JP2009537219A - Nanoelectronic respiratory analyzer and asthma monitor - Google Patents

Abstract

Several embodiments of nanoelectronic sensors are disclosed that include sensors for detecting CO ₂ , NO, anesthetic gas, and the like contained in a subject, eg, human breath. An integrated multivalent monitoring system is disclosed that enables measurement of two or more subjects in exhalation, such as monitoring of pulmonary conditions such as asthma. The monitor system may be designed as a compact, metered, low-cost system and includes a microprocessor that allows measurements to be analyzed to determine patient status and to save measurement records. You may have. The wireless implementation provides such enhancement as a remote monitoring system.

Description

  The present invention provides a nanostructured sensor system, particularly in the respiratory air, for measuring a subject by measuring changes in capacitance, impedance or other electrical properties of the nanostructured element in response to the subject, for example. The present invention relates to a nanostructured sensor system for measuring contained medical related species.

Patent Application to be Included with Priority This PCT International Patent Application is an application claiming priority in accordance with the laws and treaties applicable to the following patent applications, and the specification relating to the patent application on which these priorities are based: Is also part of this application:
(1) US Patent Application No. 11/437275 (filing date: May 18, 2006, publication number: US2007-0048180, title of invention: nanoelectronic respiratory analyzer and asthma monitor),
(2) U.S. Patent Application No. 11/488456 (filed on July 18, 2006, publication number: US2007-0048181, entitled Improved for carbon dioxide nanosensors with respiratory CO ₂ monitor) and (3 US patent application Ser. No. 11 / 588,845 (filing date: October 26, 2006, publication number: unpublished, title of invention: anesthesia monitor, capacitance nanosensor and dynamic sampling method with sensor).

In addition, this PCT international patent application is related to the disclosure content of the following patent applications, and the description content of the specifications relating to these patent applications is also a part of this specification:
(1) US Patent Application No. 11/090550 (filing date: March 25, 2005, patent number: 6894359, title of invention: sensitivity adjustment of nanotube sensor),
(2) U.S. Patent Application No. 10/846072 (filing date: May 14, 2004, publication number: US2005-018441, title of invention: flexible nanotube transistor),
(3) US Patent Application No. 10/177929 (filing date: June 21, 2002, corresponding publication: WO2004-040671, title of invention: dispersed growth of nanotubes on a substrate),
(4) US patent application Ser. No. 10 / 388,701 (filing date: March 14, 2003, patent number: 6905655, title of invention: improved selectivity for sensing nanostructured device arrays),

(5) US Patent Application No. 10/656898 (filing date: September 5, 2003, publication number: US2005-0279987, title of invention: polymer recognition layer for nanostructure sensor device),
(6) US Patent Application No. 10/940324 (filing date: September 13, 2004, publication number: US2005-0129573, title of invention: nanoelectronic sensor for carbon dioxide),
(7) US Patent Application No. 11/019792 (Filing Date: December 18, 2004, Publication Number: US2005-0245836, Title of Invention: Nanoelectronic Capnometer Adapter), and (8) Alexander Star and Alexander Kuzmike, United States provisional application (application number: undecided, filing date: January 12, 2007, publication number: unpublished, agent file number: 06-038P, express mail number: EV921433967US, title of invention: Detection of Nitric Oxide): The specification of this provisional application is included within the scope of the joint research agreement “corporate research agreement” (effective September 1, 2005) concluded between Nanomix and the University of Pittsburgh. Disclosed research details are disclosed. According to this joint research agreement, certain research activities are carried out by the participation of the University of Pittsburgh employees, including at least one inventor who is in common with the inventor of the present application, and the use of the facility.

Measuring the concentration of carbon dioxide in the respiratory air is a standard technique in intensive care and anesthesia, and is a fundamental tool in the diagnosis and treatment of respiratory function. What is necessary in this medical monitoring is to measure and track the concentration of carbon dioxide in the respiratory air, which is sometimes referred to as capnography. Techniques are generally spread to meet the requirements of the capnography device measures the concentration of CO ₂ depending on the bulky and expensive non-dispersible infrared (NDIR) sensor. Due to limiting factors such as high cost, complexity and heavy weight, the effective use of capnography in controlled environments (eg operating rooms) is constrained, and capnography The medical use of graphy is also limited.

In addition to measuring CO ₂ , many other scientific methods are used in medical analysis and monitoring of breathing to improve patient care and diagnosis. In general, exhaled breathing has a different composition from the inhaled air. Various compounds are removed from the inhaled air (eg, oxygen as O ₂ is absorbed and metabolized) or added to exhaled breathing air (eg, CO ₂ and H ₂ O, etc.) . Furthermore, treatment compounds (eg, anesthetics, etc.) may be added to the inhalation air for inhalation administration and detected in the exhaled breath.

A substantial part of the exhaled breath contains N ₂ , O ₂ , CO ₂ , water vapor and other atmospheric components (eg, argon, etc.), but is produced by metabolic processes in the body. Many volatile organic and inorganic species are released into the exhaled breath (in many cases the amount of this type of compound is trace). In many cases, such metabolic species are medically important. For example, nitric oxide (NO), nitrogen dioxide (NO ₂ ), other nitrogen-containing compounds, sulfur-containing compounds, hydrogen peroxide, carbon monoxide, hydrogen, ammonia, ketones, aldehydes, esters, alkanes, and other volatiles Organic compounds may be present in the exhaled breath. Medical symptoms associated with metabolism-related components in the exhaled breath include tissue inflammation (eg, asthma), immune response (eg, cancer cells or bacteria), metabolic disorders (eg, diabetes) Etc.), digestive process, liver disorder, kidney disorder, heart disorder, gingival disease, bad breath, blood component concentration and other physiological symptoms.

  NO detection in respiratory air is a validated marker associated with airway inflammation and other tissue inflammation, immune responses and other symptoms. Therefore, measuring NO as exhaled respiratory parameters, eg, exhaled partial nitric oxide (FeNO), is a useful tool for the diagnosis, monitoring and management of asthma and other diseases. . In this regard, see, for example, US Pat. No. 6,010,459 (Title of Invention: Method and Apparatus for Measuring Components Exhaled in Human Respiratory Air), which also describes the present specification. Part of it). However, medical systems for measuring NO are typically associated with the same constraints (eg, high cost, device weight, complexity, etc.) as capnograph devices.

Respiratory CO ₂ measurement is used as an indicator of perfusion, cardiac function and ventilator efficiency. Furthermore, CO ₂ measurements are not only useful in their own right in the diagnosis and monitoring of airway conditions and lung function, but are also useful as a means in conjunction with other measurements. In this regard, reference is made, for example, to US Pat. No. 6,648,833 (Title: Respiratory analysis using capnography), which also forms part of the present specification.

  In view of the above circumstances in the field, the present invention is a novel for measuring a subject, for example, by evaluating changes in capacitance, impedance or other electrical properties of a nanostructured element responsive to the subject. The present invention has been made to provide a nanostructured sensor system, particularly a nanostructured sensor system for measuring medical-related species contained in respiratory air.

  Embodiments having aspects of the present invention provide a capnography device that provides the following advantages of a novel nanostructured electronic sensor for medical use: i) to the performance of infrared technology Comparable or superior performance, ii) Plug-and-play ease of handling in disposable packages, iii) Small size and low power consumption required for portability and / or wireless integration, iv) The integration of sensor arrays on a single chip, and v) an order of magnitude reduction in the cost of sensor components. Regarding these points, for example, the specification of US Patent Application No. 11/019792 (filing date: December 18, 2004, title of invention: adapter for nanoelectronic capnometer, published publication: US 2005-0245836) (This specification is also a part of this specification).

It has been proposed to detect more than one metabolite and monitor medical symptoms (eg asthma, etc.) by taking into account both NO and CO _{2 in} the exhaled breath, for example. ing. In this regard, refer to, for example, US Publication No. 2003-0134427 (Title of Invention: Method and Apparatus for Determining Gas Concentration) and the following literature (the specification and literature are also described in this specification). Part of it): C.I. Roller et al., “Simultaneous measurement of NO and CO ₂ in human respiratory air by using a single IV-VI mid-infrared laser”, Optics Letters (2002), 27, 107- 109 pages.

  Several other conventional methods are known for detecting NO gas for medical respiratory analysis. In the laser detection method, the wavelength of the laser may be converted to a wavelength that is selectively absorbed by NO. Next, the transmittance of laser light passing through the sample column is measured using a photodetector, and the absorbance by the gas is correlated with the concentration of NO. In this regard, see, for example, “Experimental Breathmeter” (registered trademark), a respiratory analysis developed by Expos Technologies, Inc. of Norman OK. NO may be detected by methods such as chemiluminescence, electrochemical reaction, and other optical detection methods. In this regard, for example, US Publication Nos. 2003-0134427 (Title: Method and Apparatus for Determining Gas Concentration) and 2004-0017570 (Title: Respiratory Gas for Quantification) (These devices and systems) (these publications also form part of the present specification).

  However, in any conventional NO detection method, the size, weight, cost, and / or operational complexity of the device (ie, operational complexity that limits the usage that the patient can carry and use at low cost). There are restrictions. As in the case of using capnography, the device of the embodiment having aspects of the present invention and comprising a novel nanostructured electronic sensor is small in size, light weight, low cost, and alternative patient care aspects. On the other hand, it offers the advantage in terms of simple operation which makes the device particularly suitable.

Another embodiment having aspects of the present invention includes a system designed to measure more than one component in the exhaled breath, according to which NO, CO ₂ , Diagnosis and monitoring is possible based on the patient's inherent characteristics associated with two or more of H ₂ O ₂ and other components. Similarly, the properties of the novel nanoelectronic sensor result in a device of the embodiment comprising an array of sensors, a microprocessor and / or a wireless transceiver, thereby allowing convenient recording and analysis of patient-specific multiple measurement history and Remote monitoring of patients by medical staff is possible. In this regard, see, for example, the specification of US patent application Ser. No. 11 / 111,121 (filing date: April 20, 2005, title of the invention: telecommunication battery-operated nanostructure sensor device). The description also forms part of the present specification).

  Nanotubes were manufactured by S. It was first reported by Iijima and has since become a remarkable research theme. Single walled nanotubes (SWNTs) are strong covalent bonds, unique one-dimensional structures, exceptionally high tensile strength, high resilience, metallic to semiconducting electronic properties, high current capacity, and nanotube Characterized by extremely high sensitivity to perturbations caused by charged species close to the surface.

  In exemplary embodiments of sensor devices having aspects of the present invention, chemical structures are obtained by using nanostructures as elements for use in gas phases and liquid media (eg, biological fluids and electrolytes). Detection of species, physiological species or biomolecular species is provided. Real-time electronic detection and monitoring involves high sensitivity, is rapid and reversible, and has a large dynamic range. Since the output is performed digitally, if necessary, electronic filtering and post-processing may be performed to remove external noise. Particular embodiments include multiple assays on a single sensor platform or chip.

  Another embodiment having aspects of the invention is one or more other types of electronic devices (eg, capacitive sensors, resistive sensors, impedance sensors, field effect transistor sensors, etc., or any combination thereof) It is designed to detect an analyte by using a nanostructured sensor element designed as a mold sensor or the like. By incorporating two or more such measuring devices into the sensor device, orthogonal measurements may be performed that increase accuracy and / or sensitivity. In some embodiments, the incorporation of a material associated with a functionalizing group or nanostructured element may result in a sensitive and selective response to the analyte.

  Many sensor embodiments described herein are based on one or more carbon nanotubes, but other nanostructures known in the art (eg, semiconductor nanowires, fullerenes having various configurations). , And multi-wall nanotubes, or any combination thereof). Devices based on nanostructures such as carbon nanotubes (CNT) are known to have unique electrical properties. Furthermore, the sensitivity of these elements to environmental changes (charged molecules) can be used as a detector because it moderately adjusts the surface energy of the CNTs. Appropriate adjustment of the properties of CNTs can be examined electrically by creating a device incorporating CNTs (or CNT networks) as device elements. This can be done as a gate transistor element or a capacitive effect.

