Systems and methods for characterization of materials and combinatorial libraries with mechanical oscillators

• US 6,182,499 B1
• Filed: 10/08/1997
• Issued: 02/06/2001
• Est. Priority Date: 10/09/1996
• Status: Expired due to Fees

• Current Assignee: Freeslate Inc. (Unchained Labs Inc.)
• Original Assignee: Symyx Technologies Incorporated (Dassault Systemes SA)
• Inventors: McFarland, Eric W., Matsiev, Leonid
• Primary Examiner(s): Williams, Hezron
• Assistant Examiner(s): MILLER, ROSE MARY
• Application Number:
  US08/946,921
• Time in Patent Office: 1,217 Days
• Field of Search: 73/240.1, 73/240.3, 73/240.4, 73/240.5, 73/240.6, 73/300.1, 73/300.4, 73/310.1, 73/310.2, 73/310.3, 73/310.5, 73/310.6, 73/32.R, 73/32.A, 73/530.1, 73/540.1, 73/540.2, 73/542.3, 73/542.4, 73/542.5, 73/542.6, 73/543.8, 73/544.1, 73/614.5, 73/614.9, 73/617.5, 73/617.9, 735/79, 310/360, 310/316, 310/320, 422/68.1, 422/75, 422/98
• US Class Current: 506/12
• CPC Class Codes: B01J 19/0046 Sequential or parallel reactions, e.g. for the synthesis of polypeptides or polynucleotides; Apparatus and devices for combinatorial chemistry or for making molecular arrays synthesis methods per se C40B50/00
• CPC Class Codes: B01J 2219/00315 Microtiter plates
• CPC Class Codes: B01J 2219/00317 Microwell devices, i.e. having large numbers of wells
• CPC Class Codes: B01J 2219/00364 Pipettes
• CPC Class Codes: B01J 2219/00378 Piezoelectric or ink jet dispensers
• CPC Class Codes: B01J 2219/0043 for direct application of reagents, e.g. through openings in a shutter
• CPC Class Codes: B01J 2219/00443 Thin film deposition
• CPC Class Codes: B01J 2219/00497 Features relating to the solid phase supports
• CPC Class Codes: B01J 2219/005 Beads
• CPC Class Codes: B01J 2219/00511 Walls of reactor vessels
• CPC Class Codes: B01J 2219/00515 in the shape of strings
• CPC Class Codes: B01J 2219/0052 in the shape of elongated tubes
• CPC Class Codes: B01J 2219/00527 Sheets
• CPC Class Codes: B01J 2219/00536 in the shape of disks
• CPC Class Codes: B01J 2219/00583 Features relative to the processes being carried out
• CPC Class Codes: B01J 2219/00585 Parallel processes
• CPC Class Codes: B01J 2219/0059 Sequential processes
• CPC Class Codes: B01J 2219/00596 Solid-phase processes
• CPC Class Codes: B01J 2219/00605 the compounds being directly bound or immobilised to solid supports
• CPC Class Codes: B01J 2219/0061 The surface being organic
• CPC Class Codes: B01J 2219/00612 : the surface being inorganic
• CPC Class Codes: B01J 2219/00621 : by physical means, e.g. trenches, raised areas
• CPC Class Codes: B01J 2219/00626 : Covalent
• CPC Class Codes: B01J 2219/00628 : Ionic
• CPC Class Codes: B01J 2219/00637 : by coating it with another layer
• CPC Class Codes: B01J 2219/00641 : the porous medium being continuous, e.g. porous oxide substrates
• CPC Class Codes: B01J 2219/00659 : Two-dimensional arrays
• CPC Class Codes: B01J 2219/00675 : In-situ synthesis on the substrate
• CPC Class Codes: B01J 2219/00689 : using computers
• CPC Class Codes: B01J 2219/00702 : Processes involving means for analysing and characterising the products
• CPC Class Codes: B01J 2219/00704 : integrated with the reactor apparatus
• CPC Class Codes: B01J 2219/00722 : Nucleotides
• CPC Class Codes: B01J 2219/00738 : Organic catalysts
• CPC Class Codes: B01J 2219/00745 : Inorganic compounds
• CPC Class Codes: B01J 2219/00747 : Catalysts
• CPC Class Codes: B01J 2219/0075 : Metal based compounds
• CPC Class Codes: B01J 2219/00754 : Metal oxides
• CPC Class Codes: B82Y 30/00 : Nanotechnology for materials or surface science, e.g. nanocomposites
• CPC Class Codes: C07F 15/0066 : without a metal-carbon linkage
• CPC Class Codes: C07F 15/045 : without a metal-carbon linkage
