CA2386006A1 - Traverse shear mode piezoelectric chemical sensor - Google Patents
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- CA2386006A1 CA2386006A1 CA002386006A CA2386006A CA2386006A1 CA 2386006 A1 CA2386006 A1 CA 2386006A1 CA 002386006 A CA002386006 A CA 002386006A CA 2386006 A CA2386006 A CA 2386006A CA 2386006 A1 CA2386006 A1 CA 2386006A1
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- G01N29/02—Analysing fluids
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Abstract
The present invention relates to a process for sensing biological or chemica l changes in molecular structural shape or mass of molecules attached to the surface of a transverse shear piezoelectric oscillating molecular sensing device driven by a network analyzer. The process comprises the steps of i) exciting the sensor device at a series of predetermined frequencies, ii) collecting data to determine values for the predetermined parameters of seri es resonance frequency shift (fS), motional resistance (RM), motional inductanc e (LM), motional capacitance (CM), electrostatic capacitance (Co) and boundary layer slip parameter (.alpha.); and iii) determining relative changes in the measured parameters to detect thereby any changes in molecular structural shape or mass at sensing device surface.
Description
TRAVERSE SHEAR MODE
PIEZOELECTRIC CHEMICAL SENSOR
Field of the Invention This invention relates to a process of detecting specific molecules in a liquid (the analyte) with receiving molecules, (the receptors) which are attached to the surface of a thickness shear mode acoustic sensor (TSM). Acoustic energy generated in the sensor is transferred to and from the fluid depending on the surface coupling behaviour. The coupling is altered when the analyte binds to the receptor producing easily measured changes in the electrical characteristics of the sensor.
The invention further relates to the application of the measurement of the coupling effects to the sensing of biomolecules, and other molecules of biological significance such as drugs, in general. For example, the receptor may be a protein, a single oligonucleotide strand, DNA or RNA and the analyte a protein, drug or complementary strands of DNA or RNA. The interaction between the analyte and the sensor bound receptor can be identified through a quantitative TSM response. Other measurement scenarios are possible through the detection of changes in the acoustic coupling between the sensor surface and the surrounding liquid.
Background of the Invention A TSM sensor is a device which generates mechanical vibrations from an electrical signal and uses these vibrations to detect and/or quantify particular chemical or biochemical substances present in a medium surrounding the sensor (the analyte). Acoustic energy is stored and dissipated both in the device itself, and through interfacial coupling, in a surrounding liquid medium. By coating the sensor with one or more layers of a substance which interacts with the analyte, the energy storage and transfer processes change when the interaction occurs. This changes the acoustic resonance of the sensor, which can be observed by measuring the electrical impedance of the sensor. The applicants have published several papers in this field and they are listed as follows:
1) F. Ferrante, A.L. Kipling and M.Thompson, "Molecular Slip At The Solid-Liquid Interface Of An Acoustic Wave Sensor", J.
Appl. Phys. 76(6):3448-3462, 1994;
2) G.L. Hayward and M. Thompson, "A Transverse Shear Model Of A Piezoelectric Chemical Sensor", Amer. Inst. Physics 83(40:2194-2201, 1998;
PIEZOELECTRIC CHEMICAL SENSOR
Field of the Invention This invention relates to a process of detecting specific molecules in a liquid (the analyte) with receiving molecules, (the receptors) which are attached to the surface of a thickness shear mode acoustic sensor (TSM). Acoustic energy generated in the sensor is transferred to and from the fluid depending on the surface coupling behaviour. The coupling is altered when the analyte binds to the receptor producing easily measured changes in the electrical characteristics of the sensor.
The invention further relates to the application of the measurement of the coupling effects to the sensing of biomolecules, and other molecules of biological significance such as drugs, in general. For example, the receptor may be a protein, a single oligonucleotide strand, DNA or RNA and the analyte a protein, drug or complementary strands of DNA or RNA. The interaction between the analyte and the sensor bound receptor can be identified through a quantitative TSM response. Other measurement scenarios are possible through the detection of changes in the acoustic coupling between the sensor surface and the surrounding liquid.
