Method and apparatus for packaging a probe array

• US 6,140,044 A
• Filed: 09/14/1995
• Issued: 10/31/2000
• Est. Priority Date: 06/08/1994
• Status: Expired due to Term

• Current Assignee: Affymetrix, Inc. (Thermo Fisher Scientific Incorporated)
• Original Assignee: Affymetrix, Inc. (Thermo Fisher Scientific Incorporated)
• Inventors: Winkler, James L., Goss, Virginia W., Besemer, Donald M.
• Primary Examiner(s): Housel, James C.
• Assistant Examiner(s): HINES, JANA A
• Application Number:
  US08/528,173
• Time in Patent Office: 1,874 Days
• Field of Search: 422/55, 422/58, 422/82.05-82.09, 435/6, 435/7.1, 435/970, 435/973, 436/518, 436/527, 436/531, 436/46, 436/164, 436/809, 530/333, 530/334, 536/25.3, 536/25.31, 536/25.32, 427/2.1, 427/2.11, 427/2.13
• US Class Current: 435/6.16
• CPC Class Codes: B01F 33/30 Micromixers
• CPC Class Codes: B01F 33/40 Mixers using gas or liquid agitation, e.g. with air supply tubes
• CPC Class Codes: B01F 33/45 Magnetic mixers; Mixers with magnetically driven stirrers
• CPC Class Codes: B01J 19/0046 Sequential or parallel reactions, e.g. for the synthesis of polypeptides or polynucleotides; Apparatus and devices for combinatorial chemistry or for making molecular arrays synthesis methods per se C40B50/00
• CPC Class Codes: B01J 2219/00371 comprising electrodes
• CPC Class Codes: B01J 2219/00432 Photolithographic masks
• CPC Class Codes: B01J 2219/00527 Sheets
• CPC Class Codes: B01J 2219/00529 DNA chips
• CPC Class Codes: B01J 2219/00531 essentially square
• CPC Class Codes: B01J 2219/00536 in the shape of disks
• CPC Class Codes: B01J 2219/0054 Means for coding or tagging the apparatus or the reagents
• CPC Class Codes: B01J 2219/00547 Bar codes
• CPC Class Codes: B01J 2219/00585 Parallel processes
• CPC Class Codes: B01J 2219/0059 Sequential processes
• CPC Class Codes: B01J 2219/00596 Solid-phase processes
• CPC Class Codes: B01J 2219/00605 the compounds being directly bound or immobilised to solid supports
• CPC Class Codes: B01J 2219/00608 DNA chips
• CPC Class Codes: B01J 2219/00612 the surface being inorganic
• CPC Class Codes: B01J 2219/00626 Covalent
• CPC Class Codes: B01J 2219/00659 Two-dimensional arrays
• CPC Class Codes: B01J 2219/00662 : Two-dimensional arrays within two-dimensional arrays
• CPC Class Codes: B01J 2219/00689 : using computers
• CPC Class Codes: B01J 2219/00695 : Synthesis control routines, e.g. using computer programs
• CPC Class Codes: B01J 2219/00711 : Light-directed synthesis
• CPC Class Codes: B01J 2219/00722 : Nucleotides
• CPC Class Codes: B01J 2219/00725 : Peptides
• CPC Class Codes: B01J 2219/00731 : Saccharides
• CPC Class Codes: B01L 2200/025 : Align devices or objects to ensure defined positions relative to each other
• CPC Class Codes: B01L 2200/027 : for microfluidic devices
• CPC Class Codes: B01L 2200/0689 : Sealing
• CPC Class Codes: B01L 2200/12 : Specific details about manufacturing devices
• CPC Class Codes: B01L 2300/0636 : Integrated biosensor, microarrays
• CPC Class Codes: B01L 2300/0816 : Cards, e.g. flat sample carriers usually with flow in two horizontal directions
• CPC Class Codes: B01L 2300/0825 : Test strips
• CPC Class Codes: B01L 2300/0877 : Flow chambers
• CPC Class Codes: B01L 2400/0487 : fluid pressure, pneumatics
• CPC Class Codes: B01L 3/5027 : by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip B01L3/5023 takes precedence; micromixers B01F33/30; microreactors for synthesis B01J19/0093; microcapillary devices in general B81B1/00
• CPC Class Codes: B01L 3/502707 : characterised by the manufacture of the container or its components by shaping or joining plastic parts B29C59/00, B29C65/00; by laminating B32B37/00; manufacture of microstructural devices in general B81C
• CPC Class Codes: B01L 3/502715 : characterised by interfacing components, e.g. fluidic, electrical, optical or mechanical interfaces
• CPC Class Codes: B01L 9/527 : for microfluidic devices, e.g. used for lab-on-a-chip
• CPC Class Codes: B82Y 30/00 : Nanotechnology for materials or surface science, e.g. nanocomposites
• CPC Class Codes: C07H 21/00 : Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
• CPC Class Codes: C12Q 1/6874 : involving nucleic acid arrays, e.g. sequencing by hybridisation
• CPC Class Codes: C40B 40/06 : Libraries containing nucleotides or polynucleotides, or derivatives thereof
• CPC Class Codes: C40B 40/10 : Libraries containing peptides or polypeptides, or derivatives thereof
• CPC Class Codes: C40B 40/12 : Libraries containing saccharides or polysaccharides, or derivatives thereof
• CPC Class Codes: C40B 60/14 : for creating libraries
• CPC Class Codes: C40B 70/00 : Tags or labels specially adapted for combinatorial chemistry or libraries, e.g. fluorescent tags or bar codes
• CPC Class Codes: G01N 2035/00158 : Elements containing microarrays, i.e. "biochip"
• CPC Class Codes: G01N 33/543 : with an insoluble carrier for immobilising immunochemicals
• CPC Class Codes: G01N 33/54366 : Apparatus specially adapted for solid-phase testing
• CPC Class Codes: Y10S 435/97 : Test strip or test slide
• CPC Class Codes: Y10S 435/973 : Simultaneous determination of more than one analyte
• CPC Class Codes: Y10S 436/809 : Multifield plates or multicontainer arrays
• CPC Class Codes: Y10T 436/112499 : with sample on test slide

