The present invention relates to sensors, and in particular to nanostructured sensor systems for measurement of medically important physiologic gases during patient care, such as tissue CO2 measurement.
As described in U.S. patent application Ser. No. 09/099,293 filed Jun. 18, 1998 (now U.S. Pat. No. 6,055,447) entitled “Patient CO2 Measurement” by M. Weil et al., and other patent applications incorporated by reference herein, methods and apparatus have been developed for sampling of carbon dioxide (CO2) as present in human tissue.
Examples include measurement strategies for determining tissue CO2 by sampling gases diffused across a mucous membrane. In a further example, a system for sublingual measurement of CO2 has been made and marketed as the CapnoProbe by Nellcor Puritan Bennett (Tyco Healthcare/Mallinckrodt). Unfortunately there are challenges involved with this approach (see FDA Press Release P04-82 dated Aug. 27, 2004, which is published on the web as http://www.fda.gov/bbs/topics/news/2004/NEW01108.html).
Each such probe is packaged in a metal canister filled with a saline solution and sealed in a foil envelope labeled as non-sterile. In this instance, the probe and associated saline were reported to contain the bacteria Burkholderia Cepacia and other opportunistic pathogens that can cause serious infections, usually in persons who have decreased resistance to infection. This has resulted in the recall of certain devices. The saline storage limitations are related to the detection technology employed. See, for example, U.S. patent application Ser. No. 08/535,878 filed Sep. 28, 1995 by J. Alderete, et al. for “Optical Carbon Dioxide Sensor, and Associated Methods of Manufacture” (now U.S. Pat. No. 5,714,121 assigned to Optical Sensors Incorporated), which is incorporated by reference herein. What is needed is an inexpensive carbon dioxide sensor for reliable, and safe measurement of carbon dioxide that does not require storage in a saline solution to maintain its operational characteristics.
It should be understood that one aspect of the invention herein may be set forth in one part of the description, figures, formulas, and/or examples herein, while other aspects of the invention may be set forth in other parts of the description, figures, formulas, and/or examples herein. Certain advantageous inventive combinations may be taught in one part of the description, figures, formulas, and/or examples herein, and the detailed description, and the best mode of such combinations and their respective elements may be set forth in other parts of the description, figures, formulas, and/or examples herein. Therefore, the invention is to be understood broadly from this disclosure as read in its entirety, including the patent applications incorporated by reference, and including the claims set forth below. Likewise, any examples or cross-references included in the incorporated patent applications may be instructive with regard to the invention herein, and are therefore incorporated herein by reference.
In exemplary embodiments having aspects of the invention herein, sensors such as the carbon dioxide nanoelectronic sensor described in the co-invented pending US Published Patent Application No. 2005-0129,573 entitled “Carbon Dioxide Nanoelectronic Sensor,” which is incorporated herein by reference, are shown herein to provide a practical and economical solution to the certain limitations associated with previously-marketed medical instruments, such as sublingual probes. In contrast to such sensors, a carbon dioxide sensor such as a carbon nanotube-based sensor described in US Published Patent Application No. 2005-0129,573 does not require storage in a saline solution to maintain its operational characteristics. It may be stored in a sealed, sterile dry package (e.g., dry sterile nitrogen), which does not present an environment supportive of growth of bacteria during storage. As described in US Published Patent Application No. 2005-0129,573, and other patent applications incorporated by reference herein, electronic sensors including nanostructure elements have been developed which provide a highly compact, inexpensive (e.g., disposable), low power detector and measurement device for measuring medically important species in human blood, tissue, breath, fluids and the like, for example carbon dioxide, oxygen, hydrogen, nitrous oxide and other gases. In the alternative or in addition the system may include sensors having a sensitivity for biomolecular, biochemical or pharmaceutical species.
