News Column

Patent Issued for Nanoelectronic Electrochemical Test Device

July 30, 2014



By a News Reporter-Staff News Editor at Biotech Week -- A patent by the inventors Joshi, Kanchan A. (Emeryville, CA); Radtkey, Ray (Oakland, CA); Valcke, Christian (Orinda, CA), filed on April 22, 2011, was published online on July 15, 2014, according to news reporting originating from Alexandria, Virginia, by NewsRx correspondents (see also Nanomix, Inc.).

Patent number 8778269 is assigned to Nanomix, Inc. (Emeryville, CA).

The following quote was obtained by the news editors from the background information supplied by the inventors: "The present invention relates to sensors for chemical species using nanostructured electronic devices, and methods relating to their use and manufacture, and in particular, to devices employing nanotubes as electronic transducers for the detection and measurement of solvated biomolecules or physiologic species, such as blood glucose.

"A significant percentage of the US population suffers from diabetes (18.2 million or 6.3%). Of the 18.2 million, 13 million have been diagnosed and of the diagnosed fraction 4 million people take insulin daily. This patient group is supported through numerous foundations and professional associations who provide patient care and education.

"Sources report the market growth at 15% annually, driven mainly by increased incidence of disease (obesity, diet) and increased daily monitoring by present patients. Insulin is taken to regulate blood glucose level. The amount of insulin taken must be titrated based on food intake, exercise, physical condition of the user plus the current level of glucose. For the 4 million who follow the insulin dosing protocol blood glucose measurements are suggested 4 to 6 times per day. Diabetics who are not insulin dependent check their blood glucose less frequently, typically 1 or two times a day, to adjust oral medications as well as exercise and food intake. It is estimated that this results in about 9-10 billion glucose determinations per year worldwide.

"Self-measurement of glucose is common. Measuring one's own glucose level is typically called Self Monitoring of Blood Glucose (SMBG). Most 5 MBG readings are done on a sample of capillary blood obtained by a finger prick. The blood is applied to a disposable sensor 'strip' typically an electrochemical sensor containing Glucose Oxidase (GOX). The sensor current or voltage is read by a small electrometer referred to as a glucose meter.

"An example of a popular glucose meter is shown in FIG. 1A. The strips are contained in a cartridge. The meter automatically pushes the strips out to collect blood. After use the user must manually remove each strip and dispose of it. Most glucose meters are battery driven and have a measurement range of 20-600 mg/dL. Required blood volume varies between 0.3 and 1 uL. Most meters are provided freely to get payback on strip usage. Disposable strips contain the actual glucose sensor. Capillary action is used to move the blood into the area of the sensor.

"FIG. 1B shows a wearable glucose sensor. However, there is a need for glucose measurement and monitoring technology which is more convenient, cheaper, and better suited to integration into other systems, such as invasive or implantable diagnostic or therapeutic devices."

In addition to the background information obtained for this patent, NewsRx journalists also obtained the inventors' summary information for this patent: "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 informal claims set forth below.

"Certain exemplary embodiments having aspects of the invention comprise an electronic sensor device configured for wearable monitor, which provides the convenience of longer term monitoring (e.g., 1 week), optionally with a disposable sensor element which provides cost effective benefits to patients. See U.S. application Ser. No. 11/274,747 filed Nov. 14, 2006 entitled 'Nanoelectronic Glucose Sensors', which is incorporated by reference.

"In certain embodiments, it is advantageous to make each sensor a single-use device, the sensor being integrated into a reusable measurement system. Alternative embodiments may include an array with multiple sensor elements on a chip, wherein the multiple sensors are configured to be used sequentially by the patient or care provider, so that the device can provide a plurality of measurements. These embodiments are arranged to take advantage of the photolithographic manufacturing technology common in the electronics industry to reduce the cost-per-measurement to a low level. Known microprocessors, output devices, displays and/or power sources and the like may be included in the sensor system. See U.S. application Ser. No. 11/274,747 filed Nov. 14, 2006 (published US) entitled 'Nanoelectronic Glucose Sensors', which is incorporated by reference.

"Additional exemplary embodiments having aspects of the invention comprise an electronic sensor device which is biocompatible and configured to be operated with all or a portion of the device emplaced or inserted within a patient's body. Known biocompatible materials maybe readily used to construct the sensor device. See U.S. application Ser. No. 11/274,747 filed Nov. 14, 2006 (published US) entitled 'Nanoelectronic Glucose Sensors', which is incorporated by reference.

