionally different than the conductive material, and wherein the materials provide an electrical path through the regions of conductive material and compositionally different material of the sensor, wherein interaction of the analyte with the sensor changes the resistance of the sensor.
  • the invention provides a method of monitoring trends across populations or changes in a physical state of a subject over a period of time.
  • the method includes contacting at least one sensor with a gaseous or vapor sample obtained from the subject at two or more time points, wherein the sensor provides a detectable signal when contacted by an analyte present in the sample, transmitting data corresponding to the detectable signal to a remote location; analyzing the data received at the remote location; and identifying a change in an analyte present in the gaseous or vapor sample.
  • Figure 1 (A) is a block diagram illustrating a remote odor analysis system.
  • Figure 1 (B) is a block diagram depicting an alternate embodiment of sensor array 110.
  • Figure 2 A-B are flow diagrams illustrating two methods of remotely identifying an odor sample.
  • FIG. 3 is a block diagram of a general purpose computer system useful in the invention.
  • an array of broadly cross-reactive chemically-sensitive sensors is utilized. Upon exposure to an odorant, the array generates a detectable signal, pattern or finge rint either electrically, optically, acoustically, or combinations thereof, in form.
  • the form of the array signatures depends on the chemical characteristics of the sensors, which may be dye-impregnated coatings that change color upon exposure to an analyte, conductive polymer composites that change their electrical impedance properties upon exposure to the odorant, cantilever-based transducers coated with different polymeric films that produce a series of deflections that are translated into voltages outputted by the array, and the like.
  • the signal(s) can be coverted into a digital pattern that becomes characteristic of that odorant and/or background conditions during the analysis interval.
  • a digitized signature can then be transmitted across an information network digitally and analyzed remotely, or partially compressed and/or analyzed locally before transmission. The data can then be decompressed and subjected to further analysis either automatically or manually at the remote site.
  • FIG. 1 illustrates a system 100 for detecting an analyte in a sample.
  • System 100 includes a sensor array 110, in which an arrangement of at least one sensor 120 is present.
  • sensor array 110 can be configured to include a sample channel
  • a sample to be analyzed which may be in gaseous or liquid form, is exposed to sensor array 110 through inlet 160, for example, from reservoir 170.
  • Response signals from the sensors 120 in sensor array 110 resulting from exposure of the sample to the sensor array 110 are received and processed in detector 180, which may include, for example, signal-processing electronics, a general-purpose programmable digital computer system of conventional construction (see, for example, FIG. 3), or the like.
  • the detector 180 can be configured to generate a digital representation of the analyte and includes a communication port or transmission device 190 coupled to the detector for communicating the digital representation of the analyte to a remote location 195 for analysis and identification of the analyte or sample.
  • FIG. 2 A method 200 to remotely detect an analyte is illustrated in FIG. 2 (A-B).
  • a sample including an analyte is introduced to a sensor array 110 (FIG. 1) which interacts with a sensor or sensors providing a detectable signal.
  • Detector 180 detects the detectable signal (step 210) and converts the detectable signal to a digital representation or fingerprint of the detectable signal (step 220).
  • the digital signal (i.e., digital data) is transmitted to a remote location (step 230) by the transmission device 190.
  • the digital signals (i.e., digital data) are then processed to detect and or characterize an analyte or combination of analytes in the sample by comparing the digital data to a database of digital odor fingerprints to determine if there is a match (step 240). If a match is found the matching digital fingerprint including any data related to the matching fingerprint is identified (step 250). If there is no match, the method may include a determination of a "best fit” fingerprint (step 260). "Best fit” computations are known in the art. If a "best fit” is found, the "best fit” digital fingerprint including any data related to the fingerprint is identified (step 270). If no match or "best fit” is found "No Match” is indicated (step
  • the digital signal i.e., digital data
  • the digital signal is first processed to detect and or characterize an analyte or combination of analytes in the sample by comparing the digital data to a database of digital odor fingerprints to determine if there is a match (step 240). If a match is found the matching digital fingerprint including any data related to the matching fingerprint is identified and transmitted to a remote location (step 285) by transmission device 190. If there is no match, the method may include a determination of a "best fit" fingerprint (step 260). "Best fit" computations are known in the art.
  • the "best fit" digital fingerprint including any data related to the fingerprint is identified and transmitted to a remote location (step 290) by transmission device 190. If no match or “best fit” is found, "No Match” is indicated and transmitted to a remote location (step 295) by transmission device 190. It is to be understood the mining of the database is included in the invention even if there is no match. Comparisons, such as those described above, can provide information regarding changes that have occurred over time with respect to analyte profiles in the environment or a subject's breath, tissue, blood or other biological sample.
  • analysis of a sample from a subject's breath can indicate that there is a change or difference between the first and one or more subsequence samples due to the loss of a particular disease indicated by the presence of a particular analyte in the sample profile.
  • Sensors 120 can include any of a variety of known sensors, including, for example, surface acoustic wave sensors, quartz crystal resonators, metal oxide sensors, dye-coated fiber optic sensors, dye-impregnated bead arrays, micromachined cantilever arrays, composites having regions of conducting material and regions of insulating organic material, composites having regions of conducting material and regions of conducting or semi-conducting organic material, chemically-sensitive resistor or capacitor films, metal-oxide-semiconductor field effect transistors, bulk organic conducting polymeric sensors, and other known sensor types, such as olfactory receptor proteins (ORPs) coated onto the surface of a piezoelectric (PZ) electrode (Wu, Biosens Bioelectron, 14(l):9-18, 1999).
  • ORPs olfactory receptor proteins
  • Actuators B 1, 10:85, 1993 surface acoustic wave (SAW) devices
  • Gardner et al Sens. Actuators B, 4:117, 1991
  • Gardner et al Sens. Actuators B, 6:71, 1992
  • Corcoran et al Sens. Actuators B, 15_:32, 1993
  • Shurmer et al Sens. Actuators B, 4:29, 1991
  • Pearce et al Analyst, 118:37, 1993, (conducting organic polymers), Freund, M. S.; Lewis, N. S. Proc. Natl. Acad.
  • sensor array 110 incorporates multiple sensing modalities, for example comprising an arrangement of cross-reactive sensors 120 selected from known sensor types, such as those listed above, such that a given analyte elicits a response from multiple sensors in the array and each sensor responds to many analytes.
  • the sensors in the array 110 are broadly cross-reactive, meaning each sensor in the array responds to multiple analytes, and, in turn, each analyte elicits a response from multiple sensors.
  • analyte is meant any molecule or compound.
  • gaseous or vapor phase analyte is meant a molecule or compound that is present, for example, in the headspace of a liquid, in ambient air, in a breath sample, in a gas, or as a contaminant in any of the foregoing. It will be recognized that the physical state of the gas or vapor phase can be changed by pressure, temperature as well as by affecting surface tension of a liquid by the presence of or addition of salts etc.
  • Detecting an analyte includes generating a response profile indicative of the presence of the analyte based on changes in a detectable signal from at least one sensor.
  • detecttable signal is meant a change in the sensor from a first state to a second state, which can be visually, electronically or acoustically detected.
  • a detectable signal generated by a sensor upon adso ⁇ tion by any particular analyte generates a response finge ⁇ rint corresponding to the detectable signal from at least one or more sensors.
  • a plurality of sensors allows expanded utility because the signal for an imperfect "key" for one sensor can be recognized through information gathered on another, chemically or physically dissimilar sensor in the array.
  • a distinct pattern of responses produced over the collection of sensors in the array can provide a finge ⁇ rint that allows classification and identification of the analyte, whereas, in some instances, such information would not have been obtainable by relying on the signals arising solely from a single sensor or sensing material.
  • the finge ⁇ rint of the analyte can include a plurality of different detectable signals and includes variations in degrees or amplitude of a detectable signal.
  • a digital representation of the detectable signal generated by the sensor is created and communicated to a remote location for analysis.
  • the digital representation of the detectable signal is transmittable over any number of media.
  • digital data can be transmitted over the Internet in encrypted or in publicly available form.
  • the data can be transmitted over phone lines, fiber optic cables or various air-wave frequencies.
  • the data are then analyzed by a central processing unit at a remote site, and/or archived for compilation of a data set that could be mined to determine, for example, changes with respect to historical mean "normal" values of the breathing air in confined spaces, of human breath profiles, and of a variety of other long term monitoring situations where detection of analytes in a sample is an important value-added component of the data.
  • a computer can be configured to characterize the analyte based on the finge ⁇ rint (e.g., the detectable signal from one or more sensors).
  • the finge ⁇ rint e.g., the detectable signal from one or more sensors.
  • an analyte finge ⁇ rint in the database can be associated with its identity or a number of other criteria, including for example, where the analyte finge ⁇ rint was obtained, the temperature, subject, disease state, location and other criteria associated with a finge ⁇ rint can be contained in the database.
  • sensors can be chosen that are appropriate for the analytes expected in a particular application, their concentrations and the desired response times.
  • a structure- function-association database correlating analytes and fmge ⁇ rints can be generated. Unknown analytes can then be characterized or identified using response pattern comparison and recognition algorithms.