Background of the Invention A TSM sensor is a device which generates mechanical vibrations from an electrical signal and uses these vibrations to detect and/or quantify particular chemical or biochemical substances present in a medium surrounding the sensor (the analyte). Acoustic energy is stored and dissipated both in the device itself, and through interfacial coupling, in a surrounding liquid medium. By coating the sensor with one or more layers of a substance which interacts with the analyte, the energy storage and transfer processes change when the interaction occurs. This changes the acoustic resonance of the sensor, which can be observed by measuring the electrical impedance of the sensor. The applicants have published several papers in this field and they are listed as follows:
1) F. Ferrante, A.L. Kipling and M.Thompson, "Molecular Slip At The Solid-Liquid Interface Of An Acoustic Wave Sensor", J.
Appl. Phys. 76(6):3448-3462, 1994;
2) G.L. Hayward and M. Thompson, "A Transverse Shear Model Of A Piezoelectric Chemical Sensor", Amer. Inst. Physics 83(40:2194-2201, 1998;
3) Cavic B.A. et al., "Acoustic Waves And The Real-Time Study Of Biochemical Macromolecules At The Liquid/Solid Interface", Faraday Discuss. 107:159-176, 1997;
4) H. Su and M. Thompson, "Rheological And Interfacial Properties Of Nucleic Acid Films Studies By Thickness-Shear Mode Sensor And Network Analysis", Can. J. Chem. 74:344-358, 1996.
There are several mechanisms whereby a TSM sensor responds to chemical change on its surface when it is immersed in a liquid. Surface mass deposition occurs when the analyte binds to the receptor on the sensor surface.
This increases the storage of acoustic energy through the inertia of the added mass. Acoustic energy may also be stored through the elastic deformation of a coating on the surface. The elasticity of the coating may also change when the analyte binds to the receptor coating. These energy storage modes determine the resonant characteristics of the sensor which can easily be measured electrically. These processes are well known. Examples of piezoelectric sensors are described, for example in U.S. Patents 5,374,521 and 5,658,732.
Viscous loading occurs when acoustic energy is transferred to the liquid.
Some of the acoustic energy is stored by the inertia of the fluid moving with the sensor surface and can be transferred back to the sensor, but acoustic energy is also dissipated by internal friction within the fluid. The viscous loading effect is also well known, however in the current use of this effect, the transfer of acoustic energy at the surface is considered to be perfect, that is, there is no slip between the sensor surface and the adjacent fluid molecules.
The current practice is based on the well known Butterworth - van Dyke model of a piezoelectric resonator which consists of a resistor, inductor and capacitor in series, all in parallel with another capacitor. The series arm of this network is called the motional arm. Further details of this model and the calculation of the following parameters may be found in the above paper entitled "Rheological and Interfacial Properties of Nucleic Acid Films Studies by Thickness-Shear Mode Sensor and Network Analysis".
Motional Inductance The motional inductance, LM, represents the inertial energy stored by the sensor. It depends on the mass of the TSM sensor as well as the mass of material (the analyte) added to the surface. Since liquid coupled to the surface can store and return acoustic energy, LM is also dependent on the viscosity of the liquid.
Motional Resistance The motional resistance, RM, is intrinsically related to the energy dissipated by the sensor.
Accordingly, any imposition of material (or loss of material) that has a viscous property or changes in the viscosity of the liquid will result in a change in the energy dissipation and hence RM.
Motional Capacitance The motional capacitance, C;~, represents the elastic energy stored by the sensor. The absorption or chemical binding of the analyte to the coating can have a large effect on the viscoelastic properties of the coating. Depending on the thickness, an added (or removed) layer of material may change the elasticity of the sensor and thus affect CM. Although most fluids are considered to be viscous, at the high frequencies used in piezoelectric quartz sensors, the liquid may also have elastic properties.
