Sensor arrangement and method for operating a sensor arrangement

• US 7,756,560 B2
• Filed: 12/02/2004
• Issued: 07/13/2010
• Est. Priority Date: 06/03/2002
• Status: Active Grant

• Current Assignee: Boehringer Ingelheim Vetmedica GmbH (C.H. Boehringer Sohn AG & Co. KG)
• Original Assignee: Siemens AG
• Inventors: Thewes, Roland, Frey, Alexander, Paulus, Christian, Schienle, Meinrad
• Primary Examiner(s): Mallari; Patricia C
• Assistant Examiner(s): Toth; Karen E
• Application Number:
  US11/002,736
• Publication Number:
  US 20050194250A1
• Time in Patent Office: 2,049 Days
• Field of Search: None
• US Class Current: 600/345
• CPC Class Codes: C12M 1/00 Apparatus for enzymology or microbiology
• CPC Class Codes: C12Q 1/6837 using probe arrays or probe chips C12Q1/6874 takes precedence
• CPC Class Codes: C12Q 2565/607 being a sensor, e.g. electrode
• CPC Class Codes: G01N 1/00 Sampling; Preparing specimens for investigation
• CPC Class Codes: G01N 27/3276 being a hybridisation with immobilised receptors using a FET type sensor G01N27/4145; concerning the hybridisation C12Q1/68

Abstract

Sensor arrangement having capture molecules immobilized on any of three sensor electrodes, wherein molecules to be detected can hybridize with the capture molecules; a control circuit for applying a first electrical signal to a selected sensor electrode and simultaneously applying a second electrical signal to at least two of the other sensor electrodes; a detection device, wherein in a first operating state a reference liquid is introduced into the sensor arrangement and a reference value of an electrical signal is detected at the selected sensor electrode, and in a second operating state an analyte possibly having molecules to be detected is introduced into the sensor arrangement and a sensor value of the electrical signal is detected at the selected sensor electrode; and an evaluation circuit, which, on the basis of the reference value and the sensor value, determines whether a hybridization event has taken place at the selected sensor electrode.

Claims

1. A sensor arrangement, set up as an integrated circuit, comprising:

a substrate;

at least three sensor electrodes arranged on the substrate such that, in an operating state in which an electrically conductive substance is introduced into the sensor arrangement, the sensor electrodes are coupled to one another by means of the electrically conductive substance;

capture molecules immobilized on at least a portion of the sensor electrodes, wherein molecules to be detected can hybridize with the capture molecules;

a control circuit for applying a first electrical signal to a selected sensor electrode and simultaneously applying a second electrical signal to at least two of the other sensor electrodes, the first electrical signal being a first temporally variable electrical signal and/or the second electrical signal being a second temporally variable electrical signal;

a detection device, which is set up such that,

in a first operating state, in which a reference liquid is introduced into the sensor arrangement, a reference value of a third temporally variable electrical signal resulting from the first temporally variable electrical signal and/or from the second temporally variable electrical signal is detected at the selected sensor electrode; and

in a second operating state, in which an analyte possibly having molecules to be detected is introduced into the sensor arrangement, a sensor value of the third temporally variable electrical signal resulting from the first temporally variable electrical signal and/or from the second temporally variable electrical signal is detected at the selected sensor electrode; and

an evaluation circuit, which, on the basis of the reference value and the sensor value, determines whether a hybridization event has taken place at the selected sensor electrode,

wherein the evaluation circuit determines, based on the reference value and the sensor value of the third temporally variable electrical signal and based on the first and/or second temporally variable electrical signal, the value of the capacitance between the selected sensor electrode and an electrically conductive substance introduced into the sensor arrangement in the first operating state and in the second operating state, and

wherein the evaluation circuit determines, for at least a portion of the sensor electrodes, whether hybridization events have taken place at the selected sensor electrode and/or the quantity in which hybridization events have taken place at the selected sensor electrode, by determining the values β

(i,j)C_array(i,j) for the first and second operating states from the system of equations

