Miniaturized multi-chamber thermocycler

• US 5,939,312 A
• Filed: 12/26/1996
• Issued: 08/17/1999
• Est. Priority Date: 05/24/1995
• Status: Expired due to Term

• Current Assignee: Biometra biomedizinische Analytik GmbH (Noblex GmbH)
• Original Assignee: Institut Fur Physikalische Hochtechnologie E.V., Biometra biomedizinische Analytik GmbH (Noblex GmbH)
• Inventors: Dillner, Ulrich, Baier, Volker, Bodner, Ulrich, Schimkat, Dieter, Poser, Siegfried, Kohler, Johann Michael
• Primary Examiner(s): Sisson, Bradley L.
• Application Number:
  US08/765,649
• Time in Patent Office: 964 Days
• Field of Search: 435/6, 435/287.2, 435/287.3, 435/287.9, 435/288.4, 435/91.1, 435/91.2, 435/183, 422/50, 422/63, 422/68.1, 422/82.12, 422/99, 536/23.1, 536/24.33, 935/85
• US Class Current: 435/287.2
• CPC Class Codes: B01L 2300/0819 Microarrays; Biochips
• CPC Class Codes: B01L 2300/1827 using resistive heater
• CPC Class Codes: B01L 2300/1883 using thermal insulation
• 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 3/50851 specially adapted for heating or cooling samples laboratory heating apparatus B01L7/00; incubators C12M
• CPC Class Codes: B01L 7/52 with provision for submitting samples to a predetermined sequence of different temperatures, e.g. for treating nucleic acid samples amplification or hybridisation processes per se C12Q1/68; controlling sequential reactions for synthesis B01J19/0046

Abstract

A miniaturized multi-chamber thermocycler provides a thermocycler which is easy to handle, and permits the treatment of a great number of samples of small sample volumes at high temperature changing rates and at low heating powers. A sample receptacle body manufactured in micro-system technics provides a plurality of sample chambers which are embodied such that at least one of the sample chamber walls of the sample chamber which constitutes the sample chamber base is an efficient heat conductor and also of low mass. Said sample chambers are coupled to a coupling body, serving as heat sink, established via at least one poor heat conducting bridge which, with respect to its dimensioning and/or material selection is such that its specific heat conductance λ is smaller 5 W/K°·m. The sample chambers are provided with at least one heating element which is constructed to effect, in connection with a sample chamber wall serving as heat balancing layer which simultaneously can be the sample chamber base, a substantially homogeneous temperature distribution in a fluid insertable into the sample chambers.

Claims

1. A miniaturized multi-chamber thermocycler, comprising:

a sample receptacle mount for receiving fluids, said sample receptacle mount including sample chambers formed therein for receiving said fluids;

each of said sample chambers being bounded by sample chamber walls including a sample chamber base whereat heat is applied to and removed from said sample chambers, and sampler chamber side walls;

a coupling support body supporting said sample receptacle mount and functioning as a heat sink;

said sample receptacle mount including means for coupling said sample chambers to said coupling support body;

said means for coupling including at least one bridge coupling said sample chambers to said coupling support body and said at least one bridge having a specific heat conductance λ

less than 5 W/K·

m to limit heat transfer between said sample chambers and said coupling support body; and

said sample chamber base including at least one heating element with said sample chamber base functioning as a heat balancing layer.

2. The miniaturized multi-chamber thermocycler as claimed in claim 1, wherein:

said sample chambers are rectangular with said sample chamber bases being elongated and said side walls include end side walls, opposing one another, which are narrower than an elongate direction of said sample chamber bases;

said sample chambers are arranged in a row with said elongate direction of said sample chamber base being transverse to said row and said end side walls being disposed at opposing sides of said row; and

said at least one bridge includes a strip member, formed by etching said sample receptacle mount, extending parallel to said row and adjacent at least one of said end side walls of each of said sample chambers to connect said sample chambers to said coupling support body.

3. The miniaturized multi-chamber thermocycler as claimed in claim 2, further including an insulating bridge member disposed on said strip member and on portions of said sample receptacle mount bordering sides of said strip member.

4. The miniaturized multi-chamber thermocycler as claimed in claim 3, wherein a material of said insulating bridge member is selected from a group of materials consisting of a glass plate, a coating of SiO₂, a coating of Si₃ N₄, and coating of a varnish.

5. The miniaturized multi-chamber thermocycler as claimed in claim 2, wherein said at least one heating element is a microstructurized thin layer heater connected to said sample chamber base and having a configuration which provides greater heat at portions of said sample chambers proximate said at least one of said end side walls than at remaining portions of said sample chambers.

6. The miniaturized multi-chamber thermocycler as claimed in claim 3, wherein a material of said sample receptacle mount is silicon.

7. The miniaturized multi-chamber thermocycler as claimed in claim 6, wherein a material of said insulating bridge member is selected from a group of materials consisting of a glass plate, a coating of SiO₂, a coating of Si₃ N₄, and coating of a varnish.

8. The miniaturized multi-chamber thermocycler as claimed in claim 6, wherein said sample chambers have a volume in a range of 2 μ

l to 10 μ

l.