Static Capacitance The static capacitance Co represents the dielectric constant of the quartz, but includes that of the medium through the electric field. Charge interactions between the analyte and the sensor coating will affect this value.
Summary of the Invention According to an aspect of the invention, there is provided a process for sensing biological or chemical changes in molecular structural shape or mass of molecules attached to the surface of a transverse shear piezoelectric oscillating molecular sensing device driven by a network analyzer, said process compnsmg:
i) exciting said sensor device at a series of predetermined frequencies;
~i) collecting data to determine values for the predetermined parameters of series resonance frequency shift (f5), motional resistance (RM), motional inductance (LM), motional capacitance (CM), electrostatic capacitance (Co) and boundary layer slip parameter (a); and iii) determining relative changes in said measured parameters to detect thereby any changes in molecular structural shape or mass at sensing device surface.
In accordance with another aspect of the invention there is provided a method of determining the efficiency of acoustic coupling between a sensor and the surrounding fluid, said method comprising:
a) applying an electrical signal of known frequency and voltage to the sensor;
b) measuring the current through the sensor to determine the impedance at the known frequency;
c) repeating steps a) and b) over a range of frequencies to generate a set of impedance data; and d) fitting the measured impedance data to determine an a parameter which represents coupling strength.
Detailed Description of the Preferred Embodiments This invention is based on the measurement of phenomena based on imperfect acoustic coupling between the sensor surface and the liquid. The nature of this coupling determines the strength of the viscous loading and elastic effects depending on such parameters as the surface free energy and the molecular conformation of the sensor coating. These molecular parameters are very sensitive to chemical changes at the surface and therefore acoustic coupling provides a novel sensing mechanism.
The impedance measurements are carried out by applying an electrical signal of known frequency and voltage to the sensor and measuring the current through the sensor. Through Ohm's law, this provides the impedance at the known frequency. By performing this measurement over a range of frequencies, a set of data is generated. The above described, specifically selected parameters of LM, RM, C~1 and Co have been found to be the determining parameters for indicating a mass or conformation change at the TSM surface. Hence these parameters are fitted to the data.
While the Butterworth - van Dyke model provides useful information, it is an electrical analogy which presents the information unclearly. An alternate model of the TSM sensor is based on a solution of the equations of motion and electric fields. With this second model as set out in the aforementioned paper entitled "Molecular Slip At The Solid-Liquid Interface Of An Acoustic Wave Sensor" and "A Transverse Shear Model Of A Piezoelectric Chemical Sensor", the deposited mass and the coupling may be determined directly by fitting the electrical impedance data obtained as above. The coupling is represented by a slip parameter, a, which arises from a slip boundary condition used in solving the set of equations. The common approach is to assume perfect coupling and to set a = 1. In this invention, a is taken to be a complex number which is determined by fitting the measured impedance data.
The sensing process is understood to be occurring at the interface between the solid device and the liquid medium. Ligands for biological macromolecules include small molecules, ions, proteins, peptides, and strands of both DNA and RNA. The interaction of these entities with the biological molecules attached to the sensor will cause an alteration of the physical properties of the film resulting, in turn, in changes in the measured parameters.
These changes will very clearly result from a combination of some or all of the above response mechanisms particular for each chemical situation. In this regard, the dimensions of the newly bound ligand is an important consideration.
The signaling species coated onto the acoustic biosensor are proteins (antibodies, enzymes, hormones, molecular receptors, etc.) and nucleic acids oligonucleotides, DNA and RNA) attached to the device surface. These molecules exist in a highly hydrated form which can be considered to constitute very viscous gels.
The effect of viscous loading is the result of acoustic energy transfer to and from the surrounding medium. This in turn depends on the nature of the contact between the surface and the medium. The contact is controlled by such chemical properties as hydrogen bonding, dispersion interactions and interfacial charge. The process can be viewed as a drag existing between the surface coating and the liquid. a represents the coupling strength but also contains phase shift information. This provides additional information regarding relative mass of liquid molecules compared to those of the sensor surface and when correlated with the selected Butterworth - van Dyke model provide a determination on what is happening at the TSM surface, namely, mass and/or molecular structural shift or change in conformation.