  Certain exemplary embodiments having aspects of the invention comprise single-walled carbon nanotubes (SWNTs) as semiconducting or conductive elements. This type of element comprises one or more discrete parallel NTs in contact with or electrically connected to the electrodes of the device. However, for many applications, it is generally a semiconducting element or conductive that includes a planar network region of nanotubes (or other nanostructures) distributed substantially randomly adjacent to the substrate. Embodiments using elements are advantageous. In this case, conductivity is retained by the interconnection between the nanotubes.

  A device manufactured from a random network of SWNTs solves the nanotube alignment and assembly problems and conductivity variation problems while maintaining the sensitivity of individual nanotubes. For example, this type of device is suitable for mass production on currently popular 4-inch silicon wafers, each wafer containing more than 20000 active devices. By applying a specific recognition layer to these devices, the device functions as a transducer for the presence of the target analyte. This type of network may be formed by chemical vapor deposition (CVD), traditional lithography, solvent suspension deposition, vacuum deposition, and the like. Regarding these, for example, refer to the following documents (the contents of these documents are also a part of the present specification): 1) US Patent Application No. 10/177929 (Title of Invention) 2) U.S. Pat. No. 6,894,359 (name of invention: sensitivity control of nanotube sensor), 3) U.S. Patent Application No. 10/846072 (name of invention: soft) Nanotube transistors), and 4) Fu et al., “Percolation in Transparent Conductive Carbon Nanotube Networks”, Nano Letters, 2004, Vol. 12, No. 25, pages 2513-2517.

  Nanoscale devices can be used to form an array of devices on a single chip for multiple / multiparameter applications. In this regard, for example, refer to the following documents (the contents of these documents are also a part of the present specification): 1) US patent application Ser. No. 10 / 388,701 (of the invention) Name: Modification of selectivity for detection of arrays of nanostructured devices) 2) US patent application 10/656898 (Title: Polymer recognition layer for nanostructured sensor devices), 3) US patent applications No. 10/940324 (Title of Invention: Nanoelectronic Sensor for Carbon Dioxide) and 4) US Provisional Patent Application No. 60/564248 (Title of Invention: Battery-operated Nanostructured Sensor Device of Remote Communication Type) .

Particular embodiments having aspects of the present invention include a respiratory analyzer or medical monitor comprising the following components (i)-(iii):
(I) at least one first nanoelectronic sensor, a) a substrate, b) one or more nanostructures disposed on the substrate, c) one electrically connected to the nanostructures Or a plurality of conductive elements, and d) at least one recognition material that is operatively associated with the first nanostructure, provided that at least one of the recognition materials is present on the first subject present in the human respiratory air. The first nanoelectronic sensor (ii) having a sensitivity to the first nanoelectronic sensor (ii) at least a respiratory air collector designed to collect respiratory air exhaled from a patient, the first nanoelectronic sensor comprising: A respiratory sampler connected to a sensor; and (iii) receiving a signal from the first nanoelectronic sensor and using the signal to measure the concentration of the first analyte, Provide information related to medical conditions It designed processing unit as.

  A particular respiratory air analyzer embodiment is a second nanoelectronic sensor, more generally similar to the first sensor, that is sensitive to a second subject present in the human respiratory air. At least one second nanoelectronic sensor including a recognition material designed in the above may be provided. In this case, the processing unit receives information from the second nanoelectronic sensor and uses the signal to measure the concentration of the second analyte, thereby obtaining information related to the medical condition of the patient. Designed to provide. Certain respiratory analyzer embodiments may further include an output mechanism that provides information to the user related to the medical condition of the patient.

The arithmetic processing unit of the respiratory analyzer determines the relationship between these measured values indicative of the medical condition of the patient by comparing the measured values of the first subject and the second subject. It may be designed to. These subjects may contain carbon dioxide (CO ₂ ), the second subject may contain nitric oxide (NO), and the arithmetic processing unit may be in the collected respiratory air. by determining the relationship between the measured concentration of CO ₂ and NO, and may be designed to provide an evaluation information on airway inflammation in a patient.

  In certain embodiments, the processor may be designed to determine an asthma condition, and the output mechanism may be designed to provide information related to the asthma condition to the user. Good. The respiratory analyzer may be substantially portable by the patient or other user and is designed to provide information related to the asthma condition to the patient or nurse in substantial real time. May be.

  In certain embodiments, the one or more nanostructures may include a network of carbon nanotubes. In this case, for example, at least a part of the network is brought into contact with one or more conductive elements. The conductive element may include a source electrode and a drain electrode separated from each other by a source / drain gap. In particular embodiments, the network of carbon nanotubes has a characteristic length that is substantially less than the source / drain gap, so that the nanotubes that make up the network are at most a source electrode. And substantially one of the drain electrodes. In another embodiment, because the characteristic length is substantially greater than the source / drain gap, a substantial portion of the nanotubes comprising the network are in contact with both the source and drain electrodes.

The sensor of the respiratory analyzer may further comprise a gate electrode, and the sensor signal may be indicative of the characteristics of the nanostructure under the influence of the gate voltage. Alternatively, the sensor signal may indicate a capacitance characteristic of the nanostructure. In certain embodiments, the respiratory analyzer or monoter having aspects of the present invention is one or more analytes selected from the group consisting essentially of CO ₂ , NO, NO ₂ and H ₂ O _2. May be designed to measure. The respiratory air sampler may be designed to continuously supply a sample of respiratory air to one or both of the first sensor and the second sensor for at least a substantial exhalation time of respiratory air from the patient. In addition, the arithmetic processing unit may be designed to determine a change in the concentration of one or both of the first subject and the second subject over time during the discharge time. The respiratory sampler may also be designed to regulate the pressure of the respiratory sample during the patient's breathing exhalation time.

The attached drawings will be briefly described.
FIG. 1A is a schematic cross-sectional view showing an exemplary electronic detection apparatus for detecting a subject. In this embodiment, the electron detector is designed as an NTFET. FIG. 1B is a photograph of a sensor that is generally similar to the sensor shown in FIG. 1A. The sensor is prepared on a chip and mounted on a circuit board. FIG. 4 shows a plot of the sensor response obtained for a wide range of carbon dioxide concentrations using an exemplary carbon dioxide nanoelectronic sensor having aspects in accordance with the present invention. FIG. 5 shows a plot of the sensor response obtained for low concentrations of carbon dioxide using an exemplary carbon dioxide nanoelectronic sensor having aspects in accordance with the present invention.

FIG. 6 is a capnogram plot showing the response of a capnometer obtained for a simulated human breath using an exemplary capnometer having aspects of the present invention. FIG. 6 shows a plot of the response of an exemplary nanostructure sensor having aspects of the present invention obtained when exposed to NO in air for a short time. FIG. 6 shows a plot showing that when the NO sensor device shown in FIG. 5 is exposed to a typical CO ₂ concentration in respiratory air, the device shows little or no cross sensitivity. 1 is a schematic cross-sectional view of an exemplary capacitive sensor having an aspect according to the present invention. FIG. FIG. 8 shows a plot of the response of an exemplary nanostructured sensor as shown in FIG. 7 obtained upon brief exposure to isoflurane and halothane. 1 is a schematic perspective view of a portable multivalent respiratory analyzer having an aspect of the present invention. FIG.

A typical capnogram of a healthy person and a schematic diagram of the corresponding alveoli are shown. (FIGS. 10A-10C are graphs to further illustrate the capnogram features. These graphs are reproductions of the drawings attached to US Pat. No. 6,648,833.) A typical capnogram of a patient suffering from obstructive pulmonary disease and a schematic diagram of the corresponding alveoli are shown. A representative capnogram of a patient suffering from restrictive lung disease and a schematic diagram of the corresponding alveoli are shown. It is a graph which shows the relationship between NO density | concentration in the exhaled respiratory air, and the discharge speed. (This graph is a reproduction of the drawing attached to US Pat. No. 6,733,463) 2 shows a representative plot of the distribution of fractional composition of NO in respiratory air exhaled from a patient. It is the schematic diagram from the side surface direction of a wired capnometer sensor and an adapter system, and the schematic diagram from the cross-sectional direction of a tube. (FIGS. 13A-13G are schematic diagrams illustrating several alternative sensor mounting devices that may be used in the respiratory sampler included in FIG. 9.) It is a typical end view with respect to the tube attachment part of a wireless capnometer sensor and an adapter system. It is a typical end view with respect to a wired capnometer sensor and a tube attachment part of an adapter system. It is a schematic diagram of a capnometer sensor and an adapter. It is a schematic diagram which shows another adapter and sensor different from the adapter and sensor of the type shown to FIG. 13D. FIG. 13B is a schematic side view of a capnometer sensor and adapter generally similar to the embodiment shown in FIG. 13A. FIG. 13B is a schematic side view of a capnometer sensor and adapter that is generally similar to the embodiment shown in FIG. 13F.

FIG. 1 illustrates an exemplary electronic detection device 100 having aspects of the present invention. The detection apparatus is an apparatus for detecting an object 101 (for example, CO ₂ , H _2, NO, etc.), and includes a nanostructure sensor 102. The sensor 102 includes a substrate 104 and a conductive groove or layer 106 that includes a nanostructured material, such as a nanotube or a network of nanotubes, disposed on the substrate. The nanostructure material 106 may be in contact with the substrate, as shown, or may be spaced from the substrate with or without intervening material layers.

  In one embodiment of the invention, the conductive trench 106 may include one or more nanotubes. For example, the conductive trench 106 may include a plurality of nanotubes that form a mesh, film, or network. Certain exemplary embodiments having aspects of the invention include nanostructured devices. The nanostructured elements may be prepared by chemical vapor deposition (CVD) or traditional lithography, or may be deposited by other methods (eg, solvent suspension deposition and AFM operating methods). Particular embodiments include one or more discrete nanotubes that are in electrical contact with one or more metal electrodes. The arrangement of active nanostructures includes a number of different arrangements without departing from the technical idea of the present invention.

At least two conductive elements or contacts (110, 112) may be disposed on the substrate and electrically connected to the conductive grooves 106 containing the nanostructured material. These elements (110, 112) may include a metal electrode in contact with the conductive groove. In another embodiment, a conductive or semiconductive material (not shown) may be interposed between the contacts (110, 112) and the conductive groove 106. These contacts 110 and 112 have a source electrode and a drain electrode, respectively, to which a source / drain voltage V _sd is applied. The voltage or polarity of the source electrode 110 relative to the drain electrode 112 may be variable. For example, the applied voltage may be DC, AC, pulse voltage or variable voltage. In one embodiment of the invention, the applied voltage is a DC voltage.

In the embodiment shown in FIG. 1, the device 100 may be operated as a gated field effect transistor by using a sensor 102 further comprising a gate electrode 114. This type of device is referred to herein as a nanotube field effect transistor or NTFET. The gate 114 may include a base of the substrate 104, such as a doped silicon wafer material separated from the contacts (110, 112) and the conductive trench 106 by a dielectric layer 116, and thereby applied. it is possible occurrence of capacitance due to the gate voltage V _g that. For example, the substrate 104 may include a silicon back gate 114 separated by a dielectric layer 116 containing SiO ₂ .

  The sensor 102 may further include a suppressor or passivating material layer 118 that covers a region adjacent to the junction between the conductive elements (110, 112) and the conductive groove 106. The inhibitor may be impermeable to at least one chemical species (eg, analyte 101 or environmental material such as water or other solvent, oxygen, nitrogen, etc.). Inhibitor 118 may include passivating materials known in the art, such as silicon dioxide, aluminum oxide, silicon nitride, and other suitable materials. Details regarding the use of the suppressor in NTFET are described in the prior patent document US Pat. No. 6,894,359 (Title: Sensitivity Control of Nanotube Sensor). Are part of this).

  The conductive groove 106 (for example, a carbon nanotube layer) may be functionalized so as to exhibit sensitivity to one or more types of target analytes 101. Nanostructures, such as carbon nanotubes, may respond to the target analyte through charge transfer or other interactions between the device and the analyte, but more generally the target analyte. Specific sensitivity can be achieved by using a recognition material (also called functionalized material) 120 that induces a measurable change in the properties of the device when interacting with the analyte.

