US20100215544A1 - Handheld microcantilever-based sensor for detecting tobacco-specific nitrosamines - Google Patents
Handheld microcantilever-based sensor for detecting tobacco-specific nitrosamines Download PDFInfo
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- US20100215544A1 US20100215544A1 US12/769,338 US76933810A US2010215544A1 US 20100215544 A1 US20100215544 A1 US 20100215544A1 US 76933810 A US76933810 A US 76933810A US 2010215544 A1 US2010215544 A1 US 2010215544A1
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N29/00—Investigating or analysing materials by the use of ultrasonic, sonic or infrasonic waves; Visualisation of the interior of objects by transmitting ultrasonic or sonic waves through the object
- G01N29/02—Analysing fluids
- G01N29/022—Fluid sensors based on microsensors, e.g. quartz crystal-microbalance [QCM], surface acoustic wave [SAW] devices, tuning forks, cantilevers, flexural plate wave [FPW] devices
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2291/00—Indexing codes associated with group G01N29/00
- G01N2291/02—Indexing codes associated with the analysed material
- G01N2291/025—Change of phase or condition
- G01N2291/0255—(Bio)chemical reactions, e.g. on biosensors
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2291/00—Indexing codes associated with group G01N29/00
- G01N2291/02—Indexing codes associated with the analysed material
- G01N2291/025—Change of phase or condition
- G01N2291/0256—Adsorption, desorption, surface mass change, e.g. on biosensors
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/0004—Gaseous mixtures, e.g. polluted air
- G01N33/0009—General constructional details of gas analysers, e.g. portable test equipment
- G01N33/0027—General constructional details of gas analysers, e.g. portable test equipment concerning the detector
- G01N33/0036—Specially adapted to detect a particular component
- G01N33/0047—Specially adapted to detect a particular component for organic compounds
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T436/00—Chemistry: analytical and immunological testing
- Y10T436/17—Nitrogen containing
- Y10T436/170769—N-Nitroso containing [e.g., nitrosamine, etc.]
Definitions
- a method of detecting tobacco-specific nitrosamines comprises: at least one microcantilever beam having a molecularly-imprinted monolayer as a receptor layer, wherein the receptor layer can selectively recognize tobacco-specific nitrosamines; exposing the receptor layer coated microcantilever beam to a medium, which may contain tobacco-specific nitrosamines, and measuring a deflection of the microcantilever beam, wherein the deflection indicates a presence of tobacco-specific nitrosamines in the medium.
- a method of detecting tobacco-specific nitrosamines comprises: at least one microcantilever beam having a receptor layer of self-assembly monolayer or metal/metal oxide layer, which can selectively recognize tobacco-specific nitrosamines; exposing the receptor layer coated microcantilever beam to a medium, which may contain tobacco-specific nitrosamines, and measuring a deflection of the microcantilever beam, wherein the deflection indicates a presence of tobacco-specific nitrosamines in the medium.
- a handheld microcantilever-based sensor system adapted to identify tobacco-specific nitrosamines comprises: at least one piezo-resistive microcantilever beam having a receptor layer, wherein the receptor layer selectively indicates the presence of tobacco-specific nitrosamines; and a detection system, which outputs an electrical signal upon a resistance change of the at least one microcantilever beam upon exposure to tobacco-specific nitrosamines.
- a method of functionalizing a microcantilever beam for detection of tobacco-specific nitrosamines comprises: coating a microcantilever beam with a receptor layer of a molecularly-imprinted monolayer, which can selectively recognize tobacco-specific nitrosamines, wherein exposure of the receptor layer to a medium, which contains tobacco-specific nitrosamines causes a deflection of the microcantilever beam.
- a method of functionalizing a microcantilever beam for detection of tobacco-specific nitrosamines comprises: coating a microcantilever beam with a receptor layer of self-assembly monolayer or metal/metal oxide layer, which can selectively recognize tobacco-specific nitrosamines, wherein exposure of the receptor layer to a medium, which contains tobacco-specific nitrosamines causes a deflection of the microcantilever beam.
- FIG. 1 is the nitrosation of tobacco alkaloids of nicotine, nornicotine, anabasine, and anatabine to form tobacco-specific nitrosamines (TSNAs).
- TSNAs tobacco-specific nitrosamines
- FIG. 2 is a cross sectional view of an unexposed microcantilever beam in accordance with an embodiment.
- FIG. 3 is a cross sectional view of a microcantilever beam exposed to a medium containing tobacco-specific nitrosamines (TSNAs).
- TSNAs tobacco-specific nitrosamines
- FIG. 4 is a cross sectional view of a thiol-based self-assembly process, which can be used for functionalizing a microcantilever beam.
- FIG. 5 is a cross sectional view of the thiol-based self-assembly process as shown in FIG. 4 .
- FIG. 6 is another cross sectional view of the thiol-based self-assembly process as shown in FIG. 4 .
- FIG. 7 is a schematic diagram of a further embodiment of a thiol-based self-assembly process, which can be used for functionalizing a microcantilever beam.
- FIG. 8 is a schematic diagram of a method of formation of selective tobacco-specific nitrosamines (TSNAs) cavities on a microcantilever surface using a molecular imprinting technique.
- TSNAs tobacco-specific nitrosamines
- FIG. 9 is an array of microcantilever beams in accordance with an embodiment.
- FIG. 10 is an optical detection system for measuring a deflection of a microcantilever beam upon detection of tobacco-specific nitrosamines (TSNAs).
- TSNAs tobacco-specific nitrosamines
- FIG. 11 is a graph of microcantilever deflection versus time in accordance with one embodiment.
- FIG. 12 is a graph of microcantilever deflection versus time for microcantilever deflection vs. tobacco-specific nitrosamines (TSNAs) concentration in accordance with one embodiment.
- TSNAs tobacco-specific nitrosamines
- FIGS. 13A and B are graphs of microcantilever deflection versus time in accordance with a further embodiment.
- Tobacco and tobacco products contain a number of nitrogen-containing substances, which during burning of tobacco, can yield various components in the smoke, such as nitric oxide, nitrogen dioxide, methyl nitrate and tobacco-specific nitrosamines (TSNAs).
- nitrogen-containing substances such as nitric oxide, nitrogen dioxide, methyl nitrate and tobacco-specific nitrosamines (TSNAs).
- TSNAs tobacco-specific nitrosamines
- TSNAs tobacco-specific nitrosamines
- Samples such as tobacco are ground, extracted with methylene chloride or alkaline aqueous solutions, and subjected to extensive differential extraction. The final sample is then analyzed by gas chromatography using a thermal energy analyzer for detection (GC-TEA).
- GC-TEA thermal energy analyzer for detection
- TSNA tobacco-specific nitrosamine
- Other currently available instruments to measure tobacco-specific nitrosamines include gas chromatography (GC), high performance liquid chromatography (HPLC), gas chromatography/mass spectroscopy (GC/MS), thermal energy analyzer (TEA), or combinations thereof. These methods provide accurate identification, quantification, and high detection limits. However, these methods require sophisticated analytical devices and extensive processing of tobacco, which involves considerable amounts of time and power. Therefore, inexpensive tobacco-specific nitrosamines (TSNAs) tests that are fast and easy to perform are in high demand.
- FIG. 1 shows a series of chemical drawings showing the structure of nicotine and several examples of nicotine derivatives including tobacco-specific nitrosamines (TSNAs).
- nitrosamines are chemical compounds of the chemical structure (R 2 —N—N ⁇ O), which are typically produced from nitrites (NO 2 ) and amines (R 2 NH) under certain conditions, including strong acidic conditions.
- Tobacco-specific nitrosamines (TSNAs) can be formed during tobacco curing by nitrosation of the tobacco alkaloids.
- NNN N′-Nitrosoamine
- NAB N′-Nitrosoanabasine
- NAT N′-Nitrosoanatabine
- NNK 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone) are formed predominantly by N-nitrosation of the corresponding secondary amine.
- NNK can be formed from nicotine by oxidation N-nitrosation following ring openings of the pyrrolidine ring.
- a sensor based on microcantilever technology can be utilized to offer a reliable handheld device for the detection of trace amounts of tobacco-specific nitrosamines (TSNAs) having a detection range of 400 ppb to 50,000 ppb.
- TSNAs tobacco-specific nitrosamines
- microcantilever sensor technology can offer a handheld, real-time sensor for chemicals, either in gaseous or in liquid phase, including high sensitivity, miniature size, low power consumption, and the ability to fabricate into an array for simultaneous detection of a number of chemicals. Accordingly, it would be desirable to have a handheld microcantilever-based sensor system capable of sensing and identifying trace amounts of tobacco-specific nitrosamines (TSNAs).
- Microcantilevers are micro-electromechanical systems (MEMs) that can be micromachined and mass-produced from single crystal silicon wafers. Microcantilevers offer high sensitivity and selectivity for a wide variety of biological and chemical sensing. Ions (Hg 2+ , Cu 2+ , Ca 2+ , CrO 4 2 ⁇ , etc.) and chemical vapors can be detected with sub-parts per billion sensitivity or better. Biological applications include DNA hybridization and antigen-antibody binding.
- cantilevers or microcantilevers are microfabricated beams of silicon, which can be functionalized to detect the presence of tobacco-specific nitrosamines using the surface of a microcantilever beam. If the surface of the microcantilever beam is functionalized in such a way that a chemically active and a chemically inactive surface is obtained, chemical or physical processes on the active cantilever surface can be observed using the temporal evolvement of the cantilever's response.
- Cantilevers can be used as a nanomechanical sensor device for detecting chemical interactions between bonding partners on the cantilever surface and in its environment. At the interface between an active cantilever surface and the surrounding medium, the formation of induced stress, the production of heat or a change in mass can be detected. In general, one of the bonding partners is placed on a cantilever, while the other bonding partners are present in the environment.
- the microcantilever-based sensors can measure the induced surface stresses arising from the surface reconstruction and/or reorganization associated with a molecular adsorption or desorption on the surface of the microcantilever beam.
- Specificity and sensitivity of microcantilever-based sensors can be achieved by functionalizing one side of the microcantilever surface with a uniform specific receptor layer.
- the opposite side is typically rendered inert or chemically inactive.
- the opposite side is preferably inert or chemically inactive to a medium containing tobacco-specific nitrosamines (TSNAs).
- TSNAs tobacco-specific nitrosamines
- the microcantilever beams can coated with different receptor materials.
- the ability to select and coat a receptor material uniformly on the surface of a base layer of single crystal silicon is preferred for both selectivity and sensitivity.
- FIG. 2 shows a cross sectional view of an unexposed microcantilever beam 10 in accordance with an embodiment.
- the microcantilever beam 10 is comprised of a receptor layer 20 and a base layer 30 .