There are several mechanisms whereby a TSM sensor responds to chemical change on its surface when it is immersed in a liquid. Surface mass deposition occurs when the analyte binds to the receptor on the sensor surface.
This increases the storage of acoustic energy through the inertia of the added mass. Acoustic energy may also be stored through the elastic deformation of a coating on the surface. The elasticity of the coating may also change when the analyte binds to the receptor coating. These energy storage modes determine the resonant characteristics of the sensor which can easily be measured electrically. These processes are well known. Examples of piezoelectric sensors are described, for example in U.S. Patents 5,374,521 and 5,658,732.
Viscous loading occurs when acoustic energy is transferred to the liquid.
Some of the acoustic energy is stored by the inertia of the fluid moving with the sensor surface and can be transferred back to the sensor, but acoustic energy is also dissipated by internal friction within the fluid. The viscous loading effect is also well known, however in the current use of this effect, the transfer of acoustic energy at the surface is considered to be perfect, that is, there is no slip between the sensor surface and the adjacent fluid molecules.
The current practice is based on the well known Butterworth - van Dyke model of a piezoelectric resonator which consists of a resistor, inductor and capacitor in series, all in parallel with another capacitor. The series arm of this network is called the motional arm. Further details of this model and the calculation of the following parameters may be found in the above paper entitled "Rheological and Interfacial Properties of Nucleic Acid Films Studies by Thickness-Shear Mode Sensor and Network Analysis".
Motional Inductance The motional inductance, LM, represents the inertial energy stored by the sensor. It depends on the mass of the TSM sensor as well as the mass of material (the analyte) added to the surface. Since liquid coupled to the surface can store and return acoustic energy, LM is also dependent on the viscosity of the liquid.
Motional Resistance The motional resistance, RM, is intrinsically related to the energy dissipated by the sensor.
Accordingly, any imposition of material (or loss of material) that has a viscous property or changes in the viscosity of the liquid will result in a change in the energy dissipation and hence RM.
Motional Capacitance The motional capacitance, C;~, represents the elastic energy stored by the sensor. The absorption or chemical binding of the analyte to the coating can have a large effect on the viscoelastic properties of the coating. Depending on the thickness, an added (or removed) layer of material may change the elasticity of the sensor and thus affect CM. Although most fluids are considered to be viscous, at the high frequencies used in piezoelectric quartz sensors, the liquid may also have elastic properties.
Static Capacitance The static capacitance Co represents the dielectric constant of the quartz, but includes that of the medium through the electric field. Charge interactions between the analyte and the sensor coating will affect this value.
Summary of the Invention According to an aspect of the invention, there is provided a process for sensing biological or chemical changes in molecular structural shape or mass of molecules attached to the surface of a transverse shear piezoelectric oscillating molecular sensing device driven by a network analyzer, said process compnsmg:
i) exciting said sensor device at a series of predetermined frequencies;
~i) collecting data to determine values for the predetermined parameters of series resonance frequency shift (f5), motional resistance (RM), motional inductance (LM), motional capacitance (CM), electrostatic capacitance (Co) and boundary layer slip parameter (a); and iii) determining relative changes in said measured parameters to detect thereby any changes in molecular structural shape or mass at sensing device surface.
In accordance with another aspect of the invention there is provided a method of determining the efficiency of acoustic coupling between a sensor and the surrounding fluid, said method comprising:
a) applying an electrical signal of known frequency and voltage to the sensor;
b) measuring the current through the sensor to determine the impedance at the known frequency;
c) repeating steps a) and b) over a range of frequencies to generate a set of impedance data; and d) fitting the measured impedance data to determine an a parameter which represents coupling strength.