A nanoelectronic sensor such as described in US Published Patent Application No. 2005-0129,573 has been previously demonstrated to be effective for measuring CO2 in exhaled breath. See the co-invented pending US Published Patent Application No. 2005-0245,836 entitled “Nanoelectronic Capnometer Adapter,” which is incorporated by reference. Likewise, a nanoelectronic sensor such as described in US Published Patent Application No. 2005-0129,573 has been previously demonstrated to be conveniently suited to compact and reliable integration in low-power electronic systems including conventional power supplies, data acquisition, transmission, reception and display components. See the co-invented pending US Published Patent Application No. 2006-0055,392 entitled “Remotely Communicating, Battery-Powered Nanostructure Sensor Devices,” which is incorporated by reference.
Furthermore, the described sensors may be conveniently mass-fabricated on tiny substrates, such as a subdivided die of a silicon wafer, lending these sensors to inexpensive manufacture in very small operational packages. The use of silicon wafer technology permits processes and equipment common to the electronics industry to be used. A die comprising the circuitry of one or more sensors may be separated from the wafer. The die may then be packaged, mounted and/or encapsulated by common methods known in the electronics industry so that electrical power and signal conductors of the die communicate with extended electrical leads, either as a discrete sensor component, or as a sub-component of a larger-scale circuit board or electronic device. Alternatively, the sensor circuitry may be formed on the wafer as a functional region of an integrated circuit, and packaged in a manner known for ICs.
Alternatively, sensors such as described in U.S. patent application Ser. No. 10/940,324 may be made on flexible substrate materials, such as polymer films, for example employing devices and method described in the co-invented pending US Published Patent Application No. 2005-0184,641 entitled “Flexible Nanotube Transistors,” which is incorporated herein by reference. These devices and methods are suitable for very low cost production, lending them to use in disposable or consumable products.
In certain embodiments, a system having aspects of the invention for measuring an analyte of interest dissolved in a fluid media comprises: an insertion tube having a distal portion and a proximal portion. Note that in alternative embodiments the insertion tube may be variously configured for a particular purpose, such as for access to various body orifices (endo-tracheal tube or sublingual probe), for autonomous body passage (e.g., a gastrointestinal endoscopic capsule), as an implantable therapy device (e.g. a pacemaker), and the like. The system further comprises a nanoelectronic sensor mounted adjacent the distal portion of the tube, the insertion tube configured to place the sensor adjacent at least one lumen or tissue surface of the patient upon insertion of the distal portion into at least one body cavity or lumen of the patient, so as to permit diffusion of the analyte of interest through the surface to the sensor; and a measurement instrument in communication with the sensor and configured to receive at least a signal from the sensor indicative of a response of the sensor to at least the analyte of interest. The sensor includes: a substrate; at least one nanostructured element disposed adjacent the substrate, at least a first conductor in electrical communication with the nanostructured element; at least a second conductor disposed in operative association with the nanoelectronic sensor and configured to electrically influence the at least one nanostructured element upon application of a voltage to the second electrical conductor relative to the first electrical conductor, so as to permit the measurement of at least one electrical property of the at least one nanostructured element; wherein the nanostructured element has a sensitivity to at least one analyte of interest so that the presence of the analyte of interest produces a measurable change in the at least one electrical property of the nanostructured element.
In certain alternative embodiments, the nanostructured element includes one or more carbon nanotubes, such as SWNTs, and may include an interconnecting network of carbon nanotubes. In one alternative, the first and second conductors are configured as a space-apart pair of source-drain electrodes in electrical communication with the nanostructured element; the sensor comprises a gate electrode arranged to capacitively influence the nanostructured element; and the signal includes a transistor characteristic indicative of a response of the sensor to at least the analyte of interest. In another alternative, the second conductors is configured as a capacitive counter electrode arranged to capacitively influence the nanostructured element; and the signal includes at least a capacitance or an impedance indicative of a response of the sensor to at least the analyte of interest.
In certain alternative embodiments, the analyte at least one analyte includes CO2, and the sensor may further include a recognition material, such as an organic polymer, disposed adjacent the nanostructured element, selected to provide a sensitivity to CO2. In certain embodiments the recognition material includes at least one polymer selected from the group consisting essentially of polyvinyl pyridine, polyaniline, polyaminostyrene, PEI, polyvinyl-methylamine, PAMAM, and their cross-linked polymers, which are hydrogels.