- the receptor layer 20 is adapted to detect and sense tobacco-specific nitrosamines (TSNAs).
- the base layer 30 is preferably produced from a single crystal silicon (Si) material or wafer 32 . It can be appreciated that the receptor layer 20 can be deposited on the base layer 30 .
- the microcantilever beam 10 has a first end 42 , which is held at a fixed location 40 , and a second end 44 , which is free to deflect or bend upward and downward.
- FIG. 3 shows a cross sectional view of the microcantilever beam 10 of FIG. 2 , wherein the receptor layer 20 physically and/or chemically reacts with one or more of the molecules 52 in a medium 50 .
- the physical or chemical reaction of the one or more molecules 52 within the medium 50 produces a stressed-induced deflection or bending of the cantilever beam 10 at a nano-length scale.
- the stress-induced deflections may be brought about by volume changes due to the physical and/or chemical interactions of the receptor layer 20 and the one or more molecules 52 (e.g., tobacco-specific nitrosamines (TSNAs)) within the medium 50 .
- TSNAs tobacco-specific nitrosamines
- the deflection or bending of the microcantilever beam 10 is then preferably measured using an optical, a piezo-electric, or other suitable methods to detect and quantify the presence of the one or more molecules 52 (e.g., tobacco-specific nitrosamines (TSNAs)) within the medium 50 .
- TSNAs tobacco-specific nitrosamines
- FIG. 4 shows a cross sectional view of a thiol-based self-assembly process on a surface 12 of a gold-coated microcantilever beam 10 .
- the thiol-based self-assembly process comprises the functionalizing of the gold-coated microcantilever beam 10 with a monolayer of thiol molecules 60 .
- the microcantilever beam 10 includes a base layer 30 , which is preferably silicon, and a receptor layer 20 comprised of a gold (Au) substrate 22 . It can be appreciated that a chromium or titanium adhesion layer (not shown) can be added to the base layer 30 prior to the deposition of the gold layer 22 .
- the surface 12 on the gold substrate 22 is configured to receive a plurality of thiol molecules 60 having a sulfur atom or sulfur head group 62 with a carboxyl-terminated group 64 , —COOH, wherein the sulfur atom or sulfur head group 62 undergoes chemisorption with the gold-coated receptor layer 20 .
- FIG. 5 shows a cross sectional view of the thiol-based self-assembly process as shown in FIG. 4 , wherein the thiol molecules 60 with carboxyl-terminated group 64 , —COOH, begins the self-assembly process of forming a monolayer 70 of thiol molecules 60 with a carboxyl-terminated group 64 on the gold-coated receptor layer 20 .
- FIG. 6 shows another cross sectional view of the thiol-based self-assembly process as shown in FIG. 4 , wherein the thiol molecules 60 have formed a fully formed a self-assembled monolayer 80 (SAMs) of thiol molecules 60 .
- SAMs self-assembled monolayer 80
- FIG. 7 shows a schematic diagram of a method of formation of a thiol-based self-assembly process on a microcantilever beam 10 as show in FIGS. 4-6 .
- the thiol-based self-assembly process comprises the functionalizing of a gold (Au) coated microcantilever beam 10 with thiol molecules 60 with carboxyl-terminated groups 64 .
- the microcantilever beam 10 includes a base layer 30 comprised of a silicon substrate 31 and a gold substrate 22 .
- the gold-coated microcantilever beam 10 receives a plurality of thiol molecules 60 , wherein the sulfur atom or sulfur head 62 group undergoes chemisorption with the gold substrate 22 .
- the thiol molecules 60 which includes a carboxyl-terminated group 64 , —COOH, begins the self-assembly process of forming a monolayer 70 of thiol molecules 60 with a carboxyl-terminated group 64 on the gold surface of the microcantilever beam 10 .
- the beam 10 will undergo a bending when exposed to tobacco-specific nitrosamines (TSNAs) 110 due to the strong hydrogen bonding between the —COOH group in the self-assembled monolayer (SAMs) and the —N—N ⁇ O group, basic pyrrolidine-N and pyridine-N of the tobacco-specific nitrosamines (TSNAs).
- the terminal group in the thiol molecule is comprised of —OH, —NH 2 or —COOH moieties.
- the hydrocarbon chain of the thiol molecules preferably includes 6 to 22 carbon atoms.
- the method of detecting tobacco-specific nitrosamines can include at least one microcantilever beam 10 having a receptor layer 20 comprised of a metal, such as aluminum (Al), platinum (Pt) or palladium (Pd), or a metal oxide layer, which can selectively recognize tobacco-specific nitrosamines (TSNAs).
- the receptor layer 20 is preferably exposed to a medium, which may contain tobacco-specific nitrosamines, and wherein a deflection of the microcantilever beam 10 indicates a presence of tobacco-specific nitrosamines in the medium.
- FIG. 8 shows a schematic diagram of a method of formation of selective tobacco-specific nitrosamine (TSNA) cavities 150 on a surface 14 of a silicon microcantilever beam 10 in accordance with one embodiment.
- the microcantilever beam 10 is preferably comprised of a base layer 34 of silicon substrate, and a layer 24 of gold.
- the layer 24 of gold or gold side of the microcantilever beam 10 is first blocked by self-assembling thiol monolayer as shown in step 120 .
- the hydrocarbon chain of the thiol molecules is comprised of 6 to 18 carbon atoms.
- the selective tobacco-specific nitrosamines (TSNAs) cavities 140 are formed utilizing a silane-based self-assembly and molecular imprinting technique as shown in step 130 , wherein tobacco-specific nitrosamines (TSNAs) 110 are co-adsorbed with silane molecules 112 on the silicon microcantilever surface 14 .
- the template molecules 114 of tobacco-specific nitrosamines (TSNAs) 110 co-adsorb between the silane molecules 112 .
- the hydrocarbon chain of the silane molecules 112 is comprised of 6 to 18 carbon atoms.
- step 140 the template molecules 114 of tobacco-specific nitrosamines (TSNAs) 110 are then rinsed or washed away with a suitable solvent forming tobacco-specific nitrosamines (TSNAs) cavities 150 on the self-assembly monolayer (SAM).
- SAM self-assembly monolayer
- the self-assembled monolayer with the tobacco-specific nitrosamine cavities 150 as shown in FIG. 8 provides a method of detecting tobacco-specific nitrosamines (TSNAs) 110 as a result of the specific physical molecular recognition of the tobacco-specific nitrosamines 110 (TSNAs) within the tobacco-specific nitrosamine cavities 150 on the microcantilever beam 10 .
- FIG. 9 shows an array 160 of microcantilever beams 10 in accordance with embodiments.
- the array 160 is preferably comprised of at least two (2), and more preferably at least four (4), and most preferably four to sixteen (4-16) microcantilever beams 10 .
- the array 160 of microcantilever beams 10 is preferably independently addressable, wherein each microcantilever beam 10 effects output of a detection signal, independent of the other microcantilever beams 10 .
- the array 160 can be one-dimensional (e.g., 1 ⁇ 4) as shown in FIG. 9 , two dimensional, (e.g., 2 ⁇ 2), or any other suitable configuration.
- the microcantilever beams 10 will be separated by a space 162 between 50 to 500 micrometers wide and more preferably the space 162 is between 100 to 300 micrometers apart.
- the microcantilever beams 10 preferably have an overall length of 100-400 ⁇ m, a width of 20-70 ⁇ m, and a thickness of 0.5-1.5 ⁇ m, and more preferably an overall length of about 120-150 ⁇ m, a width of about 25-50 ⁇ m, and a thickness of about 0.75-1.25 ⁇ m.
- each microcantilever beam 10 preferably has a spring constant of between about 0.4 to 0.8 N/m.
- the array 160 of microcantilever beams 10 will preferably be fabricated into a single chip, wherein the small dimensions of the array 160 , which may render the array 160 of microcantilever beams 10 sensitive to many different parameters, such as temperature and mechanical vibrations. Therefore, it can be appreciated that any device incorporating an array 160 of microcantilever beams 10 will preferably include electronic components or devices to suppress the background noise, and monitor and evaluate the electronic output from each of the microcantilever beams 10 . It can be appreciated that any suitable fabrication technique, which can precisely functionalize each individual microcantilever beam 10 with a receptor layer, can be used.
- the microcantilever beams 10 are preferably integrated into a single chip, wherein a sample cell with a flow and volume controlled system to introduce a medium 50 having tobacco-specific nitrosamines (TSNAs) 110 so as to expose the medium 50 to the microcantilever beam 10 (e.g., the medium 50 can be a gas or a liquid).
- TSNAs tobacco-specific nitrosamines
- FIG. 10 shows an optical detection system 200 for a deflection of a microcantilever beam 10 for the detection of tobacco-specific nitrosamines 110 .
- the optical system 200 can include a test chamber 210 having an inlet 212 and an outlet 214 to circulate the tobacco-specific nitrosamine medium, and having at least one microcantilever beam 10 contained therein.
- the optical system 200 also includes a laser 220 , which is adapted to emit an incident beam 222 towards the microcantilever beam 10 and a photosensitive detector or detector 230 to receive the incident beam 222 upon reflection from the microcantilever beam 10 .
- the change in position of the incident beam 222 is typically proportionate to the deflection and rotation of the microcantilever beam 10 .
- the incident beam 222 from laser 220 is reflected along a first path 232 toward the photosensitive detector or detector 230 .
- the incident beam 212 will instead be reflected along a second path 234 toward the photosensitive detector or detector 230 .
- the system 200 also preferably includes at least one channel 260 , which is adapted to contain test sample 262 either in liquid or gas phase and a cleaning agent 264 , which are injected via a pump 250 to the test chamber 210 .
- the system 200 can include a switch 270 for directing the test sample 262 or cleaning agent 264 to the chamber 210 .
- the microcantilever beam 10 is preferably functionalized to be chemically or physically active upon exposure to tobacco-specific nitrosamines (TSNAs) contained within the test sample 262 .
- TSNAs tobacco-specific nitrosamines
- the microcantilever beam 10 Upon exposure to tobacco-specific nitrosamines (TSNAs), the microcantilever beam 10 will undergo an induced stress at the interface of receptor layer 20 of the microcantilever beam 10 and the surrounding test sample 262 , resulting in a deflection of the microcantilever beam 10 . The deflection of the microcantilever beam 10 is then measured, wherein the deflection indicates a presence of tobacco-specific nitrosamines in the test sample 262 .
- TSNAs tobacco-specific nitrosamines
- a suitable computing apparatus or device 240 e.g., a computer having a suitable software program will preferably be used, wherein the software program is adapted to receive information from the detector 230 from each microcantilever beam 10 .
