Flexible apparatus with ablation formed chamber(s) for conducting bio-chemical analyses

• US 6,334,980 B1
• Filed: 09/25/1998
• Issued: 01/01/2002
• Est. Priority Date: 09/07/1995
• Status: Expired due to Fees

• Current Assignee: Microfab Technologies, Inc.
• Original Assignee: Microfab Technologies, Inc.
• Inventors: Frederickson, Christopher J., Wallace, David B., Hayes, Donald J.
• Primary Examiner(s): Marschel, Ardin H.
• Application Number:
  US09/163,063
• Time in Patent Office: 1,194 Days
• Field of Search: 435/6, 435/5, 435/4, 435/91.2, 435/283.1, 435/285.1, 435/285.2, 435/286.1, 435/286.5, 435/287.1, 435/287.2, 435/287.3, 435/287.9, 435/289.1, 435/297.1, 435/303.142, 422/50, 422/68.1, 422/129, 422/131, 422/134, 422/138
• US Class Current: 422/68.1
• 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: G01N 2800/52 Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
• CPC Class Codes: G01N 33/553 Metal or metal coated

Abstract

Miniaturized, self-contained apparatus for conducting bio-chemical reactions and analyses is formed in a compact structure comprising a substrate which includes a plurality of reaction chambers and a plurality of analysis chambers which are in fluid communication with the reaction chambers. Independently controllable heaters and coolers are positioned in thermal contact with the reaction chambers to permit parallel processing of biological samples at different temperature cycles. The apparatus is especially useful for performing and analyzing the results of a polymerase chain reaction.

Claims

1. Apparatus having microfabricated chambers for conducting biochemical analysis, comprising:

a flexible substrate of the kind used in flexible circuit manufacturing technology comprising an ablatable polymeric material having a first major face and a bottom surface;

a plurality of ablated miniature reaction chambers spaced apart in the first major face, said chambers being produced by ablation;

a metallic layer fixed to the substrate and associated with each of the plurality of reaction chambers, the metallic layer comprising a plurality of independently controllable heaters configured to raise the temperature of the reaction chamber which a given heater is associated with;

a plurality of ablated analysis chambers spaced apart in the first major face of the substrate, each being in fluid communication with a reaction chamber, said analysis chambers being produced in the substrate by ablation;

each reaction chamber and analysis chamber having a lower surface in the substrate; and

a protective cover layer positioned over the reaction chambers.

2. Apparatus as defined in claim 1 including a solvent reservoir formed in said substrate and in fluid communication with said analysis chamber.

3. Apparatus as defined in claim 1 including reagent material useful in performing a PCR process, deposited in said reaction chamber.

4. Apparatus as defined in claim 1 wherein said analysis chamber is a channel having a first end in fluid communication with said reaction chamber and an oppositely disposed second end.

5. Apparatus as defined in claim 4 including a collection sponge in fluid communication with said second end.

9. Apparatus as defined in claim 1 including a temperature measuring device positioned in thermal communication with said reaction chamber.

10. Apparatus as defined in claim 1 including a heat sink in thermal communication with said reaction chamber.

11. Apparatus as defined in claim 10 wherein said heat sink comprises a cooler which is controllable to maintain a desired temperature.

12. Apparatus as defined in claim 1 including a plurality of reaction chambers and a plurality of controllable heaters with each heater positioned in thermal communication with at least one reaction chamber and controllable independently of the other heaters.

13. Apparatus as defined in claim 1 including a valve controlling fluid flow between said reaction chamber and said analysis chamber.

6. Apparatus as defined in 1 including an analytical material useful in performing a PCR process positioned in said analysis chamber.

7. Apparatus as defined in claim 6 wherein said analytical material comprises discrete probes anchored to said lower surface.

8. Apparatus as defined in claim 6 wherein said analytical material is an electrophoretic gel.

14. Apparatus having microfabricated chambers for conducting biochemical analysis;

comprising

a flexible substrate comprising an ablatable polymeric material having a first major face and a second major face defining a thickness therebetween;

a plurality of ablated reaction chambers spaced apart in the first major face, said chambers having an open top and a floor positioned within said thickness;

a plurality of individually controllable heaters integrally formed within said substrate, each heater positioned in thermal communication with at least one of said reaction chambers;

a plurality of ablated analyses chambers, each positioned in a path of fluid communication with at least one of the reaction chambers and having a window at one of the major faces and a lower surface positioned within said thickness; and

a plurality of valves controlling flow of fluid between each reaction chamber and a corresponding analysis chamber.

15. Apparatus as defined in claim 14 including at least one ablated solvent reservoir in fluid communication with at least one of said analysis chambers.

16. Apparatus as defined in claim 14 including at least one temperature measuring device positioned in thermal communication with at least one of said reaction chambers.

17. Apparatus as defined in claim 16 wherein said temperature measuring device is a thermocouple.

18. Apparatus as defined in claim 16 wherein said temperature measuring device is a thin film thermocouple.

19. Apparatus as defined in claim 14 including at least one controllable cooler positioned in thermal communication with at least one of said reaction chambers.