  • the present invention is not limited to any particular algorithm for comparing response finge ⁇ rints as one skilled in the art will recognize a number of ways to implement a comparison algorithm. For example, data analysis can be performed using standard chemometric methods such as principal component analysis and SEVICA, which are available in commercial software packages that run on a PC or which are easily transferred into a computer running a resident algorithm or onto a single analysis chip either integrated into, or working in conjunction with, the sensor electronics.
  • the Fisher linear discriminant is one algorithm for analysis of the data, as described in more detail below. More sophisticated algorithms and supervised or unsupervised neural network based learning/training methods can be applied as well (Duda, R.O.; Hart, P.E. Pattern Classification and Scene Analysis; John Wiley & Sons: New York, 1973, pp. 482).
  • the Fisher linear discriminant searches for the projection vector, w, in the detector space which maximizes the pairwise resolution factor, i.e., rf, for each set of analytes, and reports the value of rf along this optimal linear discriminant vector.
  • the rf value is an inherent property of the data set and does not depend on whether principal component space or original detector space is used to analyze the response data.
  • This resolution factor is basically a multi-dimensional analogue to the separation factors used to quantify the resolving power of a column in gas chromatography, and thus the rf value serves as a quantitative indication of how distinct two patterns are from each other, considering both the signals and the distribution of responses upon exposure to the analytes that comprise the solvent pair of concern.
  • the probabilities of correctly identifying an analyte as a or b from a single presentation when a and b are separated with resolution factors of 1.0, 2.0 or 3.0 are approximately 76%, 92% and 98% respectively.
  • various general pu ⁇ ose machines may be used with programs written in accordance with the teachings herein, or it may be more convenient to construct more specialized apparatus to perform the operations.
  • the embodiment is implemented in one or more computer programs executing on programmable systems each comprising at least on processor, at least one data storage system (including volatile and non- volatile memory and/or storage elements), at least one input device, and at least one output device.
  • the program is executed on the processor to perform the functions described herein.
  • Each such program may be implemented in any desired computer language (including machine, assembly, high level procedural, or object oriented programming languages) to communicate with a computer system.
  • the language may be a compiled or inte ⁇ reted language.
  • the computer program will typically be stored on a storage media or device (e.g., ROM, CD- ROM, or magnetic or optical media) readable by a general or special pu ⁇ ose programmable computer, for configuring and operating the computer when the storage media or device is read by the computer to perform the procedures described herein.
  • the system may also be considered to be implemented as a computer-readable storage medium, configured with a computer program, where the storage medium so configured causes a computer to operate in a specific and predefined manner to perform the functions described herein.
  • Embodiments of the invention include systems (e.g., internet based systems), particularly computer systems which store and manipulate the data corresponding to the detectable signal obtained from an analyte, described herein.
  • systems e.g., internet based systems
  • computer systems which store and manipulate the data corresponding to the detectable signal obtained from an analyte, described herein.
  • a computer system 100 is illustrated in block diagram form in Figure 3.
  • a computer system refers to the hardware components, software components, and data storage components used to analyze the digital information obtained from odor sensors.
  • the computer system 100 typically includes a processor for processing, accessing and manipulating the data.
  • the processor 105 can be any well-known type of central processing unit, such as, for example, the Pentium III from Intel Co ⁇ oration, or similar processor from Sun, Motorola, Compaq, AMD or International Business Machines.
  • the computer system 300 is a general pu ⁇ ose system that comprises the processor 305 and one or more internal data storage components 310 for storing data, and one or more data retrieving devices for retrieving the data stored on the data storage components.
  • the processor 305 and one or more internal data storage components 310 for storing data, and one or more data retrieving devices for retrieving the data stored on the data storage components.
  • a skilled artisan can readily appreciate that any one of the currently available computer systems are suitable.
  • the computer system 300 includes a processor 305 connected to a bus which is connected to a main memory 315 (preferably implemented as RAM) and one or more internal data storage devices 310, such as a hard drive and/or other computer readable media having data recorded thereon.
  • the computer system 300 further includes one or more data retrieving device 318 for reading the data stored on the internal data storage devices 310.
  • the data retrieving device 318 may represent, for example, a floppy disk drive, a compact disk drive, a magnetic tape drive, or a modem capable of connection to a remote data storage system (e.g., via the internet) and the like.
  • the internal data storage device 310 is a removable computer readable medium such as a floppy disk, a compact disk, a magnetic tape, and the like, containing control logic and/or data recorded thereon.
  • the computer system 300 may advantageously include or be programmed by appropriate software for reading the control logic and/or the data from the data storage component once inserted in the data retrieving device.
  • a remote analyte detection system of the invention includes at least one sensor and may include a plurality of sensors, a measuring device for detecting a signal at the sensor(s), a device for transmitting the signal data to a remote location, a computer, a data structure of sensor response profiles or finge ⁇ rints, and a comparison algorithm.
  • the measuring device is adapted for the type of sensor used (e.g., electrical measuring devices for resistor based sensors and acoustic based devices for vibrational or sound based sensors).
  • 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 different sensor(s).
  • DAC digital-analog converter
  • Embodiments of the invention include remote systems for vapor or odor phase detection of an analyte.
  • the system can be associated with robotic devices that can enter hazardous areas to detect explosives, weaponry, mines, and hazardous chemicals.
  • the robotic device can enter disaster areas (e.g., collapsed buildings) to locate hazardous chemicals or trapped persons, for example.
  • the system can assist in detecting injuries associated with such trapped persons by obtaining, for example, breath samples (as discussed more fully below).
  • the systems can be used in space or on other planets to detect chemicals, air content and the like.
  • the designing of a specific robotic system is well within the ability of one skilled in the art. For example, in view of the teaching herein, a person skilled in the art, can easily design a robotic system inco ⁇ orating the sensors of the invention.
  • Temperature and humidity can be controlled but because a preferred mode is to record changes relative to the ambient baseline condition, and because the patterns for a particular type and concentration of odorant are generally independent of such baseline conditions, it is not critical to actively control these variables in some implementations of the technology. Such control could be achieved either in open-loop or closed-loop configurations.
  • the sensors and sensor arrays disclosed herein could be used with or without preconcentration of the analyte depending on the power levels and other system constraints demanded by the user. Regardless of the sampling mode, the characteristic patterns (both from amplitude and temporal features, depending on the most robust classification algorithm for the pu ⁇ ose) associated with certain disease states and other volatile analyte signatures can be identified using the sensors disclosed herein. These patterns are then stored in a library, and matched against the signatures emanating from the sample to determine the likelihood of a particular odor falling into the category of concern (disease or nondisease, toxic or nontoxic chemical, good or bad polymer samples, fresh or old fish, fresh or contaminated air, and the like.).
  • Analyte sampling will occur differently in the various application scenarios.
  • direct headspace samples can be collected using either single breath and urine samples in the case of sampling a patient's breath for the pu ⁇ ose of disease or health state differentiation and classification.
  • extended breath samples passed over a Tenax, Carbopack, Poropak, Carbosieve, or other sorbent preconcentrator material, can be obtained when needed to obtain robust intensity signals.
  • the absorbent material of the fluid concentrator can be, but is not limited to, a nanoporous material, a microporous material, a chemically reactive material, a nonporous material and combinations thereof.
  • the absorbent material can concentrate the analyte by a factor that exceeds a factor of about 10 5 , or by a factor of about 10 2 to about 10 4 .
  • removal of background water vapor is conducted in conjunction, such as concomitantly, with the concentration of the analyte.
  • the analyte Once the analyte is concentrated, it can be desorbed using a variety of techniques, such as heating, purging, stripping, pressuring or a combination thereof.
  • Breath samples can be collected through a straw or suitable tube in a patient's mouth that is connected to the sample chamber (or preconcentrator chamber), with the analyte outlet available for capture to enable subsequent GC/MS or other selected laboratory analytical studies of the sample.
  • headspace samples of odorous specimens can be analyzed and/or carrier gases can be used to transmit the analyte of concern to the sensors to produce the desired response.
  • the analyte will be in a liquid phase and the liquid phase will be directly exposed to the sensors; in other cases the analyte will undergo some separation initially and in yet other cases only the headspace of the analyte will be exposed to the sensors.
  • the analyte can be concentrated from an initial sample volume of about 10 liters and then desorbed into a concentrated volume of about 10 milliliters or less, before being presented to a sensor or sensor array.
  • Suitable commercially available adsorbent materials include but are not limited to, Tenax TA, Tenax GR, Carbotrap, Carbopack B and C, Carbotrap C, Carboxen, Carbosieve Sill, Porapak, Spherocarb, and combinations thereof.
  • Preferred adsorbent combinations include, but are not limited to, Tenax GR and Carbopack B; Carbopack B and Carbosieve SO; and Carbopack C and Carbopack B and Carbosieve SHI or Carboxen 1000.