9. The miniaturized multi-chamber thermocycler as claimed in claim 1, wherein a material of said sample receptacle mount is silicon.

10. The miniaturized multi-chamber thermocycler as claimed in claim 9, wherein said sample chambers have a volume in a range of 2 μ

l to 10 μ

l.

11. The miniaturized multi-chamber thermocycler as claimed in claim 9, wherein said sample chambers have a volume in a range of 2 μ

l to 10 μ

l.

12. A miniaturized multi-chamber thermocycler, comprising:

a sample receptacle mount for receiving fluids, said sample receptacle mount including sample chambers formed therein for receiving said fluids;

each of said sample chambers being bounded by sample chamber walls including a sample chamber base, whereat heat is applied to and removed from said sample chambers, and sampler chamber side walls;

a coupling support body supporting said sample receptacle mount;

said sample receptacle mount including means for coupling said sample chambers to said coupling support body;

said means for coupling including at least one bridge coupling said sample chambers to said coupling support body;

said sample chamber base including at least one heating element and said sample chamber base functioning as a heat balancing layer;

said sample chambers being rectangular with said sample chamber bases being elongated and said side walls including end side walls, opposing one another, which are narrower than an elongate direction of said sample chamber bases;

said sample chambers being arranged in a row with said elongate direction of said sample chamber bases being transverse to said row and said end side walls being disposed at opposing sides of said row;

said at least one bridge including a strip member, formed by etching said sample receptacle mount, extending parallel to said row and adjacent at least one of said end side walls of each of said sample chambers to connect said sample chambers to said coupling support body;

said at least one bridge including an insulating bridge member disposed on said strip member and on portions of said sample receptacle mount bordering sides of said strip member; and

said at least one bridge satisfying a relation G'"'"'=(λ

_u d_u)/b_sp, where G'"'"' is a modified heat conductance having a value between 0.6 and 6 W/K°

·

m, λ

_u is a specific heat conductance of said at least one bridge and is smaller than 5 W/K·

m, d_u is a thickness of said at least one bridge, and b_sp is a width of said strip member extending in a direction of a thermal gradient between said sample chambers and said coupling support body.

13. The miniaturized multi-chamber thermocycler as claimed in claim 12, wherein a material of said sample receptacle mount is silicon.

14. The miniaturized multi-chamber thermocycler as claimed in claim 13, wherein said sample chambers have a volume in a range of 2 μ

l to 10 μ

l.

15. The miniaturized multi-chamber thermocycler as claimed in claim 12, wherein said sample chambers have a volume in a range of 2 μ

l to 10 μ

l.

16. A miniaturized multi-chamber thermocycler, comprising:

a sample receptacle mount for receiving fluids, said sample receptacle mount including sample chambers formed therein for receiving said fluids;

each of said sample chambers being bounded by sample chamber walls including a sample chamber base and sampler chamber side walls;

a coupling support body supporting said sample receptacle mount and functioning as a heat sink;

said sample receptacle mount including means for coupling said sample chambers to said coupling support body;

said means for coupling including at least one bridge having a specific heat conductance λ

less than 5 W/K·

m;

said sample chambers having at least one heating element;

said sample receptacle mount having a bottom surface spaced from the coupling support body to define a gap;

said sample chamber bases forming portions of said bottom surface and being arranged in a common plane; and

said at least one bridge includes a bridge substance filling said gap between said bottom surface and said coupling support body to connect the sample chambers to the coupling support body.

17. The miniaturized multi-chamber thermocycler as claimed in claim 16, wherein a relationship λ

_sp /b'"'"'_sp has a value between 300 and 3000 W/K·

m², where λ

_sp is a specific heat conductance within said gap and b'"'"'_sp is a width of said gap.

18. The miniaturized multi-chamber thermocycler as claimed in claim 17, wherein said bridge substance includes at least one material selected from a group consisting of a SiO₂ -plate, a Si₃ N₄ -plate and a glass plate.

19. The miniaturized multi-chamber thermocycler as claimed in claim 17, wherein said bridge substance includes one of a fluid and a gaseous medium.

20. The miniaturized multi-chamber thermocycler as claimed in claim 16, wherein said sample bases include said at least one heating element such that said sample chamber bases function as heat balancing layers.

21. The miniaturized multi-chamber thermocycler as claimed in claim 16, wherein a material of said sample receptacle mount is silicon.

22. The miniaturized multi-chamber thermocycler as claimed in claim 21, wherein said sample chambers have a volume in a range of 2 μ

l to 10 μ

l.

23. The miniaturized multi-chamber thermocycler as claimed in claim 16, wherein said sample chambers have a volume in a range of2 μ

l to 10 μ

l.

