Individually addressable micro-electromagnetic unit array chips

• US 6,806,050 B2
• Filed: 09/18/2001
• Issued: 10/19/2004
• Est. Priority Date: 03/15/1999
• Status: Expired due to Term

• Current Assignee: AVIVA Biosciences Corporation
• Original Assignee: AVIVA Biosciences Corporation
• Inventors: Tan, Zhimin, Li, Zhiming, Wang, Jia, Xu, Junquan, Liu, Zewen, Xie, Wenzhang, Liu, Xiumel, Zhu, Xiaoshan, He, Xuezhong, Chen, Depu, Chen, Ken, Liu, Litian, Zhou, Yuxiang
• Primary Examiner(s): Chin, Christopher L.
• Application Number:
  US09/955,343
• Publication Number:
  US 20020022276A1
• Time in Patent Office: 1,127 Days
• Field of Search: 435/4, 435/6, 435/7.1, 435/287.1, 435/287.2, 422/82.01, 436/518, 436/526, 436/806, 436/149, 436/150, 436/151
• US Class Current: 435/6.11
• 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 2219/00317 Microwell devices, i.e. having large numbers of wells
• CPC Class Codes: B01J 2219/00468 by manipulation of individual beads
• CPC Class Codes: B01J 2219/005 Beads
• 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 2219/0061 The surface being organic
• CPC Class Codes: B01J 2219/00612 the surface being inorganic
• CPC Class Codes: B01J 2219/00614 Delimitation of the attachment areas
• CPC Class Codes: B01J 2219/00626 Covalent
• CPC Class Codes: B01J 2219/0063 Other, e.g. van der Waals forces, hydrogen bonding
• CPC Class Codes: B01J 2219/00637 by coating it with another layer
• CPC Class Codes: B01J 2219/00639 the compounds being trapped in or bound to a porous medium
• CPC Class Codes: B01J 2219/00648 by the use of solid beads
• 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 2219/00722 Nucleotides
• CPC Class Codes: B01L 2200/0647 Handling flowable solids, e.g. microscopic beads, cells, particles
• CPC Class Codes: B01L 2200/0668 Trapping microscopic beads
• CPC Class Codes: B01L 2300/0636 Integrated biosensor, microarrays
• CPC Class Codes: B01L 2300/0645 : Electrodes
• CPC Class Codes: B01L 2300/0877 : Flow chambers
• CPC Class Codes: B01L 2300/089 : Virtual walls for guiding liquids
• CPC Class Codes: B01L 2400/043 : magnetic forces
• CPC Class Codes: B01L 3/5025 : for parallel transport of multiple samples
• 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: C40B 40/06 : Libraries containing nucleotides or polynucleotides, or derivatives thereof
• CPC Class Codes: C40B 60/14 : for creating libraries
• CPC Class Codes: G01N 35/0098 : involving analyte bound to insoluble magnetic carrier, e.g. using magnetic separation magnetic particles used in immunoassays G01N33/54326; magnetic separation in general B03C
• CPC Class Codes: Y10S 436/806 : Electrical property or magnetic property

Abstract

This invention provides electromagnetic chips and electromagnetic biochips having arrays of individually addressable micro-electromagnetic units, as well as methods of utilizing these chips for directed manipulation of micro-particles and micro-structures such as biomolecules and chemical reagents. An electromagnetic biochip comprises an individually addressable micro-electromagnetic unit chip with ligand molecules immobilized on its surface. By controlling the electromagnetic field at each unit of the array and combining this control with magnetic modification of biomolecules, these chips can be used for directed manipulation, synthesis and release of biomolecules in order to increase sensitivity of biochemical or chemical analysis and reduce assay time. Other advantages with these chips include minimized damages to biological molecules and increased reproducibility of assay results.