  • Those skilled in the art will know of other suitable absorbent materials.
  • removal of background water vapor is conducted in conjunction, such as concomitantly, with the concentration of the analyte.
  • concentration of the analyte Once the analyte is concentrated, it can be desorbed using a variety of techniques, such as heating, purging, stripping, pressuring or a combination thereof.
  • the sample concentrator is typically wrapped with a wire through which current can be applied to heat and thus, desorb the concentrated analyte. The analyte is thereafter transferred to the sensor array.
  • the array will not yield a distinct signature of each individual analyte in a region, unless one specific type of analyte dominates the chemical composition of a sample. Instead, a pattern that is a composite, with certain characteristic temporal features of the sensor responses that aid in formulating a unique relationship between the detected analyte contents and the resulting array response, will be obtained.
  • a sample includes a wide variety of analytes and fluids which can be analyzed by the disclosed sensors, arrays and noses so long as the subject analyte is capable generating a differential response across a plurality of sensors of the array.
  • a sample can be an environmental sample and includes atmospheric air, ambient air, water, sludge, and soil to name a few.
  • a sample can be a biological sample, including, for example, a subject's breath, saliva, blood, urine, feces, and various tissues to name a few.
  • Analyte applications include broad ranges of chemical classes such as organics including, for example, alkanes, alkenes, alkynes, dienes, alicyclic hydrocarbons, arenes, alcohols, ethers, ketones, aldehydes, carbonyls, carbanions, biogenic amines, thiols, polynuclear aromatics and derivatives of such organics, e.g., halide derivatives, etc., biomolecules such as sugars, isoprenes and isoprenoids, fatty acids and derivatives, etc.
  • organics including, for example, alkanes, alkenes, alkynes, dienes, alicyclic hydrocarbons, arenes, alcohols, ethers, ketones, aldehydes, carbonyls, carbanions, biogenic amines, thiols, polynuclear aromatics and derivatives of such organics, e.g., halide derivatives, etc., biomolecules such as sugar
  • Another application for the sensor-based fluid detection device in engine fluids is an oil/antifreeze monitor, engine diagnostics for air/fuel optimization, diesel fuel quality, volatile organic carbon measurement (NOC), fugitive gases in refineries, food quality, halitosis, soil and water contaminants, air quality momtoring, leak detection, fire safety, chemical weapons identification, use by hazardous material teams, explosive detection, breathalyzers, ethylene oxide detectors and anaesthetics.
  • OOC volatile organic carbon measurement
  • Biogenic amines such as putrescine, cadaverine, and spermine are formed and degraded as a result of normal metabolic activity in plants, animals and microorganisms and can be identified in order to assess the freshness of foodstuffs such as meats (Veciananogues, J. Agr. Food Chem., 45:2036-2041, 1997), cheeses, alcoholic beverages, and other fermented foods. Additionally, aniline and o-toluidine have been reported to be biomarkers for subjects having lung cancer (Preti et al, J. Chromat. Biomed. Appl.
  • biogenic amines and thiols are biomarkers of bacteria, disease states, food freshness, and other odor-based conditions.
  • the electronic nose sensor elements and arrays discussed herein can be used to monitor the components in the headspace of urine, blood, sweat, and saliva of human patients, as well as breath, to diagnose various states of health, such as the timing of estrus (Lane et al, J Dairy Sci 81(8):2145-50, 1998), and diseases as discussed herein.
  • the invention provides physicians and patients with a method to monitor illness and disease from remote locations. It is envisioned that the systems of the invention will be useful in medical care personnel monitoring patients who are bed-ridden at home or whom require continual monitoring of a particular disease state. Such remote monitoring ability eliminates the need for repeated trips to a doctors office or hospital and can provide physicians with real-time data regarding a patient's health and well-being.
  • breath testing has long been recognized as a nonintrusive medical technique that allows for the diagnosis of disease by linking specific volatile organic vapor metabolites in exhaled breath to medical conditions (see Table 1).
  • breath analysis offers several other potential advantages in certain instances, such as 1) breath samples are easy to obtain, 2) breath is in general a much less complicated mixture of components than either serum or urine samples, 3) direct information can be obtained on the respiratory function that is not readily obtainable by other means, 4) breath analysis offers the potential for direct real time monitoring of the decay of toxic volatile substances in the body, and 5) breath analysis can be performed at remote locations (e.g., away from a physician's office).
  • Table 1 lists some of the volatile organic analytes that have been identified as targets for specific diseases using gas chromatography/mass spectrometry (GC/MS) methods, with emphasis on amines.
  • GC/MS gas chromatography/mass spectrometry
  • Trimethylaminuria trimethylamine breath, urine, Preti, 1992; sweat, vaginal Alwaiz, 1989 discharge
  • Halitosis hydrogen sulfide, methyl mercaptan, mouth air cadaverine, putrescine, indole, skatole
  • the invention is used with subjects who potentially have a medical condition such as, for example, diabetes mellitus or any disease having a byproduct chemical analyte as described in Table 1 , to improve diagnosis and treatment of medical disorder more accurate and to assist medical practitioners in determining the proper amount of medication or other treatment to prescribe.
  • a medical condition such as, for example, diabetes mellitus or any disease having a byproduct chemical analyte as described in Table 1
  • the term medical practitioner is intended to include any individual who treats, or prescribes treatment to another individual to improve the latter' s health or well-being.
  • the focus of this invention is to gather, organize, and present data which is collected at a location away from a medical practitioner's office. The data may be collected over a long period of time in a way that best facilitates accurate diagnosis and proper treatment of such medical conditions which require long-term profiling of medical readings.
  • data is gathered, transmitted, stored, and available to the medical practitioner at their convenience.
  • the data are gathered using a sensor system as described herein.
  • a sensor system of the invention adapted, for example, with a straw to collect a breath sample can be used.
  • the data is stored and transmitted or simultaneously transmitted to a remote site.
  • the data can be added to a database for storage, such that it is available for use when required by a medical practitioner.
  • the information could be stored in a network server in a common LAN or fiber optic network if available, e.g. in hospitals and HMOs, which often have their own dedicated computer networks to connect their administrative offices, laboratories, and doctor offices, and on which their patient medical records are stored.
  • the Internet could be used, with adequate security precautions taken to prevent unauthorized access to the information, or the information could be uploaded directly to a computer system acting as a database server via modem-to- modem communication over telephone lines.
  • the sensor system of the invention is described herein with reference to resistive sensors, however, other types of sensors are applicable to the invention including, for example, heated metal oxide thin film resistors, polymer so ⁇ tion layers on the surfaces of acoustic wave resonators, arrays of electrochemical detectors, conductive polymers or composites that consist of regions of conductors and regions of insulating organic materials, quartz crystal microbalance arrays, and the like described herein.
  • a sensor and sensor array comprises a plurality of differently responding chemical sensors.
  • the array has at least one sensor comprising at least a first and second conductive lead electrically coupled to and separated by a chemically sensitive resistor.
  • the leads may be any convenient conductive material, usually a metal, and may be interdigitized to maximize signal-to-noise strength.
  • a sensor array of the invention one or more sensors are coupled individually or as groups to an applicable detector for detecting signal changes in the sensor.
  • the array is comprised of one or more sensors having regions of an electrical conductor (e.g., an organic electrical conductor) with regions of a compositionally dissimilar material that is an electrical conductor or a non-conductive material.
  • the conductive sensor forms a resistor comprising a plurality of alternating regions of differing compositions and therefore differing conductivity transverse to the electrical path between the conductive leads.
  • a sensor is fabricated by blending a conductive material with a conductive organic material, insulator, non- conductive organic polymer, blends or co-polymers.
  • the regions separating the particles provide changes in conductance relative to the conductance of the particles themselves.
  • the gaps of different conductance arising from the conductive material range in path length from about 10 to 1,000 angstroms, usually on the order of 100 angstroms.
  • the path length and resistance of a given gap is not constant but rather changes as the material absorbs, adsorbs or imbibes an analyte.
  • the dynamic aggregate resistance provided by these gaps in a given resistor is a function of analyte permeation of the conductive organic regions of the material.
  • the conductive material may 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 and is blended with another organic conducting material to form the composite).
  • one such region is comprised of an inorganic (Au, Ag) or organic (carbon black) conductive material, while the other region is comprised of a compositionally dissimilar organic conducting polymer (polyaniline, polypyrrole, polythiophene, polyEDOT, and other conducting organic polymers such as those in the Handbook of Conducting Polymers (Handbook of Conducting Polymers, second ed., Marcel Dekker, New York 1997, vols. 1 & 2)). Other combinations of conductor/organic conductor/composite materials are also useful.
  • an electrically conductive material that is dopable or undopable by protons can be used as the organic material in a composite where the compositionally different conductor is carbon black.
  • the conductive form of polyaniline commonly referred to as the emeraldine salt (ES), has been reported to deprotonate to the emeraldine base and become insulating in alkaline environments.
  • Table 2 provides exemplary conductive materials for use in sensor fabrication; blends, such as of those listed, may also be used.
  • conductors include, for example, those having a positive temperature coefficient of resistance.