"In certain embodiments, one or more sensor devices are integrated into or coupled to a drug delivery system, such as an implantable insulin delivery device. The electronic sensor device is configured so as to control the release of one or more drugs in relation to the measured blood concentration of one or more target species, such as the controlled release of insulin relative to monitored blood glucose level. See U.S. application Ser. No. 11/274,747 filed Nov. 14, 2006 (published US) entitled 'Nanoelectronic Glucose Sensors', which is incorporated by reference.

"Certain embodiments of a nanoelectronic patient medical monitor system having aspects of the invention comprise: (a) an electronic control processor disposed in a patient-portable housing; (b) an analyte fluid sampling device, comprising at least one micro-needle disposed in the patient-portable housing, and configured to draw a sample of body fluid; a plurality of nanosensors disposed in the a patient-portable housing and in fluid communication with the analyte fluid sampling device; configured to transmit at least one signal in response to a target analyte; (d) electrical measurement circuitry disposed in a patient-portable housing in communication with the electronic control processor; (e) a plurality of electronically actuated valves disposed in association with the analyte fluid sampling device, configured to regulate the fluid communication of the analyte fluid sampling device with a respective nanosensor; (f) the electronic control processor further including a memory and code instructions configured to selectably actuate one or more of the electronically actuated valves, and to cause the electrical measurement circuitry to detect a concentration of the target analyte using the at least one signal from the respective nanosensor. (g) Optionally, the nanoelectronic patient medical monitor system may further comprise an electronically controllable drug delivery system in communication with the electronic control processor, configured to deliver a selected dosage of a medication in response to the detect of a target analyte in the body fluid sample. See U.S. application Ser. No. 11/274,747 filed Nov. 14, 2006 (published US) entitled 'Nanoelectronic Glucose Sensors', which is incorporated by reference.

"Additional exemplary embodiments having aspects of the invention comprise an insulating substrate such as a polymeric base film or strip, further comprising printed or deposited conductive material configured as at least one electrode region on or adjacent the substrate surface, and further comprising a coating in communication with at least a portion of the electrode regions, the coating including at least a functionalized nanostructure such as a film of carbon nanotubes functionalized with a metal and/or an organic material. The functionalization may include a bio-selective material such as a glucose-reactive enzyme.

"Certain sensor device embodiments having aspects of the invention comprise a substrate having a conductive layer, the conductive layer comprising a plurality of nanostructures (e.g., SWNTs, MWNTs, nanowires and other nanoparticles of various compositions), and preferably a network or film of single-walled carbon nanotubes. The conductive layer preferably has functionalization material or reacted groups, which may include a quantity of platinum (Pt) nanoparticles, preferably deposited on or bound to the nanostructures, such as SWNTs. In a preferred embodiment, Pt nanoparticles are produced and bound to SWNTs in solution or dispersion phase by reduction of a soluble Pt compound in a suitable solvent, the Pt functionalized SWNTs then being printed, sprayed or otherwise deposited on the substrate to form the conductive layer. Preferably a detection enzyme, such as glucose oxidase (GOx) is dispose on or in association with the conductive layer. Sensor device may includes a counter electrode disposed adjacent the conductive layer in a spaced-apart fashion, such as on a second substrate arranged adjacent the first substrate, the space between the counter electrode and conductive layer forming a sample cell for an analyte medium, for example, blood (suitable containing elements may be included to immobilize the analyte medium during sensor operation). Both counter electrode and conductive layer may be connected to suitable measurement circuitry to a change in an electrical property of the sensor in response to the presence of a target analyte. For example, glucose in a blood sample may react with GOx to form reaction products, such as hydrogen peroxide (H202) and gluconic acid), which in turn electrochemically generate a current flow between counter electrode and the conductive layer, which can be measured as an indication of glucose concentration.

"Certain alternative sensor device embodiments having aspects of the invention comprising a conductive layer having nanostructures functionalized by binding to a conductive polymeric material, for example a polyaniline derivative such as poly (maminobenzene sulfonic acid) or PABS. This composite material may be employed with or without Pt nanoparticles. Certain alternative sensor architectures may be employed in association with a conductive layer comprising a nanostructure/conductive polymer composite (such as SWNT/PABS) for detection of analytes, without departing from the spirit of the inventions. For example the sensor may be configured as a resistance sensor, an FET, a capacitance or impedance sensor, or the like, and may be arranged as an array including a combination of these.