• CPC Class Codes: C40B 20/08 : Direct analysis of the library members per se by physical methods, e.g. spectroscopy
• CPC Class Codes: C40B 30/08 : by measuring catalytic activity
• CPC Class Codes: C40B 40/14 : Libraries containing macromolecular compounds and not covered by groups C40B40/06 - C40B40/12
• CPC Class Codes: C40B 40/18 : Libraries containing only inorganic compounds or inorganic materials
• CPC Class Codes: C40B 50/14 : Solid phase synthesis, i.e. wherein one or more library building blocks are bound to a solid support during library creation; Particular methods of cleavage from the solid support
• CPC Class Codes: C40B 60/12 : for screening libraries
• CPC Class Codes: C40B 60/14 : for creating libraries
• CPC Class Codes: G01H 13/00 : Measuring resonant frequency
• CPC Class Codes: G01J 4/00 : Measuring polarisation of light
• CPC Class Codes: G01N 11/16 : by measuring damping effect upon oscillatory body
• CPC Class Codes: G01N 2009/006 : vibrating tube, tuning fork
• CPC Class Codes: G01N 21/211 : Ellipsometry optical thickness measurement G01B11/06
• CPC Class Codes: G01N 21/253 : for batch operation, i.e. multisample apparatus analytical automats G01N35/00
• CPC Class Codes: G01N 21/6402 : Atomic fluorescence; Laser induced fluorescence
• CPC Class Codes: G01N 21/6452 : Individual samples arranged in a regular 2D-array, e.g. multiwell plates
• CPC Class Codes: G01N 21/66 : electrically excited, e.g. electroluminescence
• CPC Class Codes: G01N 2203/0094 : Visco-elasticity
• CPC Class Codes: G01N 2291/014 : Resonance or resonant frequency
• CPC Class Codes: G01N 2291/0224 : Mixtures of three or more liquids
• CPC Class Codes: G01N 2291/0255 : (Bio)chemical reactions, e.g. on biosensors
• CPC Class Codes: G01N 2291/0256 : Adsorption, desorption, surface mass change, e.g. on biosensors
• CPC Class Codes: G01N 2291/02818 : Density, viscosity
• CPC Class Codes: G01N 2291/02827 : Elastic parameters, strength or force
• CPC Class Codes: G01N 2291/02863 : Electric or magnetic parameters
• 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 2291/106 : one or more transducer arrays
• CPC Class Codes: G01N 25/4813 : concerning the measuring means
• 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 29/036 : by measuring frequency or resonance of acoustic waves
• CPC Class Codes: G01N 29/2418 : using optoacoustic interaction with the material, e.g. laser radiation, photoacoustics photoacoustic cells G01N21/1702; measuring characteristics of vibrations by using radiation-sensitive means G01H9/00; acousto-optical conversion techniques for short-range imaging G01S15/8965; sound-producing devices using laser bundle G10K15/046
• CPC Class Codes: G01N 29/2425 : optoacoustic fluid cells therefor
• CPC Class Codes: G01N 29/30 : Arrangements for calibrating or comparing, e.g. with standard objects
• CPC Class Codes: G01N 29/348 : with frequency characteristics, e.g. single frequency signals, chirp signals measuring frequency of mechanical vibrations or acoustic waves in general G01H1/06, G01H3/04; measuring frequency or analysing frequency spectra G01R23/00
• CPC Class Codes: G01N 29/42 : by frequency filtering or by tuning to resonant frequency
• CPC Class Codes: G01N 29/4418 : with a model, e.g. best-fit, regression analysis
• CPC Class Codes: G01N 29/4427 : with stored values, e.g. threshold values
• CPC Class Codes: G01N 31/10 : using catalysis
• CPC Class Codes: G01N 9/002 : using variation of the resonant frequency of an element vibrating in contact with the material submitted to analysis G01N9/34 takes precedence
• CPC Class Codes: H01J 49/0409 : Sample holders or containers containers for retaining a material to be analyzed, B01L3/50, for DNA, C12Q1/6834, for biological materials, G01N33/543
• CPC Class Codes: H01J 49/0468 : with means for heating or cooling the sample