  • the sensors are comprised of a plurality of alternating regions of a conductor with regions of a compositionally dissimilar conducting organic material. Without being bound to any particular theory, it is believed that the electrical pathway that an electrical charge traverses between the two contacting electrodes traverses both the regions of the conductor and the regions of the organic material.
  • Organic Conductors conducting polymers poly (anilines) , poly(thio- phenes, poly (pyrroles) , poly (aceylenes, etc.)), carbonaceous material
  • the conducting region can be anything that can carry electrons from atom to atom, including, but not limited to, a metal, a polymer, a substrate, an ion, an alloy, an organic material, (e.g., carbon, graphite, etc.) an inorganic material, and a biomaterial.
  • the conductive material is 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.
  • Such nanoparticles are optionally stabilized with organic ligands. Examples of colloidal nanoparticles for use in accordance with the invention are described in the literature.
  • the electrically conductive organic region can optionally be a ligand that is attached to a central core making up the nanoparticle.
  • These ligands i.e., caps, can be polyhomo- or polyhetero-functionalized, thereby being suitable for detecting a variety of chemical analytes.
  • the nanoparticles are stabilized by the attached ligands.
  • the conducting component of the resistors are nanoparticles comprising a central core conducting element and an attached ligand optionally in a polymer matrix.
  • various conducting materials are suitable for the central core.
  • the nanoparticles have a metal core.
  • Typical metal cores include, but are not limited to, Au, Ag, Pt, Pd, Cu, Ni, AuCu and regions thereof.
  • Gold (Au) is most typical.
  • the particle size can be manipulated and controlled.
  • the conductive organic material can be either an organic semiconductor or organic conductor.
  • the organic materials that are useful in one embodiment of the invention are either semiconductors or conductors.
  • Such materials are collectively referred to herein as electrically conducting organic materials because they produce a readily-measured resistance between two conducting leads separated by about 10 micron or more using readily-purchased multimeters having resistance measurement limits of 100 Mohm or less, and thus allow the passage of electrical current through them when used as elements in an electronic circuit at room temperature.
  • Insulator show very low room temperature conductivity values, typically less than about 10 "8 ohm " 'cm "1 .
  • Poly(styrene), poly(ethylene), and other polymers provide examples of insulating organic materials.
  • Metals have very high room temperature conductivities, typically greater than about 10 ohm "1 cm “1 .
  • Semi-conductors have conductivities greater than those of insulators, and are distinguished from metals by their different temperature dependence of conductivity, as described above.
  • the organic materials that are useful in one embodiment of sensors are either electrical semiconductors or conductors, and have room temperature electrical conductivities of greater than about 10 "6 ohm "1 cm “1 , typically having a conductivity of greater than about
  • the sensors of the invention include sensors comprising regions of an electrical conductor and regions of a compositionally different organic material that is an electrical conductor or semiconductor.
  • electrical conductors include, for example, Au, Ag, Pt and carbon black, other conductive materials having similar resistivity profiles are easily identified in the art (see, for example the latest edition of: The CRC Handbook of Chemistry and Physics, CRC Press, the disclosure of which is inco ⁇ orated herein by reference).
  • insulators can also be inco ⁇ orated into the composite either in place of- or in addition to- the regions of compositionally different material, as described above, to further manipulate the analyte response properties of the composites.
  • the insulating region (i.e., non-conductive region) can be anything that can impede electron flow from atom to atom, including, but not limited to, a polymer, a plasticizer, an organic material, an organic polymer, a filler, a ligand, an inorganic material, a biomaterial, and combinations thereof.
  • Table 3 provides examples of insulating or non-conducting organic materials that can be used for such pu ⁇ oses. TABLE 3 :
  • Main-chain carbon polymers poly (dienes) , poly (alkenes) , poly (acrylics) , poly(metha- crylics) , poly (vinyl ethers), poly (vinyl thioethers) , poly(vinyl alcohols), poly (vinyl ketones) , poly (vinyl halides), poly (vinyl nitrites), poly (vinyl esters), poly (styrenes) , poly (aryines) etc.
  • Main-chain acyclic heteroatom polymers poly (oxides) , poly (caronates) , poly (esters) , poly- (anhydrides ) , poly (urethanes) , poly (sulfonate) , poly- (siloxanes) , poly (sulfides) , poly (thioesters) , poly(sul- fones) , poly (sulfonamindes) , poly (amides) , poly(ureas), poly (phosphazens) , poly- (silanes) , poly (silazanes) , etc.
  • Main-chain heterocyclic polymers poly (furantetracarboxylic acid diimides) , poly (benzoxazoles) , poly (oxadiazoles) , poly(benzo- thiazinopheno-thiazines) , poly (benzothiazoles) , poly- (pyrazinoquinoxalines) , poly- (pyromenitimides) , poly(guin- oxalines) , poly (benzimida- zoles) , poly (oxidoles) , poly- (oxoisinodolines) , poly- (diaxoisoindoines) , poly(tri- azines) , poly (pyridzaines) , poly (pioeraziness) , poly- (pyridinees) , poly(pioeri- diens) , poly (triazoles) , poly (pyrazoles) , poly (pyrroli- dines) , poly (carboranes
  • Non-conductive organic polymer materials may also be used.
  • Combinations, concentrations, blend stoichiometries, percolation thresholds, etc. are readily determined empirically by fabricating and screening prototype resistors (chemiresistors) as described below.
  • the senor comprises a plurality of alternating nonconductive and conductive regions transverse to an electrical path between conductive leads.
  • these sensors are fabricated by blending a conductive material with a nonconductive organic polymer such that the electrically conductive path between the leads coupled to the sensor is interrupted by gaps of non-conductive organic polymer material.
  • the matrix regions separating the particles provide the gaps.
  • the nonconductive 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 path length and resistance of a given gap is not constant but rather is believed to change as the nonconductive organic polymer of the region absorbs, adsorbs or imbibes an analyte. Accordingly the dynamic aggregate resistance provided by these gaps in a given sensor is a function of analyte permeation of the nonconductive regions.
  • the conductive material may 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 polyprryole).
  • a wide variety of conductive materials and nonconductive organic polymer materials can be used as described herein and in U.S. Patent No. 5,571,401, which is inco ⁇ orated herein by reference in its entirety.
  • the chemiresistors can be fabricated by many techniques such as, but not limited to, solution casting, suspension casting, and mechanical mixing.
  • solution cast routes are advantageous because they provide homogeneous structures and ease of processing.
  • sensor elements may be easily fabricated by spin, spray or dip coating.
  • Suspension casting still provides the possibility of spin, spray or dip coating but more heterogeneous structures than with solution casting are expected.
  • mechanical mixing there are no solubility restrictions since it 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. A more detailed discussion of each of these follows.
  • the chemiresistors can be fabricated by solution casting.
  • the oxidation of pyrrole by phosphomolybdic acid represents such a system.
  • the phosphomolybdic acid and pyrrole are dissolved in tetrahydrofuran (THF) and polymerization occurs upon solvent evaporation.
  • THF tetrahydrofuran
  • Certain conducting organic polymers can also be synthesized via a soluble precursor polymer.
  • blends between the precursor polymer and the compositionally different material of the composite can first be formed followed by chemical reaction to convert the precursor polymer into the desired conducting polymer.
  • poly(p-phenylene vinylene) can be synthesized through a soluble sulfonium precursor.
  • Blends between this sulfonium precursor and a non-conductive or conductive polymer can be formed by solution casting. After which, the blend can be subjected to thermal treatment under vacuum to convert the sulfonium precursor to the desired poly(p-phenylene vinylene).
  • suspension casting In suspension casting, one or more of the components of the sensor is suspended and the others dissolved in a common solvent. Suspension casting is a rather general technique applicable to a wide range of species, such as carbon blacks or colloidal metals, which can be suspended in solvents by vigorous mixing or sonication.
  • the conductive organic or conductive polymer is dissolved in an appropriate solvent (such as THF, acetonitrile, water, and the like). Carbon black is then suspended in this solution and the resulting region is used to dip coat or spray coat electrodes.
  • Mechanical mixing is suitable for all of the conductive/conductive organic/non- conductive combinations possible.
  • the materials are physically mixed in a ball-mill or other mixing device.
  • carbon black/conducting organic polymer composites are readily made by ball-milling.
  • the semi-conductive or conductive or insulating organic material can be melted or significantly softened without decomposition, mechanical mixing at elevated temperature can improve the mixing process.
  • composite fabrication can sometimes be improved by several sequential heat and mix steps.
  • the individual sensors can be optimized for a particular application by varying their chemical make up and mo ⁇ hologies. The chemical nature of the sensors determines to which analytes they will respond and their ability to distinguish different analytes.
  • the relative ratio of conductive to compositionally different organic material, along with the composition of any other insulating organic or inorganic components, can determine the magnitude of the response since the resistance of the elements becomes more sensitive to sorbed molecules as the percolation threshold is approached and as the molecules interact chemically with the components of the composite that adsorb or absorb the analyte.
  • the film mo ⁇ hology is also important in determining response characteristics. For instance, uniform thin films respond more quickly to analytes than do uniform thick ones. However, it may be advantageous to include sensors of varying thickness to determine various diffusion coefficients or other physical characteristics of the analyte being analyzed.
  • sensors can be chosen that are appropriate for the analytes expected in a particular application, their concentrations, and the desired response times. Further optimization can then be performed in an iterative fashion as feedback on the performance of an array under particular conditions becomes available.
  • the resistor may itself form a substrate for attaching the lead or the resistor.
