Monolithically integrated hybridisation sensor assembly and associated production method

• US 9,645,106 B2
• Filed: 06/27/2005
• Issued: 05/09/2017
• Est. Priority Date: 06/29/2004
• Status: Active Grant

• Current Assignee: Boehringer Ingelheim Vetmedica GmbH (C.H. Boehringer Sohn AG & Co. KG)
• Original Assignee: Boehringer Ingelheim Vetmedica GmbH (C.H. Boehringer Sohn AG & Co. KG)
• Inventors: Augustyniak, Marcin, Paulus, Christian
• Primary Examiner(s): Beisner, William H
• Assistant Examiner(s): HENKEL, DANIELLE B
• Application Number:
  US11/630,964
• Publication Number:
  US 20070236224A1
• Time in Patent Office: 4,334 Days
• Field of Search: 435 6, 4352872
• 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

A monolithically integrated sensor assembly is for detecting molecules that are potentially contained in an analyte. The assembly includes: a substrate; at least one sensor electrode, which is located on or in the substrate and is coated with a sensor-active layer, on which electrochemically active particles are generated in the present of the molecules to be detected, the particles being detected via an electric sensor signal on the sensor electrode(s); at least one additional electrode that is located on or in the substrate; and an operating circuit that is integrated into the substrate for controlling the sensor electrode and the additional electrode(s).

Claims

1. A monolithically integrated sensor assembly configured for detecting DNA single strands possibly contained in an analyte, comprising:

a substrate;

at least one sensor electrode arranged at least one of on and in the substrate, and coated with a sensor-active layer at which are generated electrochemically active catcher DNA single strands in the presence of the DNA single strands to be detected, the electrochemically active catcher DNA single strands being detectable by producing an electrical sensor signal based on DNA single strands detected by the at least one sensor electrode;

a plurality of comparison electrodes, at which a plurality of electrical comparison signals independent of the electrical sensor signal is detected, wherein the plurality of comparison electrodes is configured for measuring the electrical comparison signal simultaneously with measurement of the electrical sensor signal detected by the at least one sensor electrode in the presence of the DNA single strands to be detected, and the electrical comparison signal is at least one selected from a background signal, a noise signal and a zero signal which do not originate from the sensor event; and

an operating circuit integrated at least one of on and in the substrate, and configured for driving the at least one sensor electrode, the operating circuit including at least one evaluation unit,

wherein said evaluation unit is configured to carry out a statistical averaging of the comparison signals detected from the plurality of comparison electrodes and to jointly evaluate the sensor signal and the statistical averaging of the comparison signals so as to eliminate undesirable disturbing contributions whereby detection sensitivity is increased, signal-to-noise ratio improved, and noise margin increased.

2. The monolithically integrated sensor assembly as claimed in claim 1, wherein the substrate is a CMOS chip.

3. The monolithically integrated sensor assembly as claimed in claim 1, wherein the monolithically integrated sensor assembly is at least one of a biosensor assembly and a chemosensor assembly.

4. The monolithically integrated sensor assembly as claimed in claim 1, wherein the at least one evaluation unit is configured for determining a difference between the electrical sensor signal and the statistical averaging of the electrical comparison signal.

5. The monolithically integrated sensor assembly as claimed in claim 1, wherein the at least one evaluation unit includes an operational amplifier, integrated in the substrate, and configured for processing both the electrical sensor signal and the electrical comparison signals.

6. The monolithically integrated sensor assembly as claimed in claim 5, wherein the operational amplifier is configured for integrating electrical charge carriers.

7. The monolithically integrated sensor assembly as claimed in claim 1, wherein at least one of the comparison electrodes is free of a sensor-active layer.

8. The monolithically integrated sensor assembly as claimed in claim 1, wherein at least one of the comparison electrodes includes a signaling coating configured for generating a determined quantity of the electrochemically active particles in the case of a determined change in an electrical potential, independently of the sensor event.

9. The monolithically integrated sensor assembly as claimed in claim 1, wherein the at least one sensor electrode and the plurality of comparison electrodes have an essentially identical geometry.

10. The monolithically integrated sensor assembly as claimed in claim 1, further comprising:

means for keeping constant electrical potentials at the at least one sensor electrode and at the plurality of comparison electrode.

11. The monolithically integrated sensor assembly as claimed in claim 10, wherein the means for keeping constant the electrical potentials includes at least one capacitance.

12. The monolithically integrated sensor assembly as claimed in claim 1, further comprising:

a subtraction capacitance configured to form the difference between the electrical sensor signal and the electrical comparison signal, a first terminal of the subtraction capacitance being coupled to the at least one sensor electrode, and a second terminal of the subtraction capacitance being coupled to the plurality of comparison electrode.

