Methods for fabricating multi-component devices for molecular biological analysis and diagnostics

• US 6,254,827 B1
• Filed: 01/29/1999
• Issued: 07/03/2001
• Est. Priority Date: 11/01/1993
• Status: Expired due to Term

• Current Assignee: Gamida for Life B.V.
• Original Assignee: Nanogen, Inc.
• Inventors: Ackley, Donald E., Swanson, Paul D., LeClair, Timothy L.
• Primary Examiner(s): Marschel, Ardin H.
• Application Number:
  US09/240,920
• Time in Patent Office: 886 Days
• Field of Search: 422/50, 422/68.1, 436/283.1, 436/286.1, 436/287.1, 436/299.1
• US Class Current: 422/68.1
• 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 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 2219/00315 Microtiter plates
• CPC Class Codes: B01J 2219/00317 Microwell devices, i.e. having large numbers of wells
• CPC Class Codes: B01J 2219/00527 Sheets
• 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 2219/00617 by chemical means
• CPC Class Codes: B01J 2219/00626 Covalent
• CPC Class Codes: B01J 2219/00637 by coating it with another layer
• CPC Class Codes: B01J 2219/00653 the compounds being bound to electrodes embedded in or on the solid supports
• CPC Class Codes: B01J 2219/00659 Two-dimensional arrays
• CPC Class Codes: B01J 2219/00686 Automatic
• CPC Class Codes: B01J 2219/00689 using computers
• CPC Class Codes: B01J 2219/00702 Processes involving means for analysing and characterising the products
• CPC Class Codes: B01J 2219/00713 Electrochemical synthesis
• CPC Class Codes: B01J 2219/0072 Organic compounds
• 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 2200/0647 : Handling flowable solids, e.g. microscopic beads, cells, particles
• 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 2300/0645 : Electrodes
• CPC Class Codes: B01L 2300/0654 : Lenses; Optical fibres
• 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 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 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 3/5085 : for multiple samples, e.g. microtitration plates
• CPC Class Codes: B82Y 10/00 : Nanotechnology for information processing, storage or transmission, e.g. quantum computing or single electron logic
• CPC Class Codes: B82Y 5/00 : Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• CPC Class Codes: C07B 2200/11 : Compounds covalently bound to a solid support
• 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: C07K 1/04 : on carriers C07K1/003, C07K1/006 take precedence
• CPC Class Codes: C07K 1/045 : using devices to improve synthesis, e.g. reactors, special vessels
• CPC Class Codes: C07K 1/047 : Simultaneous synthesis of different peptide species; Peptide libraries
• CPC Class Codes: C12Q 1/6813 : Hybridisation assays
• CPC Class Codes: C12Q 1/6816 : characterised by the detection means C12Q1/6804 takes precedence
• CPC Class Codes: C12Q 1/6825 : Nucleic acid detection involving sensors
• CPC Class Codes: C12Q 1/6837 : using probe arrays or probe chips C12Q1/6874 takes precedence
• CPC Class Codes: C12Q 2565/515 : characterised by the interaction between or sequential use of two or more arrays
• CPC Class Codes: C12Q 2565/607 : being a sensor, e.g. electrode
• 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: F04B 19/006 : Micropumps F04B43/043 and F04B43/095 take precedence
• CPC Class Codes: G01N 27/3276 : being a hybridisation with immobilised receptors using a FET type sensor G01N27/4145; concerning the hybridisation C12Q1/68
• CPC Class Codes: G01N 27/44743 : Introducing samples
• CPC Class Codes: G01N 33/5438 : Electrodes
• CPC Class Codes: G11C 13/0014 : comprising cells based on organic memory material
• CPC Class Codes: G11C 13/0019 : comprising bio-molecules
• CPC Class Codes: G11C 13/04 : using optical elements ; using other beam accessed elements, e.g. electron or ion beam
• CPC Class Codes: G11C 19/00 : Digital stores in which the information is moved stepwise, e.g. shift registers
• CPC Class Codes: H01L 25/50 : Multistep manufacturing processes of assemblies consisting of devices, each device being of a type provided for in group H01L27/00 or H01L29/00 H01L21/50 takes precedence
• CPC Class Codes: H01L 2924/00 : Indexing scheme for arrangements or methods for connecting or disconnecting semiconductor or solid-state bodies as covered by H01L24/00
• CPC Class Codes: H01L 2924/0002 : Not covered by any one of groups H01L24/00, H01L24/00 and H01L2224/00