- the software program will then preferably store the data, and then upon request displays the data or results in a desired format, including digital readings or printouts of instantaneous readings or quantitative readings over a specified period of time.
- the software program will be capable of positively identifying the presence of trace amounts of tobacco-specific nitrosamines 110 (TSNAs), or alternatively confirm the absence of trace amounts of tobacco-specific nitrosamines 110 (TSNAs) within the medium 50 (e.g., an assay or an analyte).
- the system 200 will also preferably includes a quantitative ability to provide a detection range for tobacco-specific nitrosamines (TSNAs) of 400 to 50,000 ppb (parts-per-billion), and more preferably a detection range of 1,000 to 5,000 ppb.
- a suitable handheld device will preferably be reusable, wherein the device can be cleaned using a cleaning agent 264 or other suitable cleansing or cleaning method.
- the system 200 can also include a syringe pump 250 , at least one medium source 260 and a switch 270 attached to the inlet of test chamber 210 .
- the deflection of the microcantilever beam 10 can be measured with subnanometer sensitivity by using any suitable method including optical, piezo-resistive, capacitance, and piezo-electric detection methods.
- the system 200 can include a plurality of microcantilever beams 10 form a sensor array 160 with integrated piezo-resistor for measuring the deflection of the microcantilever beams 10 .
- the piezo-resistor utilizes the electronic properties of the microcantilever to measure its bending, such that the laser 220 and the detector 230 can be removed.
- Highly doped silicon has the property to change its resistivity under mechanical strain. Accordingly, if such a doped layer is incorporated into the microcantilever beam 10 , its bending can easily be measured by determination of the electrical resistance of the microcantilever beam 10 .
- the piezo-resistors will contain a specific electronic material with high electrical resistivity, which converts the mechanical motion associated with the deflection or bending of the microcantilever beams 10 into an electrical signal.
- the deflection is read as a change in resistance of the integrated resistor using appropriate electronic circuits and converted to a piezo-resistive readout.
- the system 200 without the laser 220 and the detector 230 as shown in FIG. 10 can be incorporated into a handheld microcantilever-based sensor system to identify and monitor tobacco-specific nitrosamines 110 (TSNAs).
- the system 200 will preferably be comprised an array 160 of 4-16 piezo-resistive microcantilever beams 10 and an associated electronic readout system (not shown).
- the microcantilever beams 10 will preferably be functionalized with chemicals as indicated and shown in FIGS. 4-8 , which have specific bonding and recognition with tobacco-specific nitrosamine (TSNA) molecules. It can be appreciated that tobacco-specific nitrosamine 110 (TSNA) detection can be accomplished by observing the resistance difference of microcantilever beams 10 before and after exposure to tobacco-specific nitrosamines (TSNAs).
- FIG. 11 shows a graph of cantilever deflection versus time in accordance with one embodiment, wherein cantilevers are functionalized with self-assembled monolayers of octadecyltrichlorosilane (OTS) with and without TSNAs molecules as templates, respectively.
- OTS octadecyltrichlorosilane
- FIG. 11 the cantilever deflection versus time utilizing an optical detection system with a single microcantilever beam 10 with a pump rate of 4 ml/h, 1 ml sample loop and 4 ⁇ g/ml of TSNA was performed.
- FIG. 12 shows a graph of cantilever deflection versus time for microcantilever deflection vs. TSNAs concentration in accordance with one embodiment, wherein cantilever is functionalized with a self-assembled monolayer of octadecyltrichlorosilane (OTS) in presence of TSNAs as templates.
- OTS octadecyltrichlorosilane
- FIGS. 13A and B show graphs of cantilever deflection versus time in accordance with a further embodiment, wherein cantilever A is functionalized with a self-assembled monolayer of 4-mercaptobenzoic acid (4-MBA); cantilever B is modified by depositing 5 nm chromium (Cr) adhesive layer and 40 nm aluminum (Al) film.
- 4-MBA 4-mercaptobenzoic acid
- cantilever B is modified by depositing 5 nm chromium (Cr) adhesive layer and 40 nm aluminum (Al) film.
Abstract
A method and system for detecting tobacco-specific nitrosamines. The method includes exposing at least one microcantilever beam to a medium, which may contain tobacco-specific nitrosamines, and measuring a deflection of the microcantilever beam, wherein the deflection indicates a presence of tobacco-specific nitrosamines in the medium. The at least one microcantilever beam can include a silicon base layer and a gold-coated receptor layer with a plurality of thiol molecules having a sulfur head and carboxyl-terminated group. The at least one microcantilever beam can include a silicon base layer and a metal or metal oxide coated receptor layer. Alternatively, the microcantilever beam can be formed by co-absorbing tobacco-specific nitrosamines and silane molecules on a silicon microcantilever surface, wherein the template molecules of tobacco-specific nitrosamines physically co-adsorb between the silane molecules. The template molecules of tobacco-specific nitrosamines are then washed away with a solvent to form a silane monolayer having tobacco-specific nitrosamine cavities.
Description
- This application claims priority to U.S. Patent Provisional Application No. 60/846,090, filed Sep. 21, 2006, which is incorporated herein by this reference in its entirety.
- In accordance with one embodiment, a method of detecting tobacco-specific nitrosamines comprises: at least one microcantilever beam having a molecularly-imprinted monolayer as a receptor layer, wherein the receptor layer can selectively recognize tobacco-specific nitrosamines; exposing the receptor layer coated microcantilever beam to a medium, which may contain tobacco-specific nitrosamines, and measuring a deflection of the microcantilever beam, wherein the deflection indicates a presence of tobacco-specific nitrosamines in the medium.
- In accordance with a further embodiment, a method of detecting tobacco-specific nitrosamines comprises: at least one microcantilever beam having a receptor layer of self-assembly monolayer or metal/metal oxide layer, which can selectively recognize tobacco-specific nitrosamines; exposing the receptor layer coated microcantilever beam to a medium, which may contain tobacco-specific nitrosamines, and measuring a deflection of the microcantilever beam, wherein the deflection indicates a presence of tobacco-specific nitrosamines in the medium.
- In accordance with another embodiment, a handheld microcantilever-based sensor system adapted to identify tobacco-specific nitrosamines comprises: at least one piezo-resistive microcantilever beam having a receptor layer, wherein the receptor layer selectively indicates the presence of tobacco-specific nitrosamines; and a detection system, which outputs an electrical signal upon a resistance change of the at least one microcantilever beam upon exposure to tobacco-specific nitrosamines.
- In accordance with a further embodiment, a method of functionalizing a microcantilever beam for detection of tobacco-specific nitrosamines comprises: coating a microcantilever beam with a receptor layer of a molecularly-imprinted monolayer, which can selectively recognize tobacco-specific nitrosamines, wherein exposure of the receptor layer to a medium, which contains tobacco-specific nitrosamines causes a deflection of the microcantilever beam.
- In accordance with another embodiment, a method of functionalizing a microcantilever beam for detection of tobacco-specific nitrosamines comprises: coating a microcantilever beam with a receptor layer of self-assembly monolayer or metal/metal oxide layer, which can selectively recognize tobacco-specific nitrosamines, wherein exposure of the receptor layer to a medium, which contains tobacco-specific nitrosamines causes a deflection of the microcantilever beam.
-
FIG. 1 is the nitrosation of tobacco alkaloids of nicotine, nornicotine, anabasine, and anatabine to form tobacco-specific nitrosamines (TSNAs). -
FIG. 2 is a cross sectional view of an unexposed microcantilever beam in accordance with an embodiment. -
FIG. 3 is a cross sectional view of a microcantilever beam exposed to a medium containing tobacco-specific nitrosamines (TSNAs). -
FIG. 4 is a cross sectional view of a thiol-based self-assembly process, which can be used for functionalizing a microcantilever beam. -
FIG. 5 is a cross sectional view of the thiol-based self-assembly process as shown inFIG. 4 . -
FIG. 6 is another cross sectional view of the thiol-based self-assembly process as shown inFIG. 4 . -
FIG. 7 is a schematic diagram of a further embodiment of a thiol-based self-assembly process, which can be used for functionalizing a microcantilever beam. -
FIG. 8 is a schematic diagram of a method of formation of selective tobacco-specific nitrosamines (TSNAs) cavities on a microcantilever surface using a molecular imprinting technique. -
FIG. 9 is an array of microcantilever beams in accordance with an embodiment. -
FIG. 10 is an optical detection system for measuring a deflection of a microcantilever beam upon detection of tobacco-specific nitrosamines (TSNAs). -
FIG. 11 is a graph of microcantilever deflection versus time in accordance with one embodiment. -
FIG. 12 is a graph of microcantilever deflection versus time for microcantilever deflection vs. tobacco-specific nitrosamines (TSNAs) concentration in accordance with one embodiment. -
FIGS. 13A and B are graphs of microcantilever deflection versus time in accordance with a further embodiment. - Tobacco and tobacco products contain a number of nitrogen-containing substances, which during burning of tobacco, can yield various components in the smoke, such as nitric oxide, nitrogen dioxide, methyl nitrate and tobacco-specific nitrosamines (TSNAs).
- Current measurement procedures for sensing and identifying tobacco-specific nitrosamines (TSNAs) are both complicated and costly. Samples such as tobacco are ground, extracted with methylene chloride or alkaline aqueous solutions, and subjected to extensive differential extraction. The final sample is then analyzed by gas chromatography using a thermal energy analyzer for detection (GC-TEA). These currently accepted methods are expensive and time consuming, with a single analyst typically having the capacity to process only 20 samples per eight hour shift. While robotic sample preparation methods exist, the cost is prohibitive.
- In addition, tobacco-specific nitrosamine (TSNA) sample preparation generates vast quantities of waste solvent, the disposal of which is also costly. Other currently available instruments to measure tobacco-specific nitrosamines (TSNAs) include gas chromatography (GC), high performance liquid chromatography (HPLC), gas chromatography/mass spectroscopy (GC/MS), thermal energy analyzer (TEA), or combinations thereof. These methods provide accurate identification, quantification, and high detection limits. However, these methods require sophisticated analytical devices and extensive processing of tobacco, which involves considerable amounts of time and power. Therefore, inexpensive tobacco-specific nitrosamines (TSNAs) tests that are fast and easy to perform are in high demand.
- Tobacco-specific nitrosamines (TSNAs) are structurally similar to the nicotine compounds from which they are typically derived.