In certain alternative embodiments, the insertion tube is configured to place the sensor adjacent at least a surface within the mouth, such as a sublingual surface. In alternative embodiments, the insertion tube is configured to place the sensor adjacent at least a surface within the trachea. In other alternatives, the insertion tube is configured to place the sensor adjacent at least a surface within the digestive tract. Optionally, the system may include a hydrophobic filter element mounted adjacent the insertion tube and arranged to lie between the nanoelectronic sensor and the at least one mucosal surface.
The description of the invention herein includes the following figures:
Two conductive elements 808, 810 may be disposed over the substrate and electrically connected to nanostructure 806. Elements 808, and 810 may comprise metal electrodes in direct contact with nanostructure 806. In the alternative, a conductive or semi-conducting material (not shown) may be interposed between elements 808, 810 and nanostructure 806. A functionalization material 815 reactive with carbon dioxide is disposed on nanostructure sensing device 802 and in particular, on nanostructure 806. Material 815 may be deposited in a continuous layer, or in a discontinuous layer.
Material 815 may comprise more than one material and/or more than one layer of material, also referred to as “functionalization material,” “functionalization layer” or “functionalization.” The functionalization layer has two main functions: 1) it selectively recognizes carbon dioxide molecules and 2) upon the binding of CO2 it generates an amplified signal that is transferred to the nanostructure (e.g., carbon nanotube) transducer. Basic inorganic compounds (e.g., sodium carbonate), pH-sensitive polymers, such as polyaniline, poly(ethyleneimine), poly(o-phenylenediamine), poly(3-methylthiophene), and polypyrrole, as well as aromatic compounds (benzylamine, naphthalenemethylamine, anthracene amine, pyrene amine, etc.) can be used to functionalize NTFETs for CO2 sensing. The functionalization layer can be constructed using certain polymeric materials, such as polyethylene glycol, poly(vinyl alcohol) and polysaccharides, including various starches, as well as their components amylose and amylopectin. For example, a suitable reaction layer may be formed from a combination of PEI or similar polymer with a starch polymer. Other suitable materials for the functionalization layer may include, for example, metals, metal oxides, and metal hydroxides. In addition, a metallic functionalization layer may be combined with a polymeric functionalization layer.
Materials in the functionalization layer may be deposited on the NTFET using various different methods, depending on the material to be deposited. For example, inorganic materials, such as sodium carbonate, may be deposited by drop casting from 1 mM solution in light alcohols. The functionalized sensor may then be dried by blowing with nitrogen or other suitable drying agent. Polymeric materials may be deposited by dip coating. A typical procedure may involve soaking of the chip with the carbon nanotube device in 10% polymeric solution in water for 24 hours, rinsing with water several times, and blowing the chip dry with nitrogen. Polymers which are not soluble in aqueous solutions may be spin coated on the chip from their solutions in organic solvents. Values of polymer concentrations and the spin coater's rotation speeds may be optimized for each polymer.
In one exemplary embodiment having aspects of the invention, the functionalization layer 815 includes PAMAM or poly(amidoamine) dendrimer, which has a branched structure suitable for formation of hydrogels. PAMAM is available commercially in a number of types and forms, such as from Dendritic NanoTechnologies, Inc., Dendritech, Inc., and Sigma-Aldrich Co. For example, an ethylenediamine core may have poly(amidoamine) branches with terminal amine groups. See Xu-Ye Wu, Shi-Wen Huang, Jian-Tao Zhang, Ren-Xi Zhuo, “Preparation and Characterization of Novel Physically Cross-linked Hydrogels Composed of Poly(vinyl alcohol) and Amine-Terminated Polyamidoamine Dendrimer,” Macromol. Biosci. 2004, 4, 71-75, which is incorporated by reference.
The functionalization layer 815 may be comprised so as to balance hydrophobicity, hydrophilicity and basic properties (e.g., amino polymers), so as to optimize response time and cross-sensitivity to other species in the sample environment, such as relative humidity. The use of thin film coatings or assembled monolayers (SAM) can be employed to improve response time.
Alternative materials for layer 815 may include, for example, those shown in TABLE 3. Such materials may be included in sensors such as are describe herein without departing from the spirit of the invention.
