Microfabricated differential extraction device and method

• US 5,932,100 A
• Filed: 06/14/1996
• Issued: 08/03/1999
• Est. Priority Date: 06/16/1995
• Status: Expired due to Term

• Current Assignee: University of Washington
• Original Assignee: University of Washington
• Inventors: Yager, Paul, Galambos, Paul C., Brody, James P., Holl, Mark R., Forster, Fred K.
• Primary Examiner(s): Drodge, Joseph W.
• Application Number:
  US08/663,916
• Time in Patent Office: 1,145 Days
• Field of Search: 210/85, 210/94, 210/96.1, 210/511, 210/634, 210/739, 210/745, 210/748, 210/198.2, 210/243, 210/805, 422/69, 422/70, 422/101, 422/82.05, 422/82.08, 216/2, 216/56, 435/6, 435/287.1, 435/287.2, 435/287.3
• US Class Current: 210/634
• CPC Class Codes: B01D 11/0492 Applications, solvents used
• CPC Class Codes: B01D 11/0496 by extraction in microfluidic devices
• CPC Class Codes: B01F 2025/9171 Parallel flow, i.e. every point of the flow moves in parallel layers where intermixing can occur by diffusion or which do not intermix; Focusing, i.e. compressing parallel layers without intermixing them
• CPC Class Codes: B01F 33/30 Micromixers
• CPC Class Codes: B01F 33/3039 with mixing achieved by diffusion between layers
• 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 2219/00783 Laminate assemblies, i.e. the reactor comprising a stack of plates
• CPC Class Codes: B01J 2219/00828 Silicon wafers or plates
• CPC Class Codes: B01J 2219/00889 Mixing micromixers B01F33/30
• CPC Class Codes: B01J 2219/00905 Separation
• CPC Class Codes: B01J 2219/00952 Sensing operations
• CPC Class Codes: B01J 2219/0097 Optical sensors
• CPC Class Codes: B01J 2219/00995 Mathematical modeling
• CPC Class Codes: G01N 15/06 Investigating concentration of particle suspensions by weighing G01N5/00; investigating sedimentation of particle suspensions G01N15/04; investigating individual particles G01N15/10
• CPC Class Codes: G01N 2001/4072 membraneless transfer of a component between two parallel laminar flows of fluid
• CPC Class Codes: G01N 2035/00237 Handling microquantities of analyte, e.g. microvalves, capillary networks
• CPC Class Codes: G01N 30/0005 Field flow fractionation
• CPC Class Codes: Y10S 366/01 Micromixers: continuous laminar flow with laminar boundary mixing in the linear direction parallel to the fluid propagation with or without conduit geometry influences from the pathway
• CPC Class Codes: Y10T 436/255 including use of a solid sorbent, semipermeable membrane, or liquid extraction

Abstract

This invention provides a microfabricated extraction system and methods for extracting desired particles from a sample stream containing desired and undesired particles. The sample stream is placed in laminar flow contact with an extraction stream under conditions in which inertial effects are negligible. The contact between the two streams is maintained for a sufficient period of time to allow differential transport of the desired particles from the sample stream into the extraction stream. In a preferred embodiment the differential transport mechanism is diffusion. The extraction system of this invention coupled to a microfabricated diffusion-based mixing device and/or sensing device allows picoliter quantities of fluid to be processed or analyzed on devices no larger than silicon wafers.

Claims

1. A microfabricated extraction device for extracting desired particles from a sample stream containing said desired particles comprising:

a. a sample stream inlet;

b. an extraction stream inlet;

c. an extraction channel having an aspect ratio (w/d) less than 50 joining with said sample stream inlet and said extraction stream inlet for receiving a sample stream from said sample stream inlet and an extraction stream from said extraction stream inlet, and forming parallel laminar flow therewith;

d. a by-product stream outlet in fluid communication with said extraction channel for receiving a by-product stream comprising at least a portion of said sample stream from which desired particles have been extracted; and

e. a product stream outlet in fluid communication with said extraction channel for receiving a product stream comprising at least a portion of said extraction stream and comprising desired particles extracted from said sample stream;

said device being constructed and arranged such that said parallel laminar flow is preserved throughout said extraction channel.

2. The device of claim 1 wherein said extraction channel has an aspect ratio less than about 25.

3. A method for extraction of at least a portion of desired particles from a sample stream comprising said desired particles and also containing undesired particles, comprising:

a. introducing said sample stream into the sample stream inlet of a microfabricated extraction device of claim 2;

b. introducing an extraction stream into the extraction channel of said extraction device;

c. withdrawing a product stream comprising desired particles from the product stream outlet of said device.

4. The device of claim 1 wherein said extraction channel has an aspect ratio less than about 1.

5. The device of claim 1 fabricated of materials comprising a silicon wafer.

6. The device of claim 1 also comprising means for effecting differential transport of said desired particles from said sample stream into said extraction stream.

7. The device of claim 6 wherein said means for effecting differential transport are means for producing fields selected from the group consisting of magnetic, electrical, dielectrical, sedimentation, shear, centrifugal force, temperature, pressure, and concentration gradient fields.

8. The device of claim 7 wherein said field is a concentration gradient field and wherein said means for producing a concentration gradient field comprises an effectively non-diffusing absorbent or adsorbent material selective for said desired particles in said extraction stream.

9. The device of claim 1 comprising at least one additional product stream outlet.

10. A microfabricated analytical system comprising a device of claim 1 in combination with means for detecting said desired particles in said product stream.

11. The analytical system of claim 10 wherein said means for detecting said desired particles comprise optical sensing means.