Detailed Description of the Preferred Embodiments This invention is based on the measurement of phenomena based on imperfect acoustic coupling between the sensor surface and the liquid. The nature of this coupling determines the strength of the viscous loading and elastic effects depending on such parameters as the surface free energy and the molecular conformation of the sensor coating. These molecular parameters are very sensitive to chemical changes at the surface and therefore acoustic coupling provides a novel sensing mechanism.
The impedance measurements are carried out by applying an electrical signal of known frequency and voltage to the sensor and measuring the current through the sensor. Through Ohm's law, this provides the impedance at the known frequency. By performing this measurement over a range of frequencies, a set of data is generated. The above described, specifically selected parameters of LM, RM, C~1 and Co have been found to be the determining parameters for indicating a mass or conformation change at the TSM surface. Hence these parameters are fitted to the data.
While the Butterworth - van Dyke model provides useful information, it is an electrical analogy which presents the information unclearly. An alternate model of the TSM sensor is based on a solution of the equations of motion and electric fields. With this second model as set out in the aforementioned paper entitled "Molecular Slip At The Solid-Liquid Interface Of An Acoustic Wave Sensor" and "A Transverse Shear Model Of A Piezoelectric Chemical Sensor", the deposited mass and the coupling may be determined directly by fitting the electrical impedance data obtained as above. The coupling is represented by a slip parameter, a, which arises from a slip boundary condition used in solving the set of equations. The common approach is to assume perfect coupling and to set a = 1. In this invention, a is taken to be a complex number which is determined by fitting the measured impedance data.
The sensing process is understood to be occurring at the interface between the solid device and the liquid medium. Ligands for biological macromolecules include small molecules, ions, proteins, peptides, and strands of both DNA and RNA. The interaction of these entities with the biological molecules attached to the sensor will cause an alteration of the physical properties of the film resulting, in turn, in changes in the measured parameters.
These changes will very clearly result from a combination of some or all of the above response mechanisms particular for each chemical situation. In this regard, the dimensions of the newly bound ligand is an important consideration.
The signaling species coated onto the acoustic biosensor are proteins (antibodies, enzymes, hormones, molecular receptors, etc.) and nucleic acids oligonucleotides, DNA and RNA) attached to the device surface. These molecules exist in a highly hydrated form which can be considered to constitute very viscous gels.
The effect of viscous loading is the result of acoustic energy transfer to and from the surrounding medium. This in turn depends on the nature of the contact between the surface and the medium. The contact is controlled by such chemical properties as hydrogen bonding, dispersion interactions and interfacial charge. The process can be viewed as a drag existing between the surface coating and the liquid. a represents the coupling strength but also contains phase shift information. This provides additional information regarding relative mass of liquid molecules compared to those of the sensor surface and when correlated with the selected Butterworth - van Dyke model provide a determination on what is happening at the TSM surface, namely, mass and/or molecular structural shift or change in conformation.
Example The human immunodeficiency virus type I (HIV-I) is strongly regulated at the transcriptional level by the interaction of an 86-amino acid protein, Tat, with the trans activation responsive element at the 5' -end of the viral messenger RNA transcript (TAR). The TAR-Tat system is an important target for drug discovery research because the binding of the regulatory protein to TAR can be blocked by small molecules.
In this application we compute the slip parameter a , for the binding of Tat-derived peptides to TAR immobilized on a sensor surface. The TAR RNA
is synthesized, with a biotin moiety at the 5' -end, on a DNA synthesizer by standard phosphoramidite chemistry. The acoustic wave sensor is incorporated into a flow-through configuration and electrically connected to an acoustic network analyzer. A dispersion of 100-500 ~l of the reagent neutravidin is injected into the apparatus and the protein adsorbs to the gold electrode surface of the acoustic wave sensor. A dispersion of biotinylated TAR- RNA ( 100-500 ~1) is introduced into the system where the formation of the biotin-avidin complex results in attachment of TAR to the sensor surface. Various Tat-derived peptides are then introduced into the flow-trough system. In this particular application the following peptides are specified: tat,2, tatzo, and tat3o where the subscript refers to the number of amino acids in the peptide.