Device 802 may further comprise a gate 812. For example, the gate 812 may comprise bulk doped silicon base material of the substrate, electrically isolated by a dielectric or insulating layer 813, e.g. SiO2. Device 802 may further comprise a layer of inhibiting material 814 covering regions adjacent to the connections between the conductive elements 808, 810 and the first nanostructure 806. The inhibiting material may be impermeable to at least one chemical species, such as carbon dioxide. The inhibiting material may comprise a passivation material as known in the art, such as silicon dioxide. Further details concerning the use of inhibiting materials in a NTFET are described in prior U.S. patent application Ser. No. 10/280,265, filed Oct. 26, 2002, which is incorporated by reference herein.
In addition, system 800 may further comprise a second nanostructure sensing device (not shown) like device 802. It may be advantageous to provide the second device with a functionalization layer that incorporates a material different from that incorporated into layer 815. System 800 may further include a nanostructure sensing device circuit 816. Circuit 816 may include one or more electrical supplies 818, a meter 820 in electrical communication with the electrical supply or supplies 818, and electrical connections 822 between the first nanostructure sensing device 802 and both the electrical supply and the meter. System 800 may further comprise a signal control and processing unit (not shown) as known in the art, in communication with the first nanostructure sensing device circuit.
Note that the structure and method illustrated in
In other alternatives, an electronic device may contain a plurality or array of sensors (or other electronic functional components), preferably fabricated on a single “die” or sheet substrate portion. For example, different sensors may be employed to detect different analytes; may be employed for “pattern recognition” discrimination between chemically similar analytes; may be employed as a graded series of sensors to increase range of concentration sensitivity or precision; and/or as calibration, reference or redundant sensors; and the like. See, for example, U.S. patent application Ser. No. 10/388,701 filed Mar. 14, 2003 entitled “Modification Of Selectivity For Sensing For Nanostructure Device Arrays” (published as US 2003-0175,161) which is incorporated herein by reference.
In addition, the sensor may omit passivation material 814 on the contact regions, or alternatively may include further passivation material or passivation in association with other elements. In other alternatives, the sensor may include conducting or semiconducting elements (not shown in
In this example, a plenum 14 is mounted adjacent chip package 10, having a pore 15 communication with sensor opening 12. Plenum 14 has a gas-permeable membrane 16 mounted so as to communicate between plenum 14 and the adjacent external environment. The gas-permeable membrane 16 includes a material known in the art and selected so as to permit the diffusion of at least an analyte of interest, in this example carbon dioxide. The analyte of interest is permitted to diffuse through membrane 16, through plenum 14 and pore 15 to sensor package 12. The gas-permeable membrane 16 may include a material known in the art and selected to exclude species other than the analyte of interest, for example, aqueous fluids, such as saliva. For example, the gas-permeable membrane 16 may be a hydrophobic polymer. Additional encapsulation material 17 may be included. Optionally sensor device 22 may include other elements such as filters, absorbents and the like (not shown) to condition analyte media prior to communication with the sensor, e.g. to exclude, repel, deactivate or absorb a particular species (e.g., a contaminant or cross-reacting molecule).
Layer 817 may be a material, such as a polymer, applied at the “wafer level” or sheet substrate level (e.g. a flexible substrate), whereby an arbitrary plurality of sensor devices are fabricated on a collective substrate (note that a discrete die may include more than one electronic device, such as an array of sensors). Typically such devices or “dies” are subsequently cut, broken or otherwise separated from the bulk wafer or substrate sheet for final packaging and/or integration into an operational electronic system. Note that techniques such as masking, ink jet and/or drop-on-demand printing may be employed to restrict layer 817 to portions of the device if complete coverage is not desired.
Layer or coating 819 may be a material, such as a polymer, applied at the “die” level or separated substrate portion level. This permits encapsulation for the sensor as a unit, for example, a hydrophobic or water-resistant layer to protect substrate, contacts, nanostructures and recognition layer from moisture or another undesired species.
Either or both of layers 817 and 819 may be selected or configured to (a) permit the diffusion or penetration of a particular species (e.g., the analyte of interest) and/or (b) exclude, repel, deactivate or absorb a particular species (e.g., a contaminant or cross-reacting molecule).