The apparatus 100 may further comprise suitable circuitry in communication with the sensor element for performing electrical measurements. For example, the source / drain voltage V _sd may be supplied between the contacts 110 and 112 by a conventional power source. The measurement using the sensor device 100 may be performed by a circuit schematically represented by a meter 122 connected between the settings 110 and 112. In embodiments having a gate electrode 114, by connecting the conventional power supply 124 may supply the selected or controllable gate voltage V _g. The apparatus 100 may comprise one or more known feeders and / or signal control / processing units (not shown) in communication with the sensor 102.

  If desired, the device 100 can be used, for example, in earlier US patent application Ser. No. 10 / 388,701 (filing date: March 14, 2003, title of invention: modification of selectivity to detect nanostructured device arrays, As described in US Pat. No. 2003-0175161), a plurality of sensors such as sensors 102 arranged in a pattern or array may be provided (the contents of the specification are also described in the present application). Part of the description). Each device arranged in an array may be functionalized by the same or different functionalization method. The same device arranged in an array is useful in that the measurement data can be multiplexed to improve the signal / noise ratio or to increase device robustness by duplication. Different functionalizations are useful for providing sensitivity to a very wide variety of analytes using a single device.

2. Specific sensor element
The substrate substrate 104 may be insulative or may comprise a layered structure having a base 114 and another dielectric layer 116, the dielectric layer comprising contacts (110, 112) and grooves 106. Is isolated from the base portion 114 of the substrate. The substrate 104 may include a hard or soft agent that may be conductive, semiconductive, or dielectric. The substrate 104 may have a unitary structure, or may have a multilayer structure or other composite structure having different properties and compositions. Suitable substrate materials may include quartz, alumina, polycrystalline silicon, III-V semiconductor compounds, and other suitable materials. The substrate material may be selected to have particularly useful properties, such as transparency, microporosity, magnetism, single crystal, polycrystalline, amorphous, or of these properties. Any combination and other desirable properties are illustrated. For example, in one embodiment of the present invention, the substrate 104 may include a silicon wafer doped to function as the back gate electrode 114. The wafer is covered by an intermediate diffusion barrier (Si ₃ N ₄ ) and an upper dielectric layer (SiO ₂ ). If desired, additional electronic elements may be incorporated into the substrate for various purposes, such as for thermistors, heating elements, integrated circuit elements or other elements.

  In another specific embodiment, the substrate may contain a soft insulating polymer, as described in the specification of the following U.S. patent application, which may optionally include a lower gate conductor ( For example, a soft conductive polymer composition) may be included (the contents of this specification are also a part of the present specification): No. 10/846072 (filing date: May 2004) 14th, title of invention: soft nanotube transistor). In yet another embodiment, the substrate is a nanotube network from a microporous material such as a suspension or solution that allows for suction through the substrate, as described in the specification of the following US patent application: Porous groove | channel etc. for carrying out the vacuum deposition of the groove | channel 106 of this (The description content of this specification is also a part of this-application specification): No. 60/639954 (application date: Dec. 28, 2004, Title of Invention: Biosensor structure having a nanotube network on top).

Contacts or electrodes The conductors or contacts 110 and 112 used for the source and drain electrodes may be any of the conventional metals used in the semiconductor industry, or Au, Pd, Pt, Cr, Ni , ITO, W or other metallic material or alloy or mixtures thereof. In another embodiment, it may include a multilayer or composite of metallic materials, such as Ti + Au, Cr + Au, Ti + Pd, Cr + Pd, and the like. A multilayer structure may help improve the adhesion of the metal to the substrate. For example, electrical leads may be patterned from a titanium film (thickness: 30 nm) coated with a gold layer (thickness: 120 nm) to the top of the nanotube network groove. In another embodiment, other conductive materials such as a conductive polymer may be used. The distance between the source electrode 110 and the drain electrode 112 may be selected so that desired characteristics for a specific application can be obtained. One or more of each of the source and drain electrodes may be arranged as an electrode array in an alternating combination or spaced apart, so that a relatively small source to be densely arranged / The area of the nanostructure groove 106 having a drain gap can be made relatively large.

  The gate electrode 114 may contain a material generally similar to the contacts (110, 112). In another embodiment, the gate electrode 114 may have a sublayer inside the substrate 104. The gate electrode 114 may contain doped silicon, patterned metal, ITO, other conductive metals or non-metals, or a combination thereof. Another form of gate electrode may be used, such as a gate that functions via a top gate or a conductive analyte-bearing medium (eg, an aqueous solution). If desired, the device 102 may include other electrodes, such as a counter electrode, a reference electrode, a pseudo reference electrode, etc., without departing from the technical spirit of the present invention.

Conductive Groove or Nanostructure Layer In an exemplary embodiment including aspects according to the present invention, a detection device is included having at least one conductive groove 106 containing one or more nanostructures. For example, the conductive groove (conductive layer) 106 may include one or more single-walled carbon nanotubes, multi-walled carbon nanotubes, nanowires, nanofibers, nanorods, nanospheres, or other suitable nanostructures. . Additionally or alternatively, the conductive trench (conductive layer) 106 may include one or more nanostructures made of the following exemplified materials: boron, boron nitride, carbon nitride boron , Silicon, germanium, gallium nitride, zinc oxide, indium phosphide, molybdenum disulfide, silver or other suitable material. Various suitable methods are known in the art for producing nanotubes or other nanostructures, and any suitable method may be employed.

Conductive groove comprising nanostructure network In one embodiment of the invention, the conductive groove or nanostructure layer 106 provides percolation to provide at least one conductive path between the source electrode 110 and the drain electrode 112. It may include an interconnected network of smaller nanostructures arranged to form a layer, mesh or film. In this type of nanoparticle network, it is not necessary for any single nanoparticle to extend between the source / drain contacts. In operation, the conductivity between the source electrode 110 and the drain electrode 112 may be maintained by interconnection, contact or communication between adjacent nanostructures. This type of network of nanoparticles, such as nanotubes, may be designed in a form that is resistant to defects, so that any particular conductive path breakage will remain in the network Compensated by sex path.

  In one embodiment of the present invention, the conductive groove 106 containing nanostructures contains one or more single-walled or multi-walled carbon nanotubes. The nanotubes may be arranged as agglomerates, bundles or clearly separated fibers. Useful networks of nanotubes may be formed, for example, by applying a dispersion of nanotubes onto a substrate, whereby the nanotubes are oriented in a generally planar, random state. For example, the conductive groove 106 may contain a network including a plurality of dispersed single-walled carbon nanotubes (SWCNT). In the network, the nanotubes are in a substantially random, non-parallel state and separated from each other (ie, as interconnected meshes arranged generally parallel to the substrate (ie, (Non-agglomerated state).

  The electrical properties of the groove 106 may be optimized to suit a particular functionalization chemistry, or other component of the sensor that affects conductivity, or to suit the desired concentration range of the analyte. May be optimized. In a preferred embodiment, the density or thickness of the nanotube network may be varied to provide the desired conductivity between the source and drain electrodes. Alternatively or additionally, the proportion of metallic or semiconducting nanotubes in the network may be selected to obtain the desired conductivity in the network. One advantage of using a nanostructure network structure for the conductive trench 106 is as follows. That is, these factors can be varied to result in a conductive network having an upper or lower percolation limit that is selected, thereby facilitating optimization of device characteristics. is there. For example, an NT network groove may be formed somewhat below the percolation limit for an uncovered network, and the groove may be modified by deposition of a conductive recognition material such as Pd to achieve the desired A functionalized groove having electrical conductivity may be formed. In another embodiment, the conductivity of the initially dry network is manipulated in relation to the expected additional conductivity of the liquid analyte medium (eg, physiological buffer or solvent). May be selected.

  Furthermore, the conductive grooves 106, which typically contain randomly dispersed individual nanoparticles, allow a statistical method rather than a localized method for fabricating nanostructured devices. This is advantageous in that it makes it easier to solve the problem of mass production. In statistical methods, electrical contacts can be placed at any location on the dispersion of individual nanostructures that form the device. In this case, no special communication between the position of the electrode and the position of any particular nanoparticle is necessary. A random dispersion of nanoparticles ensures the following: That is, two or more electrodes disposed on the dispersion can form a complete electrical circuit with functional nanotubes that provide connectivity. By distributing a large number of randomly oriented nanotubes in the dispersion above or below the electrode array, uniform electrical properties in the individual devices are ensured. In this case, higher yields and faster processing rates are achieved than with conventional methods that provide controlled placement or growth of individual nanotubes or other nanostructures.

Formation of the Nanoparticle Network The nanostructure network may be formed by various suitable methods. One suitable method is to form an interconnected network of single-walled carbon nanotubes directly on the substrate, for example, by reaction of steam in the presence of a catalyst or growth promoter mounted on the substrate. May be included. For example, a network of single-walled nanotubes can be grown on silicon or other substrate by chemical vapor deposition from iron-containing catalyst nanoparticles using a methane / hydrogen gas mixture at about 900 ° C.

  By using highly dispersed nanostructure catalysts or growth promoters, a network of nanotubes with controlled diameter and wall structure are oriented in a substantially random and non-aggregated state relative to each other and the substrate is selected. It is advantageous to have a substantially uniform distribution with a selected average density over the region. The particle size distribution may be selected to promote specific nanotube characteristics, such as an increase in tube diameter, single-wall or multi-wall number, conductivity, or other properties.

  By using other catalyst materials and gas mixtures, nanotubes can be grown on the substrate, and other electrode materials and nanostructure configurations are disclosed in the following patent documents: Is also incorporated herein by reference: US patent application Ser. No. 10 / 099,664 (filing date: March 15, 2002, title of invention: selection to detect nanostructure detector array) International application PCT / US03 / 19808 (WO2004 / 040671) (Filing date: June 20, 2003, Title of invention: Dispersion growth of nanotubes on a substrate).

  In another aspect, the conductive layer 106 that includes a network interconnecting nanostructures may be formed by deposition from a solution or suspension of nanostructures, such as a dispersion of carbon nanotubes, and the like. . In this regard, reference is made, for example, to the method disclosed in the following patent document (the disclosure content of which is also part of the present specification): US patent application Ser. No. 10/846072. (Application date: May 14, 2004, Title of invention: Soft nanotube transistor). In order to deposit the solution or suspension of nanostructures, methods such as spin coating, spray deposition, dip coating, and ink jet printing may be used.

  Yet another suitable method may include forming a nanotube network on a porous substrate or film by a suction deposition method as described in the following patent document: Document disclosure is also part of this application): US Provisional Application No. 60/639954 (filing date: December 28, 2004, title of invention: for biosensor with nanotube network on top) Structure). The network formed in this manner may be used as the conductive groove in a state where it is attached to the deposited film or separated from the deposited film using a method such as a film dissolution method or a transfer bonding method.

  It is known that carbon nanotubes exhibit metal or semiconductor properties depending on the specific graphite lattice orientation. Various methods may be employed to select the desired composition of nanotubes for the nanostructure layer 106 of the nanosensor device 102. For example, a plurality of generally similar nanotube devices may be manufactured by simultaneous mass production, for example as an array of device dies disposed on a silicon wafer. Each device in a number of devices exhibits electrical characteristics with a statistically predictable range of properties due to the different metallic or semiconducting composition of the conductive layer 106 of each device. The manufactured dies may be individually tested, for example, using an automated or semi-automated pin probe test rig. Pay attention to a die that exhibits a selected electrical behavior or range of behavior, which die may be selected for subsequent processing and used, and whether any non-compliant die is selected Alternatively, it may be processed for another application.

  In another aspect, the network of nanostructures for the conductive trench 106 is a prefabricated original nanotube material comprising a selected composition having metallic or semiconducting properties (eg, exclusively semiconducting properties). May be constructed from nanotubes having Alternatively, the nanotube layer may be formed from any mixture of nanotube compositions. The nanotube layer was selected by selectively removing, oxidizing, severing, or deactivating all or part of the metallic nanotube, for example, by subjecting it to a treatment such as ohmic heating. Conductive grooves having characteristics (for example, exclusively semiconducting nanotubes) may be left. When the nanotube layer 2 is formed directly on top of the substrate 1 by, for example, catalytically initiated CVD, it is advantageous to employ the latter method.