FIG. 1 shows a series of chemical drawings showing the structure of nicotine and several examples of nicotine derivatives including tobacco-specific nitrosamines (TSNAs). As shown inFIG. 1 , nitrosamines are chemical compounds of the chemical structure (R2—N—N═O), which are typically produced from nitrites (NO2) and amines (R2NH) under certain conditions, including strong acidic conditions. Tobacco-specific nitrosamines (TSNAs) can be formed during tobacco curing by nitrosation of the tobacco alkaloids. NNN (N′-Nitrosoamine), NAB (N′-Nitrosoanabasine), NAT (N′-Nitrosoanatabine) and NNK (4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone) are formed predominantly by N-nitrosation of the corresponding secondary amine. NNK can be formed from nicotine by oxidation N-nitrosation following ring openings of the pyrrolidine ring. - In accordance with an embodiment, a sensor based on microcantilever technology can be utilized to offer a reliable handheld device for the detection of trace amounts of tobacco-specific nitrosamines (TSNAs) having a detection range of 400 ppb to 50,000 ppb. In addition, it can be appreciated that microcantilever sensor technology can offer a handheld, real-time sensor for chemicals, either in gaseous or in liquid phase, including high sensitivity, miniature size, low power consumption, and the ability to fabricate into an array for simultaneous detection of a number of chemicals. Accordingly, it would be desirable to have a handheld microcantilever-based sensor system capable of sensing and identifying trace amounts of tobacco-specific nitrosamines (TSNAs).
- Microcantilevers are micro-electromechanical systems (MEMs) that can be micromachined and mass-produced from single crystal silicon wafers. Microcantilevers offer high sensitivity and selectivity for a wide variety of biological and chemical sensing. Ions (Hg2+, Cu2+, Ca2+, CrO4 2−, etc.) and chemical vapors can be detected with sub-parts per billion sensitivity or better. Biological applications include DNA hybridization and antigen-antibody binding.
- According to an embodiment, cantilevers or microcantilevers are microfabricated beams of silicon, which can be functionalized to detect the presence of tobacco-specific nitrosamines using the surface of a microcantilever beam. If the surface of the microcantilever beam is functionalized in such a way that a chemically active and a chemically inactive surface is obtained, chemical or physical processes on the active cantilever surface can be observed using the temporal evolvement of the cantilever's response. Cantilevers can be used as a nanomechanical sensor device for detecting chemical interactions between bonding partners on the cantilever surface and in its environment. At the interface between an active cantilever surface and the surrounding medium, the formation of induced stress, the production of heat or a change in mass can be detected. In general, one of the bonding partners is placed on a cantilever, while the other bonding partners are present in the environment.
- In an embodiment, the microcantilever-based sensors can measure the induced surface stresses arising from the surface reconstruction and/or reorganization associated with a molecular adsorption or desorption on the surface of the microcantilever beam. Specificity and sensitivity of microcantilever-based sensors can be achieved by functionalizing one side of the microcantilever surface with a uniform specific receptor layer. The opposite side is typically rendered inert or chemically inactive. For example, in accordance with an embodiment, the opposite side is preferably inert or chemically inactive to a medium containing tobacco-specific nitrosamines (TSNAs). In the case of an array of microcantilever beams, it can be appreciated that the microcantilever beams can coated with different receptor materials. In addition, it can be appreciated that the ability to select and coat a receptor material uniformly on the surface of a base layer of single crystal silicon is preferred for both selectivity and sensitivity.
-
FIG. 2 shows a cross sectional view of anunexposed microcantilever beam 10 in accordance with an embodiment. Themicrocantilever beam 10 is comprised of areceptor layer 20 and abase layer 30. Thereceptor layer 20 is adapted to detect and sense tobacco-specific nitrosamines (TSNAs). Thebase layer 30 is preferably produced from a single crystal silicon (Si) material orwafer 32. It can be appreciated that thereceptor layer 20 can be deposited on thebase layer 30. As shown inFIG. 2 , themicrocantilever beam 10 has afirst end 42, which is held at afixed location 40, and asecond end 44, which is free to deflect or bend upward and downward. -
FIG. 3 shows a cross sectional view of themicrocantilever beam 10 ofFIG. 2 , wherein thereceptor layer 20 physically and/or chemically reacts with one or more of themolecules 52 in a medium 50. As shown inFIG. 3 , the physical or chemical reaction of the one ormore molecules 52 within the medium 50 produces a stressed-induced deflection or bending of thecantilever beam 10 at a nano-length scale. The stress-induced deflections may be brought about by volume changes due to the physical and/or chemical interactions of thereceptor layer 20 and the one or more molecules 52 (e.g., tobacco-specific nitrosamines (TSNAs)) within the medium 50. The deflection or bending of themicrocantilever beam 10 is then preferably measured using an optical, a piezo-electric, or other suitable methods to detect and quantify the presence of the one or more molecules 52 (e.g., tobacco-specific nitrosamines (TSNAs)) within the medium 50. -
FIG. 4 shows a cross sectional view of a thiol-based self-assembly process on asurface 12 of a gold-coatedmicrocantilever beam 10. The thiol-based self-assembly process comprises the functionalizing of the gold-coatedmicrocantilever beam 10 with a monolayer ofthiol molecules 60. As shown inFIG. 4 , themicrocantilever beam 10 includes abase layer 30, which is preferably silicon, and areceptor layer 20 comprised of a gold (Au)substrate 22. It can be appreciated that a chromium or titanium adhesion layer (not shown) can be added to thebase layer 30 prior to the deposition of thegold layer 22. Thesurface 12 on thegold substrate 22 is configured to receive a plurality ofthiol molecules 60 having a sulfur atom orsulfur head group 62 with a carboxyl-terminatedgroup 64, —COOH, wherein the sulfur atom orsulfur head group 62 undergoes chemisorption with the gold-coatedreceptor layer 20. -
FIG. 5 shows a cross sectional view of the thiol-based self-assembly process as shown inFIG. 4 , wherein thethiol molecules 60 with carboxyl-terminatedgroup 64, —COOH, begins the self-assembly process of forming amonolayer 70 ofthiol molecules 60 with a carboxyl-terminatedgroup 64 on the gold-coatedreceptor layer 20. -
FIG. 6 shows another cross sectional view of the thiol-based self-assembly process as shown inFIG. 4 , wherein thethiol molecules 60 have formed a fully formed a self-assembled monolayer 80 (SAMs) ofthiol molecules 60. It can be appreciated that as shown inFIG. 6 , the thiol self-assembled monolayer 80 (SAMs)coated microcantilever beam 10 will undergo a bending when exposed to tobacco-specific nitrosamines (TSNAs). -
FIG. 7 shows a schematic diagram of a method of formation of a thiol-based self-assembly process on amicrocantilever beam 10 as show inFIGS. 4-6 . As shown inFIG. 7 , the thiol-based self-assembly process comprises the functionalizing of a gold (Au)coated microcantilever beam 10 withthiol molecules 60 with carboxyl-terminatedgroups 64. Themicrocantilever beam 10 includes abase layer 30 comprised of asilicon substrate 31 and agold substrate 22. The gold-coatedmicrocantilever beam 10 receives a plurality ofthiol molecules 60, wherein the sulfur atom orsulfur head 62 group undergoes chemisorption with thegold substrate 22. Instep 90 of the thiol-based self-assembly process, thethiol molecules 60, which includes a carboxyl-terminatedgroup 64, —COOH, begins the self-assembly process of forming amonolayer 70 ofthiol molecules 60 with a carboxyl-terminatedgroup 64 on the gold surface of themicrocantilever beam 10. Once thethiol molecules 60 have formed a fully formed a self-assembled monolayer 80 (SAMs) ofthiol molecules 60, as shown instep 100, thebeam 10 will undergo a bending when exposed to tobacco-specific nitrosamines (TSNAs) 110 due to the strong hydrogen bonding between the —COOH group in the self-assembled monolayer (SAMs) and the —N—N═O group, basic pyrrolidine-N and pyridine-N of the tobacco-specific nitrosamines (TSNAs). In accordance with an embodiment, the terminal group in the thiol molecule is comprised of —OH, —NH2 or —COOH moieties. In addition, the hydrocarbon chain of the thiol molecules preferably includes 6 to 22 carbon atoms. - In accordance with a further embodiment, the method of detecting tobacco-specific nitrosamines can include at least one
microcantilever beam 10 having areceptor layer 20 comprised of a metal, such as aluminum (Al), platinum (Pt) or palladium (Pd), or a metal oxide layer, which can selectively recognize tobacco-specific nitrosamines (TSNAs). Thereceptor layer 20 is preferably exposed to a medium, which may contain tobacco-specific nitrosamines, and wherein a deflection of themicrocantilever beam 10 indicates a presence of tobacco-specific nitrosamines in the medium. -
FIG. 8 shows a schematic diagram of a method of formation of selective tobacco-specific nitrosamine (TSNA)cavities 150 on asurface 14 of asilicon microcantilever beam 10 in accordance with one embodiment. As shown inFIG. 8 , themicrocantilever beam 10 is preferably comprised of abase layer 34 of silicon substrate, and alayer 24 of gold. Thelayer 24 of gold or gold side of themicrocantilever beam 10 is first blocked by self-assembling thiol monolayer as shown instep 120. In accordance with an embodiment, the hydrocarbon chain of the thiol molecules is comprised of 6 to 18 carbon atoms. The selective tobacco-specific nitrosamines (TSNAs)cavities 140 are formed utilizing a silane-based self-assembly and molecular imprinting technique as shown instep 130, wherein tobacco-specific nitrosamines (TSNAs) 110 are co-adsorbed withsilane molecules 112 on thesilicon microcantilever surface 14. Thetemplate molecules 114 of tobacco-specific nitrosamines (TSNAs) 110 co-adsorb between thesilane molecules 112. In accordance with an embodiment, the hydrocarbon chain of thesilane molecules 112 is comprised of 6 to 18 carbon atoms. - In
step 140, thetemplate molecules 114 of tobacco-specific nitrosamines (TSNAs) 110 are then rinsed or washed away with a suitable solvent forming tobacco-specific nitrosamines (TSNAs)cavities 150 on the self-assembly monolayer (SAM). The self-assembled monolayer with the tobacco-specific nitrosamine cavities 150 as shown inFIG. 8 provides a method of detecting tobacco-specific nitrosamines (TSNAs) 110 as a result of the specific physical molecular recognition of the tobacco-specific nitrosamines 110 (TSNAs) within the tobacco-specific nitrosamine cavities 150 on themicrocantilever beam 10. -
FIG. 9 shows anarray 160 of microcantilever beams 10 in accordance with embodiments. As shown inFIG. 9 , thearray 160 is preferably comprised of at least two (2), and more preferably at least four (4), and most preferably four to sixteen (4-16) microcantilever beams 10. Thearray 160 of microcantilever beams 10 is preferably independently addressable, wherein eachmicrocantilever beam 10 effects output of a detection signal, independent of the other microcantilever beams 10. It can be appreciated that thearray 160 can be one-dimensional (e.g., 1×4) as shown inFIG. 9 , two dimensional, (e.g., 2×2), or any other suitable configuration. The microcantilever beams 10 will be separated by aspace 162 between 50 to 500 micrometers wide and more preferably thespace 162 is between 100 to 300 micrometers apart. In addition, the microcantilever beams 10 preferably have an overall length of 100-400 μm, a width of 20-70 μm, and a thickness of 0.5-1.5 μm, and more preferably an overall length of about 120-150 μm, a width of about 25-50 μm, and a thickness of about 0.75-1.25 μm. In addition, eachmicrocantilever beam 10 preferably has a spring constant of between about 0.4 to 0.8 N/m. - The