Abstract

A body 300 having a cavity 310 for mounting a substrate 120 fabricated with probe sequences at known locations according to the methods disclosed in U.S. Pat. No. 5,143,854 and PCT WO 92/10092 or others, is provided. The cavity includes inlets 350 and 360 for introducing selected fluids into the cavity to contact the probes. Accordingly, a commercially feasible device for use in high throughput assay systems is provided.

Claims

1. A method of packaging probe arrays, comprising the steps of:

forming a plurality of probe arrays on a surface of a rigid and flat substrate having a plurality of alignment marks disposed on the surface, by coupling selected monomers or biopolymers to said substrate whereby a plurality of different biopolymer sequences are formed at different known locations each having area of less than 10^-1 cm² on said surface of said substrate;

separating said rigid and flat substrate along lines determined by the alignment marks into a plurality of individual probe arrays, said individual probe arrays comprising greater than 100 probes; and

inseparably mating at least one of said individual probe arrays to a housing, said housing comprising a reaction chamber, said reaction chamber comprising an inlet for flowing fluid into said reaction chamber, and said at least one probe array being in fluid communication with said reaction chamber.

2. The method as recited in claim 1, wherein in said mating step, said housing is made by the steps of;

injection molding first and second halves of said housing; and

inseparably mating said first and second halves together to form said housing.

3. The method as recited in claim 2, wherein said first and second halves are injection molded plastic.

4. The method as recited in claim 3, wherein one of said first and second halves comprises flow channels disposed therein, said flow channels being in fluid communication with said inlet.

5. The method as recited in claim 4, further comprising the step of providing a reenterable seal to said flow channels in said housing.

6. The method as recited in claim 5, wherein said mating step comprises aligning said individual probe array relative to said housing by aligning said alignment marks relative to said housing.

7. The method as recited in claim 1, further comprising a step of aligning said individual probe array relative to said housing during said mating step, said step of aligning being carried out by aligning said individual probe array with a first alignment structure on said housing.

8. The method as recited in claim 1, further comprising the step of detecting a location of a target molecule binding to a probe on the array by,

mounting said housing on a scanner, said housing having an alignment structure for aligning said housing relative to said scanner;

flowing said target molecule into said reaction chamber; and

using a scanner to identify a location on said individual probe array where said target molecule binds to said probe on said probe array, wherein said alignment structure comprises a plurality of holes in said housing.

9. The method as recited in claim 1, wherein said step of forming said plurality of probe arrays comprises the steps of:

exposing at least first known locations on a surface of said substrate to light to activate functional groups at said first known locations;

contacting first selected monomers or biopolymers with said first known locations;

exposing at least second known locations on said surface of said substrate wafer to light to activate functional groups at said at least second known locations; and

contacting second selected monomers or biopolymers with said second known locations to form a plurality of different probe arrays on said surface of said substrate, each of said plurality of different probe arrays comprising a plurality of different biopolymer sequences at known locations on said surface of said substrate.