The functionalized layer or recognition layer sensor functionalized material 120 causes a measurable change in the electrical properties of the nanosensor device 102 by interacting with a particular analyte 101, for example a target. May be selected for. For example, the functionalized material 120 may provide electron transfer that occurs in the presence of the subject 101, or indirectly by affecting the local environmental properties (eg, pH, etc.). May be changed. Alternatively or additionally, the recognition material may induce a sensitive change in the nanostructure groove 106 upon interaction with an electrically measurable mechanical stress or target analyte. Sensitivity to the analyte or multiple analytes may be provided by communication between the nanotube conductive groove 106 and the adjacent functionalized material 120, or may be controlled by the communication. Certain suitable functionalized materials will be exemplified later in this specification. The functionalized material 120 may be disposed on the surface of the groove 106 or as a continuous or discontinuous layer adjacent to the groove.

  The functionalized material 120 may be selected for a wide range of other chemical or biomolecular analytes. Examples of such materials include functionalized materials specific to industrially or medically important gas analytes such as carbon dioxide and disclosed in the following patent documents: (The disclosure of this document is also a part of the present specification): US Patent Application No. 10/940324 (filing date: September 13, 2004, title of invention: nanoelectronic sensor for carbon dioxide ). In this regard, see also the aforementioned US patent application Ser. No. 10 / 656,898. Examples of functionalized materials specific to biomolecules, organisms, groups on cell surfaces, biochemical species, etc. are disclosed in the following patent documents (the disclosures of these documents are also part of this specification). US patent application Ser. No. 10 / 345,783 (filing date: January 16, 2003, title of invention: electronic detection of biological / chemical agents using functionalized nanostructures) (Publication publication US 2003-0134433) and said US patent application Ser. No. 10 / 704,066.

  The functionalized material 120 may contain a small amount of a single compound, element, or molecule that binds to or adjacent to the nanostructure groove 106. Additionally or alternatively, the functionalized material may contain a mixture or multilayer assembly or composite species such as synthetic components and naturally occurring biomaterials.

  Other examples of functionalized materials and a more detailed description of the materials are disclosed in the following patent document (the disclosure of which is also part of this application): US Patent Application No. 10 No./388701 (filing date: March 14, 2003, title of invention: improved sensitivity for detecting nanostructure device arrays (published US 2003-0175161); US patent application 60/604293 (filed) Date: November 19, 2004, Title of Invention: Nanotube Sensor Device for DNA Detection) The functionalized material 120 and other sensor elements may be in various physical forms of the sample medium, such as gaseous or liquid analytes. It may be selected so as to be suitable for the medium etc. In this regard, refer to the following patent document (the disclosure content of this document is also part of the present specification). US patent application Ser. No. 10 / 773,631 (filing date: February 6, 2004, title of invention: detection of analyte in liquid using carbon nanotube field effect transmission device; US patent application 60/604293) Filing date: November 13, 2004, title of invention: nanotube based glucose detection).

Other substrate elements If desired, the substrate may be equipped with integrated temperature control elements such as micro-type heater structures, Peltier-type micro coolers, thermal isolation bridges and thermistor / microprocessor feedback controllers. Also good. It should be noted that temperature control may be utilized to achieve a wide variety of sensor performance goals. For example, by utilizing temperature control, the response speed can be increased by promoting the reaction of the analyte, and the evaporation of the previous analyte or reaction product, reaction (eg, DNA hybridization and The recovery time of the sensor can be improved by optimizing the tightness control etc. and evaporating the vapor of the condensed medium. Similarly, other advantageous processing devices, power supplies or support circuits may be incorporated on the sensor chip.

  Regarding these points, refer to the following patent document (the disclosure content of which is also a part of the present specification): US Patent Application No. 10/655529 (filing date: September 2003) 4th, title: improved sensor device with heated nanotubes). See also the following non-patent documents disclosing appropriate micromachining techniques and / or etching techniques (the disclosure content of which is also a part of the present specification): Telepi et al., “Fabrication of Thermally Insulating Film Using Micromachining Method on Front of Si Substrate; Characterizing Etching Process”, J. of Micromech. And Microeng., Vol. 13, pp. 323-329. Page (2003); Tamis et al., “Preparation of a suspended porous silicon micro hot plate for thermal sensor applications”, Physica Status Solid (a), Vol. 197 (2), pages 539-543 (2003). A. Telepi et al., “Drying of porous silicon in high-density plasma”, Physica Status Solidi (a), 197 (1), 163-167 (2003).

  If desired, the substrate may have a protective layer and a surface condition adjusting layer. For example, by providing a diffusion barrier, contamination of the substrate, such as doped silicon, with metal catalysts or other materials introduced during the manufacturing process can be prevented. In this regard, please refer to the following patent document (the disclosure content of which is also a part of the present specification): US Patent Application No. 11/111121 (filing date: April 20, 2005) (Japan, title of the invention: remote-communication battery-type nanostructure sensor device).

3. Sensor Array The plurality of sensor devices 102 are arranged as an array designed to provide a number of advantageous measurement modes, as described in the patent literature referred to earlier as part of this specification. The mode to do is simple. A number of different measurement methods and advantages are obtained with the sensor array according to the invention. Examples of such advantages include the following:
a) A large number of analytes are detected by a number of specifically functionalized sensors.
b) Increased accuracy and dynamic range with multiple sensors, each sensor optimized for a different range.
c) Increasing the specificity and flexibility of the analyte by detecting the characteristic “distribution” of the response of the target analyte to a plurality of differently functionalized sensors.
d) A reference sensor separated from the self-calibration system is obtained.
e) A multi-use array is obtained in which a number of single-use sensor subunits are arranged.
f) An ultra-low cost direct digital output sensor array, wherein each of the plurality of sensors generates a binary signal and collectively has a response threshold over a selected concentration range of the analyte. A sensor array is obtained.

  A nanoelectronic sensor having an aspect of the present invention is inherently suitable for arrayed arrangements, for example, the sensor may be a respiratory analysis system incorporating a number of analytes as described herein. May be used. Such sensors and sensor arrays can be manufactured within the scope of known manufacturing techniques. In this regard, please refer to the following patent document (the disclosure content of which is also a part of the present specification): US Patent Application No. 10/846072 (Title of Invention: Soft Nanotube Transistor) .

  One preferred method is to utilize wafer processing technology developed in the semiconductor electronics industry. According to this method, not only a large number of sensors can be prepared on a single chip, but also suitable photographic printing method, masking method, controlled etching method, micro machining method, vapor deposition method, chemical ink jet type coating By simultaneously preparing different functional sensors and different structural sensors on a common substrate such as a method and a circuit printing method, various sensor device elements and related circuit elements can be manufactured.

4). Measurement System The electronic circuit described in this example is exemplary, and a wide range of other measurement circuits may be used without departing from the technical idea of the present invention. In an embodiment of an electronic sensor device having aspects of the present invention, one or more properties of the nanosensor 120 are measured, for example, by measuring electrical properties via conductive elements (110, 112). An electronic circuit designed as such may be included. For example, a transistor sensor may be scanned under controllable conditions over a selected range of gate voltages, which are compared to the measured current of the corresponding sensor (this comparison is generally I -Shown as a Vg curve or scan). Such an I-Vg scan may be performed over any selected range of gate voltages at one or more selected source / drain voltages. The range of Vg is generally selected from at least the device “on” voltage to at least the device “off” voltage. This scan can be performed by increasing Vg, decreasing Vg, or a combination thereof, and may be repeated in the positive or negative direction at any selected frequency.

  In addition to the transconductance / NTFET shown in FIG. 1, another embodiment of the analyte detection electron detection device having aspects of the present invention has a different structure and is designed to measure different characteristics. A sensor may be included. Sensor sensitivity may be provided based on any suitable electrical or magnetic properties, such as electrical resistance, conductivity, current, voltage, capacitance, impedance, inductance, transistor resistance. Examples include on-current, transistor off-current, and / or transistor threshold voltage. Alternatively, or additionally, sensitivity may be based on measuring a combination of properties, measuring a relationship between different properties, measuring a change in one or more properties over time, or the like. For example, in sensor embodiments, designed and optimized for measuring capacitance for nanostructured sensor elements (eg, measuring the response of a functionalized nanotube network capacitance to interaction with the analyte of interest). Circuit and elements may be included,

  It should be noted that the sensor system may include suitable circuitry that performs measurements of more than one characteristic of a single electronic sensor device. For example, a sensor device designed as an FET may have: a) resistance or conductivity measured across a conductive groove, b) groove resistance that may be measured under the influence of a constant or variable gate voltage. Or conductivity, c) device capacitance or impedance measured with respect to the gate electrode and conductive groove, and d) time integration characteristics (eg, hysteresis, phase shift, recovery behavior, similar characteristics or combinations thereof) ). Accuracy, sensitivity, and selectivity can be increased by a method that performs multiple measurements on a real-time basis using a single sensor.

  Based on such measurements and induced properties (eg, hysteresis, time constant, phase shift, scan speed / frequency dependence, etc.), the correlation may be determined by target detection or concentration. The electronic sensor device is a suitable microprocessor or other computer device as known in the art (these devices are suitably programmed to analyze the signal obtained by performing the above measurement method). Or may be connected to them. One skilled in the art will recognize that other electrical or magnetic properties may be measured as a measure of sensitivity. Accordingly, the embodiments disclosed herein are not meant to limit the types of device characteristics that can be measured.

  If desired, the measurement circuit may be designed to compensate for factors such as temperature, pressure and humidity. In this regard, please refer to the following patent document (the disclosure content of which is also a part of the present specification): US Patent Application No. 11/111121 (filing date: April 20, 2005) (Japan, title of the invention: remote-communication battery-type nanostructure sensor device).

5. CO ₂ Sensor Example In one embodiment of a carbon dioxide (CO ₂ ) sensor (see schematic FIG. 1), the sensitivity to CO ₂ can be either continuous or discontinuous. It may be achieved by using a material or functionalized layer 120. The functionalized layer may perform two main functions: 1) selectively recognize carbon dioxide molecules. 2) when combined with CO _2, to generate an amplified signal to be transmitted to the carbon nanotube converter. In the presence of water, carbon dioxide produces carbonic acid. Carbonic acid dissociates, changes the pH of the functionalized layer, imparts protons to the electron donating group, and makes NTFET properties more p-type. To function the CO ₂ detection NTFET are basic inorganic compounds (e.g., sodium carbonate, etc.), pH-sensitive polymers, e.g., polyaniline, poly (ethylene imine), poly (o-phenylenediamine), poly ( 3-methylthiophene) and polypyrrole, and aromatic compounds such as benzylamine, naphthalenemethylamine, anthracenamine, and pyreneamine may be used. The functionalized layer may be prepared using polymeric materials such as polyethylene glycol, poly (vinyl alcohol) and polysaccharides (including various starches and their components amylose and amylopectin).

The functionalized material 120 may include more than one material and / or more than one material layer called “functionalized material”, “functionalized layer” or “functionalized”. The functionalized layer has two main functions: 1) selectively recognize carbon dioxide molecules. 2) Generates an amplified signal that, when combined with CO ₂ , is transmitted to a nanostructure (eg, carbon nanotube, etc.) transducer. To function the CO ₂ detection NTFET are basic inorganic compounds (e.g., sodium carbonate, etc.), pH-sensitive polymers, e.g., polyaniline, poly (ethylene imine), poly (o-phenylenediamine), poly ( 3-methylthiophene) and polypyrrole, and aromatic compounds such as benzylamine, naphthalenemethylamine, anthracenamine, and pyreneamine can be used. The functionalized layer can be prepared using polymeric materials such as polyethylene glycol, poly (vinyl alcohol) and polysaccharides (including various starches and their components amylose and amylopectin). For example, a suitable reaction layer may be formed by combining PEI or a similar polymer and a starch polymer. Other suitable materials for the functionalized layer may include, for example, metals, metal oxides and metal hydroxides. Furthermore, the metal functionalized layer may be combined with the polymer functionalized layer.