20. Apparatus as defined in claim 14 wherein said substrate comprises at least one metallic layer and at least one non-metallic layer.

21. Apparatus as defined in claim 20 wherein at least one of said heaters comprises at least a portion of said metallic layer.

22. Apparatus as defined in claim 14 wherein at least one of said heaters is a resistance heater.

23. Apparatus as defined in claim 14 wherein at least one of said heaters is an ohmic heater.

24. Apparatus as defined in claim 14 wherein at least one of said heaters includes magnetic beads positioned in said substrate adjacent a reaction chamber.

25. Apparatus as defined in claim 14 wherein at least one of said heaters comprises a thermoelectric device positioned to encircle said reaction chamber and pump heat into the chamber.

26. Apparatus as defined in claim 14 wherein at least one of said analysis chambers comprises a channel having a first end and a second end with said first end in fluid communication said reaction chamber.

27. Apparatus as defined in claim 26 wherein said channel is sized to draw fluids from said reaction chamber through capillary action.

28. Apparatus as defined in claim 27 wherein said second end is in fluid communication with a sponge.

29. Apparatus as defined in claim 14 wherein at least one of said valves is pressure operated.

30. Apparatus as defined in claim 14 wherein at least one of said valves is chemically operated.

31. Apparatus as defined in claim 14 wherein at least one said valves is electrically operated.

32. Apparatus as defined in claim 14 wherein said analysis chambers and said reaction chambers have at least some opposite walls within the chambers spaced apart within the range of 10 to 1000 micrometers.

33. Apparatus having microfabricated chambers for conducting biochemical analysis, comprising:

a plurality of flexible substrates of the kind used in flexible circuit manufacturing technology comprising an ablatable polymeric material, each substrate having first and second oppositely disposed major faces defining a thickness therebetween;

at least one ablated reaction chamber formed within each substrate, having an open top at one of said major faces and a floor positioned within said thickness wherein said at least one reaction chamber is produced by ablation;

a thermo-electric module positioned in thermal communication with each said substrate; and

an ablated analysis chamber in a path of fluid communication with each said reaction chamber, said analysis chamber having a window at one of said major faces and a lower surface positioned within said thickness.

34. Apparatus as defined in claim 33 including a solvent reservoir formed in at least one said substrate and in fluid communication with said analysis chamber.

35. Apparatus as defined in claim 33 including reagent material useful in performing a PCR process, deposited in said reaction chamber.

36. Apparatus as defined in claim 33 wherein at least one said analysis chamber is a channel having a first end in fluid communication with said reaction chamber and an oppositely disposed second end.

37. Apparatus as defined in claim 36 including a collection sponge in fluid communication with said second end.

41. Apparatus as defined in claim 33 wherein at least one substrate includes a temperature measuring device.

42. Apparatus as defined in claim 33 wherein at least one substrate includes a valve controlling fluid flow between said reaction chamber and said analysis chamber.

43. Apparatus as defined in claim 33 including individual controls for controlling the polarity and flow of current through each said thermo-electric module.

38. Apparatus as defined in 33 including an analytical material useful in performing a PCR process, positioned in said analysis chamber.

39. Apparatus as defined in claim 38 wherein said analytical material comprises discrete probes anchored to said lower surface.

40. Apparatus as defined in claim 38 wherein said analytical material is an electrophoretic gel.

44. Apparatus having microfabricated chamber for conducting biochemical analysis, comprising:

a plurality of flexible substrates of the kind used in flexible circuit manufacturing technology comprising an ablatable polymeric material, each substrate having first and second oppositely disposed major faces defining a thickness therebetween;

at least one ablated reaction chamber formed within each substrate, having an open top at one of said major faces and a floor positioned within said thickness wherein said at least one reaction chamber is produced by ablation;

a thermo-electric module positioned in thermal communication with each said substrate; and

individual controls for controlling the polarity and flow of current through each said thermo-electric module.

45. Apparatus as defined in claim 44 wherein at least one said substrate includes an analysis chamber in fluid communication with said reaction chamber having a window at one of said major faces and a lower surface positioned within said thickness.

46. Apparatus as defined in claim 45 wherein said chamber is a channel sized to draw fluids from said reaction chamber through capillary action.

47. Apparatus as defined in claim 45 including a solvent reservoir formed in at least one said substrate and in fluid communication with said analysis chamber.

48. Apparatus as defined in claim 44 wherein at least one substrate includes a temperature measuring device.

49. Apparatus as defined in claim 44 wherein at least one substrate includes a valve controlling fluid flow between said reaction chamber and said analysis chamber.

50. Apparatus as defined in claim 49 wherein said valve is pressure operated.

51. Apparatus as defined in claim 49 wherein at least one of said valves is chemically operated.

52. Apparatus as defined in claim 49 wherein at least one of said valves is electrically operated.

53. Apparatus as defined in claim 44 further comprising an analysis chamber in fluid communication with each said reaction chamber having a window at one of said major faces and a lower surface positioned within said thickness.