  • the structural rigidity of the resistors may be enhanced through a variety of techniques: chemical or radiation cross-linking of polymer components (dicumyl peroxide radical cross-linking, UV-radiation cross-linking of poly(olefins), sulfur cross- linking of rubbers, e-beam cross-linking of Nylon, etc.), the inco ⁇ oration of polymers or other materials into the resistors to enhance physical properties (for instance, the inco ⁇ oration of a high molecular weight, high melting temperature (T ⁇ polymers), the inco ⁇ oration of the resistor elements into supporting matrices such as clays or polymer networks (forming the resistor blends within poly-(methylmethacrylate) networks or within the lamellae of montmorillonite, for instance), etc.
  • the resistor is deposited as a surface layer on a solid matrix which provides means for supporting the leads.
  • Sensor arrays particularly well-suited to scaled up production are fabricated using integrated circuit (IC) design technologies.
  • the chemiresistors can easily be integrated onto the front end of a simple amplifier interfaced to an A/D converter to efficiently feed or transmit the data stream directly into a neural network software or hardware analysis section at a remote location.
  • Micro-fabrication techniques can integrate the chemiresistors directly onto a micro-chip which contains the circuitry for analog 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 array can be induced in a method analogous to how a color ink-jet printer deposits and mixes multiple colors.
  • a sensor array of a million distinct elements only requires a 1 cm x 1 cm sized chip employing lithography at the 10 micrometer 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.
  • the sensor arrays have a predetermined inter-sensor variation in the structure or composition of the organic materials as well as in the conductive components and any insulating or plastizing components of the composites.
  • the variation may be quantitative and or qualitative.
  • the concentration of the organic material in the composite can be varied across sensors.
  • a variety of different organic materials may be used in different sensors.
  • the anions that accompany conducting or semi-conducting organic polymers such as polyaniline in some doping states can be compositionally varied to add diversity to the array, as can the polymer composition itself, either structurally (through use of a different family of materials) or through modification of the backbone and/or side chains of the basic polymer structure.
  • This ability to fabricate many chemically different materials allows ready inco ⁇ oration of a wide range of chemical diversity into the sensor elements, and also allows facile control over the electrical properties of the sensor elements through control over the composition of an individual sensor element in the array.
  • Insulating organic materials can also be used and blended into the array in order to further increase the diversity in one embodiment of the invention.
  • organic polymers can provide the basic sensor components that respond differently to different analytes, based on the differences in polarity, molecular size, and other properties of the analyte in order to achieve the chemical diversity amongst array elements in the electronic nose sensors.
  • Such insulators would include main-chain carbon polymers, main chain acyclic heteroatom polymers, main- chain heterocyclic polymers, and other insulating organic materials. Otherwise, these properties can be obtained by modification in the composition of the organic component of the sensor composition by use of capping agents on a colloidal metal part of the conductive phase, by use of different plasticizers added to otherwise compositionally identical sensor elements to manipulate their analyte so ⁇ tion and response properties, by variation in the temperature or measurement frequency of the sensors in an array of sensors that are otherwise compositionally identical, or a combination thereof and with sensors that are compositionally different as well.
  • the sensors in an a array can readily be made by combinatorial methods in which a limited number of feedstocks is combined to produce a large number of chemically distinct sensor elements.
  • One method of enhancing the diversity of polymer based conductor/conductor or conductor/semiconductor chemiresistors is through the use of polymer blends or copolymers (Doleman, et al, Anal. Chem. 20:2560-2654, 1998).
  • Immiscible polymer blends may also be of interest because carbon black or other conductors can be observed to preferentially segregate into one of the blend components. Such a distribution of carbon black conduction pathways may result in valuable effects upon analyte so ⁇ tion, such as the observance of a double percolation threshold.
  • Binary polymer blend sensors can be prepared from a variety of polymers at incrementally different blend stoichiometries.
  • a spray gun with dual controlled-flow feedstocks could be used to deposit a graded- composition polymer film across a series of electrodes.
  • Such automated procedures allow extension of the sensor compositions beyond simple binary blends, thereby providing the opportunity to fabricate chemiresistors with so ⁇ tion properties incrementally varied over a wide range.
  • a combinatorial approach aided by microjet fabrication technology is one approach that will be known to those skilled in the art. For instance, a continuous jet fed by five separate feedstocks can fabricate numerous polymer blends in a combinatorial fashion on substrates with appropriately patterned sets of electrodes.
  • the resistors can include nanoparticles comprising a central core conducting element and an attached ligand, with these nanoparticles dispersed in a semi-conducting or conducting or insulating organic matrix.
  • the nanoparticles have a metal core.
  • metal cores include, but are not limited to, Au, Ag, Pt, Pd, Cu, Ni, AuCu and regions thereof.
  • These metallic nanoparticles can be synthesized using a variety of methods. In one method of synthesis, a modification of the protocol developed by House et al. (the teachings of which are inco ⁇ orated herein by reference), can be used.
  • alkanethiolate gold clusters as an illustrative example, and not in any way to be construed as limiting, the starting molar ratio of HAuCl 4 to alkanethiol is selected to construct particles of the desired diameter.
  • HAuCl 4 by an alkanethiol and sodium borohydride leads to stable, modestly poly disperse, alkanethiolate-protected gold clusters having a core dimension of about 1 nm to about 100 nm.
  • the nanoparticles range in size from about 1 nm to about 50 nm, but may also range in size from about 5 nm to about 20 nm.
  • sensors are prepared as composites of "naked” nanoparticles and a semi-conducting or conducting organic material is added.
  • naked nanoparticles means that the core has no covalently attached ligands or caps.
  • organic materials can be used in this embodiment.
  • Preferred semi-conducting or conducting materials are organic polymers. Suitable organic polymers include, but are not limited to, polyaniline, polypyrrole, polyacetylene, polythiophene, polyEDOT and derivatives thereof. Varying the semi-conducting or conducting material types, concentration, size, etc., provides the diversity necessary for an array of sensors.
  • the conductor to semi-conducting or conducting organic material ratio is about 50% to about 90% (wt/wt).
  • a typical sensor array would produce a unique signature for every different analyte to which it was exposed.
  • detectors that probe important, but possibly subtle, molecular parameters such as chirality.
  • 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. For instance, because the active sites of enzymes are chiral, only the correct enantiomer is recognized as a substrate.
  • One optical form (or enantiomer) of a racemic region 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.
  • Plasticizers can also be used to obtain improved mechanical, structural, and so ⁇ tion properties of the sensing films.
  • Suitable plasticizers for use in the present invention include, but are not limited to, phthalates and their esters, adipate and sebacate esters, polyols such as polyethylene glycol and their derivatives, tricresyl phosphate, castor oil, camphor etc. Those of skill in the art will be aware of other plasticizers suitable for use in the present invention.
  • the plasticizer can also be added to an organic polymer forming an inte ⁇ enetrating network (IPN) comprising a first organic polymer and a second organic polymer formed from an organic monomer polymerized in the presence of the first organic polymer.
  • IPN inte ⁇ enetrating network
  • This technique works particularly well when dealing with polymers that are immiscible in one another, where the polymers are made from monomers that are volatile. Under these conditions, the preformed polymer is used to dictate the properties (e.g., viscosity) of the polymer-monomer region. Thus, the polymer holds the monomer in solution.
  • Examples of such a system are (1) polyvinyl acetate with monomer methylmethacrylate to form an IPN of pVA and pMMA, (2) pVA with monomer styrene to form an IPN of pVA and polystyrene, and (3) pVA with acrylonitrile to form an EPN of pVA and polyacrylonitrile.
  • Each of the example compositions would be modified by the addition of an appropriate plasticizer. More than one monomer can be used where it is desired to create an IPN having one or more copolymers.
  • the senor for detecting the presence of a analyte in a sample comprises a chemically sensitive resistor electrically connected to an electrical measuring apparatus where the resistor is in thermal communication with a temperature control apparams.
  • the chemically sensitive resistor(s) comprise regions of a conductive material and regions of a material which is compositionally different than the conductive material.
  • the chemically sensitive resistor provides an electrical path through which electrical current may flow and a resistance (R) at a temperature (T) when contacted with a fluid comprising a chemical analyte.
  • the chemically sensitive resistor(s) of the sensor for detecting the presence of a chemical analyte in a fluid provide an electrical resistance ( ⁇ ) when contacted with a fluid comprising a chemical analyte at a particular temperature (T ⁇ .
  • the electrical resistance observed may vary as the temperature varies, thereby allowing one to define a unique profile of electrical resistances at various different temperatures for any chemical analyte of interest.
  • a chemically sensitive resistor when contacted with a fluid comprising a chemical analyte of interest, may provide an electrical resistance R,,, at temperature T m where m is an integer greater than 1, and may provide a different electrical resistance Renfin at a different temperature T n .
  • the difference between R TM and R vom is readily detectable by an electrical measuring apparatus.
  • the chemically sensitive resistor(s) of the sensor are in thermal communication with a temperature control apparatus, thereby allowing one to vary the temperature at which electrical resistances are measured.
  • the sensor comprises an array of two or more chemically sensitive resistors each being in thermal communication with a temperature control apparatus, one may vary the temperature across the entire array (i.e., generate a temperature gradient across the array), thereby allowing electrical resistances to be measured simultaneously at various different temperatures and for various different resistor compositions.