  The functionalization layer material may be deposited on the NTFET by a variety of different methods, depending on the material to be deposited. For example, an inorganic material such as sodium carbonate may be deposited by a drop casting method using a 1 mM lower alcohol solution. The functionalized sensor may then be dried by blowing with nitrogen gas or other suitable desiccant. The polymeric material may be deposited by a dip coating method. The general procedure for this method is to immerse a chip with a carbon nanotube device in a 10% aqueous polymer solution for 24 hours, then subject the chip to several rinses with water, then nitrogen gas. A process of drying the chips by blowing is included. The polymer insoluble in the aqueous solution may be deposited by a spin coating method using a polymer solution containing an organic solvent as a solvent. The polymer concentration and the rotational speed of the rotary coater may be optimized depending on the polymer used.

  In one embodiment having aspects of the present invention, functionalized layer 815 contains PAMAM or poly (amidoamine) dendrimer, which compound has a branched structure suitable for the formation of a hydrogel. Numerous types and forms of PAMAM are commercially available from, for example, Dendritic Nanotechnology, Dendritech and Sigma-Aldrich. For example, the ethylenediamine core may have poly (amidoamine) branches with terminal amine groups. In this regard, reference is made to the following non-patent documents (the disclosure content of which is also a part of the present specification): Huye Wu, Siwen Huan, Gian Tao Tsang and Ren-Hu Tsuo, “Preparation and Characterization of Novel Physically Crosslinked Hydrogels Consisting of Poly (vinyl alcohol) and Amine-Terminated Polyamidoamine Dendrimers”, Macromol. Biosci., 2004, Volume 4. 71-75.

  Functionalized material 120 maintains a balance of hydrophobicity, hydrophilicity and basicity (eg, aminopolymers, etc.) while optimizing cross-sensitivity and response time for different species in sample environments such as relative humidity The composition is as follows. Thin film coatings or assembled monolayers (SAM) can be employed to improve response time.

  Alternative materials for functionalized layer 120 include, for example, those shown in Table 1 below. This type of material may be included in the sensor as described herein without departing from the technical spirit of the present invention.

Table 1
Examples of other recognition materials: polyacrylic acid, polyurethane resin, poly (acrylic acid-co-isooctyl acrylate), polycarbazole, poly (ethyleneimine) ("PEI"), poly (sulfone), poly ( 4-vinylphenol), poly (vinyl acetate), poly (alkyl methacrylate), poly (vinyl alcohol), poly (α-methylstyrene), poly (vinyl butyral), poly (caprolactone), polyacrylamide, poly (carbonate bisphenol) A), polyacrylonitrile, poly (dimethylsiloxane), polyaniline, poly (ethylene glycol), polybutadiene, poly (ethylene oxide), polycarbonate, poly (ethyleneimine), polyethylene, poly (methyl vinyl ether-co-anhydrous maleic) ), Polyoxyethylene, poly (N-vinylpyrrolidone), polypyrrole, poly (propylene), polytetrafluoroethylene, poly (styrene), polythiophene, polyvinyl-methyl-amine, polyvinylpyridine, polyaminostyrene, chitosan, chitosan HCl, Polyallylamine, polyallylamine HCl, poly (diallylamine), poly (diallylamine) HCl, poly (ethylene-co-vinyl acetate) (ethylene: about 82%), poly- (m-aminobenzenesulfonic acid) (“PABS”) Poly (styrene-co-allyl alcohol) (hydroxyl: about 5.7%), poly (vinyl chloride-co-vinyl acetate) (vinyl acetate: about 10%), poly (styrene-co-maleic anhydride) ( Styrene: approx. 50%), poly (Vinylidene chloride-co-acrylonitrile) (vinylidene chloride: about 80%), metalloporphyrin (“M-porph”), poly-L-lysine, α-fetoprotein profile for (“AFP4”), glycerol, polymethyl methacrylate ( “PMMA”), polyglycerol, “Nafion NR50”, metal coatings and nanoparticles (Fe, V, Au, Pt, Pd, Ag, Ni, Ti, Cr, Cu, Mg, Al, Co, Zn, Mo, Rh , Sn, W, Pb, Ir, Ru, Os, and alloys or mixtures), inorganic coatings and nanoparticles (V ₂ O ₅ , WO ₃ , Cu (SO ₄ ), boric acid, ZnO, boron trichloride, Fe _2. O _3, CaCl _2).

  The functionalization layer material may be deposited on the NTFET by a variety of different methods, depending on the material to be deposited. For example, an inorganic material such as sodium carbonate may be deposited by a drop casting method using a 1 mM lower alcohol solution. The functionalized sensor may then be dried by blowing with nitrogen gas or other suitable desiccant. The polymeric material may be deposited by a dip coating method. The general procedure for this method is to immerse a chip with a carbon nanotube device in a 10% aqueous polymer solution for 24 hours, then subject the chip to several rinses with water, then nitrogen gas. A process of drying the chips by blowing is included. The polymer insoluble in the aqueous solution may be deposited by a spin coating method using a polymer solution containing an organic solvent as a solvent. The polymer concentration and the rotational speed of the rotary coater may be optimized depending on the polymer used.

FIG. 2 illustrates the response signal of an exemplary nanoelectronic carbon dioxide sensor having aspects of the present invention over a wide range of carbon dioxide concentrations ranging from low to high concentrations contained in air, ie, 500 ppm to 100,000 ppm (0 .5% to 10%). Sensor indicates wide dynamic range, also the response to CO ₂ gas, a quick at various concentrations, is reproducible.

  FIG. 3 is a graph plotting the response signal of an exemplary nanoelectronic carbon dioxide sensor having aspects of the present invention versus a low concentration of carbon dioxide contained in air. The sensor exhibits a wide dynamic range in the concentration range of 500 ppm to 10000 ppm. Appropriate chemical recognition and specificity allowed operation of the sensor at different relative humidity and resulted in low cross-sensitivity for anesthetic gases (oxygen and nitrous oxide).

  FIG. 4 shows a capnogram plot showing the response of an exemplary capnometer having aspects of the present invention to simulated human respiration. The performance of the sensor under this clinically relevant condition indicates that this type of sensor may be very useful in medical applications related to capnography and anesthesia.

  Other aspects of carbon dioxide detection nanosensors are disclosed in the following patent document (the disclosure of which is also part of this application): US patent application Ser. No. 10 / 940,324. (Application date: September 13, 2004, Title of invention: Nanoelectronic sensor for carbon dioxide).

6). Example of NO Sensor FIG. 5 shows an exemplary nanostructure sensor having aspects of the present invention for short exposure to air containing 50 ppm NO (temperature: room temperature, relative humidity: 8%). A plot of the response is shown. The results shown show data regarding the response of the functionalized NTFET as a packaged device to nitric oxide (see packaged device 100 ′ shown in FIG. 1B). In these measurements, the packaged device was tested in a flow cell under conditions of conditioned humidity and selected concentrations of NO gas conditioned with air. The functionalized NTFET device showed a reliable response to low concentrations of NO gas such as 50 ppm contained in air under ambient conditions. The degree of response indicated that a very low threshold (eg, a low value in the ppb region) is possible.

As shown in FIG. 6, the sensor device for NO shows little or no cross sensitivity to CO ₂ which is an interferent in the respiratory air. In this case, the sensor device was exposed to 5% CO ₂ , which is a typical concentration contained in the exhaled human breath (temperature: room temperature, relative humidity: 8%).

The sensor platform used in this example comprises a field effect transistor (FET) manufactured from single-walled carbon nanotubes (NTFET) exhibiting semiconductor properties (see schematic FIG. 1A). Non-functionalized NTFET devices are sensitive to highly electron donating and electron accepting gases (NO, NO ₂ , NH ₃ ), but are not specific. In contrast, functionalized NTFET devices have been found to be specific for nitric oxide. The functionalized layer has two main functions: 1) selectively recognizes nitric oxide molecules; 2) generates an amplified signal that is transmitted to the carbon nanotube converter upon binding to NO. Therefore, this surface modification imparts sensitivity and selectivity for the determination of NO in the low concentration range to the NTFET.

  The functionalization method described above is a function of basic inorganic compounds, organic polymers, aromatic compounds and biorelevant molecular acceptors, ie, electron donation that can result in favorable doping of NTFETs by supplying electrons to the nanotubes. Based on sexual function. For this purpose, a thin, stable and reproducible film is formed on the network of carbon nanotubes by using electropolymerization and / or deposition methods of suitable electroactive species. Furthermore, the polymerization rate and degree of polymerization, i.e. the thickness and physicochemical properties of the resulting electrodeposited film, can be precisely adjusted by carefully monitoring the electrochemical parameters.

In the case of detecting NO, materials that may be used for the surface modification of carbon nanotubes include many metal complexes of porphyrin and phthalocyanine, and conductive polymers such as polyaniline and polypyrrole. NOx recognition recognizes amino-containing polymers, ie poly (ethyleneimine), bis-amino-terminated poly (ethylene glycol), and aromatic compounds (eg benzylamine, naphthalenemethylamine and calix [4] allene). Can be achieved by using. The following points should also be noted. That is, in another sensor embodiment for detecting NO, a method of oxidizing NO in a sample may be adopted without departing from the technical idea of the present invention. For example, the NO ₂ obtained can be detected by using a sensor designed to be sensitive to NO ₂ after NO ₂ is formed, for example by oxidizing NO with a catalyst. May be.

7). Capacitive Sensor Example FIG. 7 is a schematic diagram of an exemplary sensor device 70 having aspects of the present invention, which is manufactured by the method generally described in connection with the sensor shown in FIG. The nanostructure sensor 71 is provided. The sensor 71 comprises a nanostructured conductive element 72 (in this example, a carbon nanotube network) 72. The conductive element is disposed on a substrate including a dielectric isolation layer 74 disposed on a substrate 73 (in this example, the back gate of a doped silicon wafer) 73. The carbon nanotube network 72 is in contact with at least one conductive electrode 75 (in this example, a pair of electrodes is shown and these electrodes are optionally on the electrode-nanotube contact area. With passivation). The sensor device 70 further includes at least one capacitance measurement circuit 36 that is in electrical communication with the contact 75 and the back gate 73. This allows the capacitance and / or impedance of the spaced nanotube network / backgate assembly (ie, to be on one of the conductors to generate a predetermined voltage potential between the conductors). The total charge required (C = Q / V) can be easily measured.

  It should be understood that other capacitor conductors may be used in place of the back gate counter electrode 73 without departing from the technical spirit of the present invention. Examples of such conductors include an upper counter electrode, a liquid counter electrode, and a second nanotube network conductor that is spaced apart. The effect of the counter electrode includes the generation of an electric field potential between the counter electrode and the nanostructure electrode (eg, a nanotube network, etc.), so that the capacitance can be measured, resulting in problems. Changes in capacitance in response to the interaction of one or more analytes can be measured. In general, the subject induces a change in effective dielectric constant within the separation interval between the electrodes. In addition, many different functional configurations are possible for each conductor. Such structural forms include recognition materials that bind or immobilize analytes in question in connection with the electrodes.

  The capacitance C of the sensor 71 may be calibrated and then analytically compared to the capacitance during exposure to the analyte in question (eg, isoflurane, halothane, etc.). In particular, species with large dipole moments can act to change capacitance when interacting with the nanotube network 72.

  FIG. 8 shows the response of the capacitance of an exemplary nanostructure sensor as shown in FIG. 7 and plots the response to a subject in the respiratory tract, which is an anesthetic in this example. FIG. 8 shows the response of the sensor to isoflurane for a short time in the presence of ambient air and after the recovery period, and further exposure to halothane. In this embodiment, the nanotube network 72 of the sensor 71 is directly exposed to the subject's medium. In this case, the following points should be noted. That is, the sudden change in the amplitude of the capacitance shown in FIG. 8 is not caused by noise but is caused by turbulent mixing between the sample medium adjacent to the sensor and the subject. What is the response to a constant analyte concentration? Such an effect is not brought about. In practice, as shown in FIG. 8, the response of the sensor changes very rapidly with respect to the subject.