array 160 of microcantilever beams 10 will preferably be fabricated into a single chip, wherein the small dimensions of thearray 160, which may render thearray 160 of microcantilever beams 10 sensitive to many different parameters, such as temperature and mechanical vibrations. Therefore, it can be appreciated that any device incorporating anarray 160 of microcantilever beams 10 will preferably include electronic components or devices to suppress the background noise, and monitor and evaluate the electronic output from each of the microcantilever beams 10. It can be appreciated that any suitable fabrication technique, which can precisely functionalize eachindividual microcantilever beam 10 with a receptor layer, can be used. In addition, as set forth above, the microcantilever beams 10 are preferably integrated into a single chip, wherein a sample cell with a flow and volume controlled system to introduce a medium 50 having tobacco-specific nitrosamines (TSNAs) 110 so as to expose the medium 50 to the microcantilever beam 10 (e.g., the medium 50 can be a gas or a liquid). -
FIG. 10 shows anoptical detection system 200 for a deflection of amicrocantilever beam 10 for the detection of tobacco-specific nitrosamines 110. As shown inFIG. 10 , theoptical system 200 can include atest chamber 210 having aninlet 212 and anoutlet 214 to circulate the tobacco-specific nitrosamine medium, and having at least onemicrocantilever beam 10 contained therein. Theoptical system 200 also includes alaser 220, which is adapted to emit anincident beam 222 towards themicrocantilever beam 10 and a photosensitive detector ordetector 230 to receive theincident beam 222 upon reflection from themicrocantilever beam 10. It can be appreciated that the change in position of theincident beam 222 is typically proportionate to the deflection and rotation of themicrocantilever beam 10. For example, when themicrocantilever beam 10 is not deflected, theincident beam 222 fromlaser 220 is reflected along afirst path 232 toward the photosensitive detector ordetector 230. However, after themicrocantilever 10 has been deflected, theincident beam 212 will instead be reflected along asecond path 234 toward the photosensitive detector ordetector 230. - The
system 200 also preferably includes at least onechannel 260, which is adapted to containtest sample 262 either in liquid or gas phase and acleaning agent 264, which are injected via apump 250 to thetest chamber 210. Thesystem 200 can include aswitch 270 for directing thetest sample 262 or cleaningagent 264 to thechamber 210. As shown inFIG. 10 , themicrocantilever beam 10 is preferably functionalized to be chemically or physically active upon exposure to tobacco-specific nitrosamines (TSNAs) contained within thetest sample 262. Upon exposure to tobacco-specific nitrosamines (TSNAs), themicrocantilever beam 10 will undergo an induced stress at the interface ofreceptor layer 20 of themicrocantilever beam 10 and the surroundingtest sample 262, resulting in a deflection of themicrocantilever beam 10. The deflection of themicrocantilever beam 10 is then measured, wherein the deflection indicates a presence of tobacco-specific nitrosamines in thetest sample 262. - In addition, a suitable computing apparatus or device 240 (e.g., a computer) having a suitable software program will preferably be used, wherein the software program is adapted to receive information from the
detector 230 from eachmicrocantilever beam 10. The software program will then preferably store the data, and then upon request displays the data or results in a desired format, including digital readings or printouts of instantaneous readings or quantitative readings over a specified period of time. It can be appreciated that based on the received information, the software program will be capable of positively identifying the presence of trace amounts of tobacco-specific nitrosamines 110 (TSNAs), or alternatively confirm the absence of trace amounts of tobacco-specific nitrosamines 110 (TSNAs) within the medium 50 (e.g., an assay or an analyte). It can be appreciated that thesystem 200 will also preferably includes a quantitative ability to provide a detection range for tobacco-specific nitrosamines (TSNAs) of 400 to 50,000 ppb (parts-per-billion), and more preferably a detection range of 1,000 to 5,000 ppb. - In use, a suitable handheld device will preferably be reusable, wherein the device can be cleaned using a
cleaning agent 264 or other suitable cleansing or cleaning method. Thesystem 200 can also include asyringe pump 250, at least onemedium source 260 and aswitch 270 attached to the inlet oftest chamber 210. - The deflection of the
microcantilever beam 10 can be measured with subnanometer sensitivity by using any suitable method including optical, piezo-resistive, capacitance, and piezo-electric detection methods. - In accordance with another embodiment, the
system 200 can include a plurality of microcantilever beams 10 form asensor array 160 with integrated piezo-resistor for measuring the deflection of the microcantilever beams 10. The piezo-resistor utilizes the electronic properties of the microcantilever to measure its bending, such that thelaser 220 and thedetector 230 can be removed. Highly doped silicon has the property to change its resistivity under mechanical strain. Accordingly, if such a doped layer is incorporated into themicrocantilever beam 10, its bending can easily be measured by determination of the electrical resistance of themicrocantilever beam 10. Typically, the piezo-resistors will contain a specific electronic material with high electrical resistivity, which converts the mechanical motion associated with the deflection or bending of the microcantilever beams 10 into an electrical signal. The deflection is read as a change in resistance of the integrated resistor using appropriate electronic circuits and converted to a piezo-resistive readout. - In accordance with another embodiment, the
system 200 without thelaser 220 and thedetector 230 as shown inFIG. 10 can be incorporated into a handheld microcantilever-based sensor system to identify and monitor tobacco-specific nitrosamines 110 (TSNAs). Thesystem 200 will preferably be comprised anarray 160 of 4-16 piezo-resistive microcantilever beams 10 and an associated electronic readout system (not shown). The microcantilever beams 10 will preferably be functionalized with chemicals as indicated and shown inFIGS. 4-8 , which have specific bonding and recognition with tobacco-specific nitrosamine (TSNA) molecules. It can be appreciated that tobacco-specific nitrosamine 110 (TSNA) detection can be accomplished by observing the resistance difference of microcantilever beams 10 before and after exposure to tobacco-specific nitrosamines (TSNAs). -
FIG. 11 shows a graph of cantilever deflection versus time in accordance with one embodiment, wherein cantilevers are functionalized with self-assembled monolayers of octadecyltrichlorosilane (OTS) with and without TSNAs molecules as templates, respectively. As shown inFIG. 11 , the cantilever deflection versus time utilizing an optical detection system with asingle microcantilever beam 10 with a pump rate of 4 ml/h, 1 ml sample loop and 4 μg/ml of TSNA was performed. -
FIG. 12 shows a graph of cantilever deflection versus time for microcantilever deflection vs. TSNAs concentration in accordance with one embodiment, wherein cantilever is functionalized with a self-assembled monolayer of octadecyltrichlorosilane (OTS) in presence of TSNAs as templates. -
FIGS. 13A and B show graphs of cantilever deflection versus time in accordance with a further embodiment, wherein cantilever A is functionalized with a self-assembled monolayer of 4-mercaptobenzoic acid (4-MBA); cantilever B is modified by depositing 5 nm chromium (Cr) adhesive layer and 40 nm aluminum (Al) film. - It will be understood that the foregoing description is of the preferred embodiments, and is, therefore, merely representative of the article and methods of manufacturing the same. It can be appreciated that variations and modifications of the different embodiments in light of the above teachings will be readily apparent to those skilled in the art. Accordingly, the exemplary embodiments, as well as alternative embodiments, may be made without departing from the spirit and scope of the articles and methods as set forth in the attached claims.
Claims (24)
1. (canceled)
2. (canceled)
3. (canceled)
4. (canceled)
5. (canceled)
6. (canceled)
7. (canceled)
8. (canceled)
9. (canceled)
10. A handheld microcantilever-based sensor system useful for identifying tobacco-specific nitrosamines comprising:
at least one microcantilever beam having a receptor layer and a piezo-resistor, wherein exposure of the receptor layer to a medium causes a deflection of the microcantilever beam and the piezo-resistor converts the deflection into an electrical signal; and
a detection system, which reads the electrical signal.
11. The system of claim 10 , wherein:
(a) the microcantilever beam comprises a silicon base layer and the receptor layer comprising a metal or a metal oxide coating;
(b) the receptor layer is formed by co-absorbing tobacco-specific nitrosamines and silane molecules on a surface of the microcantilever beam wherein template molecules of tobacco-specific nitrosamines physically co-adsorb between the silane molecules, and washing away the template molecules of tobacco-specific nitrosamines with a solvent to form a silane monolayer having tobacco-specific nitrosamine cavities;
(c) the system does not comprise a laser, or a photosensitive detector;
(d) the medium is in either a liquid or a gas phase;
(e) the piezo-resistor comprises a highly doped silicon layer of the microcantilever beam;
(f) the deflection changes electrical resistivity of the piezo-resistor;
(g) the deflection is caused by a physical or chemical reaction of the receptor layer and one or more molecules in the medium, and/or a volume change of the receptor layer;
(h) the at least one microcantilever beam has an overall length of 100 to 400 micrometers, a width of 20 to 70 micrometers, a thickness of 0.5 to 1.5 micrometers, and a spring constant of about 0.4 to 0.8 N/m; and/or
(i) the electrical signal indicates the presence of tobacco-specific nitrosamines in the medium and a detection range for tobacco-specific nitrosamines is from 400 to 50000 ppb in the medium.
The system of claim 11 , wherein the metal or metal oxide coating is comprised of aluminum (Al), platinum (Pt), or palladium (Pd) and wherein the at least one microcantilever undergoes deflection due to an interaction between the metal or metal oxide coating and the medium.
12. (canceled)
13. The system of claim 10 , further comprising:
an array of microcantilever beams, and wherein the array of microcantilevers comprises at least one microcantilever beam having a receptor layer has a combination of a silicon base layer and a receptor layer comprising a gold coating with a plurality of thiol molecules having a sulfur head and a carboxyl-terminated group on the gold coating: and at least one microcantilever beam having a silicon base layer and a receptor layer comprising a metal or metal oxide coating;
(b) a test chamber having an inlet and an outlet to circulate the medium, at least one channel adapted to contain a test sample and a cleaning agent, a syringe pump, at least one medium source and optionally a switch attached to the inlet and adapted to direct the test sample or the cleaning agent to the test chamber; and/or
(c) a computing apparatus adapted to receive information from the detection system, store data and display data.