  • an array of chemically sensitive resistors one may vary the composition of the resistors in the horizontal direction across the array, such that resistor composition in the vertical direction across the array remains constant.
  • One may then create a temperature gradient in the vertical direction across the array, thereby allowing the simultaneous analysis of chemical analytes at different resistor compositions and different temperatures.
  • Methods for placing chemically sensitive resistors in thermal communication with a temperature control apparatus include, for example, attaching a heating or cooling element to the sensor and passing electrical current through said heating or cooling element.
  • the temperature range across which electrical resistance may be measured will be a function of the resistor composition, for example the melting temperature of the resistor components, the thermal stability of the analyte of interest or any other component of the system, and the like.
  • the temperature range across which electrical resistance will be measured will be about 10 °C to 80 °C, preferably from about 22 °C to about 70 °C and more preferably from about 20 °C to 65 °C.
  • the senor can be subjected to an alternating electrical current at different frequencies to measure impedance. Impedance is the apparent resistance in an alternating electrical current as compared to the true electrical resistance in a direct current.
  • the present invention is also directed to a sensor for detecting the presence of a chemical analyte in a fluid, said sensor comprising a chemically sensitive resistor electrically connected to an electrical measuring apparatus, said chemically sensitive resistor comprising regions of conductive material and regions of a material compositionally different than the conductive material and wherein the resistor provides an electrical impedance Z m at frequency m when contacted with a fluid comprising said chemical analyte, where m is an integer greater than 1 and m does not equal 0.
  • the frequencies employed will generally range from about 1 Hz to 5 GHz, usually from about 1 MHZ to 1 GHz, more usually from about 1 MHZ to 10 MHZ and preferably from about 1 MHZ to 5 MHZ.
  • Chemical analytes of interest will exhibit unique impedance characteristics at varying alternating current frequencies, thereby allowing one to detect the presence of any chemical analyte of interest in a fluid by measuring Z m at alternating frequency m.
  • the resistor/sensor is held in an Al chassis box to shield it from external electronic noise.
  • the present invention is also directed to a sensor for detecting the presence of a chemical analyte in a fluid, said sensor comprising a chemically sensitive resistor electrically connected to an electrical measuring apparams and being in thermal communication with a temperature control apparatus, said chemically sensitive resistor comprising regions of conductive material and regions of a material compositionally different than the conductive material, wherein said resistor provides (1) an electrical path through the material, and (2) an electrical impedance Z ⁇ n at frequency m and temperature T n when contacted with a fluid comprising said chemical analyte, where m and/or n is an integer greater than 1.
  • the frequencies employed will generally not be higher than 10 MHZ, preferably not higher than 5 MHZ.
  • Chemical analytes of interest will exhibit unique impedance characteristics at varying alternating current frequencies and varying temperatures, thereby allowing one to detect the presence of any chemical analyte of interest in a fluid by measuring Z ⁇ n at frequency m and temperature T n .
  • one particular sensor composition can be used in an array and the response properties can be varied by maintaining each sensor at a different temperature from at least one of the other sensors, or by performing the electrical impedance measurement at a different frequency for each sensor, or a combination thereof.
  • An electronic nose for detecting an analyte in a fluid is fabricated by electrically coupling the sensor leads of an array of differently responding sensors to an electrical measuring device.
  • the device measures changes in signal at each sensor of the array, preferably simultaneously and preferably over time.
  • the signal is an electrical resistance, although it could also be an impedance or other physical property of the material in response to the presence of the analyte in the fluid.
  • the device includes signal 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.
  • such a nose comprises usually at least ten, often at least 100, and perhaps at least 1000 different sensors though with mass deposition fabrication techniques described herein or otherwise known in the art, arrays of on the order of at least one million sensors are readily produced.
  • the temporal response of each sensor is recorded.
  • the temporal response of each sensor may be normalized to a maximum percent increase and percent decrease in signal which produces a response pattern associated with the exposure of the analyte.
  • the desired signals if monitored as dc electrical resistances for the various sensor elements in an array can be read merely by imposing a constant current source through the resistors and then monitoring the voltage across each resistor through use of a commercial multiplexable 20 bit analog-to-digital converter.
  • signals are readily transmited and stored in a computer that contains a resident algorithm for data analysis and archiving.
  • Signals can also be preprocessed either in digital or analog form; the latter might adopt a resistive grid configuration, for example, to achieve local gain control.
  • long time adaptation electronics can be added or the data can be processed digitally after it is collected from the sensors themselves. This processing could be on the same chip as the sensors but also could reside on a physically separate chip or computer.
  • a system acquires data from a sensor array when exposed to an unknown analyte, compares the sensor data for the unknown to data stored in a database, then provides the name of the analyte if the unknown matches a member of the database within some threshold accuracy. If no match is found the system returns the word "UNKNOWN".
  • the system does four things: 1) collect response data from an array of chemiresistive vapor detectors exposed to an unknown analyte, 2) analyze the data and calculate the array response to the unknown, 3) compare the unknown's response values to values stored in a database, and, if a match is found that is within a desired accuracy, identifies the unknown.
  • a database of the signatures for the analytes that are exposed to the sensor array is compiled, which can be used for historical analysis of change detection of that analyte as well as other transverse studies amongst groups of exposures to look for correlations between members of the group entries into the database.
  • the system was implemented with sensors consisting of conductive carbon black/polymer composite thin film chemiresistors that respond to analytes through a change in dc electrical resistance.
  • the response was calculated as a differential relative resistance change ( ⁇ R/ R ⁇ ) for each detector that occurs when the analyte molecules absorb into the films.
  • the array consisted of 8 detectors each having a unique polymer component, each of which responds uniquely to an analyte vapor creating a pattern of response that is unique to that analyte vapor/detector array combination.
  • the resistance data from the detector array were collected using a Keithely 2002 DMM coupled to a Keithely 7001 MUX that were controlled by a Lab VIEW custom software program that integrated both units in to a real-time data acquisition system.
  • the data collection and analysis protocols were written as Lab VIEW programs. These programs controlled the Keithely data acquisition system, stored the training sets, and compared unknowns to the training sets to make identifications. Additionally, a graphical user interface (GUI) was constructed consisting of dialog boxes, pull-down menus, operational buttons, and data output graphs. On the front panel of the GUI, the user defines the training analytes, sets an identification threshold, and can observe, in real-time, response histograms for both the training and unknown analytes.
  • GUI graphical user interface
  • the procedure for unknown identification is to first conduct training sets on the analytes of interest.
  • the detector array was exposed to the test analytes in the same manner as will be used during subsequent identification attempts.
  • the exposure established a baseline value for each of the detectors by observing on the computer screen the response by the array to baseline conditions. Once a steady-state response was achieved, a virtual-button was clicked on front panel of the GUI causing the program to save those response values and label them as baseline values (R b values).
  • R is the baseline resistance value stored for each sensor when the user clicked the "zero" button on the GUI
  • R is the real-time resistance value for each resistor
  • Q is defined as the response by a detector to an analyte.
  • Q is calculated for every 1 x 8 array (8 detectors) of resistance values received from the Keithely system (approximately one set every second) and these response values are displayed on the GUI as a histogram, the abscissa of which corresponds to the detector number.
  • the Q values are labeled with the analyte descriptor and added to a training database for later use during identification tests. This procedure is done for each analyte trained into the system.
  • the user can identify analytes for which training data exists.
  • the user places the array into baseline conditions and clicks the "Zero" button thus saving those R t , values to be used in equation 1.
  • the user places the array in the presence of the test analyte and the program calculates Q values.
  • T is the response value in each training set for each of n detectors in the array
  • m is the number of training sets
  • D m is a scalar indicating the Euclidian distance between the Q values and the training set
  • T m in detector-space.
  • the minimum distance (D ⁇ ⁇ is compared to a user-defined threshold. If D ⁇
  • the program can normalize the patterns and can save the data to a tab- delimited text file.
  • the algorithm can again be "zeroed", and a subsequent identification test can begin immediately.
  • This hardware and software package is a stand-alone electronic nose that can detect and identify an analyte vapor without requiring data collection, manipulation, and synthesis by a user.
  • the system allows for archiving and transmitting data to a remote location.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Health & Medical Sciences (AREA)
  • Analytical Chemistry (AREA)
  • Food Science & Technology (AREA)
  • Medicinal Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • Combustion & Propulsion (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Immunology (AREA)
  • Pathology (AREA)
  • Alarm Systems (AREA)
  • Investigating Or Analyzing Materials By The Use Of Fluid Adsorption Or Reactions (AREA)

