EP0876218A1 - Heating - Google Patents

Heating

Info

Publication number
EP0876218A1
EP0876218A1 EP97901166A EP97901166A EP0876218A1 EP 0876218 A1 EP0876218 A1 EP 0876218A1 EP 97901166 A EP97901166 A EP 97901166A EP 97901166 A EP97901166 A EP 97901166A EP 0876218 A1 EP0876218 A1 EP 0876218A1
Authority
EP
European Patent Office
Prior art keywords
sheet
heating
carrier
specimen
metallic
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP97901166A
Other languages
German (de)
French (fr)
Other versions
EP0876218B1 (en
Inventor
Ian Alan Gunter
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
BJS Co Ltd
Original Assignee
BJS Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB9601471.7A external-priority patent/GB9601471D0/en
Priority claimed from GBGB9603717.1A external-priority patent/GB9603717D0/en
Application filed by BJS Co Ltd filed Critical BJS Co Ltd
Publication of EP0876218A1 publication Critical patent/EP0876218A1/en
Application granted granted Critical
Publication of EP0876218B1 publication Critical patent/EP0876218B1/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/508—Containers for the purpose of retaining a material to be analysed, e.g. test tubes rigid containers not provided for above
    • B01L3/5085—Containers for the purpose of retaining a material to be analysed, e.g. test tubes rigid containers not provided for above for multiple samples, e.g. microtitration plates
    • B01L3/50851—Containers for the purpose of retaining a material to be analysed, e.g. test tubes rigid containers not provided for above for multiple samples, e.g. microtitration plates specially adapted for heating or cooling samples
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F33/00—Other mixers; Mixing plants; Combinations of mixers
    • B01F33/45—Magnetic mixers; Mixers with magnetically driven stirrers
    • B01F33/452—Magnetic mixers; Mixers with magnetically driven stirrers using independent floating stirring elements

Definitions

  • the present invention relates to heating and more particularly to the thermal cycling of specimen carriers.
  • specimen carriers in the form of support blocks or platterns are used for various processes where small samples are thermally cycled.
  • a particular example is the Polymerase Chain Reaction method (often referred to as PCR) for replicating DNA samples.
  • PCR Polymerase Chain Reaction method
  • Such samples require rapid and accurate thermal cycling, and are typically placed in a multi-well block and cycled between several selected temperatures in a pre-set repeated cycle.
  • the present invention solves this problem by applying direct electrical resistive heating to a metallic specimen carrier.
  • the invention provides a method of heating a specimen carrier in the form of a metallic sheet and applying a heating current to said sheet.
  • the metallic sheet will be of silver which has a high thermal and electrical conductivity.
  • the sheet will generally have a thin section in the region of 0.3mm thickness, and may be in a form where a matrix of sample wells is incorporated in the sheet.
  • the metallic sheet may be a solid sheet or block of silver (which may have cavities forming wells)
  • a metallised plastic tray which may have impressed wells
  • deposited metal forms a resistive heating element
  • Another alternative is to electro form a thin metal tray (which again may have impressed wells), and to coat the metal with a bio-compatible polymer.
  • the plastic trays are conventionally single use disposable items.
  • the incorporation of the heating element into the plastic trays may increase their cost, but the reduction in cycling time for the PCR reaction more than compensates for any increased cost of the disposable item.
  • the bottom of the composite tray should be unobstructed when fan cooling is employed. If sub-ambient cooling is required at the end of the PCR cycles, either with a composite tray or a block, chilled liquid spray-cooling may be employed.
  • the boiling point of the liquid should be below the low point of the PCR cycle so that liquid does not remain on the metal of the tray or block to impede heating. This also allows for the latent heat of evaporation of the liquid to increase the cooling effect.
  • the heating current may be an AC current supplied from the secondary winding of a transformer. This allows cycling control to be applied to the primary circuit of the transformer (higher voltage, lower current) in a convenient way without encountering problems which arise when operating with high current devices .
  • the transformer may comprise a toroidal core having an appropriate mains primary winding and a single bus bar looped through the core and connected in series with the metallic sheet to form a single turn secondary circuit.
  • Figure 1 is a side elevation of a heating apparatus
  • Figure 2 is a plan view of the apparatus of Figure 1.
  • a metallic specimen carrier in the form of a multi-well block (1) measuring 110mm x 75mm and having 96 wells (2) disposed in a grid layout is formed in silver nominally 0.3mm thick. This is attached to bus bars (3) of substantial cross-sectional area.
  • the bus bars loop once through a transformer (toroidal or square), core (4).
  • the core (4) has a primary winding (5) appropriate for the mains voltage employed.
  • the transformer primary current is controlled using a triac device (6).
  • the triac device receives current from an AC source and is controlled by a temperature control circuit (7) which uses a fine wire thermocouple (8) soldered to a central underside region of the block to sense the temperature of the block.
  • the temperature control circuitry may be operated manually or by a personal computer (9).
  • Cooling of the block is by means of a fan (10) mounted under the block, blowing ambient air over the protruding well forms (2), the air being directed by the enclosure in which the block is mounted.
  • the fan is controlled by the same temperature control circuitry that drives the heater triac .
  • the measured performance of the example apparatus gives rates of change of temperature in excess of 6 degrees per second and over/under shoots of less than 0.25 degrees within the typical PCR working range of 50-100 degrees.
  • the described examples use a silver block with cavities, but metalised plastic tray inserts, or electro formed thin metal trays, as previously described, may also be used.
  • the system as described has several important advantages . 1.1
  • the block is heated directly with no requirement for heat transfer from an attached heat source. This is very efficient and taken together with the very low specific heat capacity of silver allows very rapid temperature changes.
  • Direct heating means that there is no thermal lag at all. Temperature control functions are immediate so that the block may be cycled in temperature with little or no over or undershoot. Temperature control is therefore inherently precise.
  • thermocouple is soldered directly to the block so as to provide close temperature measurement and control . Any other temperature measurement device may be used as long as it does not introduce significant sensor lag.
  • the temperature distribution around the surface of the block is dependent on the evenness of heating and the thermal conductivity of the block.
  • the thermal conductivity of silver is very high, and the distribution of heat energy around the block is dependent upon the distribution of the heating current. This may be regulated by varying the geometry of the multi-well block.
  • the large currents required may be easily produced and controlled since the block becomes part of a heavy secondary circuit of the transformer.
  • the cross- sectional area of the winding bars is made considerably larger than the cross-sectional area of the block so that significant heat generation only occurs in the block.
  • the current can be easily controlled in the primary winding (where the current is small), using thyristors, triacs or other devices.
  • the primary winding may be driven by a high frequency, switch mode, controllable power supply. This allows the same degree of control of the current induced in the secondary winding incorporating the block, but the high frequency allows the use of a more compact core in the transformer, and reduces inrush current surges when switching the current on and off.

