Microfluidic devices and methods for optimizing reactions

• US 6,440,722 B1
• Filed: 06/27/2000
• Issued: 08/27/2002
• Est. Priority Date: 04/04/1997
• Status: Expired due to Term

• Current Assignee: Caliper Life Sciences Incorporated (Revvity, Inc.)
• Original Assignee: Caliper Holdings Incorporated
• Inventors: Parce, John Wallace, Kopf-Sill, Anne R., Bousse, Luc J., Knapp, Michael
• Primary Examiner(s): Siew, Jeffrey
• Application Number:
  US09/605,692
• Time in Patent Office: 791 Days
• Field of Search: 435/6, 435/91.1, 435/91.2, 435/174, 435/283.1, 435/285.1, 435/285.2, 435/286.5, 435/286.6, 435/287.2, 435/289.1, 422/68.1, 436/518, 436/536, 536/22.1, 536/23.1, 536/24.3, 536/24.31, 536/24.32, 536/24.33
• US Class Current: 702/20
• CPC Class Codes: B01F 33/30 Micromixers
• CPC Class Codes: B01L 2200/0605 Metering of fluids
• CPC Class Codes: B01L 2200/0673 Handling of plugs of fluid surrounded by immiscible fluid
• CPC Class Codes: B01L 2300/0816 Cards, e.g. flat sample carriers usually with flow in two horizontal directions
• CPC Class Codes: B01L 2300/0838 Capillaries
• CPC Class Codes: B01L 2300/0864 comprising only one inlet and multiple receiving wells, e.g. for separation, splitting
• CPC Class Codes: B01L 2300/0867 Multiple inlets and one sample wells, e.g. mixing, dilution
• CPC Class Codes: B01L 2300/18 Means for temperature control
• CPC Class Codes: B01L 2300/1833 using electrical currents in the sample itself
• CPC Class Codes: B01L 2400/0415 electrical forces, e.g. electrokinetic
• CPC Class Codes: B01L 2400/0418 electro-osmotic flow [EOF]
• CPC Class Codes: B01L 2400/0421 electrophoretic flow
• CPC Class Codes: B01L 2400/0487 fluid pressure, pneumatics
• CPC Class Codes: B01L 3/0262 using touch-off at substrate or container
• CPC Class Codes: B01L 3/502715 characterised by interfacing components, e.g. fluidic, electrical, optical or mechanical interfaces
• CPC Class Codes: B01L 3/502753 characterised by bulk separation arrangements on lab-on-a-chip devices, e.g. for filtration or centrifugation separation in general B01D; microapparatus for analysis using electrophoresis G01N27/44791; sample preparation G01N1/28
• CPC Class Codes: B01L 3/502784 specially adapted for droplet or plug flow, e.g. digital microfluidics automatic analysis using a stream of discrete samples in a tube system G01N35/08
• CPC Class Codes: B01L 7/52 with provision for submitting samples to a predetermined sequence of different temperatures, e.g. for treating nucleic acid samples amplification or hybridisation processes per se C12Q1/68; controlling sequential reactions for synthesis B01J19/0046
• CPC Class Codes: C12Q 1/6869 Methods for sequencing
• CPC Class Codes: C12Q 2535/101 Sanger sequencing method, i.e. oligonucleotide sequencing using primer elongation and dideoxynucleotides as chain terminators
• CPC Class Codes: C12Q 2565/629 : being a microfluidic device
• CPC Class Codes: G01N 2035/1053 : for separating part of the liquid, e.g. filters, extraction phase
• CPC Class Codes: G01N 2035/1058 : for mixing
• CPC Class Codes: G01N 27/44791 : Microapparatus sample containers with integrated microfluidic structures B01L3/5027

Abstract

Integrated systems, apparatus, software, and methods for performing biochemical analysis, including DNA sequencing, genomic screening, purification of nucleic acids and other biological components and drug screening are provided. Microfluidic devices, systems and methods for using these devices and systems for performing a wide variety of fluid operations are provided. The devices and systems of are used in performing fluid operations which require a large number of iterative, successive or parallel fluid manipulations, in a microscale, or sealed and readily automated format.