Abstract

L'invention concerne des compositions et des systèmes permettant une surveillance à distance des risques chimiques, de la qualité de l'air et de pathologies, par exemple des systèmes robotiques permettant de rechercher et de détecter des explosifs, des mines et des produits chimiques dangereux. Ces procédés, systèmes et compositions offrent la possibilité d'explorer les données d'une base de données contenant une pluralité d'empreintes chimiques de référence.
PCT/US2000/016770 1999-06-16 2000-06-15 Procede de caracterisation a distance d'une odeur WO2000078204A2 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US14002799P 1999-06-16 1999-06-16
US60/140,027 1999-06-16
US09/409,644 US8394330B1 (en) 1998-10-02 1999-10-01 Conductive organic sensors, arrays and methods of use
US09/409,644 1999-10-01
US09/568,784 2000-05-10
US09/568,784 US6455319B1 (en) 1999-05-10 2000-05-10 Use of spatiotemporal response behavior in sensor arrays to detect analytes in fluids

Publications (2)

Publication Number Publication Date
WO2000078204A2 true WO2000078204A2 (fr) 2000-12-28
WO2000078204A3 WO2000078204A3 (fr) 2001-07-26

Family

ID=27385433

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2000/016770 WO2000078204A2 (fr) 1999-06-16 2000-06-15 Procede de caracterisation a distance d'une odeur

Country Status (1)

Country Link
WO (1) WO2000078204A2 (fr)

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002035494A1 (fr) * 2000-10-25 2002-05-02 NYSTART 15 i AROS AB Detecteur, systeme et procede de surveillance d'un environnement et de comparaison d'informations detectees a des donnees de reference
DE10104968A1 (de) * 2001-02-03 2002-08-08 Deutsche Telekom Ag Verfahren zur gleichzeitigen Übertragung von verschiedenen sensorischen Daten über das Telekommunikationsnetz
WO2002068953A1 (fr) * 2001-02-28 2002-09-06 Basf Aktiengesellschaft Procede et dispositif pour detecter la presence de fumigenes dans des echantillons d'air
WO2002077636A2 (fr) * 2001-03-27 2002-10-03 Centre National De La Recherche Scientifique Detecteur d'une signature volatile et procedes associes
EP1969361A2 (fr) * 2005-12-23 2008-09-17 Itt Manufacturing Enterprises, Inc. Systeme de base de donnees et procede pour l'analyse et l'association de donnees observables avec des substances, materiel, et processus
DE102008012444A1 (de) * 2008-03-04 2009-09-10 Aweco Appliance Systems Gmbh & Co. Kg Vorrichtung zum Testen des Frischegrades von Lebensmitteln
US8828733B2 (en) * 2007-01-19 2014-09-09 Cantimer, Inc. Microsensor material and methods for analyte detection
WO2016177374A1 (fr) 2015-05-01 2016-11-10 Aminic Aps Dispositif muni d'un capteur basé sur la micromécanique ou la nanomécanique pour la détection de molécules de décomposition telles que des amines biogènes (associées à la détérioration des aliments et certaines maladies humaines entre autres) et calcul consécutif pour déterminer la fraîcheur et la date d'expiration
WO2017109432A1 (fr) * 2015-12-24 2017-06-29 Partnering 3.0 Systeme de surveillance de qualite d'air et station d'accueil pour robot mobile equipe de capteurs de qualite d'air
CN106940340A (zh) * 2017-04-14 2017-07-11 中国石油化工股份有限公司 危险气氛综合状态指纹识别系统
EP3267192A1 (fr) * 2016-07-07 2018-01-10 Alpha M.O.S. Chromatographe en phase gazeuse
CN113358798A (zh) * 2021-07-16 2021-09-07 天津市生态环境科学研究院(天津市环境规划院、天津市低碳发展研究中心) 热脱附-气相色谱质谱检测杂环类异味物质的方法
CN113358817A (zh) * 2021-04-22 2021-09-07 上海工程技术大学 一种基于气体浓度梯度驱动的气体源定位装置
US11163311B2 (en) 2015-12-24 2021-11-02 Partnering 3.0 Robotic equipment including a mobile robot, method for recharging a battery of such mobile robot, and mobile robot docking station