$C_{\mathrm{meas}}<br><br>\left(n,m\right)=\mathrm{\beta <br><br>}<br><br>\left(n,m\right)<br><br>C_{\mathrm{array}}<br><br>\left(n,m\right)\times <br><br>\left[1-\frac{\mathrm{\beta <br><br>}<br><br>\left(n,m\right)<br><br>C_{\mathrm{array}}<br><br>\left(n,m\right)}{\underset{x=1}{\overset{N}{\sum <br><br>}}<br><br>\underset{y=1}{\overset{M}{\sum <br><br>}}<br><br>\mathrm{\beta <br><br>}<br><br>\left(x,y\right)<br><br>C_{\mathrm{array}}<br><br>\left(x,y\right)}\right]$

where n,m are indices of a selected sensor electrode in the cell array;

where x,y are indices of the sensor electrodes in the cell array;

where N*M is the number of sensor electrodes in the cell array;

where C_array(i,j) is the value of the capacitance between the sensor electrode having the indices i,j and the reference liquid in the first operating state;

where β

(i,j)C_array(i,j) is the value of the capacitance between the sensor electrode having the indices i,j and the analyte in the second operating state; and

where C_meas(n,m) is the value of the capacitance determined between the selected sensor electrode having the indices n,m and an electrically conductive substance introduced into the sensor arrangement.

2. The sensor arrangement as claimed in claim 1, which determines, for at least a portion of the sensor electrodes, sequentially in each case for a selected sensor electrode whether a hybridization event has taken place at the respectively selected sensor electrode.

3. The sensor arrangement as claimed in claim 2, which determines, for each selected sensor electrode, the quantity in which hybridization events have taken place at the selected sensor electrode.

4. The sensor arrangement as claimed in claim 1, wherein the sensor electrodes are arranged essentially in matrix form on the surface of the substrate.

5. The sensor arrangement as claimed in claim 1, wherein the sensor electrodes are grouped to form a plurality of sensor groups such that each sensor group can optionally be operated separately from the other sensor groups or jointly with at least a portion of the other sensor groups.

6. The sensor arrangement as claimed in claim 1, wherein at least one sensor electrode is square, rectangular, circular, elliptical, honeycomb-shaped, octagonal, or composed of a plurality of non-contiguous regions.

7. The sensor arrangement as claimed in claim 1, wherein the substrate is a ceramic substrate, a silicon substrate, a glass substrate, or a plastic substrate.

8. The sensor arrangement as claimed in claim 1, wherein

the first and/or the second temporally variable electrical signal is a temporally variable electrical voltage and the third temporally variable electrical signal is a temporally variable electric current;

or

the first and/or the second temporally variable electrical signal is a temporally variable electric current and the third temporally variable electrical signal is a temporally variable electrical voltage.

9. The sensor arrangement as claimed in claim 1, wherein a time dependence of the first and/or of the second temporally variable electrical signal and/or a time dependence of the third temporally variable electrical signal is a mathematical sine function, rectangular function, sawtooth function, triangular function, or step function.

10. The sensor arrangement as claimed in claim 1, wherein in the control circuit

the first electrical signal is a first temporally variable electrical signal and the second electrical signal is a constant reference potential;

or

the second electrical signal is a second temporally variable electrical signal and the first electrical signal is a constant reference potential;

or

the first electrical signal is a first temporally variable electrical signal, the second electrical signal is a second temporally variable electrical signal, the first and second temporally variable electrical signals being in antiphase with respect to one another.

11. The sensor arrangement as claimed in claim 10, wherein the electrical reference potential is the ground potential or a time average value of the first or of the second temporally variable electrical signal.

12. The sensor arrangement as claimed in claim 1, wherein the reference liquid is a different liquid than the analyte and is free of molecules to be detected.

13. The sensor arrangement as claimed in claim 1, wherein the reference liquid is the analyte, and in the sensor arrangement

the first operating state is a first time period, in which essentially no hybridization events have taken place;

and

the second operating state is a second time period, temporally after the first time period, in which essentially all hybridization events have taken place.

14. The sensor arrangement as claimed in claim 1, further comprising an analog/digital converter circuit, which is integrated in the substrate, for converting an analog temporally variable electrical signal into a digital signal and providing the digital signal to the evaluation circuit.