Abstract

A method for manufacturing a multicomponent flip-chip device is disclosed. The device includes a chip disposed adjacent to a substrate, the substrate including a via therethrough. The device is adapted to receive a fluid to be placed on the substrate, wherein the fluid then flows through the via down to the chip. The chip includes a sealant free region and a sealant receiving region. The method includes the steps of placing a chip adjacent to a substrate. Light is exposed to the substrate and through the via, down onto the surface of the chip. A light-curable, wickable sealant is applied to the interface between the substrate and the chip, wherein the light at least partially cures the sealant to preclude the sealant from flowing to the sealant free region. Additional curing of sealant may also be performed.

Claims

1. A method for manufacturing a flip-chip device for performing active biological operations, the device including a substrate having first and second surfaces, the substrate including a via between the first and second surfaces, the substrate further including electrically conductive traces on at least one of the first and second surfaces, the device further including a chip having first and second surfaces, the chip including electrically conductive traces on the first surface connecting to an array of microlocations, the array of microlocations adapted to receive a fluid placed upon the substrate and through the via, the array of microelectrodes being disposed within a sealant free reaion on the first surface of the chip, the method comprising the steps of:

placing the chip adjacent to the substrate;

forming electrically conductive interconnects, interconnecting the electrically conductive traces on the first surface of the chip with the electrically conductive traces on either the first or second surfaces of the substrate;

exposing light onto the substrate and through the via, down to the first surface of the chip; and

applying a light curable, wickable sealant to the interface between the substrate and the chip, said interface between the substrate and the chip lying outside the sealant free region, wherein the light at least partially cures the sealant, whereby the sealant is precluded from flowing to the sealant free region so as to leave the array of microlocations free of sealant.

2. A method according to claim 1, wherein the electrically conductive interconnects are bumps.

3. A method according to claim 1 further including the step of completing the cure of the sealant.

4. A method according to claim 1, wherein the light exposed to the substrate is UV light.

5. A method according to claim 3, wherein the step of completing the cure of the sealant is done by heat treatment.

6. A method according to claim 1, wherein the sealant is applied to the interface between the chip and substrate by wicking.

7. A method according to claim 1 further including the step of placing a flow cell on either the first or second surfaces of the substrate, the flow cell residing on a surface of the substrate opposite to the surface of the substrate adjacent to the chip.

8. A method for manufacturing a flip-chip device for performing active biological operations, the device including a substrate having first and second surfaces, the substrate including a via between the first and second surfaces, the substrate further including electrically conductive traces on at least one of the first and second surfaces, the device further including a chip having first and second surfaces, the chip including electrically conductive traces on the first surface connecting to an array of microlocations, the array of microlocations adapted to receive a fluid placed upon the substrate and through the via, the array of microelectrodes being disposed within a sealant free region on the first surface of the chip, the method comprising the steps of:

placing the chip adjacent to the substrate;

forming electrically conductive interconnects, interconnecting the electrically conductive traces on the first surface of the chip with the electrically conductive traces on either the first or second surfaces of the substrate;

applying a curable, wickable sealant to the interface between the substrate and the chip, said interface between the substrate and the chip lying outside the sealant free region, said applied sealant being of a sufficient viscosity and amount such that said sealant is precluded from flowing to the sealant free region so as to leave the array of microlocations free of sealant; and

completing the cure of said sealant.

9. A method according to claim 8, wherein the electrically conductive interconnects are bumps.

10. A method according to claim 8, wherein the step of completing the cure of the sealant is done by heat treatment.

11. A method according to claim 8, wherein the sealant is applied to the interface between the chip and substrate by wicking.

12. A method according to claim 8 further including the step of placing a flow cell on either the first or second surfaces of the substrate, the flow cell residing on a surface of the substrate opposite to the surface of the substrate adjacent to the chip.