In this embodiment, sensor assembly instrument 100 is held in position by a sensor holder 102 that lies primarily in a patient's mouth. The sensor holder has a sublingual inner portion 104 that is shaped to fit under the patient's tongue (T), and especially near the location where the tongue merges with the bottom or floor K of the mouth and to lie on the bottom of the mouth. The holder has an outer portion 106 that lies outward of the inner portion and that is accessible from outside the mouth. The particular outer portion 106 lies outside the mouth and has a laterally (L) extending groove or recess 108 with groove walls that rest on the lower denture (M) and lower lip (P) of the patient. The holder 102 forms a holder passage 110 that extends between the inner and outer portions 104, 106 of the holder. The passage has at least inner and outer ports 112, 114 and preferably extends along the entire length of the holder in the inner and outer directions (I), (O).
The sensor assembly 100 has a frame 120 with an inner end 122 that supports a CO2 sensor 124. Sensor 124 of
In an alternative embodiment, the sensor can be placed adjacent any mucosal surface accessible by the mouth or nose and connecting with any region of the GI tract or upper respiratory/digestive tract. For example, in
In another embodiment, as shown in
A pCO2 sensor 38 is shown attached to the exterior of cuff 28 and lying against the inside wall of the patient's trachea, but as will be appreciated by those skilled in the art and as described elsewhere herein, the pCO2 sensor is not necessarily positioned on cuff 28. The sensor 38 of
To place the device so that pCO2 measurements can be made within the patient's trachea, the endotracheal tube 10 may be inserted into the mouth or nose of the patient, or through a tracheotomy, extended through the pharynx and larynx, and into the trachea 26. The tube 10 is preferably sufficiently long so that the proximal end 18 of the cannula and the terminus 32 of the cuff inflation line 30 extend beyond the patient's mouth while the distal end 20 of the cannula is in the patient's trachea 26. After insertion of the endotracheal tube 10, the proximal end 18 of the cannula is attached through terminal orifice 22 and connector 24 to a supply of breathable air (not shown). A positive pressure of air in the lungs is maintained by pumping air from the breathable air supply by introduction of air into terminal orifice 22, through cannula 16 and into the patient's trachea 26 through aperture 40 present at the distal end of the cannula. Prior to introducing air in this way, cuff 28 is inflated by introducing air into the cuff inflation line 30 by a syringe or the like. When the cuff is inflated, the cuff 28 conforms to the natural shape of the trachea while providing a seal with the trachea wall. Inflation of the cuff also forces pCO2 sensor against the trachea wall.
As a result, it is common for physicians to assess perfusion failure by taking measurements in the stomach and intestine which indicate the level of blood flow thereat. A useful measurement is the partial pressure of carbon dioxide (pCO2). A large partial pressure of CO2 indicates that there is a low blood flow to carry away carbon dioxide resulting from metabolism. It is noted that an increase in CO2 results in a decrease in pH, and it is also common to measure the pH in the stomach and intestines in perfusion failure. Measurements of CO2 in the stomach or intestines may have deleterious side effects. One side effect is the trauma or harm to the patient caused by insertion of a catheter with a CO2 sensor through the nasal passages, esophagus, esophageal sphincter, into the stomach. Another side effect which affects accuracy of the measurement, is that digestion fluids remaining in the stomach or intestines, can produce CO2. This is especially likely for foods, such as carbohydrates, that are being decomposed and that produce bicarbonate that reacts with stomach acid.
As shown in
One advantage of this procedure is that there is reduced invasion of the patient because the catheter does not have to pass through the esophageal sphincter (F) or lie in the stomach (D). Another advantage is that CO2 generated in the stomach (D) by digestion fluids does not affect the measurement of CO2 since the esophageal sphincter (F) blocks such gas. It is noted that sometimes the catheter must extend to the stomach as to evacuate it, as indicated at 16. In that case, the sensor 12 will lie along the catheter and be spaced from the distal end of the catheter.