15. The sensor arrangement as claimed in claim 1, further comprising an external supply unit, which provides the control circuit with electrical voltage signals and/or electric current signals.

16. The sensor arrangement as claimed in claim 15, further comprising a digital/analog converter circuit, which is integrated in the substrate, for converting a digital voltage signal and/or current signal of the external supply unit into an analog signal and providing the analog signal to the control circuit.

17. The sensor arrangement as claimed in claim 1, further comprising a selection circuit, which is integrated in the substrate, for sequentially selecting in each case one of the sensor electrodes.

18. The sensor arrangement as claimed in claim 1, wherein different capture molecules are immobilized on different sensor electrodes.

19. The sensor arrangement as claimed in claim 1, set up as a biosensor arrangement.

20. The sensor arrangement as claimed in claim 1, wherein the evaluation circuit determines, based on the reference value and the sensor value of the third temporally variable electrical signal and based on the first and/or second temporally variable electrical signal, the value of the impedance between the selected sensor electrode and an electrically conductive substance introduced into the sensor arrangement in the first operating state and in the second operating state.

21. The sensor arrangement as claimed in claim 1, wherein the evaluation circuit determines, based on the quotient of the values of the capacitance between the selected sensor electrode and an electrically conductive substance introduced into the sensor arrangement in the first operating state and in the second operating state, whether hybridization events have taken place at the selected sensor electrode and/or the quantity in which hybridization events have taken place at the selected sensor electrode.

22. The sensor arrangement as claimed in claim 1, wherein when the evaluation circuit is determining the values β

(i,j)C_array(i,j), the evaluation circuit uses at least one of the following approximations;

$N*M<br><br><br><br>1;<br><br>\mathrm{and}<br><br><br><br>\underset{x=1}{\overset{N}{\sum <br><br>}}<br><br>\underset{y=1}{\overset{M}{\sum <br><br>}}<br><br>\mathrm{\beta <br><br>}<br><br>\left(x,y\right)<br><br>C_{\mathrm{array}}<br><br>\left(x,y\right)<br><br><br><br>\mathrm{\beta <br><br>}<br><br>\left(n,m\right)<br><br>C_{\mathrm{array}}<br><br>\left(n,m\right).$

23. A method for operating a sensor arrangement, comprising:

providing a sensor arrangement, set up as an integrated circuit, having;

a substrate;

at least three sensor electrodes arranged on the substrate such that, in an operating state in which an electrically conductive substance is introduced into the sensor arrangement, the sensor electrodes are coupled to one another by means of the electrically conductive substance;

capture molecules immobilized on at least a portion of the sensor electrodes, wherein molecules to be detected can hybridize with the capture molecules;

a control circuit;

a detection device; and

an evaluation circuit;

the control circuit applying a first electrical signal to a selected sensor electrode and simultaneously applying a second electrical signal to at least two of the other sensor electrodes, the first electrical signal being a first temporally variable electrical signal and/or the second electrical signal being a second temporally variable electrical signal;

in a first operating state, in which a reference liquid is introduced into the sensor arrangement, the detector device detecting at the selected sensor electrode a reference value of a third temporally variable electrical signal resulting from the first temporally variable electrical signal and/or from the second temporally variable electrical signal;

in a second operating state, in which an analyte possibly having molecules to be detected is introduced into the sensor arrangement, the detector device detecting at the selected sensor electrode, a sensor value of a third temporally variable electrical signal resulting from the first temporally variable electrical signal and/or from the second temporally variable electrical signal; and

the evaluation circuit determining, on the basis of the reference value and the sensor value, whether a hybridization event has taken place at the selected sensor electrode,

wherein the evaluation circuit determines, based on the reference value and the sensor value of the third temporally variable electrical signal and based on the first and/or second temporally variable electrical signal, the value of the capacitance between the selected sensor electrode and an electrically conductive substance introduced into the sensor arrangement in the first operating state and in the second operating state, and

wherein the evaluation circuit determines, for at least a portion of the sensor electrodes, whether hybridization events have taken place at the selected sensor electrode and/or the quantity in which hybridization events have taken place at the selected sensor electrode, by determining the values β

