Apparatus and methods for high throughput and high-resolution assays

• US 7,189,370 B2
• Filed: 02/21/2003
• Issued: 03/13/2007
• Est. Priority Date: 02/11/2002
• Status: Expired due to Fees

• Current Assignee: Microchem Solutions
• Original Assignee: Microchem Solutions
• Inventors: Liu, Shaorong
• Primary Examiner(s): SINES, BRIAN J
• Application Number:
  US10/371,981
• Publication Number:
  US 20030175165A1
• Time in Patent Office: 1,481 Days
• Field of Search: 422/50, 422/55, 422/58, 422/63, 422/68.1, 422/81, 422/82, 422/100, 422/101, 422/102, 422/103, 422/104, 436/43, 436/63, 436/164, 436/174, 436/180, 436/177, 436/178, 73/10.1, 73/10.2, 73/530.1, 435/283.1, 435/286.5, 435/286.6, 435/287.1, 435/287.2, 435/287.3, 435/288.4, 435/288.5, 435/288.7, 204/403.01, 204/403.02, 204/403.03, 204/193
• US Class Current: 422/502
• CPC Class Codes: B01D 61/28 Apparatus therefor
• CPC Class Codes: B01D 61/56 Electro-osmotic dewatering
• CPC Class Codes: B01L 2200/027 for microfluidic devices
• CPC Class Codes: B01L 2200/0605 Metering of fluids
• CPC Class Codes: B01L 2300/0809 rectangular shaped
• CPC Class Codes: B01L 2300/0816 Cards, e.g. flat sample carriers usually with flow in two horizontal directions
• CPC Class Codes: B01L 2300/0832 cylindrical, tube shaped
• CPC Class Codes: B01L 2300/0864 comprising only one inlet and multiple receiving wells, e.g. for separation, splitting
• CPC Class Codes: B01L 2400/0415 electrical forces, e.g. electrokinetic
• CPC Class Codes: B01L 2400/0421 electrophoretic flow
• CPC Class Codes: B01L 2400/0487 fluid pressure, pneumatics
• CPC Class Codes: B01L 2400/0622 distribution valves, valves having multiple inlets and/or outlets, e.g. metering valves, multi-way valves
• CPC Class Codes: B01L 2400/0644 rotary valves
• CPC Class Codes: B01L 2400/065 sliding valves
• CPC Class Codes: B01L 3/0241 Drop counters; Drop formers making arrays for combinatorial libraries B01J19/0046; automation of dispensing for analysis G01N35/10
• CPC Class Codes: B01L 3/0293 for liquids
• CPC Class Codes: B01L 3/5025 for parallel transport of multiple samples
• CPC Class Codes: B01L 3/502738 characterised by integrated valves microvalves F16K99/0001
• CPC Class Codes: B01L 3/502746 characterised by the means for controlling flow resistance, e.g. flow controllers, baffles B01L3/502738 takes precedence
• 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: B81B 1/004 : Through-holes, i.e. extending from one face to the other face of the wafer
• CPC Class Codes: B81B 2201/058 : Microfluidics not provided for in B81B2201/051 - B81B2201/054
• CPC Class Codes: G01N 2001/4016 : being a selective membrane, e.g. dialysis or osmosis
• CPC Class Codes: G01N 2030/204 : Linearly moving valves, e.g. sliding valves
• CPC Class Codes: G01N 2035/00158 : Elements containing microarrays, i.e. "biochip"
• CPC Class Codes: G01N 2035/00247 : Microvalves
• CPC Class Codes: G01N 2035/1032 : Dilution or aliquotting
• CPC Class Codes: G01N 27/44743 : Introducing samples
• CPC Class Codes: G01N 27/44791 : Microapparatus sample containers with integrated microfluidic structures B01L3/5027
• CPC Class Codes: G01N 30/20 : using a sampling valve
• CPC Class Codes: G01N 30/463 : for multidimensional chromatography
• CPC Class Codes: G01N 30/466 : with separation columns in parallel
• CPC Class Codes: G01N 30/6095 : Micromachined or nanomachined, e.g. micro- or nanosize
• CPC Class Codes: G01N 35/10 : Devices for transferring samples or any liquids to, in, or from, the analysis apparatus, e.g. suction devices, injection devices G01N35/0099 takes precedence
• CPC Class Codes: G01N 35/1016 : Control of the volume dispensed or introduced
• CPC Class Codes: Y10T 436/11 : Automated chemical analysis
• CPC Class Codes: Y10T 436/25 : including sample preparation
• CPC Class Codes: Y10T 436/25375 : Liberation or purification of sample or separation of material from a sample [e.g., filtering, centrifuging, etc.]
• CPC Class Codes: Y10T 436/255 : including use of a solid sorbent, semipermeable membrane, or liquid extraction
• CPC Class Codes: Y10T 436/2575 : Volumetric liquid transfer

Abstract

An apparatus integrates one dimensional separation to another dimensional separation and automates the operation of the two dimensional separation. The first dimensional separation is performed in one column while the second dimensional separation is performed in multiple separation columns. The integration is achieved using a one-piece, a two-piece, or a three-piece interface.