Dispersions of peptide (100-500 ~.1) are injected into the system. On binding of peptide to TAR in real time transient responses in the aforementioned parameters are obtained. The computed ~ parameter for the various responses, which distinguishes the nature on binding, are as follows:
Tat,, baseline 1.978 @20.85 degrees signal 1.964 @ 20.97 degrees Tat2obaseline 1.985 @21.42 degrees signal 1.926@ 18.15 degrees _7_ Tat3o baseline 1.982 @ 22.61 degrees signal 1.994 @ 23.03 degrees Tatl2 displays a small decrease in slip magnitude with an increase in phase, whereas tat,o shows large decreases in magnitude and phase. Tat3o depicts smaller increase in magnitude and phase.
Although preferred embodiments of the invention have been described herein in detail, it will be understood by those skilled in the art that variations may be made thereto without departing from the spirit of the invention or the scope of the appended claims.
_g_
In this application we compute the slip parameter a , for the binding of Tat-derived peptides to TAR immobilized on a sensor surface. The TAR RNA
is synthesized, with a biotin moiety at the 5' -end, on a DNA synthesizer by standard phosphoramidite chemistry. The acoustic wave sensor is incorporated into a flow-through configuration and electrically connected to an acoustic network analyzer. A dispersion of 100-500 ~l of the reagent neutravidin is injected into the apparatus and the protein adsorbs to the gold electrode surface of the acoustic wave sensor. A dispersion of biotinylated TAR- RNA ( 100-500 ~1) is introduced into the system where the formation of the biotin-avidin complex results in attachment of TAR to the sensor surface. Various Tat-derived peptides are then introduced into the flow-trough system. In this particular application the following peptides are specified: tat,2, tatzo, and tat3o where the subscript refers to the number of amino acids in the peptide.
Dispersions of peptide (100-500 ~.1) are injected into the system. On binding of peptide to TAR in real time transient responses in the aforementioned parameters are obtained. The computed ~ parameter for the various responses, which distinguishes the nature on binding, are as follows:
Tat,, baseline 1.978 @20.85 degrees signal 1.964 @ 20.97 degrees Tat2obaseline 1.985 @21.42 degrees signal 1.926@ 18.15 degrees _7_ Tat3o baseline 1.982 @ 22.61 degrees signal 1.994 @ 23.03 degrees Tatl2 displays a small decrease in slip magnitude with an increase in phase, whereas tat,o shows large decreases in magnitude and phase. Tat3o depicts smaller increase in magnitude and phase.
Although preferred embodiments of the invention have been described herein in detail, it will be understood by those skilled in the art that variations may be made thereto without departing from the spirit of the invention or the scope of the appended claims.
_g_
Claims (13)
1. A process for sensing a change in molecular structural shape of a molecule attached to the surface of a transverse shear piezoelectric sensing device driven by a network analyser, said process comprising:
i) exciting said sensing device at a series of predetermined frequencies;
ii) measuring electrical impedance of the sensing device at the predetermined frequencies by determining the overall parameters of series resonant frequency (Fs), motional resistance (Rm), motional inductance (Lm), motional capacitance (Cm) and static capacitance (Co); and iii) determining relative changes in electrical impedence over said series of predetermined frequencies indicative of a change in molecular structural shape of a molecule attached to the surface.
i) exciting said sensing device at a series of predetermined frequencies;
ii) measuring electrical impedance of the sensing device at the predetermined frequencies by determining the overall parameters of series resonant frequency (Fs), motional resistance (Rm), motional inductance (Lm), motional capacitance (Cm) and static capacitance (Co); and iii) determining relative changes in electrical impedence over said series of predetermined frequencies indicative of a change in molecular structural shape of a molecule attached to the surface.