14. A method of functionalizing a microcantilever beam having a piezo-resistor, comprising:
coating a microcantilever beam with a receptor layer, wherein exposure of the receptor layer to a medium causes a deflection of the microcantilever beam;
wherein the piezo-resistor converts the deflection into an electrical signal.
15. The method of claim 15 , wherein:
(a) the microcantilever beam comprises a silicon base layer and the receptor layer having a gold coating;
(b) the receptor layer is formed by depositing a plurality of thiol molecules having a sulfur head and a carboxyl-terminated group onto the gold-coated receptor layer, and forming a monolayer of thiol molecules with the carboxyl-terminated group on the gold-coated receptor layer of the microcantilever beam, wherein the microcantilever beam undergoes a chemical reaction when exposed the medium;
(c) the microcantilever beam has a silicon base layer, the receptor layer has a metal or metal oxide coating, the receptor layer comprises aluminum (Al), platinum (Pt), or palladium (Pd), and the at least one microcantilever undergoes deflection due to an interaction between the metal or metal oxide coating and the medium;
(d) the receptor layer is formed by co-absorbing tobacco-specific nitrosamines and silane molecules on a surface of the microcantilever beam wherein template molecules of tobacco-specific nitrosamines physically co-adsorb between the silane molecules, and washing away the template molecules of tobacco-specific nitrosamines with a solvent to form a silane monolayer having tobacco-specific nitrosamine cavities;
(e) one side of the microcantilever beam includes silane molecules and the other side includes a gold coating having a plurality of thiol molecules having a sulfur head group and a methyl-terminated group, which blocks absorption of the silane molecules;
(f) the medium is in either a liquid or a gas phase;
(g) the piezo-resistor comprises a highly doped silicon layer of the microcantilever beam;
(h) the deflection changes electrical resistivity of the piezo-resistor; and/or
(i) the deflection is caused by a physical or chemical reaction of the receptor layer and tobacco-specific nitrosamines in the medium, and/or a volume change of the receptor layer.
16. (canceled)
17. The method of claim 16 , wherein the terminal group in the thiol molecule comprises —OH., —NH2 or —COOH moieties.
18. (canceled)
19. (canceled)
20. (canceled)
21. The method of claim 16 , wherein the thiol molecules are comprised of a hydrocarbon chain of 6 to 18 carbon atoms.
22. The system of claim 11 , wherein the metal or metal oxide coating comprises a gold coating with a plurality of thiol molecules having a sulfur head and a carboxyl-terminated group.
23. The system of claim 14 , wherein the system includes the array of microcantilever beams and:
(a) each microcantilever beam in the array is independently addressable;
(b) each microcantilever beam in the array has a receptor layer and a piezo-resistor;
(c) the array is a one-dimensional or two-dimensional array;
(d) the array has four to sixteen microcantilever beams;
(e) the microcantilever beams in the array are separated by a space between 50 to 500 micrometers wide;
(f) the microcantilever beams in the array are on a single chip;
(g) the computing apparatus is adapted to positively identify the presence of or confirm the absence of trace amounts of tobacco-specific nitrosamines in the medium;
and/or
(h) the thiol molecules are comprised of a hydrocarbon chain of 6 to 18 carbon atoms.
24. The system of claim 14 , further comprising electronic components or devices to suppress background noise and to monitor and evaluate electronic output from each microcantilever beam in the array.
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Families Citing this family (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7709264B2 (en) * | 2006-09-21 | 2010-05-04 | Philip Morris Usa Inc. | Handheld microcantilever-based sensor for detecting tobacco-specific nitrosamines |
WO2009143373A1 (en) * | 2008-05-21 | 2009-11-26 | Triton Systems, Inc. | Detection of peroxide radicals and reaction initiators |
US20110177606A1 (en) * | 2008-06-30 | 2011-07-21 | Yissum Research Development Company Of The Hebrew University Of Jerusalem, Ltd. | Detection of trinitrotoluene |
DE102008039624B4 (en) * | 2008-08-25 | 2010-05-20 | Kist-Europe Forschungsgesellschaft Mbh | MIP nanoparticle chip sensor, its use and analytical detection method |
EP2169400A1 (en) * | 2008-09-25 | 2010-03-31 | IEE INTERNATIONAL ELECTRONICS & ENGINEERING S.A. | Hydrogen sensor |
US9594080B2 (en) * | 2009-03-09 | 2017-03-14 | Yanxiu Zhou | Molecular recognition matrix and method for making same |
US9547968B2 (en) * | 2010-10-15 | 2017-01-17 | Nevada Nanotech Systems Inc. | Pre-smoke detector and system for use in early detection of developing fires |
CN103257196B (en) * | 2013-05-10 | 2014-08-20 | 云南省烟草农业科学研究院 | Method for detecting alkaloids and nitrosamines in tobaccos simultaneously |
US9128106B2 (en) | 2013-11-05 | 2015-09-08 | King Fahd University Of Petroleum And Minerals | Dispersive liquid-liquid microextraction method of detecting N-nitrosoamines |
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CN107271584B (en) * | 2017-06-15 | 2020-07-03 | 国家烟草质量监督检验中心 | Method for trapping carbonyl compounds and tobacco-specific nitrosamines in cigarette mainstream smoke, extraction method and determination method |
CN110128590A (en) * | 2019-05-15 | 2019-08-16 | 南通市产品质量监督检验所 | A kind of preparation method of the N- N-nitrosodimethylamine molecularly imprinted polymer using acrylamide as function monomer |
CN113023667B (en) * | 2021-03-04 | 2023-11-10 | 中国科学院物理研究所 | Three-dimensional micro-nano bending structure and method for preparing same by utilizing electron beam |
JP2023166245A (en) * | 2022-05-09 | 2023-11-21 | 国立大学法人 東京大学 | Robust molecule recognition element, sensor, and production method thereof |
Citations (57)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5095401A (en) * | 1989-01-13 | 1992-03-10 | Kopin Corporation | SOI diaphragm sensor |
US5177661A (en) * | 1989-01-13 | 1993-01-05 | Kopin Corporation | SOI diaphgram sensor |
US5444244A (en) * | 1993-06-03 | 1995-08-22 | Park Scientific Instruments Corporation | Piezoresistive cantilever with integral tip for scanning probe microscope |
US5490034A (en) * | 1989-01-13 | 1996-02-06 | Kopin Corporation | SOI actuators and microsensors |
US5719324A (en) * | 1995-06-16 | 1998-02-17 | Lockheed Martin Energy Systems, Inc. | Microcantilever sensor |
US5810020A (en) * | 1993-09-07 | 1998-09-22 | Osmotek, Inc. | Process for removing nitrogen-containing anions and tobacco-specific nitrosamines from tobacco products |
US6051372A (en) * | 1997-09-09 | 2000-04-18 | Nimbus Biotechnologie Gmbh | Template induced patterning of surfaces and their reversible stabilization using phase transitions of the patterned material |
US6057377A (en) * | 1998-10-30 | 2000-05-02 | Sandia Corporation | Molecular receptors in metal oxide sol-gel materials prepared via molecular imprinting |
US6203983B1 (en) * | 1997-06-16 | 2001-03-20 | Affymetrix, Inc. | Method for detecting chemical interactions between naturally occurring bio-polymers which are non-identical binding partners |
US6251280B1 (en) * | 1999-09-15 | 2001-06-26 | University Of Tennessee Research Corporation | Imprint-coating synthesis of selective functionalized ordered mesoporous sorbents for separation and sensors |
US6289717B1 (en) * | 1999-03-30 | 2001-09-18 | U. T. Battelle, Llc | Micromechanical antibody sensor |
US20020094531A1 (en) * | 1999-06-14 | 2002-07-18 | Frederic Zenhausern | Apparatus and method for monitoring molecular species within a medium |
US20020092359A1 (en) * | 2000-10-04 | 2002-07-18 | Dirk Lange | Sensor apparatus and cantilever for it |
US20020092340A1 (en) * | 2000-10-30 | 2002-07-18 | Veeco Instruments Inc. | Cantilever array sensor system |
US20030027354A1 (en) * | 2001-06-08 | 2003-02-06 | Francois Geli | Device for the analysis of chemical or biochemical specimens, comparative analysis, and associated analysis process |
US20030054355A1 (en) * | 2000-09-04 | 2003-03-20 | Peter Warthoe | Microsensors and method for detecting target analytes |
US20030068655A1 (en) * | 2001-09-12 | 2003-04-10 | Protiveris, Inc. | Microcantilever apparatus and methods for detection of enzymes |
US20030089182A1 (en) * | 2001-09-07 | 2003-05-15 | Jacob Thaysen | Flexible structure with integrated sensor/actuator |
US6575020B1 (en) * | 1999-05-03 | 2003-06-10 | Cantion A/S | Transducer for microfluid handling system |
US20030166039A1 (en) * | 2002-03-04 | 2003-09-04 | Hubler Urs Christian | Apparatus and method for detecting microorganisms |
US20030209058A1 (en) * | 2002-05-07 | 2003-11-13 | Merrill John H. | MIP microcantilever sensor and a method of using thereof |
US20030215816A1 (en) * | 2002-05-20 | 2003-11-20 | Narayan Sundararajan | Method for sequencing nucleic acids by observing the uptake of nucleotides modified with bulky groups |
US20040007051A1 (en) * | 2002-03-20 | 2004-01-15 | Purdue Research Foundation | Microscale sensor element and related device and method of manufacture |
US6709597B1 (en) * | 2002-11-29 | 2004-03-23 | Council Of Scientific And Industrial Research | Process for the separation of racemic mixtures |
US20040058380A1 (en) * | 2002-09-12 | 2004-03-25 | Kalle Levon | Surface imprinting: integration of molecular recognition and transduction |