  Preferably, the sensor 71 comprises an additional functionalized layer 78. Examples of such functionalized layers include selective reactive or binding species to enhance selectivity, sensitivity and / or signal strength, selectively permeable polymer layers and absorbent filters, and the like. The In this regard, refer to the following patent document (the disclosure content of which is also a part of the present specification): US Provisional Application No. 60/669126 (filing date: April 6, 2005) (Japan, title of invention: system comprising an integrated cell membrane and a nanoelectronic device and a nanocapacitive biomolecular sensor).

8). FIG. 9 is a schematic perspective view showing an example of an integrated multi-specimen-containing respiratory analysis system 90 having an aspect of the present invention. As a general design of this embodiment, the system 90 comprises an analyzer-processor-I / O unit 100 that communicates with the collector 91 via a respiratory air collector 91 and a signal cable 103. The collector 91 includes a collector body 92 having a central cavity 98 that communicates with the mouthpiece 93. In operation, the inhaled air is supplied into the central cavity 98 via the attached inflow valve / filter 94 and then introduced into the patient's mouth via the mouthpiece 93 during patient inhalation. The At the time of exhalation, the patient's breath is released through the mouthpiece 93 and the central cavity 98 and through the outflow regulator 95. During this exhalation and optionally during inspiration, at least one (preferably multiple) respiratory component is measured by the sensor (this will be further described below). In this embodiment, the sensor is mounted on a removable multi-sensor unit 96 that communicates with the central cavity 98 via a collection tube 97. One or more measurement signals are transmitted to the analyzer-processor-I / O unit 100 by the multi-sensor unit 96 via the signal cable 103.

The breathing flow mode shown in FIG. 9 is one exemplary having the aspect of the present invention, and another flow mode can be adopted without departing from the technical idea of the present invention. is there. For example, inhalation may occur via another device, a routing valve and routing tube (not shown), or nasal inhalation, or may be done with the mouthpiece removed from the patient's mouth. However, a mode in which inflow and outflow via the nasal cavity is avoided by systematically adjusting inhalation and discharge by the collector 91 is preferable. By including a filter or absorbent material according to the desired the inlet valve / filter 94, adversely affect potential contaminants measurement (e.g., NO _X and the like in the air) noted that the may be removed from the intake air Should. Instead of the mouthpiece 93, various forms of masks and tracheal tubes known in the art may be used as a collection member for exhaled breath.

  The volume of the central cavity 98 is preferably minimized to reduce device dead space, and the inflow valve / filter 94 and outflow regulator 95 function as a check valve or equivalent function to prevent backflow. It is preferable to have the member which fulfills. That is, this results in inhalation being effected substantially only through the inflow valve / filter 94, while exhalation is effected substantially solely by the outflow regulator 95, minimizing rebreathing.

  Similarly, further sensor arrangements are possible without departing from the technical idea of the present invention. For example, the sensor may be mounted in a unit 100 that includes an analyzer that communicates with the collector 91 at a location remote from the collector 91, for example, via an extended air sample tube (not shown). In yet another embodiment, the sensor may be disposed within the mouthpiece 93 or within an extension tube into the patient's mouth or throat.

  The illustrated collector 91 has the following advantages. That is, because the removable multi-sensor unit 96 is placed very close to the patient's mouth, measurement time delay and dead space are minimized, and the sensor or the entire sensor unit can be easily replaced as needed. be able to. Such an arrangement provides a high degree of operational flexibility to meet the demands for cost, often competing, simplification of equipment, avoiding contamination and maintaining sensor accuracy. For example, the collector body 92 and / or the intake valve 94 may be disposable for the patient and may be removed to protect the multi-sensor unit 96 and / or the flow regulator 95 from the wash solution.

  Preferably, the flow regulator 95 is designed so that the measurement accuracy and reproducibility of the test species is maximized by maintaining a generally constant discharge rate during the measurement. Also, preferably, the flow regulator 95 is adjusted or preset to maintain a selected discharge rate and / or selected flow resistance or other flow parameters, so Maximize sensitivity and selectivity in seed collection (more on this point below). Preferably, the discharge speed may be adjusted to suit the patient's body size, age, and the like.

  In certain other embodiments, the operation of the flow regulator may be performed automatically or remotely. For example, the flow regulator 95 may provide a variable discharge rate. That is, a first flow rate is provided at the start of discharge, and a different discharge flow rate or a variable discharge flow rate that is distributed as the discharge phase proceeds. Furthermore, in another specific embodiment, the discharge rate is determined by the analyzer-processor-I / by placing one or more remotely operable drivers, eg, inside the flow regulator 95. It is advantageously adjusted by the signal from the processor of the O unit 100. Thus, for example, the normal operating procedure of the measurement may be adjusted by the processor, whereby a specific discharge rate or discharge rate distribution is selected 1) for maximum sensitivity to a specific subject, Also, 2) selected to maximize the sensitivity limit (eg, discrimination between bronchial and alveolar contributions to exhaled NO) between subject sources, and 3) continuous exhalation steps A different discharge speed is selected at.

  Preferably, the analyzer-processor-I / O unit 100 comprises at least one display 101 or other output mechanism for communicating with a patient or operator (in the embodiment shown, an LCD display is shown). . Also preferably, the unit includes at least one user input mechanism 102 (in the illustrated embodiment, several buttons are shown), which allows for convenient input by the patient. In addition, the analyzer-processor-I / O unit 100 may include conventional components such as power supplies, batteries, cable connectors, and electronic devices commonly operated by consumers. Preferably, the analyzer-processor-I / O unit 100 provides the medical usefulness and suitability of the measurements of the multi-sensor unit 96 as well as the measurement history (even if the history is specific to multiple patients). A signal analyzer to make the best use of the memory for holding

  In certain embodiments, the analyzer-processor-I / O unit 100 may include circuitry that enables, for example, a wireless connection and / or an internet connection, thereby 1) patient-specific. Remote monitoring by a medical practitioner, 2) normal operation of the measurement taking into account patient measurements and remote programming of the processor / memory to modify the parameters, and 3) responsive drug administration It is possible to communicate advice.

9. As the analysis of CO ₂ in the breath above, measurement of CO ₂ is an important indicator of pulmonary / circulatory function. In particular, the measurement value and concentration distribution over time of the component species contained in the respiratory tract are medically useful indices associated with specific medical symptoms. For example, the measured patient capnogram characteristics (concentration of CO ₂ in exhaled air relative to exhalation time) have been associated with symptoms such as bronchospasm, asthma, obstructive lung disease and limited lung disease. It has also been demonstrated that capnogram features can be associated with real-time expiratory flow rates and other spirometric parameters.

  In this regard, reference is made to the following documents (the disclosure content of these documents is also a part of the present specification): US Pat. No. 6,648,833 (Title: Respiratory analysis using capnography) B. Yu et al., “Respiratory Capnography in Asthma: Evaluation of Various Shape Indices”, Eur. Respir. J., 1994, 7 (2), 318-323; Yaron et al., “Usefulness of respiratory capnograms in the assessment of bronchospasm”, Ann. Emerg. Med., 1996, 28 (4), 403-407; Yu et al., “Respiratory Capnography in Asthma; Prospects for Use and Monitoring in Children,” Rev. Mal. Respir., 1992, 9 (5), 547-552.

  FIGS. 10A-10C (these figures correspond to FIGS. 1A-1C according to the above-referenced US Pat. No. 6,648,833, with the original reference numbers), are a series of three capnogram plots. Each figure is a typical graph and a schematic diagram showing the state of alveoli of a healthy person and a sick person.

FIG. 10A shows the capnogram of a healthy person, i.e. a person who does not have substantial lung disease. There is an initial lag time when the first start of exhalation called “dead space”, which indicates the amount of air exhaled from the trachea and bronchial passages located at the periphery of the alveoli (generally about 150 ml) It should be noted that. In this case, a negligible amount of CO ₂ from metabolism is exchanged. As breath from the alveoli is exhaled and mixed with air from the dead space, the concentration of carbon dioxide generally increases with a characteristic linear gradient. When most of the dead space breath is exhaled, the carbon dioxide concentration distribution flattens to show a plateau (the plateau is generally not flat and exhibits a characteristic small slope) The area is maintained until the exhalation process is complete.

  FIG. 10B shows the capnogram of a patient suffering from obstructive pulmonary disease with an obstruction 24 in the airway. Although the alveolar sac 18 may expand and exert a gas exchange function, exhalation of breath is inhibited by the occlusion 24. Plot 20 shows a gradually increasing slope compared to plot 12 for a healthy person, which is caused by the inability to exhale rapidly. Patient ventilation is sufficient in quantity, but with difficulties.

  FIG. 10C shows a capnograph 30 of a patient suffering from an obstructive pulmonary disease having an obstruction 34 such as the illustrated fibrous tissue. The occlusion may inhibit alveolar sac 18 expansion and / or limit gas exchange. Although the airway 16 is open enough to allow breathing without injuries, the obstruction 34 limits the amount of gas contained in the breath. Plot 30 generally shows an equivalent upslope when compared to plot 12, but shows a plateau at a lower concentration than plot 12, which indicates that the patient is more than healthy. Indicates that proper ventilation is not possible.

10. Analysis of respiratory air NO As mentioned above, the measurement of respiratory air NO is an important indicator of inflammatory diseases, immune responses and many other symptoms. In particular, exhaled nitric oxide (NO) has the potential to be an important diagnostic / treatment indicator for airway diseases and especially bronchial asthma. In general, asthmatic patients exhale at high NO concentrations compared to those who do not suffer from asthma, so medication in effective anti-inflammatory therapy is associated with a significant reduction in the NO concentration.

  Testing the presence of exhaled NO using expensive, large and complex devices may facilitate the diagnosis and treatment of occasional asthma symptoms in a clinical outpatient setting. However, it is a NO measurement unit that provides a general asthma patient or the patient's parents or nurses with a real-time indication of the need for self-medication or response to such treatment, which is practically low-cost. There is a need for such a unit that is portable and operable by the patient. Rapid response with treatment programs tailored to the daily (or shorter time interval) symptoms of the patient's bronchial inflammation can prevent the emergence of symptoms requiring emergency treatment. In addition, accurate preventive measures for chronic inflammatory airway disease without drug overdose can reduce cumulative tissue damage and improve long-term patient outcomes.

  Regarding these points, refer to the following documents (the disclosures of these documents are also part of the present specification): A. Karitonov et al., “Nitric Oxide Increased in Exhaled Asthmatic Patients,” The Lancet, 1994, 343, 133-135; Kimberley et al., "Nasal involvement in nitric oxide exhaled during human resting and breathing arrest", Am. J. Resp. Critical Care Med., 1996, 153, 829-836; A . F. Massaro et al., “Nitric oxide concentration exhaled during the treatment of acute asthma”, Am. J. Resp. Critical Care Med., 1995, 152 (2), pages 800-803; E. Sirkov et al., “Airway diffusion of nitric oxide in asthma; role in lung function and bronchial response”, Am. J. Resp. Critical Care Med., 2000, 161, pp. 1218-1228.

Unlike CO ₂ (typically 1-5%), the main component in exhaled breath, NO is generally present in trace amounts (typically on the order of a few ppb). is there). For example, the measured concentration of NO contained in exhaled breath of non-asthmatic patients is in the range of 5-25 ppb, while in the case of asthmatic patients it is in the range of 30-100 ppb. Of course, measurement of these concentrations requires higher detection sensitivity than in the case of CO ₂ . Importantly, however, NO is produced by metabolic processes in reactions in many different tissues and cells, and this amount is not negligible when trace amounts are a medical problem. In the respiratory process, NO is generated in the bronchial airways and not only by gas exchange from alveolar blood, but also in nasal cavity, oral cavity, trachea and throat tissues. Furthermore, it affects the measurement of the NO _X and local air pollution NO in air. For this reason, substantial research ensures that the NO contained in the collected breath is sourced from the tracheal airway and the contribution of other sources is minimized. It has been done for.