Abstract

Methods and apparatus for screening diverse arrays of materials are provided. In one aspect, systems and methods are provided for imaging a library of materials using ultrasonic imaging techniques. The system includes one or more devices for exciting an element of the library such that acoustic waves are propagated through, and from, the element. The acoustic waves propagated from the element are detected and processed to yield a visual image of the library element. The acoustic wave data can also be processed to obtain information about the elastic properties of the library element. In another aspect, systems and methods are provided for generating acoustic waves in a tank filled with a coupling liquid. The library of materials is then placed in the tank and the surface of the coupling liquid is scanned with a laser beam. The structure of the liquid surface disturbed by the acoustic wave is recorded, the recorded disturbance being representative of the physical structure of the library. In another aspect of the invention, a mechanical resonator is used to evaluate various properties (e.g., molecular weight, viscosity, specific weight, elasticity, dielectric constant, conductivity, etc.) of the individual liquid elements of a library of materials. The resonator is designed to ineffectively excite acoustic waves. The frequency response of the resonator is measured for the liquid element under test, preferably as a function of time. By calibrating the resonator to a set of standard liquids with known properties, the properties of the unknown liquid can be determined. An array of library elements can be characterized by a single scanning transducer or by using an array of transducers corresponding to the array of library elements. Alternatively, multiple resonators of differing design may be used to evaluate each element of a library of elements, thus providing improved dynamic range and sensitivity.

Claims

1. A method of screening an array of liquid materials for a selected property, the method comprising:

providing an array of liquid materials;

contacting the array of liquid materials with low frequency tuning fork resonators, the resonators designed to minimize excitation of acoustic waves and calibrated against a set of standard liquids to yield calibrations relating the selected property to responses of the resonators to an oscillation stimulus;

applying a stimulus to the resonators causing the resonators to oscillate;

periodically monitoring responses of the resonators to the stimulus as functions of frequency; and

measuring the selected property of the array of liquid materials based on the monitored frequency responses and calibrations.

2. The method of claim 1, wherein the selected property is selected from the group consisting of molecular weight, viscosity, specific weight, elasticity, dielectric constant, and conductivity.

3. The method of claim 1, wherein the stimulus is an excitation frequency varying in a predefined manner.

4. The method of claim 1, wherein the array of liquid materials is a combinatorial array.

5. The method of claim 1, further comprising monitoring heat generated or consumed by the array of liquid materials.

6. The method of claim 1, further comprising agitating the array of liquid materials during monitoring.

7. The method of claim 6, wherein agitation is performed by an array of individual agitators.

8. The method of claim 1, wherein the stimulus is a voltage spike.

9. The method of claim 1, wherein in the array of liquid materials comprises an array of gels.

10. The method of claim 1, further comprising:

contacting at least one sample of the array of liquid materials with at least two of the low frequency resonators.

11. The method of claim 1, wherein at least one sample of the array of liquid materials includes a catalyst.

12. A system for determining a selected property of an array of liquid materials, the system comprising:

an array of sample wells for containing the array of liquid materials;

low frequency tuning fork resonators disposed in the array of sample wells, the low frequency resonators designed to minimize excitation of acoustic waves and calibrated against a set of standard liquids to yield calibrations relating the selected property to responses of the resonators to an oscillation stimulus;

a stimulus source coupled to the resonators for exciting oscillation of the resonators;

a receiver coupled to the resonators for periodically monitoring responses of the resonators to the stimulus as a function of frequency; and

a processor coupled to the stimulus source and the receiver, the processor activating the stimulus source for the resonators at predefined times and calculating the selected property of the array of liquid materials based on the frequency response and calibrations.

13. The system of claim 12, the array of liquid materials comprising an array of gels.

14. The system of claim 12, wherein at least two low frequency resonators are disposed within each of the sample wells.

15. The system of claim 12, wherein the selected property is selected from the group consisting of molecular weight, viscosity, specific weight, elasticity, dielectric constant and conductivity.

16. The system of claim 12, wherein the array of sample wells is a microtitrate plate.

17. The system of claim 12, wherein the stimulus source applies an excitation frequency varying in a predefined manner to the resonators.