2. The process according to claim 1 wherein the step of determining relative changes in electrical impedence comprises the steps of:
a) determining the boundary layer slip parameter (a) from the overall parameters;
b) determining relative changes in the boundary layer slip parameter (a) to detect changes in energy coupling indicative of changes in the molecular structural shape of a molecule attached to the surface; and c) correlating said changes in a with a calibrated set of data to determine the molecular structural shape of a molecule attached to the surface.
a) determining the boundary layer slip parameter (a) from the overall parameters;
b) determining relative changes in the boundary layer slip parameter (a) to detect changes in energy coupling indicative of changes in the molecular structural shape of a molecule attached to the surface; and c) correlating said changes in a with a calibrated set of data to determine the molecular structural shape of a molecule attached to the surface.
3. The process according to claim 1 or 2 wherein a change in the boundary layer slip parameter (a) and an essentially zero change in the series resonant frequency (Fs) indicates a change in the molecular structural shape of a molecule attached to the surface and essentially zero change in mass.
4. The process according to claims 1 and 2 wherein changes in molecular structural shape are generated by an interaction between a molecule attached to the surface of the sensing device and an entity in a surrounding liquid medium.
5. The process according to claim 4 wherein said molecule is selected from the group consisting of proteins and nucleic acids.
6. The process according to claim 5 wherein said proteins are selected from the group consisting of antibodies, enzymes, molecular receptors, receptor ligands and polypeptides.
7. The process according to claim 5 wherein said nucleic acids are selected from the group consisting of DNA, RNA and oligonucleotides.
8. The process according to claim 4 wherein said entities in said surrounding liquid medium are selected from the group consisting of proteins and nucleic acids.
9. The process according to claim 8 wherein said proteins are selected from the group consisting of antibodies, enzymes, molecular receptors, receptor ligands and polypeptides.
10. The process according to claim 8 wherein said nucleic acids are selected from the group consisting of DNA, RNA and oligonucleotides.
11. A process for detecting a change in conformation of a molecule attached to the surface of a transverse shear piezoelectric sensor, said change in conformation being imposed by interaction of said molecule with an entity in a fluid; said process comprising the steps of:
a) contacting the molecule with a fluid suspected to contain an entity capable of changing the conformation of the molecule;
b) exciting the sensor at a series of predetermined frequencies;
c) measuring electrical impedance of the sensor at the predetermined frequencies by determining the overall parameters of series resonant frequency (Fs), motional resistance (Rm), motional inductance (Lm), motional capacitance (Cm) and static capacitance (Co);
d) determining the boundary layer slip parameter (a) from the electrical impedance determined from the overall parameters;
e) determining relative changes in the boundary layer slip parameter (a) to detect changes in energy coupling indicative of a change in the conformation of the molecule;
f) correlating changes in the boundary layer slip parameter (a) with data obtained using calibrated quantities of the entity in the fluid; and g) determining a change in conformation of the molecule attributable to interaction with the entity in the fluid.
a) contacting the molecule with a fluid suspected to contain an entity capable of changing the conformation of the molecule;
b) exciting the sensor at a series of predetermined frequencies;
c) measuring electrical impedance of the sensor at the predetermined frequencies by determining the overall parameters of series resonant frequency (Fs), motional resistance (Rm), motional inductance (Lm), motional capacitance (Cm) and static capacitance (Co);
d) determining the boundary layer slip parameter (a) from the electrical impedance determined from the overall parameters;
e) determining relative changes in the boundary layer slip parameter (a) to detect changes in energy coupling indicative of a change in the conformation of the molecule;
f) correlating changes in the boundary layer slip parameter (a) with data obtained using calibrated quantities of the entity in the fluid; and g) determining a change in conformation of the molecule attributable to interaction with the entity in the fluid.
12. The process of claim 11 wherein a change in the conformation of a molecule comprises a change in mass or a change in shape.
13. The process of claim 11 wherein said fluid flows through a chamber to contact the molecule bound to the sensor, and wherein step f) comprises correlating the boundary layer slip parameter (a) for:
(i) a baseline value of a for fluid without said entity; and (ii) a test value of a for fluid containing said entity.