Abstract

A method and apparatus for heating specimens in wells of a metallic specimen carrier. The specimen carrier is heated by applying resistive heating directly to the carrier. An AC source and transformer may be used where the specimen carrier is in series with a single turn secondary winding of the transformer.

Description

" Heating "
The present invention relates to heating and more particularly to the thermal cycling of specimen carriers.
In many fields specimen carriers in the form of support blocks or platterns are used for various processes where small samples are thermally cycled.
A particular example is the Polymerase Chain Reaction method (often referred to as PCR) for replicating DNA samples. Such samples require rapid and accurate thermal cycling, and are typically placed in a multi-well block and cycled between several selected temperatures in a pre-set repeated cycle.
Previous methods of heating such specimen carriers have involved use of resistance wire coiled around the wells, use of Peltier effect devices or hot air methods. However such methods are difficult to control to the precision required, necessitate slow cycle times and can give rise to thermal over shoot.
The present invention solves this problem by applying direct electrical resistive heating to a metallic specimen carrier. Thus the invention provides a method of heating a specimen carrier in the form of a metallic sheet and applying a heating current to said sheet.
Preferably the metallic sheet will be of silver which has a high thermal and electrical conductivity. The sheet will generally have a thin section in the region of 0.3mm thickness, and may be in a form where a matrix of sample wells is incorporated in the sheet.
While the metallic sheet may be a solid sheet or block of silver (which may have cavities forming wells) an alternative is to use a metallised plastic tray (which may have impressed wells) , in which deposited metal forms a resistive heating element.
Another alternative is to electro form a thin metal tray (which again may have impressed wells), and to coat the metal with a bio-compatible polymer.
These measures enable intimate contact to be achieved between the metallic heating element and the bio¬ compatible sample receptacles. This gives greatly improved thermal performance in terms of temperature control and rate of change of temperature when the actual temperatures of the reagents in the wells is measured.
The plastic trays are conventionally single use disposable items. The incorporation of the heating element into the plastic trays may increase their cost, but the reduction in cycling time for the PCR reaction more than compensates for any increased cost of the disposable item.
The bottom of the composite tray should be unobstructed when fan cooling is employed. If sub-ambient cooling is required at the end of the PCR cycles, either with a composite tray or a block, chilled liquid spray-cooling may be employed. The boiling point of the liquid should be below the low point of the PCR cycle so that liquid does not remain on the metal of the tray or block to impede heating. This also allows for the latent heat of evaporation of the liquid to increase the cooling effect.
The heating current may be an AC current supplied from the secondary winding of a transformer. This allows cycling control to be applied to the primary circuit of the transformer (higher voltage, lower current) in a convenient way without encountering problems which arise when operating with high current devices .
The transformer may comprise a toroidal core having an appropriate mains primary winding and a single bus bar looped through the core and connected in series with the metallic sheet to form a single turn secondary circuit.
An embodiment of the invention will now be described by way of example with reference to the accompanying diagrammatic drawings in which:
Figure 1 is a side elevation of a heating apparatus, and
Figure 2 is a plan view of the apparatus of Figure 1.
A metallic specimen carrier in the form of a multi-well block (1) measuring 110mm x 75mm and having 96 wells (2) disposed in a grid layout is formed in silver nominally 0.3mm thick. This is attached to bus bars (3) of substantial cross-sectional area. The bus bars loop once through a transformer (toroidal or square), core (4). The core (4) has a primary winding (5) appropriate for the mains voltage employed. The transformer primary current is controlled using a triac device (6). The triac device receives current from an AC source and is controlled by a temperature control circuit (7) which uses a fine wire thermocouple (8) soldered to a central underside region of the block to sense the temperature of the block. The temperature control circuitry may be operated manually or by a personal computer (9). Cooling of the block is by means of a fan (10) mounted under the block, blowing ambient air over the protruding well forms (2), the air being directed by the enclosure in which the block is mounted. The fan is controlled by the same temperature control circuitry that drives the heater triac .