  For example, an intake filter may be used to remove NO from the ambient air that is inhaled. Techniques for eliminating air released from the nasal cavity after passing through the nasopharynx from the sample may be employed. Furthermore, the concentration of NO exhaled depends substantially on the expiration rate. Regarding these points, refer to the following documents (the disclosures of these documents are also part of the present specification): Sirkov et al., “Flow-dependent dependence of exhaled nitric oxide by using a novel technique to eliminate nitric oxide from the nasal cavity”, Am. J. Respir. Crit. Care Med., 1997, 155. Vol. 260-267; U.S. Pat. No. 5,795,787 (Title of Invention: Method and Apparatus for Measuring Exhaled Nitric Oxide in Humans); U.S. Pat. No. 6010459 (Title of Invention: Exhaled Nitric Oxide in Humans) U.S. Pat. No. 6,067,983 (Title of Invention: Method and Apparatus for Taking Samples from the Airway Under Control); U.S. Pat. No. 6,733,463 (Title of Invention: in exhaled breath) Method and apparatus for measuring nitric oxide concentration); U.S. Patent Application No. 2004-0017570 (Title: Apparatus and system for quantifying respiratory air).

  FIG. 11 is a graph showing the dependence of exhaled NO concentration on exhalation rate, comparing the data of healthy persons with the data of patients suffering from respiratory tract disease (this graph is the US mentioned above). (Cited from Japanese Patent No. 6733463). For any subject, there is a significant non-linear reduction in NO concentration with increasing exhalation rate. Given this strong dependence, systematic control of exhalation rate during the measurement process allows reproducibility to reflect airway symptoms rather than to reflect the subject's effort or response to instructions. It is desirable to obtain a certain result. FIG. 11 shows the following. That is, the proportional effect of the expiratory rate on the concentration of NO is generally equivalent for each subject group, but the difference in absolute NO concentration (ppb) in the subject group is the most Appears at low expiratory rates.

FIG. 12 shows a graph plotting NO concentration in exhaled exhaled air as a function of expiration time or duration of expiration. In this case, the following points should be noted. That is, the fractional concentration of NO reaches a plateau generally similar to the case of CO ₂ capnogtam shown in FIG. 10A (however, the concentration value is much lower than that of CO ₂ ). is there). The following points should be recalled. That is, unlike the case of CO ₂ (most of CO ₂ contained in exhaled breath is released from the alveoli), NO contained in exhaled breath is supplied as an important component from many tissues, The concentration distribution as shown in FIG. 12 varies depending on the sampling factor and the expiration rate.

11. Multiple analysis of gases contained in respiratory air Measurements of various components contained in exhaled breaths may be related in various ways. For example, CO ₂ measurements may be used to confirm the sampling status of exhaled breath (eg, the sample is derived from the bronchi) before analyzing another gas such as NO or a test species. For example, to confirm the arrangement of the inhaler, and to confirm whether the nasal cavity can be removed from the source). In this regard, reference is made to the above-mentioned US Pat. No. 6,010,459.

Furthermore, since the concentration distribution of CO ₂ in the respiratory air can be correlated with the discharge flow rate, a sampling procedure for collecting trace amounts of test species such as NO that shows a significant dependence on the discharge rate. It may be used in management. In this regard, reference is made to US Pat. No. 6,648,833 referred to above. By measuring CO ₂ at the same time, useful estimates of a number of related spirometry parameters can be obtained.

Metabolically, one component in the respiratory tract may have a regulatory effect on another component. For example, in mammals, CO ₂ may have a regulatory or feedback effect on exhaled NO (eg, exhaled NO can be reduced by exhaled CO ₂ ). Such effects are independent of changes in the central nervous system and extracellular pH. In this regard, please refer to the following document (the disclosure content of this document is also a part of the present specification): C. "Adjusting nitric oxide from the lung with carbon dioxide is inherent to the lung," Acta Physiol. Scand., 1999, 167 (2), 167-174. In addition, the following is known. That is, a high concentration of CO ₂ in the alveoli suppresses exhaled NO, but an increase in the concentration of CO _{2 in} the blood does not bring about such an effect. The following has been proposed. That is, alveolar CO ₂ non-competitively suppresses epithelial tissue NO synthesis activity, and NO production suppressed by hypercapnia promotes hypoxic vasoconstriction of the lung. In this regard, see the following literature: Yamamoto et al., “The role of airway nitric oxide on the regulation of pulmonary circulation by carbon dioxide”, J. Appl. Physiol., 2001, 91 (3), 1121 to 1130.

Monitoring the patient's symptoms may be improved by measuring additional test species contained in the exhaled breath. For example, the following is known. That is, the concentrations of exhaled hydrogen peroxide (H ₂ O ₂ ) and nitric oxide (NO) increase in the case of asthmatic patients. By measuring H ₂ O ₂ , NO and eosinophils contained in sputum induced by asthma, the following has been found:
a) Compared to normal subjects, the concentrations of exhaled H ₂ O ₂ and NO increase in steroid-deficient asthma patients.
b) In patients with stable disease treated with steroids, the concentrations of exhaled H ₂ O ₂ and NO are reduced.
c) In asthmatic patients treated with steroids and unstable in pathology, the concentration of exhaled H ₂ O ₂ increases, but the concentration of NO decreases.
d) Exhaled H ₂ O ₂ is associated with eosinophils in the sputum and airway hyperresponsiveness.
e) In contrast, exhaled NO is associated with sputum eosinophils but not with airway hyperresponsiveness.
Therefore, measuring the exhaled H ₂ O ₂ and NO provides supplementary data for monitoring disease activity. In this regard, see the following literature: Holbas et al., “Combination of exhaled hydrogen peroxide and nitric oxide in asthma monitoring”, Am. J. Respir. Crit. Care Med., 1998, 158 (4), pp. 1042-1046.

It has been proposed to measure NO or other trace amounts of analyte and CO ₂ simultaneously. In this case, the concentration of CO ₂ contained in the exhaled breath (a known concentration or a concentration that can be measured with appropriate accuracy) is used as an internal reference to reduce measurement errors in NO or other trace amounts of gas. . Such techniques typically require inherent modifications of many conventional measurement systems (eg, temperature sensitivity, laser power fluctuations, expensive consumable calibration gases, etc.). In this regard, for example, refer to the following documents (the disclosure content of these documents is also a part of the present specification): US Patent Application Publication No. 2003-0134427 (Title of Invention: Gas Method and apparatus for measuring concentration); C. Roller et al., “Simultaneous measurement of NO and CO ₂ in human respiratory air using a single IV-VI mid-infrared laser”, OPTICS LETTERS, 2002, 27 (2), 107-109. page. A stable nanoelectronic sensor having an aspect of the present invention can reduce the dependence on such compensatory techniques.

As is apparent from the above discussion, due to the particular features of the multi-faceted respiratory analyzer shown in FIG. 9, the analyzer has expired breaths having substantially different physiological / chemical features. Suitable for collection, measurement and analysis of gases (eg, CO ₂ and NO) contained therein.

12 Another Sensor / Sampler Configuration FIG. 9 shows a multi-sensor unit 96 having a collector tube 97 extending downwardly toward the interior of the central cavity 98 of the sampler body 92. In this case, the respiratory air is transferred upward and interacts with the sensor of the sensor unit 86. There are many practical alternatives regarding the placement of the sensor relative to the central cavity, and the selection of a particular sensor attachment may be determined to optimize sensor performance, useful life, etc.

  FIGS. 13A-13G illustrate several alternative sensor mountings that may be used in the respiratory air collector 91. FIGS. 13A to 13G are reprinted from US Patent Application No. 11/019792 (filing date: December 18, 2004, title of invention: nanoelectronic capnometer adapter) assigned as the above-mentioned joint application. (The disclosure of the patent application is also a part of the present specification). These drawings illustrate an airway capnometer adapter having specific features and operating principles that are generally similar to the sampler 91. These adapters may be used as another embodiment in the sensor unit described above without departing from the technical idea of the present invention and without undue experimentation.

  The reference numbers in FIGS. 13A-13G generally do not indicate the same elements as those shown in the other drawings. In the different embodiments shown in FIGS. 13A-13G, identical or generally similar elements are designated with the same numerals. The last digit of the multi-digit number is made to correspond as much as possible to the equivalent or corresponding element. In each figure, the number preceding the last number corresponds to the figure number in each embodiment. In each of the embodiments shown in FIGS. 13A-13G, the central cavity 98 (see FIG. 9) through which the discharge flow passes is indicated by a reference number ending with “9” in the last digit.

In the exemplary embodiment detailed in US patent application Ser. No. 11/019792, the nanoelectronic sensor exhibits selectivity and sensitivity to CO ₂ , but its construction and operating principles are problematic. It is also generally applied to sensors that are compatible with other analytes (eg, analytes as described herein), as well as multi-analyte sensors and the present invention as described herein. The same applies to a sensor array having the above viewpoint.

  In the embodiment having the aspects of the present invention shown in FIG. 13A, including front and side views, the unit has inputs and outputs for connecting pipes to an air groove (19) extending inside the housing (14). It may be designed in a form. The adapter (10) may be connected to a power source and a signal cable (15). The cable (15) may be used for relaying the gas monitoring data to the display unit or may be used for power transmission to the sensor. The cable may be connected directly to the electronic module (11). This module may be designed in such a way that it can process and analyze signals and supply data values and waveforms to the user. The module (11) may comprise a microprocessor with embedded software and a backup power battery. Such an electronic module is connected to a connector (17) to a solid state sensor (12) (eg, a nanoelectronic capnometer sensor as disclosed in US patent application Ser. No. 10 / 940,324) and has an upper portion thereof. May be installed. The module (11) may be designed so that it can be easily removed and reattached to facilitate the replacement operation of the adapter with the sensor. If desired, the electronic module (11) and sensor (12) may be attached to a single integrated semiconductor device such as a silicon chip.

  The solid sensor (nanoelectronic sensor) (12) may be arranged to communicate with respiratory air passing through the groove (19) via fluid. In order to supply a predetermined amount of sample to the capnometer, a small window or opening (13) may be installed between the solid sensor (12) and the groove (19). A membrane and / or filter (18) may be placed in the sample window to reduce the condensation of the patient's secretions and the resulting blockage and maintain overall sensor stability. For example, a gas permeable hydrophobic membrane such as a PFC membrane may be used.

  Unlike conventional NDIR sensors for detecting carbon dioxide, when using a nanotube electronic sensor, the optical path need not be kept transparent. Furthermore, because the activity sensing area of the nanotube electronic sensor is very small, the sensor is easily protected from contamination in the air stream from the patient. For example, only very little power is required to heat the sensor to a stable temperature that prevents condensation. The sensor may also be protected from non-volatile contaminants by a simple mechanical filter and / or gas permeable membrane. In this case, the filter or membrane need only be large enough to minimize the possibility of excessive blockage, such as a filter, during the expected lifetime of the sensor. In the case of a reusable sensor, the filter unit can be removed and discarded and replaced with a new filter unit before the next use. However, for most applications, it is desirable to have the entire unit (10) including the associated filter discarded and replaced. The unit (10) may inherently comprise a mechanically stable housing (14). The housing (14) is constructed from any suitable plastic or other material having similar chemical and physical properties to those used in medical tubing fittings as known in the art. It may be.

  The capnometer sensor (12) is based on nanoscale components as described in the parent patent application US patent application Ser. No. 10 / 940,323, the parent patent application of this application, for selectively detecting carbon dioxide. It may be. Detection of other gases may be performed by using a nanotube sensor designed in an appropriate form. Examples of such sensors include sensors as described in the specification of the following US patent applications: provisional application 60/457597 (filed in March 2003), 60/466621 (2003). Non-provisional application No. 10/177929 (filed in June 2002), No. 10/656898 (filed on September 5, 2003), No. 10/655529 (filed on September 4, 2003), No. 10/388701 (filed on Mar. 14, 2003) and No. 10/34583 (filed on Jan. 16, 2003). Note that the descriptions in the specifications of these patent applications also form part of the present specification.