Claims

1. A method of optimizing a chemical reaction, comprising:

a) providing a microfluidic device or system which includes a reaction chamber or channel having at least one region with a cross sectional dimension of between about 0.1 μ

m and about 500 μ

m, a source of at least a first fluid reactant, a source of at least a second fluid reactant, and a fluid direction system for delivering a selected volume of the first and second reactants to the reaction chamber or channel;

b) delivering a selected volume of the first reactant to the reaction chamber or channel;

c) delivering a selected volume of the second reactant to the reaction chamber or channel;

d) mixing the first reactant and the second reactant and incubating the mixed reactants for a selected time;

e) detecting a product of a reaction between the first and second reactant;

f) repeating steps b, c, d and e, wherein at least one selected parameter selected from the group consisting of the selected volume of the first reactant, the selected volume of the second reactant and the selected incubation time is varied as the steps are repeated, wherein the fluid direction system is operably coupled to a control system comprising programmed instructions for performing steps b, c, d, e and f; and

,

g) determining an optimal level for the selected volume of the first reactant, the selected volume of the second reactant, or the selected incubation time for producing the product.

2. The method of claim 1, wherein the selected parameter is varied systematically.

3. The method of claim 1, wherein the fluid direction system is an electrokinetic fluid direction system.

4. The method of claim 1, wherein the optimal level is determined by serially testing the effect of systematically varying the at least one selected parameter in successive mixing experiments.

5. The method of claim 1, wherein the optimal level is determined by testing the effect of changing the at least one selected parameter in parallel mixing experiments.

6. The method of claim 1, wherein the results of a first mixing experiment are used to select the at least one selected parameter.

7. The method of claim 1, wherein the first and second reactant are mixed at a selected temperature.

8. The method of claim 1, wherein the first and second reactant are separately mixed at multiple selected temperatures and an optimal temperature for reaction is determined.

9. The method of claim 8, wherein the temperature is varied systematically.

10. The method of claim 8, wherein the temperature is serially varied in successive mixing experiments.

11. The method of claim 8, wherein the temperature is varied in parallel mixing experiments.

12. The method of claim 1, wherein the reaction chamber or channel is maintained at a selected temperature.

13. The method of claim 1, wherein the first and second reactant are mixed at a selected pH.

14. The method of claim 1, wherein the first and second reactant are separately mixed at multiple selected pH and an optimal pH for reaction is determined.

15. The method of claim 14, wherein the pH is varied systematically.

16. The method of claim 14, wherein the pH is serially varied in successive mixing experiments.

17. The method of claim 14, wherein the pH is varied in parallel mixing experiments.

18. A system for optimizing and performing a desired chemical reaction, comprising:

a microfluidic device which includes a reaction chamber or channel, a source of a first reactant and a source of at least a second reactant, fluidly connected to the reaction chamber or channel;

an electrokinetic fluid direction system for transporting a selected volume of the first reactant to the reaction chamber or channel;

a detection system for detecting a result of the chemical reaction; and

a control system operably coupled to the fluid direction system and programmed with instructions which direct the fluid direction system to deliver a first selected volume of first reactant and a first selected volume of second reactant to the reaction chamber or channel for mixing, which mixing produces a first chemical reaction, and instructions which direct the fluid direction system to deliver a second selected volume of first reactant and a second selected volume of the second reactant to the reaction chamber or channel for mixing, which mixing produces a second chemical reaction to produce a second chemical reaction, wherein the second selected volume of first reactant is varied from the first selected volume of first reactant.

19. The system of claim 18, wherein the control system comprises a computer.

20. The system of claim 18, wherein the microfluidic device includes an element selected from the group consisting of a temperature control element for controlling temperature of reaction of the first reactant and second reactant, a source of acid, and a source of base.

21. The system of claim 18, wherein the control system controls an element of reaction of the first and second reactant selected from the group consisting of temperature, pH, and time.

22. The system of claim 21, wherein the control system directs a plurality of mixings of the first and second reactant, wherein a reaction condition selected from the group consisting of temperature, pH, and time is systematically varied in separate mixings.