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5911872A (en) * 1996-08-14 1999-06-15 California Institute Of Technology Sensors for detecting analytes in fluids
US6013229A (en) * 1995-03-27 2000-01-11 California Institute Of Technology Sensor arrays for detecting analytes in fluids
US6017440A (en) * 1995-03-27 2000-01-25 California Institute Of Technology Sensor arrays for detecting microorganisms

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6013229A (en) * 1995-03-27 2000-01-11 California Institute Of Technology Sensor arrays for detecting analytes in fluids
US6017440A (en) * 1995-03-27 2000-01-25 California Institute Of Technology Sensor arrays for detecting microorganisms
US5911872A (en) * 1996-08-14 1999-06-15 California Institute Of Technology Sensors for detecting analytes in fluids

Cited By (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002035495A1 (fr) * 2000-10-25 2002-05-02 NYSTART 15 i AROS AB Detecteur, systeme et procede de surveillance d'un environnement et de comparaison d'informations detectees a des donnees de reference
WO2002035494A1 (fr) * 2000-10-25 2002-05-02 NYSTART 15 i AROS AB Detecteur, systeme et procede de surveillance d'un environnement et de comparaison d'informations detectees a des donnees de reference
DE10104968A1 (de) * 2001-02-03 2002-08-08 Deutsche Telekom Ag Verfahren zur gleichzeitigen Übertragung von verschiedenen sensorischen Daten über das Telekommunikationsnetz
JP2004530116A (ja) * 2001-02-28 2004-09-30 ビーエーエスエフ アクチェンゲゼルシャフト 空気サンプル中の燻蒸剤を検出するための方法および装置
WO2002068953A1 (fr) * 2001-02-28 2002-09-06 Basf Aktiengesellschaft Procede et dispositif pour detecter la presence de fumigenes dans des echantillons d'air
US7459483B2 (en) 2001-02-28 2008-12-02 Kanesho Soil Treatment Sprl/Bvba Method and device for detecting fumigants in air samples
WO2002077636A3 (fr) * 2001-03-27 2003-03-13 Centre Nat Rech Scient Detecteur d'une signature volatile et procedes associes
US7096714B2 (en) 2001-03-27 2006-08-29 Centre National De La Recherche Scientifique Volatile signature detector and associated methods
FR2822952A1 (fr) * 2001-03-27 2002-10-04 Seres Detecteur d'une signature volatile et procedes associes
WO2002077636A2 (fr) * 2001-03-27 2002-10-03 Centre National De La Recherche Scientifique Detecteur d'une signature volatile et procedes associes
EP1969361A4 (fr) * 2005-12-23 2010-03-10 Itt Mfg Enterprises Inc Systeme de base de donnees et procede pour l'analyse et l'association de donnees observables avec des substances, materiel, et processus
EP1969361A2 (fr) * 2005-12-23 2008-09-17 Itt Manufacturing Enterprises, Inc. Systeme de base de donnees et procede pour l'analyse et l'association de donnees observables avec des substances, materiel, et processus
JP2009521437A (ja) * 2005-12-23 2009-06-04 アイティーティー マニュファクチャリング エンタープライジーズ， インコーポレイテッド 関連する化学物質、器具、およびプロセスを用いて観察可能なデータを分析し、関連付けるためのデータベースシステムおよび方法
US8828733B2 (en) * 2007-01-19 2014-09-09 Cantimer, Inc. Microsensor material and methods for analyte detection
DE102008012444A1 (de) * 2008-03-04 2009-09-10 Aweco Appliance Systems Gmbh & Co. Kg Vorrichtung zum Testen des Frischegrades von Lebensmitteln
WO2016177374A1 (fr) 2015-05-01 2016-11-10 Aminic Aps Dispositif muni d'un capteur basé sur la micromécanique ou la nanomécanique pour la détection de molécules de décomposition telles que des amines biogènes (associées à la détérioration des aliments et certaines maladies humaines entre autres) et calcul consécutif pour déterminer la fraîcheur et la date d'expiration
US10684264B2 (en) 2015-12-24 2020-06-16 Partnering 3.0 System for monitoring air quality and docking station for a mobile robot equipped with air quality sensors
FR3046245A1 (fr) * 2015-12-24 2017-06-30 Partnering 3 0 Systeme de surveillance de qualite d'air et station d'accueil pour robot mobile equipe de capteurs de qualite d'air
WO2017109432A1 (fr) * 2015-12-24 2017-06-29 Partnering 3.0 Systeme de surveillance de qualite d'air et station d'accueil pour robot mobile equipe de capteurs de qualite d'air
US11163311B2 (en) 2015-12-24 2021-11-02 Partnering 3.0 Robotic equipment including a mobile robot, method for recharging a battery of such mobile robot, and mobile robot docking station
EP3267192A1 (fr) * 2016-07-07 2018-01-10 Alpha M.O.S. Chromatographe en phase gazeuse
WO2018007543A1 (fr) * 2016-07-07 2018-01-11 Alpha M.O.S Chromatographe à phase gazeuse
CN107589182A (zh) * 2016-07-07 2018-01-16 阿尔法莫斯公司 气相体色谱仪
US10371670B2 (en) 2016-07-07 2019-08-06 Alpha M.O.S. Gas chromatograph
CN106940340A (zh) * 2017-04-14 2017-07-11 中国石油化工股份有限公司 危险气氛综合状态指纹识别系统
CN106940340B (zh) * 2017-04-14 2023-03-28 中国石油化工股份有限公司 危险气氛综合状态指纹识别系统
CN113358817A (zh) * 2021-04-22 2021-09-07 上海工程技术大学 一种基于气体浓度梯度驱动的气体源定位装置
CN113358798A (zh) * 2021-07-16 2021-09-07 天津市生态环境科学研究院(天津市环境规划院、天津市低碳发展研究中心) 热脱附-气相色谱质谱检测杂环类异味物质的方法

Also Published As

Publication number Publication date
WO2000078204A3 (fr) 2001-07-26

Similar Documents

Publication Publication Date Title
US6631333B1 (en) Methods for remote characterization of an odor
US7595023B2 (en) Spatiotemporal and geometric optimization of sensor arrays for detecting analytes in fluids
US8394330B1 (en) Conductive organic sensors, arrays and methods of use
US6759010B2 (en) Use of an array of polymeric sensors of varying thickness for detecting analytes in fluids
EP1192454B1 (fr) Utilisation d'un comportement de reponse spatio-temporelle dans des groupements de capteurs pour detecter des analytes dans des fluides
US20050263394A1 (en) Sensors and sensor arrays of conducting and insulating composites and methods of use thereof
US20050150778A1 (en) Use of basic polymers in carbon black composite vapor detectors to obtain enhanced sensitivity and classification performance for volatile fatty acids
US6170318B1 (en) Methods of use for sensor based fluid detection devices
US7342479B2 (en) Sensor device utilizing carbon nanotubes
US8519726B2 (en) Sensor having integrated electrodes and method for detecting analytes in fluids
US20060034731A1 (en) Sensor arrays for detecting analytes in fluids
WO2000078204A2 (fr) Procede de caracterisation a distance d'une odeur
US20090261987A1 (en) Sensor instrument system including method for detecting analytes in fluids
WO2001013087A2 (fr) Capteurs et reseaux de capteurs a base de composites conducteurs et isolants et leurs procedes d'utilisation
WO2002023134A1 (fr) Optimisation spatio-temporelle et geometrique de reseaux de capteurs destines a la detection d'analytes dans des fluides
EP1141690A1 (fr) Elements detecteurs bases sur des particules alignes
Chandrapalan et al. Cross-reactive Sensors (or e-Noses)
Nanto Outline of electronic nose
Lewis Methods of use for sensor based fluid detection devices

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): CA JP

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE

121 Ep: the epo has been informed by wipo that ep was designated in this application
AK Designated states

Kind code of ref document: A3

Designated state(s): CA JP

AL Designated countries for regional patents

Kind code of ref document: A3

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase in:

Ref country code: JP