High throughput screening assay systems in microscale fluidic devices

• US 7,067,263 B2
• Filed: 04/08/2004
• Issued: 06/27/2006
• Est. Priority Date: 06/28/1996
• Status: Expired due to Fees

• Current Assignee: Caliper Life Sciences Incorporated (Revvity, Inc.)
• Original Assignee: Caliper Life Sciences Incorporated (Revvity, Inc.)
• Inventors: Parce, J. Wallace, Kopf-Sill, Anne R., Bousse, Luc J.
• Primary Examiner(s): Chin, Christopher L.
• Application Number:
  US10/821,503
• Publication Number:
  US 20040241733A1
• Time in Patent Office: 810 Days
• Field of Search: 435/7.2, 435/7.21, 435/287.1, 435/288.5, 435/288.7, 436/514, 436/63, 436/164, 436/172, 436/804, 436/805
• US Class Current: 435/7.2
• CPC Class Codes: B01J 19/0093 Microreactors, e.g. miniaturised or microfabricated reactors laboratory containers with capillary fluid transport in microfabricated channels or chambers B01L3/5027
• CPC Class Codes: B01J 2219/00828 Silicon wafers or plates
• CPC Class Codes: B01J 2219/00831 Glass
• CPC Class Codes: B01J 2219/00833 Plastic
• CPC Class Codes: B01J 2219/00853 Employing electrode arrangements
• CPC Class Codes: B01J 2219/00952 Sensing operations
• CPC Class Codes: B01J 2219/00961 Temperature
• CPC Class Codes: B01J 2219/0097 Optical sensors
• CPC Class Codes: B01L 2200/027 for microfluidic devices
• CPC Class Codes: B01L 2200/0605 Metering of fluids
• CPC Class Codes: B01L 2200/0647 Handling flowable solids, e.g. microscopic beads, cells, particles
• CPC Class Codes: B01L 2200/0668 Trapping microscopic beads
• 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 2300/0861 Configuration of multiple channels and/or chambers in a single devices
• 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 2300/0877 Flow chambers
• CPC Class Codes: B01L 2300/0887 Laminated structure
• 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 2400/0487 : fluid pressure, pneumatics
• CPC Class Codes: B01L 3/5025 : for parallel transport of multiple samples
• CPC Class Codes: B01L 3/502715 : characterised by interfacing components, e.g. fluidic, electrical, optical or mechanical interfaces
• CPC Class Codes: B01L 3/50273 : characterised by the means or forces applied to move the fluids micropumps F04B19/006, of the membrane type F04B43/043
• 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 3/502761 : specially adapted for handling suspended solids or molecules independently from the bulk fluid flow, e.g. for trapping or sorting beads, for physically stretching molecules investigating characteristics of particles G01N15/00
• 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: G01N 27/44791 : Microapparatus sample containers with integrated microfluidic structures B01L3/5027
• CPC Class Codes: G01N 33/5008 : for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
• CPC Class Codes: G01N 33/5011 : for testing antineoplastic activity
• CPC Class Codes: G01N 33/502 : for testing non-proliferative effects
• CPC Class Codes: G01N 33/5064 : Endothelial cells
• CPC Class Codes: G01N 33/5091 : for testing the pathological state of an organism
• CPC Class Codes: G01N 33/5097 : involving plant cells immunoassays of plant cells G01N33/56961
• CPC Class Codes: G01N 33/5304 : Reaction vessels, e.g. agglutination plates for solid-phase systems G01N33/543
• CPC Class Codes: G01N 33/57415 : of breast
• CPC Class Codes: G01N 35/08 : using a stream of discrete samples flowing along a tube system, e.g. flow injection analysis
• CPC Class Codes: Y10S 366/02 : Micromixers: segmented laminar flow with boundary mixing orthogonal to the direction of fluid propagation with or without geometry influences from the pathway
• CPC Class Codes: Y10S 435/81 : Packaged device or kit
• CPC Class Codes: Y10S 435/817 : Enzyme or microbe electrode
• CPC Class Codes: Y10S 436/804 : Radioisotope, e.g. radioimmunoassay
• CPC Class Codes: Y10S 436/805 : Optical property
• CPC Class Codes: Y10S 436/806 : Electrical property or magnetic property
• CPC Class Codes: Y10T 436/11 : Automated chemical analysis
• CPC Class Codes: Y10T 436/110833 : Utilizing a moving indicator strip or tape
• CPC Class Codes: Y10T 436/113332 : with conveyance of sample along a test line in a container or rack
• CPC Class Codes: Y10T 436/117497 : with a continuously flowing sample or carrier stream
• CPC Class Codes: Y10T 436/25 : including sample preparation

Abstract

The present invention provides novel microfluidic devices and methods that are useful for performing high-throughput screening assays. In particular, the devices and methods of the invention are useful in screening large numbers of different compounds for their effects on a variety of chemical, and preferably, biochemical systems.