  Detection of two or more gases (eg, carbon dioxide and oxygen) may be performed by using a sensor, such as one or more sensors (12). A single sensor may have multiple nanotube sensors, each sensor being designed to be configured to detect a different gas. Additionally or alternatively, each sensor of the plurality of nanotube sensors may be designed to detect the same gas for surrogate functionality. The size of the nanotube sensor is so small that many nanometer-sized sensors can be cost-effectively integrated into a single gas sensing unit (12). In this case, the unit may consist essentially of a very compact silicon chip or other device. Alternatively, one or more nanotube sensing devices may be incorporated together in a sensing unit having multiple sensors. Each device is so small that space and / or cost is not a limiting factor.

  The capnometer according to the present invention can be easily designed in a form that can be operated wirelessly. FIG. 13B shows a wireless unit (20) that does not require a power or signal cable. To compensate for this alternative, wireless communication capability can be provided to the wireless communication electronic module (21) to the base (26). Since the capnometer consumes very little power, the small battery (23) mounted on the substrate supplies enough power during its lifetime. The housing (24) and the groove (29) may be designed to have a configuration similar to that of the capnometer (10).

  Alternatively, the capnometer (30) may be designed to function with all electronic components (31) separated from the sensor (32), as shown in FIG. 13C. The sensor (32) has a cable connecting the sensor to the electronic module (31), which is remotely located. For example, the module (31) may be integrated into the display / base (36). The base may be reused in another capnometer unit (30). The base (36) may be combined with more complex hardware and software (eg, a display system or analysis system) for capnography. The signal / power cord (35) to the sensor may be detachably connected to the unit (30), and only the sensor unit (30) may be discarded and replaced.

  There is also a need to provide a detection adapter for a disposable capnometer, where the detection package is mounted directly in the main air channel of the respiratory system. 113D and 13E show an exemplary embodiment of this type. FIG. 13D shows a capnometer sensing / airflow adapter unit (40) comprising a tubular adapter (44) with an internal air groove (49). The nanoelectronic unit (42) may be attached to the wall of the groove (49), and the unit may be connected by a wire to a cable connector (47) attached to the outside of the adapter (44). . For example, by incorporating the detection unit (42) and its connecting wire into the adapter (44) during the plastic molding process, the possibility of leakage inside or outside the groove (49) adjacent to the sensor (42) Can be minimized. As described above, the sensor (42) may comprise a nanotube device. The nanotube device may be protected from contamination by suitable filters and / or gas permeable membranes (not shown) placed around or on the sensor. For example, the sensor (12) may be encapsulated in a gas permeable membrane and / or a suitable filter and / or membrane may be mounted inside the groove (49).

  Or you may arrange | position a detection unit more directly in airflow. For example, FIG. 13E shows a capnometer sensor and adapter (50). In this case, the nanoelectronic sensor is installed using a plurality of ribs (58) at the center of the groove (59). The rib (58) may be integrally formed with the sensor (52) and / or the adapter housing (54) and may be integrally formed with the cable (55). Alternatively, the rib (58) and sensor (52) may comprise sub-assemblies that are later assembled in the housing. This type of subassembly may be attached to an integrally molded electrical connector (not shown) that passes through the wall of the housing (54). Either configuration substantially eliminates the possibility of inaccurate sensor readings due to air leakage to the outside. A protective filter or membrane may be held around the sensor (52) by using ribs (58) or any other suitable sensor (52) mounting structure. Such a configuration is particularly suitable for monitoring respiratory air from a subject in a breath test device (eg, a device for blood alcohol testing, etc.).

  FIG. 13F is a schematic side view of a capnometer sensor and adapter (30) generally similar to the embodiment shown in FIG. 13A. However, in this case, the sensor (62) is located adjacent to the second parallel lumen (66) communicating with the airway passage (69). The window or opening (63) communicates directly with the parallel lumen (66) but indirectly with the passage (69).

  FIG. 13G shows a capnometer sensor and adapter (typically similar to the embodiment shown in FIG. 13F, except that a second parallel lumen projecting into the airway passageway (79) into the exhalation flow path ( 76) is a schematic side view of an inlet end portion (66a) and an outlet end portion (76b).

  It should be noted that the embodiment shown in FIGS. 13F and 13G shows parallel lumens located proximate to the adapter housing and the first passage. Alternatively, the parallel lumens may extend such that sensors, electronics, display devices and / or data storage devices are located away from the airway.

  Although preferred embodiments of the method and apparatus having aspects of the present invention have been described, it will be apparent to those skilled in the art that certain advantages are obtained by systems according to such embodiments. Various modifications, improvements, and alternatives of the above-described embodiments can also be implemented within the technical scope and technical idea of the present invention. For example, the methods and apparatus described above may be used for detection of biopolymers (eg, nucleic acids and proteins, etc.), detection of organisms or fragments of organisms, and / or forensic assessments such as genetic identity, etc. May be.

Explanation of sign

DESCRIPTION OF SYMBOLS 10 Adapter 11 Electronic module 12 Sensor 20 Adapter 21 Electronic module 23 Small battery 30 Adapter 31 Electronic module 36 Capacitance measurement circuit 40 Adapter unit 42 Sensor 44 Adapter 50 Adapter 52 Sensor 62 Sensor 66 Lumen 69 Airway passage 70 Sensor device 71 Nanostructure Sensor 72 Conductive element 73 Substrate 74 Dielectric isolation layer 75 Conductive electrode 76 Lumen 79 Airway passage 90 Multi-analyte-containing respiratory analysis system 91 Sampling device 93 Mouthpiece 94 Inlet valve / filter 95 Flow regulator 96 Detachable Multi-sensor unit 97 Collector 98 Central cavity 100 Electronic detection device 101 Subject 102 Nanostructure sensor 103 Signal cable 104 Substrate 106 Conductive groove 11 Contact 112 Contact 114 gate electrode 116 dielectric layer 118 suppressor layer 120 function reducing material 122 meter

Claims (34)

Respiratory analyzer comprising the following components (i) to (iii):
(I) at least one first nanoelectronic sensor, a) a substrate, b) one or more nanostructures disposed on the substrate, c) one electrically connected to the nanostructures Or a plurality of conductive elements, and d) at least one recognition material that is operatively associated with the first nanostructure, provided that at least one of the recognition materials is present on the first subject present in the human respiratory air. The first nanoelectronic sensor (ii) having a sensitivity to the first nanoelectronic sensor (ii) at least a respiratory air collector designed to collect respiratory air exhaled from a patient, the first nanoelectronic sensor comprising: A respiratory sampler connected to a sensor; and (iii) receiving a signal from the first nanoelectronic sensor and using the signal to measure the concentration of the first analyte, Provide information related to medical conditions It designed processing unit as.   The respiratory analyzer of claim 1, further comprising an output mechanism for providing information related to the medical condition of the patient to the user.   a) a substrate, b) one or more nanostructures disposed on the substrate, c) one or more conductive elements electrically connected to the nanostructures, and d) a first nanostructure And at least one recognition material that is operatively associated with, wherein at least one of the recognition materials is designed to be sensitive to a second subject present in the human respiratory air Further comprising a second nanoelectronic sensor, wherein the processing unit receives the signal from the second nanoelectronic sensor and uses the signal to measure the concentration of the second analyte, The respiratory analyzer of claim 1, wherein the respiratory analyzer is designed to provide information related to a patient's medical condition. .
The respiration according to claim 3, wherein the arithmetic processing unit determines a relationship between the measurement values indicating the medical state of the patient by comparing the measurement values of the first subject and the second subject. Qi analyzer. The respiratory analyzer according to claim 4, wherein the first subject contains carbon dioxide (CO ₂ ) and the second subject contains nitric oxide (NO). The respiratory air analyzer according to claim 5, wherein the arithmetic processing unit provides evaluation information related to airway inflammation of the patient by determining a relationship between CO ₂ in the collected respiratory air and a measured concentration of NO.   The respiratory air analyzer according to claim 6, wherein the evaluation information of the patient's airway inflammation indicates an asthma state, and the output mechanism provides the user with information related to the asthma state.   The respiratory analyzer of claim 1, wherein the respiratory analyzer is substantially portable and provides information related to an asthma condition to a patient on a substantially real-time basis.   The respiratory analyzer of claim 1, wherein the one or more nanostructures disposed on the substrate comprise a network of carbon nanotubes.   The respiratory analyzer of claim 9, wherein at least a portion of the network is in contact with one or more conductive elements.   The respiratory analyzer of claim 10, wherein the one or more conductive elements comprise a source electrode and a drain electrode separated from each other by a source / drain gap.   The network of carbon nanotubes has a characteristic length, which is substantially smaller than the source / drain gap, so that the nanotubes that make up the network are substantially at least one of the source and drain electrodes. The respiratory analyzer according to claim 11, which comes into contact.   The network of carbon nanotubes has a characteristic length that is substantially larger than the source / drain gap, and a substantial portion of the nanotubes that make up the network are in contact with both the source and drain electrodes The respiratory analyzer according to claim 11.   The respiratory analyzer according to claim 1, further comprising a gate electrode, wherein the signal of the sensor indicates the characteristics of the nanostructure under the influence of the gate voltage.   The respiratory analyzer of claim 1, wherein the sensor signal is indicative of a capacitance characteristic of the nanostructure. First analyte and the second analyte _is, CO 2, NO, breath analyzer of claim 4, wherein the NO ₂ and _H 2 _{O 2} is selected from substantially the group consisting.   A respiratory sampler continuously supplies a sample of respiratory air to one or both of the first sensor and the second sensor for at least a substantial exhalation time of the respiratory air from the patient; The respiratory analyzer according to claim 5, wherein a change with time in the concentration of one or both of the first subject and the second subject during the exhalation time is determined.   The respiratory air analyzer of claim 1, wherein the respiratory air collector adjusts the pressure of the respiratory air sample during the patient's exhalation time.   A system for detecting nitric oxide in a gaseous sample, comprising a converter for oxidizing nitric oxide to nitrogen dioxide, and a nitrogen dioxide sensor comprising carbon nanotubes.   The system of claim 19, wherein the nitrogen dioxide sensor comprises a recognition layer on the carbon nanotubes adapted to enhance sensitivity to nitrogen dioxide.   21. The system of claim 20, wherein the recognition layer contains at least one polymer.   21. The system of claim 20, wherein the recognition layer comprises a polymer having amino functionality.   The recognition layer comprises at least one polymer selected from polyethyleneimine (PEI), polyamidoamine (PAMAM), polydi (carbazol-3-yl) phenylamine, nylon and poly (N-isopropylacylamide) (PNISAM). 21. The system of claim 20, containing.   21. The system of claim 20, wherein the recognition layer contains polyethyleneimine.   The system of claim 19, wherein the converter contains a catalyst.   20. The system of claim 19, further comprising at least one other sensor comprising carbon nanotubes that sense gases other than nitrogen dioxide.   20. The system of claim 19, further comprising a plurality of other sensors including nanotubes that sense gases other than nitrogen dioxide.   28. The system of claim 27, wherein the other sensors include a carbon monoxide sensor and a carbon dioxide sensor.   The system of claim 19, further comprising a flow sensor for measuring at least one of flow rate and flow rate.   20. The system of claim 19, wherein at least the nitric oxide sensor is a disposable sensor.   A system for detecting nitric oxide in a gaseous sample, comprising a nitric oxide sensor comprising carbon nanotubes. A method for detecting nitric oxide in a gaseous sample comprising the following steps (i) and (ii):
(1) Nitric oxide in a gaseous sample is oxidized to nitrogen dioxide, and (2) nitrogen dioxide is detected using a nitrogen dioxide sensor containing nanotubes.   A method for detecting exhaled nitric oxide in breathing air, the method comprising detecting exhaled nitric oxide in breathing air using a nitric oxide sensor including a nanotube. A method for detecting exhaled nitric oxide in respiratory air, comprising the following steps (i) and (ii):
(1) Nitrogen oxide in exhaled breathing air is oxidized to nitrogen dioxide, and (2) nitrogen dioxide is detected using a nitrogen dioxide sensor containing nanotubes.

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