(i) a baseline value of a for fluid without said entity; and (ii) a test value of a for fluid containing said entity.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US15671499P | 1999-09-30 | 1999-09-30 | |
| US60/156,714 | 1999-09-30 | ||
| PCT/CA2000/001139 WO2001023892A1 (en) | 1999-09-30 | 2000-09-29 | Traverse shear mode piezoelectric chemical sensor |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2386006A1 true CA2386006A1 (en) | 2001-04-05 |
Family
ID=22560754
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002386006A Abandoned CA2386006A1 (en) | 1999-09-30 | 2000-09-29 | Traverse shear mode piezoelectric chemical sensor |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP1221049A1 (en) |
| AU (1) | AU7502100A (en) |
| CA (1) | CA2386006A1 (en) |
| WO (1) | WO2001023892A1 (en) |
Families Citing this family (10)
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|---|---|---|---|---|
| KR100442822B1 (en) | 2001-10-23 | 2004-08-02 | 삼성전자주식회사 | Methods for detecting binding of biomolecules using shear stress measurements |
| EP1517140A3 (en) * | 2003-03-19 | 2005-04-06 | TF Instruments GmbH | Method and device for diagnostic investigation of biological samples |
| WO2005066092A2 (en) * | 2003-12-30 | 2005-07-21 | 3M Innovative Properties Company | Acoustic sensors and methods |
| US7943388B2 (en) | 2003-11-14 | 2011-05-17 | 3M Innovative Properties Company | Acoustic sensors and methods |
| US7342082B2 (en) | 2004-12-17 | 2008-03-11 | 3M Innovative Properties Company | Soluble polymers as amine capture agents and methods |
| US7402678B2 (en) | 2004-12-17 | 2008-07-22 | 3M Innovative Properties Company | Multifunctional amine capture agents |
| US7544755B2 (en) | 2005-09-30 | 2009-06-09 | 3M Innovative Properties Company | Crosslinked polymers with amine binding groups |
| US7544754B2 (en) | 2005-09-30 | 2009-06-09 | 3M Innovative Properties Company | Crosslinked polymers with amine binding groups |
| US7544756B2 (en) | 2005-09-30 | 2009-06-09 | 3M Innovative Properties Company | Crosslinked polymers with amine binding groups |
| GB0705088D0 (en) * | 2007-03-16 | 2007-04-25 | Akubio Ltd | Improvements in or relating to detection and/or characterisation of aggregates |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US4735906A (en) * | 1984-11-28 | 1988-04-05 | Texas A&M University | Sensor having piezoelectric crystal for microgravimetric immunoassays |
| US5306644A (en) * | 1988-09-29 | 1994-04-26 | Hewlett-Packard Company | Mass sensor method for measuring analytes in a sample |
| DE69010506T2 (en) * | 1989-10-04 | 1994-12-22 | Du Pont | DETERMINATION METHOD FOR BIOLOGICAL TARGET COMPLEXES ON THE SURFACE OF A BIOSENSOR. |
| US5374521A (en) * | 1991-09-17 | 1994-12-20 | Kipling; Arlin L. | Acoustic reflection process for molecular sensing using a bulk acoustic wave quartz sensor |
| JPH10115648A (en) * | 1996-10-11 | 1998-05-06 | Advantest Corp | Measuring method for equivalent circuit constant of piezoelectric vibrator |
-
2000
- 2000-09-29 CA CA002386006A patent/CA2386006A1/en not_active Abandoned
- 2000-09-29 AU AU75021/00A patent/AU7502100A/en not_active Abandoned
- 2000-09-29 EP EP00963840A patent/EP1221049A1/en not_active Withdrawn
- 2000-09-29 WO PCT/CA2000/001139 patent/WO2001023892A1/en not_active Application Discontinuation
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| Publication number | Publication date |
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| EP1221049A1 (en) | 2002-07-10 |
| WO2001023892A1 (en) | 2001-04-05 |
| AU7502100A (en) | 2001-04-30 |
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