24. A miniaturized multi-chamber thermocycler, comprising:

a sample receptacle mount for receiving fluids, said sample receptacle mount including sample chambers formed therein for receiving said fluids;

each of said sample chambers being bounded by sample chamber walls including a sample chamber base, whereat heat is applied to and removed from said sample chambers, and sampler chamber side walls;

a coupling support body supporting said sample receptacle mount;

said sample receptacle mount including at least one bridge coupling said sample chambers to said coupling support body;

said sample chamber base including at least one heating element and said sample chamber base functioning as a heat balancing layer;

said sample chambers being rectangular with said sample chamber bases being elongated and said side walls including end side walls, opposing one another, which are narrower than an elongate direction of said sample chamber bases;

said sample chambers being arranged in a row with said elongate direction of said sample chamber bases being transverse to said row and said end side walls being disposed at opposing sides of said row;

said at least one bridge including a strip member, formed by etching said sample receptacle mount, extending parallel to said row and adjacent at least one of said end side walls of each of said sample chambers to connect said sample chambers to said coupling support body;

said at least one bridge including an insulating bridge member disposed on said strip member and on portions of said sample receptacle mount bordering sides of said strip member; and

said at least one bridge satisfying a relation G'"'"'=(λ

_u d_u)/b_sp, where G'"'"' is a a modified heat conductance having a value between 0.6 and 6 W/K°

·

m, λ

_u is specific heat conductance of said at least one bridge and is smaller than 5 W/K·

m, d_u is a thickness of said at least one bridge, and b_sp is a width of said strip member extending in a direction of a thermal gradient between said sample chambers and said coupling support body.

25. The miniaturized multi-chamber thermocycler as claimed in claim 24, wherein said sample chambers have a volume in a range of 2 μ

l to 10 μ

l.

26. A miniaturized multi-chamber thermocycler, comprising:

a sample receptacle mount for receiving fluids, said sample receptacle mount including sample chambers formed therein for receiving said fluids;

each of said sample chambers being bounded by sample chamber walls including a sample chamber base and sampler chamber side walls;

a coupling support body supporting said sample receptacle mount and functioning as a heat sink;

said sample receptacle mount including at least one bridge having a specific heat conductance λ

less than 5 W/K·

m;

said sample chambers having at least one heating element;

said sample receptacle mount having a bottom surface spaced from the coupling support body to define a gap;

said sample chamber bases forming portions of said bottom surface and being arranged in a common plane; and

said at least one bridge includes a bridge substance filling said gap between said bottom surface and said coupling support body to connect the sample chambers to the coupling support body.

27. The miniaturized multi-chamber thermocycler as claimed in claim 26, wherein said sample chambers have a volume in a range of 2 μ

l to 10 μ

l.

28. A miniaturized multi-chamber thermocycler, comprising:

a sample receptacle mount for receiving fluids, said sample receptacle mount including sample chambers formed therein for receiving said fluids;

each of said sample chambers being bounded by sample chamber walls including a sample chamber base whereat heat is applied to and removed from said sample chambers, and sampler chamber side walls;

a coupling support body supporting said sample receptacle mount and functioning as a heat sink;

said sample receptacle mount including at least one bridge coupling said sample chambers to said coupling support body and said at least one bridge having a specific heat conductance A less than 5 W/K·

m to limit heat transfer between said sample chambers and said coupling support body; and

said sample chamber base including at least one heating element with said sample chamber base functioning as a heat balancing layer.

29. The miniaturized multi-chamber thermocycler as claimed in claim 28, wherein said sample chambers have a volume in a range of 2 μ

l to 10 μ

l.

30. A miniaturized multi-chamber thermocycler, comprising:

a sample receptacle mount for receiving fluids, said sample receptacle mount including sample chambers formed therein for receiving said fluids;

each of said sample chambers being bounded by sample chamber walls including a sample chamber base, whereat heat is applied to and removed from said sample chambers, and sampler chamber side walls;

a coupling support body supporting said sample receptacle mount;

said sample receptacle mount including at least one bridge coupling said sample chambers to said coupling support body so as to thermally insulate said sample chambers from said coupling support body;

said sample chamber base including at least one heating element and said sample chamber base functioning as a heat balancing layer; and

said at least one bridge being a strip member formed in said receptacle mount such that said strip member has a thickness less than a thickness of a remainder of said sample receptacle mount surrounding said sample chambers and connects said sample chambers to said coupling support body so as to thermally insulate said sample chambers from said coupling support body.

31. The miniaturized multi-chamber thermocycler as claimed in claim 30, wherein said at least one bridge satisfies a relation G'"'"'=(λ

_u d_u)/b_sp, where G'"'"' is a a modified heat conductance having a value between 0.6 and 6 W/K°

·

m, λ

_u is specific heat conductance of said at least one bridge and is smaller than 5 W/K·

m, d_u is a thickness of said at least one bridge, and b_sp is a width of said strip member extending in a direction of a thermal gradient between said sample chambers and said coupling support body.

32. The miniaturized multi-chamber thermocycler as claimed in claim 31, wherein said sample chambers have a volume in a range of 2 μ

l to 10 μ

l.

33. The miniaturized multi-chamber thermocycler as claimed in claim 30, wherein said at least one bridge has a specific heat conductance λ

less than 5 W/K·

m.

34. The miniaturized multi-chamber thermocycler as claimed in claim 33, wherein said sample chambers have a volume in a range of 2 μ

l to 10 μ

l.