"Additional embodiments of the invention relate to methods of fabricating nanoelectronic sensors that involve single step deposition of the carbon nanotubes and functional biomolecules (having a functionalization that allows interact with the analyte) on the sensor surface. The biomolecule and carbon nanotubes interact prior to deposition, enabling single step deposition. The biomolecule (e.g., an enzyme, mediator, nucleic acid, antibody, etc.) retains its activity and stability after immobilization on the electrode.

"Additional aspects and embodiments of the invention are set forth in the various Examples in the Figures and in the Detailed Description Of The Embodiments

BRIEF DESCRIPTION OF DRAWINGS

"The figures and drawings may be summarized as follows:

"FIG. 1A shows an existing glucose sensor;

"FIG. 1B shows an existing wearable glucose sensor;

"FIG. 2A is a schematic cross section view of a nanostructure device having aspects of the invention with a recognition layer specific to a selected analyte.

"FIG. 2B is a schematic diagram of GOx functionalization of a nanotube sensor embodiment;

"FIG. 3 is a plot showing the response of a sensor embodiment to glucose in water;

"FIGS. 4A-4C illustrate alternative embodiments of sensors having solution deposited nanotube networks, wherein:

"FIG. 4A shows a sensor in which a recognition layer is applied following deposition of nanotube film;

"FIG. 4B shows a sensor in which a layer of recognition material is deposited upon the substrate prior to application of a nanotube film 2; and

"FIG. 4C shows a sensor which includes a layer of pre-functionalized nanotubes without a distinct recognition layer.

"FIG. 5 illustrates an alternative embodiment of a sensor having aspects of the invention and including nanotube networks fabricated by deposition of a solution upon flexible substrates with pre-patterned conductor traces, including a gate dielectric and gate electrode.

"FIG. 6 shows an exemplary embodiment of a sensor device 50 having aspects of the invention and including a nanotube networks fabricated by deposition of a solution of pre-functionalized nanotubes upon a substrate.

"FIG. 7 shows architecture of a sensor device embodiment having aspects of the invention for detection and measurement of biomolecular species such as polynucleotides, proteins, polysaccharides and the like.

"FIG. 8 shows an example of square wave voltammetry (SWV) response of a nanotube electrode such as shown in FIG. 7, illustrating the effect of a ferrocyanide/ferricyanide redox couple.

"FIG. 9 shows an example of differentiating cyclic voltagrams (CV) illustrating the response of a nanotube electrode such as shown in FIG. 7 with a ferrocyanide/ferricyanide redox couple.

"FIG. 10 (Views A-C) illustrate an exemplary electrochemical sensor configured as a blood test strip.

"FIG. 11 is a plot showing the response of a electrochemical sensor embodiment functionalized with SWNT-PABS.

"FIGS. 12A-12B illustrate an exemplary electrochemical test strip having a CNT working electrode and a vented capillary path.

"FIG. 13 is a plot showing cyclic voltammmetry data for strips having CNT-functionalized conductive carbon layer and strips having a conductive carbon layer without CNTs.

"FIG. 14A is a plot showing glucose detection in blood spiked with various concentrations of glucose using glucose oxidase enzyme and potassium ferricyanide mediator with a CNTs modified electrode.

"FIG. 14B shows glucose detection in PBS spiked with various concentrations of glucose using glucose oxidase enzyme and potassium ferricyanide mediator with a CNTs modified electrode.

"FIGS. 15A-15B are plots showing responses of electrochemical sensor embodiments functionalized with antibodies."

URL and more information on this patent, see: Joshi, Kanchan A.; Radtkey, Ray; Valcke, Christian. Nanoelectronic Electrochemical Test Device. U.S. Patent Number 8778269, filed April 22, 2011, and published online on July 15, 2014. Patent URL: http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=8778269.PN.&OS=PN/8778269RS=PN/8778269

Keywords for this news article include: Carbon Nanotubes, Chemistry, Electrochemical, Electrolytes, Emerging Technologies, Enzymes and Coenzymes, Ferric Compounds, Ferricyanides, Food Intake, Fullerenes, Inorganic Chemicals, Ions, Nanomix, Nanomix Inc., Nanoparticle, Nanotechnology, Peptide Hormones, Proinsulin, Technology.

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Source: Biotech Week


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