12. The analytical system of claim 10 comprising means for mixing said product stream with an indicator substance capable of interacting with said desired particles so as to enable their detection.

13. A microfabricated analytical system comprising a device of claim 1 wherein desired particles are extracted from a sample stream containing desired and undesired particles, which system comprises means for detecting said undesired particles in said product stream.

14. The analytical system of claim 13 wherein said means for detecting said undesired particles comprise optical sensing means.

15. A method for extraction of at least a portion of desired particles from a sample stream comprising said desired particles and also containing undesired particles, comprising:

a. introducing said sample stream into the sample stream inlet of a microfabricated extraction device of claim 1;

b. introducing an extraction stream into the extraction channel of said extraction device;

c. withdrawing a product stream comprising desired particles from the product stream outlet of said device.

16. The method of claim 15 conducted as a continuous process.

17. The method of claim 15 conducted as a batch process.

18. The method of claim 15 wherein a field selected from the group consisting of magnetic, electrical, dielectrical, sedimentation, shear, centrifugal force, temperature gradient, pressure gradient, and concentration gradient fields is produced across said extraction channel to aid in differential transport of desired particles into said extraction stream in said extraction channel.

19. The method of claim 18 wherein said field is a concentration gradient field and said differential transport is effected by diffusion.

20. The method of claim 18 wherein said sample fluid volume is at least about 1 picoliter.

21. The method of claim 18 wherein said sample fluid volume is between about 1 nanoliter and about 10 microliters.

22. The method of claim 18 wherein said sample fluid volume is between about 1 microliter and about 10 microliters.

23. The method of claim 15 wherein the sample and extraction stream have different properties.

24. The method of claim 15 also comprising detecting the presence of said desired particles or said undesired particles in said product stream.

25. The method of claim 15 also comprising determining the concentration of said desired particles or said undesired particles in said product stream.

26. The method of claim 15 also comprising determining the concentration of said desired particles in said sample stream.

27. The method of claim 15 and further comprising detecting the presence and/or concentration of said desired and/or undesired particles in said product stream wherein the presence and/or concentration of said desired and/or undesired particles in said product stream is determined in less than about 1 second after said sample stream is introduced into said sample stream inlet.

28. The method of claim 15 and further comprising detecting the presence and/or concentration of said desired and/or undesired particles in said product stream wherein the presence and/or concentration of said desired and/or undesired particles in said product stream is determined between about 1 second and about 5 minutes after said sample stream is introduced into said sample stream inlet.

29. The method of claim 15 and further comprising detecting the presence and/or concentration of said desired and/or undesired particles in said product stream wherein the presence and/or concentration of said desired and/or undesired particles in said product stream is determined within about 1 to about 4 minutes after said sample stream is introduced into said sample stream inlet.

30. The method of claim 15 wherein said device is flushed to remove both desired and undesired particles after said product stream has been withdrawn, and said extraction method is repeated.

31. The method of claim 15 comprising withdrawing a by-product stream and repeating said method by introducing said by-product stream as sample stream into said sample stream inlet.

32. The method of claim 15 comprising detecting the concentration of a blood component wherein the sample stream comprises whole blood, and particles of a cleaned blood component are extracted into the product stream.

33. The method of claim 15 comprising withdrawing a by-product stream and introducing said by-product stream into a microfabricated flow cytometer.

34. The method of claim 15 comprising withdrawing a product stream and introducing said product stream into a microfabricated flow cytometer.

35. A microfabricated extraction device for extracting desired particles from a sample stream containing said desired particles comprising:

a. a sample stream inlet;

b. an extraction stream inlet;

c. an extraction channel having a depth less than about 100 micrometers joining with said sample stream inlet and said extraction stream inlet for receiving a sample stream from said sample stream inlet and an extraction stream from said extraction stream inlet, and forming parallel laminar flow therewith;

d. a by-product stream outlet in fluid communication with said extraction channel for receiving a by-product stream comprising at least a portion of said sample stream from which desired particles have been extracted; and

e. a product stream outlet in fluid communication with said extraction channel for receiving a product stream comprising at least a portion of said extraction stream and comprising desired particles extracted from said sample stream;

said device being constructed and arranged such that said parallel laminar flow is preserved throughout said extraction channel.

36. An analytical system microfabricated on a silicon wafer comprising:

a. extraction means for extracting desired particles of an analyte comprising;

(1) a sample stream inlet;

(2) an extraction stream inlet;

(3) an extraction channel having an aspect ratio (w/d) less than 50 joining with said sample stream inlet and said extraction stream inlet for receiving a sample stream from said sample stream inlet and an extraction stream from said extraction stream inlet, and forming parallel laminar flow therewith;

(4) a by-product stream outlet in fluid communication with said extraction channel for receiving a by-product stream comprising at least a portion of said sample stream from which at least a portion of said desired analyte particles have been extracted; and

(5) a product stream outlet in fluid communication with said extraction channel for receiving a product stream comprising at least a portion of said extraction stream and comprising desired analyte particles extracted from said sample stream;

(6) said extraction means being constructed and arranged such that said parallel laminar flow is preserved throughout said extraction channel;

b. a diffusion-based mixing device for mixing said product stream with an indicator substance capable of interacting with said desired analyte particles so as to enable their detection;

c. a detection chamber wherein the presence of said desired analyte particles may be detected.

37. The analytical system of claim 36 in combination with sensing means whereby the presence of said desired analyte particles in said detection chamber may be detected.

38. The analytical system of claim 37 in combination with quantitation means whereby the concentration of said desired analyte particles in said detection chamber may be measured.