Capsule 110 includes one or more sensors 160 having aspects of the invention, for example for measuring CO2 concentration within the intestinal lumen 112. Transmitter 28 is configured to transmit either or both of video and sensor data to a receiving a corresponding reception system (not shown).
In existing implantable pacing devices, the stimulation therapy may be adjusted by internal electronic logic controls so that the heart rate approximates the demands created by variable patient activity level. Typically on-board accelerometers are used for this purpose, using a variety of algorithms to estimate patient cardiac demand. See, for example, the above referenced U.S. Pat. No. 7,006,868, and also U.S. Pat. No. 6,937,900 entitled “AC/DC multi-axis accelerometer for determining patient activity and body position,” which is incorporated herein by reference.
Device 10 includes one or more implantable sensors (e.g., 11a and/or 11b as shown) having aspects of the invention, for example for measuring arterial, venous and/or interstitial CO2 concentration. Sensor 11a is configured to be mounted compactly adjacent a selected electrode of the stimulation leads, e.g., adjacent electrode 22, communicating to device 10 via conductors within lead 20. Sensor 11b is mounted within device 10 so as to communicate with the adjacent tissue. In contrast to or in addition to accelerometers as sensors of activity level, data from the sensors 11a,b may be used for, among other things, determining an activity level, oxygen demand and/or perfusion status of a patient. Cardiac stimulation may then be adjusted in response to such sensor data using conventional electronic controls.
Having thus described preferred embodiments of the methods and devices having aspects of the invention, it should be apparent to those skilled in the art that certain advantages of the within system have been achieved. It should also be appreciated that various modifications, adaptations, and alternative embodiments thereof may be made within the scope and spirit of the present invention. For example, devices and methods generally similar to those described above may be employed for measurement of gases and other analytes in different environments and industrial fields, such as the measurement of CO2 concentration in soils, aqueous environments and the like.
This application is also a continuation-in-part of U.S. patent application Ser. No. 10/656,898 filed Sep. 5, 2003 now abandoned entitled “Polymer Recognition Layers For Nanostructure Sensor Devices” (published as US 2005-0279,987), which in turn claims priority to Provisional Application No. 60/408,547 filed Sep. 5, 2002, which applications are incorporated by reference. This application is also a continuation-in-part of U.S. patent application Ser. No. 10/773,631 filed Feb. 6, 2004 now abandoned entitled “Analyte Detection In Liquids With Carbon Nanotube Field Effect Transmission Devices”, which claims priority to US Provisional Patent Application No. 60/445,654 filed Feb. 6, 2003, which applications are incorporated by reference. This application is also a continuation-in-part of co-pending U.S. patent application Ser. No. 10/846,072 filed May 14, 2004 entitled “Flexible nanotube transistors” (published as US 2005-0184,641), which claims priority to U.S. Provisional Patent Application No. 60/471,243 filed May 16, 2003, which applications are incorporated by reference. This application is a continuation-in-part of and claims priority to U.S. patent application Ser. No. 10/940,324 filed Sep. 13, 2004 entitled “Carbon Dioxide Nanoelectronic Sensor” (published as US 2005-0129,573), which in turn claims priority to U.S. Provisional Patent Application No. 60/502,485 filed Sep. 12, 2003, which applications are incorporated by reference. This application is a continuation-in-part of and claims priority to U.S. patent application Ser. No. 11/019,792 filed Dec. 20, 2004 now U.S. Pat. No. 7,547,931 entitled “Nanoelectronic capnometer adapter” (published as US 2005-0245,836); which in turn claims priority to U.S. Provisional Patent Application No. 60/531,079, filed Dec. 18, 2003, which applications are incorporated by reference. This application claims priority to U.S. Provisional Patent Applications No. 60/665,153 filed Mar. 25, 2005 entitled “Nanoelectronic Measurement System For Physiologic Gases”; No. 60/668,879 filed Apr. 5, 2005 entitled “Nanoelectronic System For Virus Detection and Identification”; and No. 60/748,834 filed Dec. 9, 2005 entitled “Nanoelectronic Sensors Having Substrates With Pre-Patterned Electrodes, And Environmental Ammonia Control System,” which applications are incorporated herein by reference.
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