10. The method as recited in claim 1, wherein said step of separating comprises the steps of:

scribing said substrate in desired locations to produce scribe lines on a surface of said substrate;

breaking said substrate along said scribe lines.

11. The method as recited in claim 1, wherein in said forming step, said plurality of different biopolymer sequences comprises a plurality of different nucleic acid sequences on said surface of said substrate.

12. The method as recited in claim 1, further comprising the step of providing a temperature sensor in thermal contact with said reaction chamber for monitoring a temperature of said reaction chamber.

13. The method as recited in claim 3, wherein said first and second halves of said housing are inseparably mated by acoustically welding said first and second halves of said housing together.

14. The method as recited in claim 1, wherein said mating step comprises the step of binding said individual probe array to said housing with an adhesive.

15. The method as recited in claim 14, wherein in said mating step, said housing comprises a recessed region thereon, whereby said individual probe array does not extend above a surface of said housing.

16. The method as recited in claim 1, further comprising the step of detecting a location of a target molecule binding to a probe on the array by,

mounting said housing on a scanner, said housing having an alignment structure for aligning said housing relative to said scanner;

flowing said target molecule into said reaction chamber; and

using a scanner to identify a location on said individual probe array where said target molecule binds to said probe on said probe array, wherein said reaction chamber is a rectangular reaction chamber, and said step of flowing comprises flowing a fluid containing said target molecule from an inlet along a first diagonal of said rectangular reaction chamber to an outlet along said diagonal of said rectangular reaction chamber.

17. The method as recited in claim 1, further comprising the step of detecting a location of a target molecule binding to a probe on the array by,

mounting said housing on a scanner, said housing having an alignment structure for aligning said housing relative to said scanner;

flowing said target molecule into said reaction chamber; and

using a scanner to identify a location on said individual probe array where said target molecule binds to said probe on said probe array, wherein said reaction chamber is a rectangular reaction chamber comprising;

an inlet septum; and

an outlet septum, and said step of flowing a target molecule through said reaction chamber comprises the steps of;

piercing an inlet septum; and

flowing said target molecule in a fluid through said reaction chamber.

36. The method as recited in claim 1, wherein said step of forming a plurality of probe arrays on said surface of said substrate comprises the steps of:

activating at least first selected regions on said surface of said substrate;

contacting first selected monomers with said first selected regions;

activating at least second selected regions on said surface of said substrate wafer; and

contacting second selected monomers with said second selected regions to form a plurality of different probe arrays on said surface of said substrate, each of said plurality of different probe arrays comprising a plurality of different biopolymer sequences at known locations on said surface of said substrate.

18. A packaged probe array, comprising:

a substrate comprising a first surface and a second surface, said first surface comprising said probe array disposed thereon, said probe array comprising greater than 100 different probes at known locations on said first surface; and

a housing comprising;

a mounting surface;

a fluid cavity;

said fluid cavity comprising an inlet port and an outlet port;

said inlet port and said outlet port permitting fluid to flow into said cavity through said inlet port and out of said cavity through said outlet port, wherein said first surface of said substrate is inseparably mated to said mounting surface, thereby sealably covering said cavity and whereby said probe array is in fluid connection with said cavity wherein said inlet and outlet ports comprise a reenterable seal.

19. A packaged probe array comprising:

a substrate comprising a first surface and a second surface, said first surface comprising said probe array disposed thereon, said probe array comprising greater than 100 different probes at known locations on said first surface; and

a housing comprising;

a mounting surface;

a fluid cavity;

said fluid cavity comprising an inlet port and an outlet port;

said inlet port and said outlet port permitting fluid to flow into said cavity through said inlet port and out of said cavity through said outlet port, wherein said first surface of said substrate is inseparably mated to said mounting surface, thereby sealably covering said cavity and whereby said probe array is in fluid connection with said cavity wherein said housing comprises a means for receiving a temperature controller for controlling a reaction temperature in said cavity.

20. A packaged probe array comprising:

a substrate comprising a first surface and a second surface, said first surface comprising said probe array disposed thereon, said probe array comprising greater than 100 different probes at known locations on said first surface; and

a housing comprising a first half inseparably mounted to a second half, a mounting surface;

a fluid cavity disposed therein, said fluid cavity comprising an inlet port and an outlet port, said inlet port and said outlet port permitting fluid to flow into said cavity through said inlet port and out of said cavity through said outlet port, wherein said first surface of said substrate is inseparably mated to said mounting surface, thereby sealably covering said cavity and whereby said probe array is in fluid connection with said cavity wherein said first and second halves of said housing are injection molded plastic.

