High throughput microfluidic systems and methods

• US 6,495,369 B1
• Filed: 04/07/2000
• Issued: 12/17/2002
• Est. Priority Date: 08/10/1998
• Status: Expired due to Term

• Current Assignee: Caliper Technologies Corp (Revvity, Inc.)
• Original Assignee: Caliper Technologies Corp (Revvity, Inc.)
• Inventors: Toth, Andrew W., Kercso, Joseph E., Parce, J. Wallace, Chow, Calvin Y. H., Wolk, Jeffrey A., Sundberg, Steven A.
• Primary Examiner(s): Soderquist, Arlen
• Assistant Examiner(s): Gordon, Brian R.
• Application Number:
  US09/545,241
• Time in Patent Office: 984 Days
• Field of Search: 422/68.1, 422/63, 422/65-67, 422/81, 422/82.05, 422/99, 422/100, 422/52, 422/55, 422/58, 436/179, 436/180, 204/450-451, 204/600-601, 436/54, 436/47
• US Class Current: 436/47
• CPC Class Codes: G01N 2035/00148 Test cards, e.g. Biomerieux or McDonnel multiwell test cards
• CPC Class Codes: G01N 35/028 having reaction cells in the form of microtitration plates
• CPC Class Codes: Y10T 436/11 Automated chemical analysis
• CPC Class Codes: Y10T 436/113332 with conveyance of sample along a test line in a container or rack
• CPC Class Codes: Y10T 436/119163 with aspirator of claimed structure
• CPC Class Codes: Y10T 436/25625 Dilution
• CPC Class Codes: Y10T 436/2575 Volumetric liquid transfer

Abstract

The invention provides improved systems, devices, and methods for analyzing a large number of sample compounds contained in standard multi-well microtiter plates or other array structures. The multi-well plates travel along a conveyor system to a test station having a microfluidic device. At the test station, each plate is removed from the conveyor and the wells of the multi-well plate are sequentially aligned with an input port of the microfluidic device. After at least a portion of each sample has been input into the microfluidic channel system, the plate is returned to the conveyor system. Pre and/or post testing stations may be disposed along the conveyor system, and the use of an X-Y-Z robotic arm and novel plate support bracket allows each of the samples in the wells to be input into the microfluidic network through a probe affixed to a microfluidic chip. A clamshell structure having a hinged lid can releasably support the chip while providing and/or accommodating the electrical, optical, structural, and other interface connections between the microfluidic device and the surrounding system.

Claims

1. A system for analyzing a large number of sample compounds, the system comprising:

a plurality of arrays, each array having a plurality of regions for holding samples;

an array transport system for translating the arrays sequentially along an array path;

an analysis station comprising at least one microfluidic device disposed off the array path the microfluidic device having a sample input port and a channel system with a channel cross sectional dimension in a range from about 0.1 μ

m to about 500 μ

m;

a transportation mechanism which moves each array from the array path and sequentially aligns each region of the array with the sample input port of the microfluidic device; and

a detection system for monitoring a characteristic of the samples in said analysis station.

2. The system of claim 1, further comprising a microfluidic device interface structure supporting the microfluidic device at a fixed position.

3. The system of claim 2, wherein the interface structure comprises a fixed base and a lid, the lid being pivotally coupled to the base so that the microfluidic device is removably restrainable therebetween, at least one of the lid and the base defining a window, and wherein an optical detection system is optically coupled to the channel system through the window for monitoring an optical characteristic of a reaction within the channel system.

4. The system of claim 2, wherein the interface structure further comprises at least one electrode extending fixedly from one of the base and the lid for coupling an electrical potential source to fluid within the channel system.

5. The system of claim 1, wherein the arrays comprise plates and the regions comprise wells wherein a group of the wells on each plate are aligned along a first well alignment axis, and wherein the transportation mechanism can translate the plate with a first degree of freedom along the first well axis to sequentially introduce samples from the group into the sample input port.