(i,j)C_array(i,j) for the first and second operating states from the system of equations

$C_{\mathrm{meas}}<br><br>\left(n,m\right)=\mathrm{\beta <br><br>}<br><br>\left(n,m\right)<br><br>C_{\mathrm{array}}<br><br>\left(n,m\right)\times <br><br>\left[1-\frac{\mathrm{\beta <br><br>}<br><br>\left(n,m\right)<br><br>C_{\mathrm{array}}<br><br>\left(n,m\right)}{\underset{x=1}{\overset{N}{\sum <br><br>}}<br><br>\underset{y=1}{\overset{M}{\sum <br><br>}}<br><br>\mathrm{\beta <br><br>}<br><br>\left(x,y\right)<br><br>C_{\mathrm{array}}<br><br>\left(x,y\right)}\right]$

where n,m are indices of a selected sensor electrode in the cell array;

where x,y are indices of the sensor electrodes in the cell array;

where N*M is the number of sensor electrodes in the cell array;

where C_array(i,j) is the value of the capacitance between the sensor electrode having the indices i,j and the reference liquid in the first operating state;

where β

(i,j)C_array(i,j) is the value of the capacitance between the sensor electrode having the indices i,j and the analyte in the second operating state; and

where C_meas(n,m) is the value of the capacitance determined between the selected sensor electrode having the indices n,m and an electrically conductive substance introduced into the sensor arrangement.

24. The method as claimed in claim 23, wherein the reference liquid is essentially the same substance as the analyte, except that the reference liquid is free of molecules to be detected.

25. A sensor arrangement, set up as an integrated circuit, comprising:

a substrate;

at least three sensor electrodes arranged on the substrate such that, in an operating state in which an electrically conductive substance is introduced into the sensor arrangement, the sensor electrodes are coupled to one another by means of the electrically conductive substance;

capture molecules immobilized on at least a portion of the sensor electrodes, wherein molecules to be detected can hybridize with the capture molecules;

a control means for applying a first electrical signal to a selected sensor electrode and simultaneously applying a second electrical signal to at least two of the other sensor electrodes, the first electrical signal being a first temporally variable electrical signal and/or the second electrical signal being a second temporally variable electrical signal;

a detection means, which is set up such that,

in a first operating state, in which a reference liquid is introduced into the sensor arrangement, a reference value of a third temporally variable electrical signal resulting from the first temporally variable electrical signal and/or from the second temporally variable electrical signal is detected at the selected sensor electrode; and

in a second operating state, in which an analyte possibly having molecules to be detected is introduced into the sensor arrangement, a sensor value of the third temporally variable electrical signal resulting from the first temporally variable electrical signal and/or from the second temporally variable electrical signal is detected at the selected sensor electrode; and

an evaluation means, which, on the basis of the reference value and the sensor value, determines whether a hybridization event has taken place at the selected sensor electrodes,

wherein the evaluation circuit determines, based on the reference value and the sensor value of the third temporally variable electrical signal and based on the first and/or second temporally variable electrical signal, the value of the capacitance between the selected sensor electrode and an electrically conductive substance introduced into the sensor arrangement in the first operating state and in the second operating state, and

wherein the evaluation circuit determines, for at least a portion of the sensor electrodes, whether hybridization events have taken place at the selected sensor electrode and/or the quantity in which hybridization events have taken place at the selected sensor electrode, by determining the values β

(i,j)C_array(i,j) for the first and second operating states from the system of equations