US20040152211A1 (en) * | 2002-11-15 | 2004-08-05 | The Regents Of The University Of California | System and method for multiplexed biomolecular analysis |
US20040223884A1 (en) * | 2003-05-05 | 2004-11-11 | Ing-Shin Chen | Chemical sensor responsive to change in volume of material exposed to target particle |
US20050043515A1 (en) * | 2003-05-29 | 2005-02-24 | Brown Michael Craig | Tobacco-specific nitrosamine detection assays and reagents |
US20050043894A1 (en) * | 2003-08-22 | 2005-02-24 | Fernandez Dennis S. | Integrated biosensor and simulation system for diagnosis and therapy |
US6866819B1 (en) * | 2001-11-13 | 2005-03-15 | Raytheon Company | Sensor for detecting small concentrations of a target matter |
US20050133877A1 (en) * | 2002-06-07 | 2005-06-23 | Jacob Thaysen | Chemical sensor |
US20050164299A1 (en) * | 2003-06-03 | 2005-07-28 | Bay Materials Llc | Phase change sensor |
US20050199047A1 (en) * | 2003-03-11 | 2005-09-15 | Adams Jesse D. | Liquid cell and passivated probe for atomic force microscopy and chemical sensing |
US20050221081A1 (en) * | 2004-03-23 | 2005-10-06 | Liu Gang-Yu | Stabilization of self-assembled monolayers |
US6960645B2 (en) * | 2004-03-26 | 2005-11-01 | Council Of Scientific And Industrial Research | Synthesis of ion imprinted polymer particles |
US20050244820A1 (en) * | 2002-09-24 | 2005-11-03 | Intel Corporation | Detecting molecular binding by monitoring feedback controlled cantilever deflections |
US20050260423A1 (en) * | 2004-05-18 | 2005-11-24 | Mohan Natesan | Modified microsurfaces and methods of their manufacture |
US20060060003A1 (en) * | 2002-12-27 | 2006-03-23 | Jacob Thaysen | Cantilever sensor using both the longitudinal and the transversal piezoresistive coefficients |
US7034677B2 (en) * | 2002-07-19 | 2006-04-25 | Smiths Detection Inc. | Non-specific sensor array detectors |
US20060191320A1 (en) * | 2004-02-19 | 2006-08-31 | Pinnaduwage Lal A | Chemically-functionalized microcantilevers for detection of chemical, biological and explosive material |
US7105301B2 (en) * | 2002-09-24 | 2006-09-12 | Intel Corporation | Detecting molecular binding by monitoring feedback controlled cantilever deflections |
US20070023851A1 (en) * | 2002-04-23 | 2007-02-01 | Hartzell John W | MEMS pixel sensor |
US20070059211A1 (en) * | 2005-03-11 | 2007-03-15 | The College Of Wooster | TNT sensor containing molecularly imprinted sol gel-derived films |
US20070095129A1 (en) * | 2005-10-31 | 2007-05-03 | Donaldson Jeremy H | Cantilevers for sensing fluid properties |
US20070116607A1 (en) * | 2005-11-23 | 2007-05-24 | Pharmacom Microlelectronics, Inc. | Microsystems that integrate three-dimensional microarray and multi-layer microfluidics for combinatorial detection of bioagent at single molecule level |
US20070141721A1 (en) * | 2002-04-29 | 2007-06-21 | The Regents Of The University Of California | Microcantilevers for biological and chemical assays and methods of making and using thereof |
US20070172960A1 (en) * | 1998-08-21 | 2007-07-26 | Abdul Malik | Capillary column and method of making |
US20070213611A1 (en) * | 2003-07-25 | 2007-09-13 | Simpson Peter C | Dual electrode system for a continuous analyte sensor |
US7340941B1 (en) * | 2002-10-01 | 2008-03-11 | Xsilogy, Inc. | Dense thin film-based chemical sensors and methods for making and using same |
US20080090259A1 (en) * | 2006-06-08 | 2008-04-17 | Eric Toone | Methods, devices, systems and computer program products for stochastic, competitive, force-based analyte detection |
US20080206103A1 (en) * | 2004-09-14 | 2008-08-28 | Ut-Battelle, Llc | Method For The Preparation Of Very Stable, Self-Assembled Monolayers On The Surface Of Gold Coated Microcantilevers For Application To Chemical Sensing |
US20090005270A1 (en) * | 2004-09-20 | 2009-01-01 | University Of Florida Research Foundation, Inc. | Systems and Methods for Evaluating Enzyme Competency |
US7560070B1 (en) * | 1999-11-03 | 2009-07-14 | International Business Machines Corporation | Cantilever sensors and transducers |
US20090203930A1 (en) * | 2004-11-25 | 2009-08-13 | Total Petrochemicals Research Feluy | Process for dispersing functional molecules on the surface of a support and support made by this process |
US20090308742A1 (en) * | 2005-12-09 | 2009-12-17 | Makarand Paranjape | Flexible Apparatus and Method for Monitoring and Delivery |
US7709264B2 (en) * | 2006-09-21 | 2010-05-04 | Philip Morris Usa Inc. | Handheld microcantilever-based sensor for detecting tobacco-specific nitrosamines |
US20100120023A1 (en) * | 2005-04-22 | 2010-05-13 | Ozgur Sahin | Detection of macromolecular complexes with harmonic cantilevers |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2565129C (en) * | 2004-05-24 | 2012-12-11 | British American Tobacco (Investments) Limited | Molecularly imprinted polymers selective for nitrosamines and methods of using the same |
WO2005119233A1 (en) | 2004-06-01 | 2005-12-15 | Cantion A/S | Stress sensor with capture coating for detecting a target substance |
-
2007
- 2007-09-18 US US11/902,041 patent/US7709264B2/en not_active Expired - Fee Related
- 2007-09-21 WO PCT/IB2007/003738 patent/WO2008035220A2/en active Application Filing
-
2010
- 2010-04-28 US US12/769,338 patent/US20100215544A1/en not_active Abandoned
Patent Citations (65)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5177661A (en) * | 1989-01-13 | 1993-01-05 | Kopin Corporation | SOI diaphgram sensor |
US5490034A (en) * | 1989-01-13 | 1996-02-06 | Kopin Corporation | SOI actuators and microsensors |
US5095401A (en) * | 1989-01-13 | 1992-03-10 | Kopin Corporation | SOI diaphragm sensor |
US5444244A (en) * | 1993-06-03 | 1995-08-22 | Park Scientific Instruments Corporation | Piezoresistive cantilever with integral tip for scanning probe microscope |
US5810020A (en) * | 1993-09-07 | 1998-09-22 | Osmotek, Inc. | Process for removing nitrogen-containing anions and tobacco-specific nitrosamines from tobacco products |
US5719324A (en) * | 1995-06-16 | 1998-02-17 | Lockheed Martin Energy Systems, Inc. | Microcantilever sensor |
US6203983B1 (en) * | 1997-06-16 | 2001-03-20 | Affymetrix, Inc. | Method for detecting chemical interactions between naturally occurring bio-polymers which are non-identical binding partners |
US6051372A (en) * | 1997-09-09 | 2000-04-18 | Nimbus Biotechnologie Gmbh | Template induced patterning of surfaces and their reversible stabilization using phase transitions of the patterned material |
US20070172960A1 (en) * | 1998-08-21 | 2007-07-26 | Abdul Malik | Capillary column and method of making |
US6057377A (en) * | 1998-10-30 | 2000-05-02 | Sandia Corporation | Molecular receptors in metal oxide sol-gel materials prepared via molecular imprinting |
US6289717B1 (en) * | 1999-03-30 | 2001-09-18 | U. T. Battelle, Llc | Micromechanical antibody sensor |
US6575020B1 (en) * | 1999-05-03 | 2003-06-10 | Cantion A/S | Transducer for microfluid handling system |
US20020094531A1 (en) * | 1999-06-14 | 2002-07-18 | Frederic Zenhausern | Apparatus and method for monitoring molecular species within a medium |
US6251280B1 (en) * | 1999-09-15 | 2001-06-26 | University Of Tennessee Research Corporation | Imprint-coating synthesis of selective functionalized ordered mesoporous sorbents for separation and sensors |
US7560070B1 (en) * | 1999-11-03 | 2009-07-14 | International Business Machines Corporation | Cantilever sensors and transducers |
US20030054355A1 (en) * | 2000-09-04 | 2003-03-20 | Peter Warthoe | Microsensors and method for detecting target analytes |
US20020092359A1 (en) * | 2000-10-04 | 2002-07-18 | Dirk Lange | Sensor apparatus and cantilever for it |
US20020092340A1 (en) * | 2000-10-30 | 2002-07-18 | Veeco Instruments Inc. | Cantilever array sensor system |
US20030027354A1 (en) * | 2001-06-08 | 2003-02-06 | Francois Geli | Device for the analysis of chemical or biochemical specimens, comparative analysis, and associated analysis process |
US20030089182A1 (en) * | 2001-09-07 | 2003-05-15 | Jacob Thaysen | Flexible structure with integrated sensor/actuator |
US20030068655A1 (en) * | 2001-09-12 | 2003-04-10 | Protiveris, Inc. | Microcantilever apparatus and methods for detection of enzymes |
US6866819B1 (en) * | 2001-11-13 | 2005-03-15 | Raytheon Company | Sensor for detecting small concentrations of a target matter |
US20030166039A1 (en) * | 2002-03-04 | 2003-09-04 | Hubler Urs Christian | Apparatus and method for detecting microorganisms |
US6935165B2 (en) * | 2002-03-20 | 2005-08-30 | Purdue Research Foundation | Microscale sensor element and related device and method of use |
US20040007051A1 (en) * | 2002-03-20 | 2004-01-15 | Purdue Research Foundation | Microscale sensor element and related device and method of manufacture |
US20070023851A1 (en) * | 2002-04-23 | 2007-02-01 | Hartzell John W | MEMS pixel sensor |
US7695951B2 (en) * | 2002-04-29 | 2010-04-13 | Kambiz Vafai | Innovative biosensors for chemical and biological assays |
US20070287185A1 (en) * | 2002-04-29 | 2007-12-13 | The Regents Of The University Of California | Microcantilevers for Biological and Chemical Assays and Methods of Making and Using Thereof |
US20070141721A1 (en) * | 2002-04-29 | 2007-06-21 | The Regents Of The University Of California | Microcantilevers for biological and chemical assays and methods of making and using thereof |
US20040080319A1 (en) * | 2002-05-07 | 2004-04-29 | Merrill John H. | MIP microcantilever sensor and a method of using thereof |
US20030209058A1 (en) * | 2002-05-07 | 2003-11-13 | Merrill John H. | MIP microcantilever sensor and a method of using thereof |