6. The system of claim 5, wherein the wells of the plate define an array having a second well alignment axis between a plurality of groups, and wherein the transportation mechanism can translate the plate with a second degree of freedom along the second well axis to introduce samples from the groups into the sample input port.

7. The system of claim 5, wherein the transportation mechanism can move the plate horizontally along the first degree of freedom so that the wells are aligned sequentially with the sample input port, and can lift the plate so that the sample input port extends into the samples within the aligned well, the sample input port comprising a pipettor rigidly coupled to the channel system of the microfluidic device.

8. The system of claim 5, wherein the transportation system comprises a robotic arm having at least two degrees of freedom.

9. The system of claim 1, wherein each array comprises a plate having a top surface defining an upward orientation, two pairs of horizontally opposed edge surfaces, and a lower surface, the regions defining wells and the lower surface defining a recess between the wells and an edge surface, and wherein the transportation mechanism comprises a rigid support bracket having a beam extending from a proximal pair of horizontally spaced sidewalls to an upwardly oriented tab, wherein the recess of the plate fittingly receives the tab and the sidewalls fittingly receive a pair of the edge surfaces when the plate rests on the bracket.

10. The system of claim 9, wherein the plate transport system comprises a conveyor, wherein the transportation mechanism further comprises a plurality of lifting pins disposed along the array path to engage the bottom surfaces of the plates and wherein the pins receive the beam therebetween so as to facilitate transferring the plates between the conveyor and the bracket.

11. The system of claim 1, further comprising a dilution station disposed along the array path before the transportation mechanism for diluting the samples.

12. The system of claim 1, wherein the array path is linear.

13. The system of claim 1, wherein the array path is a loop.

14. A system for analyzing a large number of samples, the system comprising:

a plurality of plates, each having an array of wells;

a plate conveyor for translating the plates along a plate path;

at least one test station disposed along the plate path, the at least one test station comprising;

a microfluidic substrate having a sample input port in fluid communication with at least one channel disposed within the substrate, the channel having a cross sectional dimension in a range from about 0.1 μ

m to about 500 μ

m;

a plurality of lifting pins to sequentially lift the plates from the conveyor; and

a plate transportation mechanism which moves the lifted plates from the plate path with at least two degrees of freedom to sequentially align the wells of the plate with the sample input port of the substrate;

wherein the transportation mechanism comprises a rigid plate support bracket which fittingly receives the plate when the plate rests on the bracket;

and a detection system for monitoring a characteristic of the samples in said test station.

15. The system of claim 14, wherein the bracket comprises a beam extending from adjacent a proximal pair of horizontally spaced sidewalls to an upwardly oriented distal tab, wherein the pins receive the beam and tabs therebetween, and wherein a recess of the plate fittingly receives the tab and the sidewalls fittingly receive a pair of horizontally opposed edge surfaces of the plate when the beam lifts the plate.

16. A method for testing a large number of samples the method comprising:

Arranging the samples at a plurality of regions, the regions disposed on a plurality of arrays;

transporting the arrays along an array path using an array transportation system, removing the arrays from the path and sequentially aligning the regions of the removed array with a sample input port of a microfluidic device using a transportation mechanism so that the samples are transferred sequentially from the regions into a channel system, the channel system having a cross sectional dimension in a range from about 0.1 μ

m to about 500 μ

m, and detecting a characteristic of the samples in the microfluidic device.

17. A system for analyzing a large number of samples, the system comprising;

a plurality of arrays, each array having a plurality of regions for holding samples;

an array transport system for translating the arrays sequentially along an array path;

a batch process station disposed along the array path for simultaneously processing the samples of the array;

an analysis station comprising at least one microfluidic device disposed off the array path, the microfluidic device having a sample input port and a microfluidic channel system;

a transportation mechanism which moves each array from the array path sequentially and aligns each region of the array with the sample input port of the microfluidic device;

and a detection system for monitoring a characteristic of the samples in said analysis station.