Claims

1. A device for high-resolution sample separation, comprising:

a substrate that comprises at least first and second blocks that are configured to slide relative to each other from a first position to a second position;

at least a first separation channel defined on the first block containing separation medium;

at least a second separation channel defined on the second block containing separation medium;

wherein at the first position, the device is configured for separation of a sample along the first separation channel containing separation medium, whereby the sample is partially separated along the first channel, and

wherein at the second position, the device is configured with at least a section of the first channel, less than entire length of first channel, in fluid communication with at least a section of the second channel for separation in said at least a section of the second channel at least a portion of the sample which is located in said at least a section of the first separation channel and has been partially separated in the first separation channel.

4. The device as in claim 1, wherein at least one of the first and second separation channels is microfabricated on the respective first and second blocks.

5. The device as in claim 1, wherein at least one of the first and second blocks comprise glass or polymeric material, which may be one of plastic, PTFE (polytetrafluoroethylene), Nylon, PVC (polyvinyl chloride), PMMA (poly(methyl methacrylate)), polycarbonate, polystyrene, polypropylene, nitrocellulose, poly(ethylene terephthalate).

6. The device of claim 1, wherein at least one of the first and second channels comprises curved or straight channel sections.

7. The device of claim 1, wherein at least one of the first and second blocks comprises repeated units of channel sections.

8. The device of claim 1, wherein at the first position, the device is configured for at least one of IEF (Isoelectric focusing), capillary electrophoresis (CE), HPLC, SEC (size exclusion chromatograph), IC (ion-exchange chromatograph) or affinity chromatograph.

9. The device of claim 1, wherein the first and second separation channels each comprises at least two channel sections, wherein at the second position, one of the two channel sections of the first separation channel is in fluid communication with one of the two channel sections of the second separation channel, and the other one of the two channel section of the first separation channel is in fluid communication with the other one of the two channel sections of the second separation channel.

10. The device of claim 1, wherein separated samples in the second separation channel are subject to a detection system, which comprises at least one of MALDI-MS and ESI-MS, or a fraction collector.

11. The device of claim 1, wherein separated samples in the second separation channel are subject to a device for chemical reaction including protein digestion.

12. The device of claim 1, wherein the first and second blocks are configured to slide relative to each other by relative rotation.

2. A method for high-resolution sample separation, comprising the steps of:

providing a substrate comprising at least first and second blocks that are configured to slide relative to each other;

partially separating a sample in a first separation channel defined in the first block;

sliding the first block relative to the second block; and

effecting separation along a second separation channel defined in the second block a portion of the sample which is located in a section of the first separation channel and which has been partially separated in the first separation channel.

13. The method as in claim 2, wherein at least one of the first and second separation channels is microfrabricated on the respective first and second blocks.

14. The method as in claim 2, wherein at least one of the first and second blocks comprise glass or polymeric material, which may be one of plastic, PTFE (polytetrafluoroethylene), Nylon, PVC (polyvinyl chloride), PMMA (poly(methyl methacrylate)), polycarbonate, polystyrene, polypropylene, nitrocellulose, poly(ethylene terephthalate).

15. The method as in claim 2, wherein the step of partially separating the sample in the first separation channel comprises at least one of IEF (Isoelectric focusing), capillary electrophoresis (CE), HPLC, SEC (size exclusion chromatograph), IC (ion-exchange chromatogaph) or affinity chromatograph.

16. The method as in claim 2, further comprising subjecting the separated samples in the second separation channel to detection, which comprises at least one of MALDI-MS and ESI-MS, or a fraction collector.

17. The method as in claim 2, further comprising subjecting the separated samples in the second separation channel to chemical reaction, including protein digestion.

18. The method as in claim 2, wherein the step of sliding the first block relative to the second block comprises relative rotating the first block relative to the second block.

21. The method of claim 2, wherein the second separation channel comprises a plurality of separate channel sections, and wherein the sample is partially separated into different portions at different sections of the first separation channel, and the different portions of partially separated sample at the different sections of the first separation channel are simultaneously separated along the plurality of different channel sections of the second separation channel.

3. A microfluidic device, comprising:

a reconfigurable substrate, configured for separation of a sample in a first and a second configurations;

a first fluid channel defined on the substrate containing separation medium, for partial separation of the sample;

a second fluid channel defined on the substrate containing separation medium, for further separation of a portion of the sample which has been partially separated in the first fluid channel, wherein at least a section of the first channel, less than entire length of first channel, is in fluid communication with at least a section of the second fluid channel in the second configuration of the substrate but not in fluid communication in the first configuration of the substrate.

19. The device as in claim 3, wherein the reconfigurable substrate comprises a first block on which the first fluid channel is defined, and a second block on which the second fluid channel is defined.

20. The device as in claim 19, wherein the first block is movable relative to the second block, by relative sliding or rotation.