21. The packaged probe array of claim 20 wherein one of said halves comprises a cavity, said cavity having an inlet port and an outlet port.

22. The packaged probe array of claim 21, wherein one of said halves comprises flow channels, said flow channels being in fluid communication with said inlet and outlet ports when said first and second halves are mated together.

23. The packaged probe array of claim 22 wherein said flow channels comprise a reenterable seal for sealing fluid in said cavity.

24. A packaged probe array comprising:

a substrate comprising a first surface and a second surface, said first surface comprising said probe array disposed thereon, said probe array comprising greater than 100 different probes at known locations on said first surface; and

a housing, comprising a mounting surface;

a fluid cavity disposed therein, said fluid cavity comprising an inlet port and an outlet port said inlet port and said outlet port permitting fluid to flow into said cavity through said inlet port and out of said cavity through said outlet port, wherein said first surface of said substrate is inseparably mated to said mounting surface, thereby sealably covering said cavity and whereby said probe array is in fluid connection with said cavity, wherein said housing further comprises an alignment structure for maintaining said housing in a desired position when said housing is mounted on a detection system.

25. The packaged probe array of claim 24, wherein said alignment structure comprises a plurality of holes disposed in said housing.

26. The packaged probe array of claim 24, wherein said alignment structure comprises a non-flush edge on said housing.

27. A method of forming and operating a probe array, comprising the steps of:

forming a plurality of probe arrays on a surface of a rigid and flat substrate, having a plurality of alignment marks disposed on the surface by coupling selected monomer or biopolymers to to said substrate whereby a plurality of different biopolymer sequences are formed at different known locations on said surface of said substrate, each of the known locations having an area of less than 0.1 cm² ;

separating said substrate into a plurality of individual probe arrays along lines determined by the alignment marks, each of said individual probe arrays comprising at least one probe array thereon;

inseparably mating at least one of said individual probe arrays to a housing, said housing comprising a reaction chamber, said reaction chamber comprising an inlet for flowing fluid into said reaction chamber and an outlet for flowing fluid out of said reaction chamber, said at least one probe array being in fluid communication with said reaction chamber; and

flowing labeled target molecules into said reaction chamber, said labeled target molecules reacting with probes attached to said at least one probe array.

28. The method as recited in claim 27, wherein in said step of forming a plurality of probe array said plurality of different biopolymer sequences at known locations comprises a plurality of different nucleic acid oligonucleotide sequences at known locations.

29. The method as recited in claim 27, wherein said inlet and said outlet comprise reenterable seals, and said step of flowing labeled target molecules into said reaction chamber comprises the steps of:

piercing said seal of said inlet;

piercing said seal of said outlet; and

flowing said labeled target molecules into said cavity through said inlet and out of said cavity through said outlet.

30. The method as recited in claim 27, further comprising the step of agitating said target molecules to facilitate reaction between said at least one probe array and said labeled target molecules.

31. The method as recited in claim 30, further comprising the step of identifying at least one location where said labeled target molecules are located on said at least one probe array.

32. The method as recited in claim 31, wherein said identifying step comprises the step of placing said housing in a scanner, said scanner being capable of imaging said labeled target molecules reacting with said at least one probe in the array.

33. The method as recited in claim 32, wherein in said step of placing said housing in said scanner, said housing includes an alignment structure for maintaining said housing in a desired position in said scanner.

34. The method as recited in claim 33, wherein said alignment structure comprises a non-flush edge on said housing.

35. The method as recited in claim 33, wherein said alignment structure comprises a plurality of alignment holes disposed in said housing.

37. The method of claim 32, wherein the housing further comprises an alignment structure for aligning said housing relative to said scanner.

38. A packaged probe array, comprising:

a substrate comprising a first surface and a second surface, said first surface comprising said probe array disposed thereon, said probe array comprising greater than 100 different probes at known locations each having an area smaller than 10^-1 cm² on said first surface; and

a housing comprising;

a mounting surface;

a fluid cavity;

said fluid cavity comprising an inlet port and an outlet port;

said inlet port and said outlet port permitting fluid to flow into said cavity through said inlet port and out of said cavity through said outlet port, wherein said first surface of said substrate is inseparably mated to said mounting surface, thereby sealably covering said cavity and whereby said probe array is in fluid connection with said cavity.