18. The system of claim 12, further comprising at least one catalyst in each of the sample wells.

19. The system of claim 18, wherein the array of liquid materials is a combinatorial array.

20. The system of claim 12, further comprising an array of heat regulators corresponding to the array of sample wells.

21. The system of claim 20, wherein the array of heat regulators maintains a constant temperature within the array of sample wells.

22. The system of claim 20, the array of heat regulators comprising an array of thermistors.

23. The system of claim 21, wherein the array of heat regulators is coupled to the receiver, the receiver periodically monitoring an amount of energy required to maintain constant temperature, and wherein the processor calculates an amount of heat produced as a function of time within each of the sample wells from the monitored amount of required energy.

24. The system of claim 12, further comprising an agitator within each of the sample wells, the agitators providing substantially uniform concentration distribution within each of the sample wells.

25. The system of claim 12, wherein the stimulus source applies a voltage spike to the resonators.

26. A method of screening an array of liquid materials for a selected property, the method comprising:

providing an array of liquid materials, at least one sample of the array of liquid materials containing a catalyst;

contacting the array of liquid materials with low frequency resonators, the resonators designed to minimize excitation of acoustic waves and calibrated against a set of standard liquids to yield calibrations relating the selected property to responses of the resonators to an oscillation stimulus;

applying a stimulus to the resonators causing the resonators to oscillate;

periodically monitoring responses of the resonators to the stimulus as functions of frequency; and

measuring the selected property of the array of liquid materials based on the monitored frequency responses and calibrations.

27. A method of screening an array of liquid materials for a selected property, the method comprising:

providing an array of liquid materials;

contacting the array of liquid materials with low frequency resonators, the resonators designed to minimize excitation of acoustic waves and calibrated against a set of standard liquids to yield calibrations relating the selected property to responses of the resonators to an oscillation stimulus;

monitoring heat generated or consumed by the array of liquid materials;

applying a stimulus to the resonators causing the resonators to oscillate;

periodically monitoring responses of the resonators to the stimulus as functions of frequency; and

measuring the selected property of the array of liquid materials based on the monitored frequency responses and calibrations.

28. A system for determining a selected property of an array of liquid materials, the system comprising:

a microtiter plate having wells for containing the array of liquid materials;

low frequency resonators at least partially disposed in the wells of the microtiter plate, the low frequency resonators designed to minimize excitation of acoustic waves and calibrated against a set of standard liquids to yield calibrations relating the selected property to responses of the resonators to an oscillation stimulus;

a stimulus source coupled to the resonators for exciting oscillation of the resonators;

a receiver coupled to the resonators for periodically monitoring responses of the resonators to the stimulus as a function of frequency; and

a processor coupled to the stimulus source and the receiver, the processor activating the stimulus source for the resonators at predefined times and calculating the selected property of the array of liquid materials based on the frequency response and calibrations.

29. A system for determining a selected property of an array of liquid materials, the system comprising:

vessels for containing the array of liquid materials;

low frequency resonators at least partially disposed in the vessels, the low frequency resonators designed to minimize excitation of acoustic waves and calibrated against a set of standard liquids to yield calibrations relating the selected property to responses of the resonators to an oscillation stimulus;

a catalyst in at least one of the vessels;

a stimulus source coupled to the resonators for exciting oscillation or the resonators;

a receiver coupled to the resonators for periodically monitoring responses of the resonators to the stimulus as a function of frequency; and

a processor coupled to the stimulus source and the receiver, the processor activating the stimulus source for the resonators at predefined times and calculating the selected property of the array of liquid materials based on the frequency response and calibrations.

30. A system for determining a selectcd property of an array of liquid materials, the system comprising:

vessels for containing the array of liquid materials;

low frequency resonators at least partially disposed in the vessels, the low frequency resonators designed to minimize excitation of acoustic waves and calibrated against a set of standard liquids to yield calibrations relating the selected property to responses of the resonators to an oscillation stimulus;

a stimulus source coupled to the resonators for exciting oscillation of the resonators;

a receiver coupled to the resonators for periodically monitoring responses of the resonators to the stimulus as a function of frequency;

a processor coupled to the stimulus source and the receiver, the processor activating the stimulus source for the resonators at predefined times and calculating the selected property of the array of liquid materials based on the frequency response and calibrations; and

heat regulators coupled to the vessels for monitoring heat generated or consumed by the array of liquid materials.