Mass sensor method for measuring analytes in a sample

• US 5,306,644 A
• Filed: 04/01/1993
• Issued: 04/26/1994
• Est. Priority Date: 09/29/1988
• Status: Expired due to Fees

• Current Assignee: Agilent Technologies, Inc.
• Original Assignee: Hewlett-Packard Company (HP Inc.)
• Inventors: Baer, Richard L., Myerholtz, Carl A., Tom-Moy, May, Doherty, Thomas P., Spira-Solomon, Darlene J.
• Primary Examiner(s): Housel, James C.
• Assistant Examiner(s): Cano, Milton I.
• Application Number:
  US08/041,662
• Time in Patent Office: 390 Days
• Field of Search: 73/61.45, 73/61.49, 310/313 R, 310/313 D, 310/312, 310/311, 422/68.01, 422/82.01, 436/149, 436/151
• US Class Current: 436/149
• CPC Class Codes: G01N 2291/0256 Adsorption, desorption, surface mass change, e.g. on biosensors
• CPC Class Codes: G01N 2291/02809 Concentration of a compound, e.g. measured by a surface mass change
• CPC Class Codes: G01N 2291/02818 Density, viscosity
• CPC Class Codes: G01N 2291/02845 Humidity, wetness
• CPC Class Codes: G01N 2291/0422 Shear waves, transverse waves, horizontally polarised waves
• CPC Class Codes: G01N 2291/0423 Surface waves, e.g. Rayleigh waves, Love waves
• CPC Class Codes: G01N 2291/0427 Flexural waves, plate waves, e.g. Lamb waves, tuning fork, cantilever
• CPC Class Codes: G01N 29/022 Fluid sensors based on microsensors, e.g. quartz crystal-microbalance [QCM], surface acoustic wave [SAW] devices, tuning forks, cantilevers, flexural plate wave [FPW] devices microdevices per se B81B
• CPC Class Codes: G01N 33/54353 with ligand attached to the carrier via a chemical coupling agent coatings G01N33/54393
• CPC Class Codes: G01N 33/54373 involving physiochemical end-point determination, e.g. wave-guides, FETS, gratings
• CPC Class Codes: G01N 33/552 Glass or silica
• CPC Class Codes: G01N 35/08 using a stream of discrete samples flowing along a tube system, e.g. flow injection analysis

Abstract

A system for accurate and precise measurements of analyte(s) in a system. The measurement system comprises piezoelectric surface wave sample devices, at least one piezoelectric surface wave reference device, and the measurement instrument.

Claims

1. A measurement system for determining the amount of at least one analyte in a liquid sample suspected of containing such analytes comprising:

a plurality of piezoelectric surface transverse wave sample devices comprising a receptor layer attached to the surface thereof, which receptor layer contains receptor molecules which are complementary to the analytes and which device generates data relating to the mass change on the surface of the device arising from contacting the device with the sample;

at least one piezoelectric surface transverse wave reference device comprising a receptor layer having little or no affinity for the analyte(s) and which generates data as to the interferences arising from contacting the device with the liquid sample; and

a measurement instrument capable of correlating the data from the sample and reference devices so as to provide data on at least one of the presence and amount of the analytes in the liquid sample.

2. The system as defined in claim 1 wherein said receptor is selected from the group consisting of antibodies, antibody fragments, antigens, haptens, nucleic acids, cells, receptors, hormones, binding proteins, and oligosaccharides.

3. The system as defined in claim 2 wherein the sample and reference devices further comprise a surface layer.

4. The system as defined in claim 3 wherein the surface layer is SiO₂.

5. The system as defined in claim 4 wherein said surface layer further comprises a reactive surface layer bound to said surface layer wherein said reactive surface layer is derived from the group consisting of organic silanes, avidin, strepavidin, proteins, polymers, lipid layers, or synthetic coatings.

6. A method for determining at least the amount and presence of at least one analyte in a liquid sample suspected of containing such analytes comprising:

(a) contacting the liquid sample with a measurement system for determining the amount of analyte in a liquid sample suspected of containing the analyte which comprises;

a plurality of piezoelectric surface transverse wave sample devices comprising a receptor layer attached to the surface thereof which receptor layer contains receptor molecules which are complementary to the analytes and which device generates data relating to the mass change on the surface of the device arising from contacting the device with the sample;

at least one piezoelectric surface transverse wave reference device comprising a receptor layer having little or no affinity for said analytes and which generates data as to the interference arising from contacting the device with the liquid sample; and

a measurement instrument capable of correlating the data from the sample and reference devices so as to provide data on at least one of the presence and amount of the analyte in the liquid sample;

(b) obtaining data from both the sample and reference devices; and

(c) determining at least one of the presence and concentration of the analyte in the liquid sample.