US20050026163A1 (en) * | 2002-05-20 | 2005-02-03 | Narayanan Sundararajan | Method for sequencing nucleic acids by observing the uptake of nucleotides modified with bulky groups |
US20030215816A1 (en) * | 2002-05-20 | 2003-11-20 | Narayan Sundararajan | Method for sequencing nucleic acids by observing the uptake of nucleotides modified with bulky groups |
US20050133877A1 (en) * | 2002-06-07 | 2005-06-23 | Jacob Thaysen | Chemical sensor |
US20090200163A1 (en) * | 2002-06-07 | 2009-08-13 | Nanonord A/S | Chemical Sensor |
US7034677B2 (en) * | 2002-07-19 | 2006-04-25 | Smiths Detection Inc. | Non-specific sensor array detectors |
US20040058380A1 (en) * | 2002-09-12 | 2004-03-25 | Kalle Levon | Surface imprinting: integration of molecular recognition and transduction |
US20050244820A1 (en) * | 2002-09-24 | 2005-11-03 | Intel Corporation | Detecting molecular binding by monitoring feedback controlled cantilever deflections |
US7105301B2 (en) * | 2002-09-24 | 2006-09-12 | Intel Corporation | Detecting molecular binding by monitoring feedback controlled cantilever deflections |
US7340941B1 (en) * | 2002-10-01 | 2008-03-11 | Xsilogy, Inc. | Dense thin film-based chemical sensors and methods for making and using same |
US20040152211A1 (en) * | 2002-11-15 | 2004-08-05 | The Regents Of The University Of California | System and method for multiplexed biomolecular analysis |
US6709597B1 (en) * | 2002-11-29 | 2004-03-23 | Council Of Scientific And Industrial Research | Process for the separation of racemic mixtures |
US20060060003A1 (en) * | 2002-12-27 | 2006-03-23 | Jacob Thaysen | Cantilever sensor using both the longitudinal and the transversal piezoresistive coefficients |
US20050199047A1 (en) * | 2003-03-11 | 2005-09-15 | Adams Jesse D. | Liquid cell and passivated probe for atomic force microscopy and chemical sensing |
US20040223884A1 (en) * | 2003-05-05 | 2004-11-11 | Ing-Shin Chen | Chemical sensor responsive to change in volume of material exposed to target particle |
US20050043515A1 (en) * | 2003-05-29 | 2005-02-24 | Brown Michael Craig | Tobacco-specific nitrosamine detection assays and reagents |
US20050164299A1 (en) * | 2003-06-03 | 2005-07-28 | Bay Materials Llc | Phase change sensor |
US20070213611A1 (en) * | 2003-07-25 | 2007-09-13 | Simpson Peter C | Dual electrode system for a continuous analyte sensor |
US20090076356A1 (en) * | 2003-07-25 | 2009-03-19 | Dexcom, Inc. | Dual electrode system for a continuous analyte sensor |
US20050043894A1 (en) * | 2003-08-22 | 2005-02-24 | Fernandez Dennis S. | Integrated biosensor and simulation system for diagnosis and therapy |
US20060178841A1 (en) * | 2003-08-22 | 2006-08-10 | Fernandez Dennis S | Integrated biosensor and simulation system for diagnosis and therapy |
US20060191320A1 (en) * | 2004-02-19 | 2006-08-31 | Pinnaduwage Lal A | Chemically-functionalized microcantilevers for detection of chemical, biological and explosive material |
US20050221081A1 (en) * | 2004-03-23 | 2005-10-06 | Liu Gang-Yu | Stabilization of self-assembled monolayers |
US6960645B2 (en) * | 2004-03-26 | 2005-11-01 | Council Of Scientific And Industrial Research | Synthesis of ion imprinted polymer particles |
US20050260423A1 (en) * | 2004-05-18 | 2005-11-24 | Mohan Natesan | Modified microsurfaces and methods of their manufacture |
US20080206103A1 (en) * | 2004-09-14 | 2008-08-28 | Ut-Battelle, Llc | Method For The Preparation Of Very Stable, Self-Assembled Monolayers On The Surface Of Gold Coated Microcantilevers For Application To Chemical Sensing |
US20090005270A1 (en) * | 2004-09-20 | 2009-01-01 | University Of Florida Research Foundation, Inc. | Systems and Methods for Evaluating Enzyme Competency |
US20090203930A1 (en) * | 2004-11-25 | 2009-08-13 | Total Petrochemicals Research Feluy | Process for dispersing functional molecules on the surface of a support and support made by this process |
US20070059211A1 (en) * | 2005-03-11 | 2007-03-15 | The College Of Wooster | TNT sensor containing molecularly imprinted sol gel-derived films |
US20100120023A1 (en) * | 2005-04-22 | 2010-05-13 | Ozgur Sahin | Detection of macromolecular complexes with harmonic cantilevers |
US20070095129A1 (en) * | 2005-10-31 | 2007-05-03 | Donaldson Jeremy H | Cantilevers for sensing fluid properties |
US20070116607A1 (en) * | 2005-11-23 | 2007-05-24 | Pharmacom Microlelectronics, Inc. | Microsystems that integrate three-dimensional microarray and multi-layer microfluidics for combinatorial detection of bioagent at single molecule level |
US20090308742A1 (en) * | 2005-12-09 | 2009-12-17 | Makarand Paranjape | Flexible Apparatus and Method for Monitoring and Delivery |
US20080090259A1 (en) * | 2006-06-08 | 2008-04-17 | Eric Toone | Methods, devices, systems and computer program products for stochastic, competitive, force-based analyte detection |
US7709264B2 (en) * | 2006-09-21 | 2010-05-04 | Philip Morris Usa Inc. | Handheld microcantilever-based sensor for detecting tobacco-specific nitrosamines |
Non-Patent Citations (55)
Title |
---|
Arlett, J. L. et al, Nono Letters 2006, 6, 1000-1006. * |
Backmann, N. et al, Proceedings of the National Academy of Sciences of the United States of America 2005, 102, 14587?14592. * |
Backmann, N. et al, Proceedings of the National Academy of Sciences of the United States of America 2005, 102, 14587â€"14592. * |
Backmann, N. et al, Proceedings of the National Academy of Sciences of the United States of America 2005, 102, 14587â14592. * |
Betts, T. A. et al, Analytica Chimica Acta 2000, 422, 89-99. * |
Boisen, A. et al, Ultramicroscopy 2000, 82, 11-16. * |
Butt, H.-J., Journal of Colloid and Interface Science 1996, 180, 251-260. * |
Campbell, G. A. et al, Biosensors and Bioelectronics 2005, 21, 597-607. * |
Carraro, C. et al, Electrochimica Acta 2002, 46, 2583-2588. * |
Chatzandroulis, S. et al, Microelectronic Engineering 2002, 61-62, 955-961. * |
Collins, R. J. et al, Langmuir 1995, 11, 2322-2324. * |
de Boer, M. P. et al, Acta Materialia 2000, 48, 4531-4541. * |
Fagan, B. C. et al, Talanta 2000, 53, 599-608. * |
Hansen, K. M. et al, Methods 2005, 37, 57-64. * |
Harder, P. et al, Langmuir 1997, 13, 445-454. * |
Hierlemann, A. et al, (2004) "Hand-Held and Palm-Top Chemical Microsensor Systems for Gas Analysis", in Handbook of Machine Olfaction: Electronic Nose Technology 2004, eds Pearce, T. C. et al., Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany. * |
Hilt, J. Z. et al, Biomedical Devices 2003, 5:3, 177-184. * |
Jensenius, H. et al, Applied Physics Letters 2000, 76, 2615-2617. * |
Jeon, S. et al, Applied Physics Letters 2004, 85, 1083-1084. * |
Kim, J.-H. et al, in "Molecular Electronics" Hong, F. T. editor, Plenum Press, New York 1989, pages 329-337. * |
Kim, J.-H. et al, Journal of Physical Chemistry 1988, 92, 5575-5578. * |
Larvik. N. V. et al, Biomedical Devices 2001, 3, 35-44. * |
Larvik. N. V. et al, Chemical Physics Letters 2001, 336, 371-376. * |
Lavrik, N. V. et al, Review of Scientific Instruments 2004, 75, 2229-2253. * |
Li, P. et al, Journal of Micromechanics and Microengineering 2006, 16, 2539-2546. * |
Linseisen, F. M. et al, Biophysical Journal 1997, 72, 1659-1667. * |
Lisichkin, G. V. et al, Colloid Journal 2004, 66, 387-399. * |
Liu, J. et al, Journal of Physical Chemistry A 2000, 104, 8328-8339. * |
Martin, P. et al, Langmuir 2005, 21, 6934-6943. * |
Niwa, D. et al, Journal of Physical Chemistry B 2004, 108, 3240-3245. * |
Paci, D. et al, Analog Integrated Circuits and Signal Processing, 2005, 44, 119-128. * |
Pera, I. et al, Langmuir 2007, 23, 1543-1547. * |
Pinnaduwage, L. A. et al, Langmuir 2004, 20, 2690-2694. * |
Raiteri, R. et al, Electrochimica Acta 2000, 46, 157-163. * |
Sagiv, J., Journal of the American Chemical Society 1980, 102, 92-98. * |
Saya, D. et al, Sensors and Actuators A 2005, 123-124, 23-29. * |
Sepaniak, M. et al, Analytical Chemistry 2002, 74, 568A-575A. * |
Shin, Y. et al, Angewandt Chemie International Edition 2000, 39, 2702-2707. * |
Singh, S. et al, Thin Solid Films 1999, 339, 209-215. * |
Smith, R. K. et al, Progreass in Surface Science 2004, 75, 1-68. * |
Song, S. et al, Langmuir 2006, 22, 6010-6015. * |
Tang, Y. et al, Sensors and Actuators B 2004, 97, 109-113. * |
Tao, Y.-T. et al, Journal of the Chemical Society, Chemical Communications 1988, 417-418. * |
Tipple, C. A. et al, Analytical Chemistry 2002, 74, 3118-3126. * |
Tortonese, M. et al, International Conference on Solid-State Sensors and Actuators, 1991, Digest of Technical Papers, TRANSDUCERS '91., 448 - 451. * |
Tortonese, M., in "Atomic Force Microscopy/Scanning Tunneling Microscopy 2" Cohen, S. H. et al, editors Plenum Press, New York 1997, pages 147-153. * |
Villanueva, G. et al, Microelectronic Engineering 2004, 73-74, 480-486. * |
Wasserman, S. R. et al, Langmuir 1989, 5, 1074-1087. * |
Xia, Y. et al, Analytical Chemistry 2005, 77, 7639-7645. * |
Yamamura, K. et al, Journal of the Chemical Society, Chemical Communications 1988, 79-81. * |
Yan, X, et al, Organic and Biomelecular Chemistry 2003, 1, 460-462. * |
Zeng, Z.-R. et al, Chromatographia 1992, 34, 85-90. * |
Zhong, C.-J. et al, Analytical Chemistry 1995, 67, 709A-715A. * |
Zhou, Y. et al, Chemistry of Materials 2003, 15, 2774-2779. * |
Ziegler, C., Analytical and Bioanalytical Chemistry 2004, 379, 946-959. * |
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US20080102532A1 (en) | 2008-05-01 |
WO2008035220A2 (en) | 2008-03-27 |
US7709264B2 (en) | 2010-05-04 |
WO2008035220A3 (en) | 2008-06-19 |
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