$C_{\mathrm{meas}}<br><br>\left(n,m\right)=\mathrm{\beta <br><br>}<br><br>\left(n,m\right)<br><br>C_{\mathrm{array}}<br><br>\left(n,m\right)\times <br><br>\left[1-\frac{\mathrm{\beta <br><br>}<br><br>\left(n,m\right)<br><br>C_{\mathrm{array}}<br><br>\left(n,m\right)}{\underset{x=1}{\overset{N}{\sum <br><br>}}<br><br>\underset{y=1}{\overset{M}{\sum <br><br>}}<br><br>\mathrm{\beta <br><br>}<br><br>\left(x,y\right)<br><br>C_{\mathrm{array}}<br><br>\left(x,y\right)}\right]$

where n,m are indices of a selected sensor electrode in the cell array;

where x,y are indices of the sensor electrodes in the cell array;

where N*M is the number of sensor electrodes in the cell array;

where C_array(i,j) is the value of the capacitance between the sensor electrode having the indices i,j and the reference liquid in the first operating state;

where β

(i,j)C_array(i,j) is the value of the capacitance between the sensor electrode having the indices i,j and the analyte in the second operating state; and

where C_meas(n,m) is the value of the capacitance determined between the selected sensor electrode having the indices n,m and an electrically conductive substance introduced into the sensor arrangement.

26. A method for operating a sensor arrangement, which set up as an integrated circuit, and has a substrate, at least three sensor electrodes arranged on the substrate such that, in an operating state in which an electrically conductive substance is introduced into the sensor arrangement, the sensor electrodes are coupled to one another by means of the electrically conductive substance, capture molecules immobilized on at least a portion of the sensor electrodes, wherein molecules to be detected can hybridize with the capture molecules, a control circuit, a detection device, and an evaluation circuit, the method comprising:

the control circuit applying a first electrical signal to a selected sensor electrode and simultaneously applying a second electrical signal to at least two of the other sensor electrodes, the first electrical signal being a first temporally variable electrical signal and/or the second electrical signal being a second temporally variable electrical signal;

in a first operating state, in which a reference liquid is introduced into the sensor arrangement, the detector device detecting at the selected sensor electrode a reference value of a third temporally variable electrical signal resulting from the first temporally variable electrical signal and/or from the second temporally variable electrical signal;

in a second operating state, in which an analyte possibly having molecules to be detected is introduced into the sensor arrangement, the detector device detecting at the selected sensor electrode, a sensor value of a third temporally variable electrical signal resulting from the first temporally variable electrical signal and/or from the second temporally variable electrical signal; and

the evaluation circuit determining, on the basis of the reference value and the sensor value, whether a hybridization event has taken place at the selected sensor electrode,

wherein the evaluation circuit determines, based on the reference value and the sensor value of the third temporally variable electrical signal and based on the first and/or second temporally variable electrical signal, the value of the capacitance between the selected sensor electrode and an electrically conductive substance introduced into the sensor arrangement in the first operating state and in the second operating state, and

wherein the evaluation circuit determines, for at least a portion of the sensor electrodes, whether hybridization events have taken place at the selected sensor electrode and/or the quantity in which hybridization events have taken place at the selected sensor electrode, by determining the values β

(i,j)C_array(i,j) for the first and second operating states from the system of equations

$C_{\mathrm{meas}}<br><br>\left(n,m\right)=\mathrm{\beta <br><br>}<br><br>\left(n,m\right)<br><br>C_{\mathrm{array}}<br><br>\left(n,m\right)\times <br><br>\left[1-\frac{\mathrm{\beta <br><br>}<br><br>\left(n,m\right)<br><br>C_{\mathrm{array}}<br><br>\left(n,m\right)}{\underset{x=1}{\overset{N}{\sum <br><br>}}<br><br>\underset{y=1}{\overset{M}{\sum <br><br>}}<br><br>\mathrm{\beta <br><br>}<br><br>\left(x,y\right)<br><br>C_{\mathrm{array}}<br><br>\left(x,y\right)}\right]$

where n,m are indices of a selected sensor electrode in the cell array;

where x,y are indices of the sensor electrodes in the cell array;

where N*M is the number of sensor electrodes in the cell array;

where C_array(i,j) is the value of the capacitance between the sensor electrode having the indices i,j and the reference liquid in the first operating state;

where β

(i,j)C_array(i,j) is the value of the capacitance between the sensor electrode having the indices i,j and the analyte in the second operating state; and

where C_meas(n,m) is the value of the capacitance determined between the selected sensor electrode having the indices n,m and an electrically conductive substance introduced into the sensor arrangement.