13. A method for manufacturing a flip-chip device for performing active biological operations, the device including a substrate having first and second surfaces, the substrate including a via between the first and second surfaces, the substrate further including electrically conductive traces on at least one of the first and second surfaces, the device further including a chip having first and second surfaces, the chip including electrically conductive traces on the first surface connecting to an array of microlocations, the array of microlocations adapted to receive a fluid placed upon the substrate and through the via, the array of microelectrodes being disposed within a sealant free region on the first surface of the chip, the method comprising the steps of:

placing the chip adjacent to the substrate;

forming electrically conductive interconnects, interconnecting the electrically conductive traces on the first surface of the chip with the electrically conductive traces on either the first or second surfaces of the substrate;

affixing an illumination member to the substrate such that the illumination member is disposed adjacent to and substantially coplanar with the first surface of the chip;

exposing light onto the substrate and through the via, down to the first surface of the chip; and

applying a light curable, wickable sealant to the interface between the substrate and the chip, said interface between the substrate and the chip lying outside the sealant free region, wherein the light at least partially cures the sealant, whereby the sealant is precluded from flowing to the sealant free region so as to leave the array of microlocations free of sealant.

14. A method according to claim 13, wherein the electrically conductive interconnects are bumps.

15. A method according to claim 13 further including the step of completing the cure of the sealant.

16. A method according to claim 13, wherein the light exposed to the substrate is UV light.

17. A method according to claim 15, wherein the step of completing the cure of the sealant is done by heat treatment.

18. A method according to claim 13, wherein the sealant is applied to the interface between the chip and substrate by wicking.

19. A method for manufacturing a flip-chip device for performing active biological operations, the device including a substrate having first and second surfaces, the substrate including a via between the first and second surfaces, the substrate further including electrically conductive traces on at least one of the first and second surfaces, the device further including a chip having first and second surfaces, the chip including electrically conductive traces on the first surface connecting to an array of microlocations, the array of microlocations adapted to receive a fluid placed upon the substrate and through the via, the array of microlocations being disposed within a sealant free region on the first surface of the chip, the method comprising the steps of:

placing the chip adjacent to the substrate;

forming electrically conductive interconnects, interconnecting the electrically conductive traces on the first surface of the chip with the electrically conductive traces on either the first or second surfaces of the substrate;

affixing an illumination member to the substrate such that the illumination member is disposed adjacent to and substantially coplanar with the first surface of the chip;

applying a curable, wickable sealant to the interface between the substrate and the chip, the interface between the substrate and the chip lying outside the sealant free region, said applied sealant being of a sufficient viscosity and amount such that said sealant is precluded from flowing to the sealant free region so as to leave the array of microlocations free of sealant; and

completing the cure of said sealant.

20. A method according to claim 19, wherein the electrically conductive interconnects are bumps.

21. A method according to claim 19, wherein the step of completing the cure of the sealant is done by heat treatment.

22. A method according to claim 19, wherein the sealant is applied to the interface between the chip and substrate by wicking.

23. A method for manufacturing a multicomponent flip-chip device for performing active biological operations, the device including a chip disposed adjacent to a substrate, the substrate including a via therethrough, wherein the device is adapted to receive a fluid to be placed on the substrate, and to flow through the via down to the chip, the method comprising the consecutively performed steps of:

placing a chip adjacent to a substrate;

applying a curable, wickable sealant to the interface between the substrate and the chip, said applied sealant being of a sufficient viscosity and amount such that said sealant is precluded from flowing to at least a portion of the chip bounded by the via; and

completing the cure of said sealant by heat treatment.

24. A method for manufacturing a multicomponent flip-chip device for performing active biological operations, the device including a chip disposed adjacent to a substrate, the substrate including a via therethrough, wherein the device is adapted to receive a fluid to be placed on the substrate, and to flow through the via down to the chip, the method comprising the consecutively performed steps of:

placing a chip adjacent to a substrate;

wicking a curable, wickable sealant to the interface between the substrate and the chip, said sealant being of a sufficient viscosity and amount such that said sealant is precluded from flowing to at least a portion of the chip bounded by the via; and

completing the cure of said sealant.