Claims

1. A method for directing reactions between ligand molecules and target molecules, comprising the steps of:

providing a unit having a plurality of individually addressable micro-electromagneticcores;

forming a functional layer for immobilizing ligand molecules above said cores;

providing modified ligand molecules capable of being positioned by magnetic fields;

disposing a solution containing said modified ligand molecules on said functional layer;

creating a pattern of immobilized ligand molecules by selectively energizing said cores to form magnetic fields which position said modified ligand molecules at predetermined locations where said ligand molecules become immobilized on said functional layer;

providing modified target molecules able to be positioned by magnetic fields;

disposing a solution containing said modified target molecules on said pattern of immobilized ligand molecules; and

selectively energizing said cores to form magnetic fields which position said modified target molecules in juxtaposition to predetermined immobilized ligand molecules thereby directing a reaction between said target molecules and said ligand molecules.

2. The method of claim 1, further comprising a step of detecting said reaction between said target molecules and said ligand molecules.

3. The method of claim 2, wherein the step of detecting said reaction comprises optical detection.

4. The method of claim 1, wherein said functional layer is selected from the group consisting of a hydrophilic molecular monolayer, a hydrophilic molecular monolayer with functional groups, a hydrophobic molecular monolayer, a hydrophobic molecular monolayer with functional groups, a hydrophilic membrane, a hydrophilic membrane with functional groups, a hydrophobic membrane, a hydrophobic membrane with functional groups, a hydrophilic gel, a hydrophilic gel with functional groups, a hydrophobic gel, a hydrophobic gel with functional groups, a porous material, a porous material with functional groups, a non-porous material and a non-porous material with functional groups.

5. The method of claim 4, wherein said functional groups are selected from the group consisting of aldehydes, carbodiimides, succinimydyl esters, antibodies, receptors, and lectins.

6. The method of claim 1, wherein said modified ligand molecules are ligand molecules linked to magnetic material.

7. The method of claim 6, wherein said ligand molecules are linked to magnetic material by a cleavable linker.

8. The method of claim 7, wherein said cleavable linker is cleavable by light, heat, enzymatic activity or chemical reaction.

9. The method of claim 6, wherein said ligand molecules are linked to magnetic material by a covalent bond.

10. The method of claim 6, wherein said ligand molecules are linked to magnetic material by biological affinity to a molecule coupled to said magnetic material.

11. The method of claim 10, wherein said biological affinity is selected from the group consisting of antibody-antigen affinity, lectin-hapten affinity and receptor-ligand affinity.

12. The method of claim 1, wherein said modified target molecules are target molecules linked to magnetic material.

13. The method of claim 12, wherein said target molecules are linked to magnetic material by a cleavable linker.

14. The method of claim 13, wherein said cleavable linker is cleavable by light, heat, enzymatic activity or chemical reaction.

15. The method of claim 12, wherein said target molecule is linked to magnetic material by a covalent bond.

16. The method of claim 12, wherein said target molecule is linked to magnetic material by biological affinity to a molecule coupled to said magnetic material.

17. The method of claim 16, wherein said biological affinity is selected from the group consisting of antibody-antigen affinity, lectin-hapten affinity and receptor-ligand affinity.

18. The method of claim 1, further comprising the steps of cleaving said modified ligand molecules from a magnetic material or said modified target molecules from a magnetic material or both after the step of selectively energizing magnetic cores, wherein the cleaved modified ligands or cleaved modified target molecules are not substantially positionable by magnetic fields.

19. The method of claim 18, wherein said magnetic material is removed by a magnetic field.

20. The method of claim 18, wherein said magnetic material is removed by a fluid wash.

21. The method of claim 1, wherein said modified ligand molecules are modified by mixing a solution of said ligand molecules with magnetic material, and freezing droplets of ligand molecules mixed with magnetic material to form small solid magnetic particles.

22. The method of claim 21, further comprising the step of using magnetic dispensers to position the small solid magnetic particles on at least one unit.

23. The method of claim 1, wherein said modified ligand and said modified target molecules comprise biological molecules, chemical reagents or pharmaceutical molecules.

24. The method of claim 1, wherein said modified ligand and said modified target molecules comprise nucleic acid molecules.

25. The method of claim 1, wherein one or both of said modified ligand and said modified target molecules comprise antibodies and antigens.