13. The monolithically integrated sensor assembly as claimed in claim 1, further comprising:

a first comparison electrode at which a zero signal is generated;

a second comparison electrode at which a full signal is generated.

14. The monolithically integrated sensor assembly as claimed in claim 1, further comprising:

an analog/digital converter configured for determining a digital output signal based on the electrical sensor signal and the plurality of electrical comparison signals.

15. The monolithically integrated sensor assembly as claimed in claim 13, further comprising:

an analog/digital converter configured for determining a digital output signal based on the electrical sensor signal and the electrical comparison signals, wherein the zero signal and the full signal form an upper and a lower electrical reference potential of the analog/digital converter.

21. The monolithically integrated sensor assembly as claimed in claim 1, further comprising at least one additional electrode coated with a sensor-active layer at which are generated other electrochemically active catcher DNA single strands in the presence of other DNA single strands to be detected that are different than the DNA single strands to be detected by the at least one sensor electrode, the other electrochemically active DNA single strands being detectable via detection of another electrical sensor signal at the at least one additional electrode.

24. The monolithically integrated sensor assembly as claimed in claim 1, wherein the operating circuit is adapted for autonomously operating the potentiostat circuit so as to stabilize the determined electrical potential measured in an electrolyte at a reference potential.

16. A sensor array, comprising a plurality of monolithically integrated sensor assemblies, each of which is formed at least one of on and in a substrate, each of the monolithically integrated sensor assemblies comprising:

at least one sensor electrode arranged at least one of on and in the substrate, and coated with a sensor-active layer at which are generated electrochemically active catcher DNA single strands in the presence of the DNA single strands to be detected, the electrochemically active catcher DNA single strands being detectable by producing an electrical sensor signal based on DNA single strands detected by the at least one sensor electrode; and

a plurality of comparison electrodes, at which a plurality of electrical comparison signals independent of the electrical sensor signal are detected, wherein the plurality of comparison electrodes is configured for measuring the electrical comparison signal simultaneously with measurement of the electrical sensor signal detected by the at least one sensor electrode in the presence of the DNA single strands to be detected, and the electrical comparison signal is at least one selected from a background signal, a noise signal and a zero signal which do not originate from the sensor event.

17. The sensor array as claimed in claim 16, wherein at least one of the comparison electrodes is provided jointly for at least one portion of the monolithically integrated sensor assemblies.

18. The sensor array as claimed in claim 16, further comprising:

a drive unit configured for selectively driving one of the monolithically integrated sensor assemblies, a portion of the monolithically integrated sensor assemblies or all of the monolithically integrated sensor assemblies.

20. The sensor array as claimed in claim 17, further comprising:

a drive unit configured for setting up to selectively drive one of the monolithically integrated sensor assemblies, a portion of the monolithically integrated sensor assemblies or all of the monolithically integrated sensor assemblies.

19. A method for producing a monolithically integrated sensor assembly configured for detecting DNA single strands possibly contained in an analyte, the method comprising:

forming, at least one of on and in a substrate, at least one sensor electrode coated with a sensor-active layer at which are generated electrochemically active catcher DNA single strands in the presence of the DNA single strands contained in the analyte to be detected, the electrochemically active catcher DNA single strands being detectable by producing an electrical sensor signal detected by the at least one sensor electrode;

forming at plurality of comparison electrode for producing a plurality of comparison signals from exposure to the analyte simultaneously with the electrical sensor signal detected by the at least one sensor electrode in the presence of the DNA single strands to be detected, the plurality of electrical comparison signals being at least one selected from a background signal, a noise signal and a zero signal which do not originate from the sensor event; and

integrating an operating circuit, configured for driving the at least one sensor electrode, the operating circuit including at least one evaluation unit by which a sensor event is determined at the at least one sensor electrode based on the electrical sensor signal and the plurality of electrical comparison signal,

wherein the comparison electrode lacks the sensor-active layer provided on the sensor electrode,

wherein the operating circuit is operative for producing statistical averaging of the plurality of the electrical comparison signals and a difference signal from the signals of the measuring electrode and the statistical averaging as a measurement signal which is free of undesirable disturbing contributions based on charge reversals of double-layer capacitances at the electrode surfaces.

22. The method as claimed in claim 19, further comprising at least one additional electrode coated with a sensor-active layer at which are generated other electrochemically active catcher DNA single strands in the presence of other DNA single strands to be detected that are different than the particles to be detected by the at least one sensor electrode, the other electrochemically active particles being detectable via detection of another electrical sensor signal at the at least one additional electrode.

23. The method as claimed in claim 19, further wherein the determined electrical potential is measured with respect to an electrolyte and the potentiostat circuit is autonomously operated so as to stabilize the electrical potential in the electrolyte at a reference potential.