7. A chemical analyzer apparatus comprising:

a plurality of piezoelectric surface transverse wave sample device means for, when in contact with a chemical sample, varying a characteristic of an applied radio-frequency signal in accordance with particular properties of said chemical sample;

piezoelectric surface transverse wave reference device means for, when in contact with said chemical sample, varying said characteristic of an applied radio-frequency signal in accordance with extraneous influences other than said particular properties of said chemical sample, and in accordance with said particular properties of said chemical sample only to a degree much less than said sample device;

means for applying a radio-frequency signal to said plurality of sample device means and to said reference device means, said means for applying including means for switching a single radio-frequency signal from one of said sample device means to another of said sample device means;

means for selecting a radio-frequency signal varied by one of said sample device means, said means for selecting including means for switching between radio-frequency signals varied by respective ones of said device means; and

means for combining a radio-frequency signal varied by said reference device means with a selected radio-frequency signal varied by said one of said sample device means to produce an output signal containing information regarding at least one of said particular properties of said chemical sample.

8. The apparatus of claim 7, wherein said means for combining comprises means for phase shifting relative to each other said radio frequency signal varied by said reference device means and said selected radio-frequency signal varied by said one of said sample device means.

9. The apparatus of claim 8, wherein said means for combining further comprises control means for controlling said means for phase shifting such that said signals are phase shifted substantially 90°

relative to each other when a buffer solution is caused to contact said reference device means and said one of said sample device means.

10. The apparatus of claim 9, wherein said means for controlling said means for phase shifting comprises means for storing phase shift amounts for each of said plurality of sample device means.

11. The apparatus of claim 10, wherein said control means is further for controlling said means for applying, said means for selecting, and said means for phase shifting such that when said single radio-frequency signal is applied to a particular one of said sample device means, said means for selecting selects a radio-frequency signal varied by said particular one of said sample device means and said means for phase shifting is controlled in accordance with a phase shift amount for said particular one of said sample device means.

12. The apparatus of claim 11, wherein said means for switching included in said means for applying is for switching the single radio-frequency signal from one of said sample device means to another device from among other sample device means and said reference device means, and said means for switching included in said means for selecting is for switching between radio-frequency signals varied by respective ones of said sample device means and said reference device.

13. The apparatus of claim 12, further comprising sample flow path means for containing a flow of said chemical sample, said reference device means and a plurality of sample device means being arranged serially in a direction of flow along said flow path means.

14. The apparatus of claim 13, wherein said means for controlling is further for causing both of said switching means to switch in unison in accordance with flow delays between respective ones of said devices and a first device in said flow direction.

15. A chemical analyzer comprising:

piezoelectric surface transverse wave sample device means for, when in contact with a chemical sample, varying a characteristic of an applied radio-frequency signal in accordance with a particular property of said chemical sample;

piezoelectric surface transverse wave reference device means for, when in contact with said chemical sample, varying said characteristic of an applied radio-frequency signal in accordance with extraneous influences other than said particular properties of said chemical sample, and in accordance with said particular properties of said chemical sample only to a degree much less than said sample device;

means for applying a radio-frequency signal to said sample device means and to said reference device means, said means for applying including means for switching a single radio-frequency signal from said sample device means to said reference device means;

means for selecting a radio-frequency signal varied by one of said sample device means and said reference device means, said means for selecting including means for switching between radio-frequency signals varied by respective ones of said sample device means and said reference device means; and

means for combining a radio-frequency signal varied by said reference device means with a selected radio-frequency signal varied by said one of said sample device means to produce an output signal containing information regarding said particular property of said chemical sample; and

a single fluid flow path through which a fluid sample flows across one of said sample device means and said reference device means and then across another of said sample device means and said reference device means.

16. A chemical sensor for testing for a plurality of analytes in a fluid sample, comprising:

a piezoelectric substrate; and

a plurality of piezoelectric surface transverse wave sample devices formed on said piezoelectric substrate, each of said piezoelectric surface wave sample devices having a different receptor layer attached to a surface thereof, each receptor layer containing receptor molecules complementary to a different one of said plurality of analytes.

17. A measurement system for testing for an analyte in a liquid sample, comprising:

a plurality of piezoelectric surface transverse wave sample devices each having a receptor layer attached to the surface thereof, each receptor layer containing receptor molecules which are complementary to the same analyte, each device generating data relating to the mass change on the surface of the device arising from contacting the device with the sample;

at least one piezoelectric surface transverse wave reference device comprising a receptor layer having little or no affinity for the analyte and which generates data as to the interferences arising from contacting the device with the liquid sample; and

a measurement instrument capable of correlating the data from the sample and reference devices and statistically evaluating data from said plurality of piezoelectric surface wave sample devices so as to provide data on at least the presence and amount of the analyte in the liquid sample.

18. The system of claim 17 wherein said plurality of piezoelectric surface wave sample devices are formed on a single piezoelectric substrate.