Claims

1. A method of screening one or more test compounds for an effect on at least one cell using an analytical device comprising:

flowing one or more test compounds from one or more test compound sources through one or more microfluidic channels of an analytical device fabricated in a planar substrate, wherein the one more microfluidic channels have at least one cross-sectional dimension in a range from about 0.1 to 500 μ

m;

contacting the one or more test compounds with at least a first cell; and

detecting a cellular response of the at least first cell to the one or more test compounds in a detection zone of the device, wherein the cellular response is selected from the group consisting of cell proliferation, cell differentiation, cell activation, activation of a cell activity mediating enzyme, stimulation of messenger turnover in the cell, alteration of cell ion flux, activation of cellular enzymes, changes in cell shape, and an alteration in expression of a gene.

2. The method of claim 1, wherein the one or more test compounds comprise a plurality of test compounds which are each fluidly coupled to a respective test compound source.

3. The method of claim 2, wherein the one or more microfluidic channels comprises at least 10 microfluidic channels.

4. The method of claim 2, wherein the one or more microfluidic channels comprises between 10 to about 500 microfluidic channels.

5. The method of claim 1, wherein the at least first cell is isolated from an in vitro source.

6. The method of claim 1, wherein the at least first cell is isolated from an in viva source.

7. The method of claim 1, wherein to at least first cell is selected from the group consisting of a bacterial cell, a plant cell, a fungal cell, and an animal cell.

8. The method of claim 1, wherein a pressure based fluid direction system is used for flowing said one or more test compounds within said one or more microfluidic channels.

9. The method of claim 1, wherein an electrokinetic fluid direction system is used for flowing said one or more test compounds within said one or more microfluidic channels.

10. The method of claim 1, wherein the analytical device comprises or is connectable to a computer so that the computer controls the device.

11. The method of claim 10, wherein the computer controls fluid flow and direction within the device.

12. The method of claim 10, wherein the computer is connected to the device via an adaptor module which provides environmental control over the device.

13. The method of claim 1, further comprising a fluid interface for introducing the one or more test compounds into the device.

14. The method of claim 13, wherein the fluid interface is one or more micropipettors.

15. The method of claim 1, wherein the one or more test compounds comprise a plurality of test compounds which are each contained within a separate reservoir of the analytical device.

16. The method of claim 15, further comprising transporting the plurality of test compounds from the separate reservoirs into a plurality of respective microfluidic channels using a pressure-based fluid direction system.

17. A method of screening one or more test compounds for an effect on at least one cell using an analytical device comprising:

flowing one or more test compounds from one or more test compound sources through one or more microfluidic channels of an analytical device fabricated in a planar substrate, wherein the one more microfluidic channels have at least one cross-sectional dimension in a range from about 0.1 to 500 μ

m;

contacting the one or more test compounds with at least a first cell; and

detecting a cellular response of the at least first cell to the one or more test compounds in a detection zone of to device, wherein the method is for characterizing one or mare receptors present in the at least first cell, wherein the one or more test compounds have an effect on at least one of the one or more receptors in the at least first cell.

18. A method of screening one or more test compounds for an effect on at least one cell using an analytical device comprising:

flowing one or more test compounds from one or more test compound sources through one or more microfluidic channels of an analytical device fabricated in a planar substrate, wherein the one more microfluidic channels have at least one cross-sectional dimension in a range from about 0.1 to 500 μ

m;

contacting the one or more test compounds with at least a first cell; and

detecting a cellular response of the at least first cell to the one or more test compounds in a detection zone of the device, wherein the detection zone is configured to be coupled to a detector for measuring an effect of the one or more test compounds on the at least first cell by measuring a level of a detectable signal, and wherein the detectable signal is provided by a label or a change in molecular weight.

19. The method of claim 18, wherein the detectable signal results from an effect of the one or more test compounds on a cellular function of the at least first cell.

20. The method of claim 19, wherein the cellular function is cellular viability or cellular activity.

21. The method of claim 18, wherein the label is a chromophoric label or a fluorescent label.

22. The method of claim 18, wherein the detectable signal is radioactive decay, electron density, change in pH, temperature or salt concentration.

23. The method of claim 18, wherein the cellular response comprises alteration in cell ion flux.