The measured performance of the example apparatus gives rates of change of temperature in excess of 6 degrees per second and over/under shoots of less than 0.25 degrees within the typical PCR working range of 50-100 degrees.
The described examples use a silver block with cavities, but metalised plastic tray inserts, or electro formed thin metal trays, as previously described, may also be used.
The system as described has several important advantages . 1.1 The block is heated directly with no requirement for heat transfer from an attached heat source. This is very efficient and taken together with the very low specific heat capacity of silver allows very rapid temperature changes.
1.2 Direct heating means that there is no thermal lag at all. Temperature control functions are immediate so that the block may be cycled in temperature with little or no over or undershoot. Temperature control is therefore inherently precise.
1.3 Since there are no obstructions or thermal barriers attached to the block, simple forced-air cooling of the back of the block (which may be shaped to increase its surface area), provides rapid and controllable cooling.
1.4 The fine wire thermocouple is soldered directly to the block so as to provide close temperature measurement and control . Any other temperature measurement device may be used as long as it does not introduce significant sensor lag.
1.5 The temperature distribution around the surface of the block is dependent on the evenness of heating and the thermal conductivity of the block. The thermal conductivity of silver is very high, and the distribution of heat energy around the block is dependent upon the distribution of the heating current. This may be regulated by varying the geometry of the multi-well block.
The large currents required may be easily produced and controlled since the block becomes part of a heavy secondary circuit of the transformer. The cross- sectional area of the winding bars is made considerably larger than the cross-sectional area of the block so that significant heat generation only occurs in the block. The current can be easily controlled in the primary winding (where the current is small), using thyristors, triacs or other devices. Alternatively, the primary winding may be driven by a high frequency, switch mode, controllable power supply. This allows the same degree of control of the current induced in the secondary winding incorporating the block, but the high frequency allows the use of a more compact core in the transformer, and reduces inrush current surges when switching the current on and off.

Claims

CLAIMS ;
1. A method of heating a specimen carrier of the kind comprising a plurality of specimen sites such as wells, which carrier is in the form of a metallic sheet and the method comprising applying a current to said sheet so as to provide resistive heating of said sheet so as to heat specimens carried by said carrier.
2. A method according to Claim 1 in which the heating is applied as an alternating current providing resistive heating, and is controlled to provide repeated cycles of heating.
3. A method according to any preceding claim in which said metallic sheet is a solid block of silver.
4. A method according to any preceding claim in which said sheet is a metallised plastic tray.
5. A method according to any preceding claim in which said sheet is an electro-formed thin metal tray.
6. A method according to any preceding claim in which said metallic sheet includes a plurality of wells to contain a plurality of specimens.
7. Apparatus for carrying out the method of any preceding claim comprising a specimen carrier of the kind carrying a plurality of specimen sites such as wells, which carrier is in the form of a metallic electrically conductive sheet, power supply means, and a transformer having a primary winding connected to said power supply means, and a secondary winding directly connected to said conductive sheet.
8. Apparatus according to claim 7 in which said secondary winding is a single turn winding.
9. Apparatus according to any of Claims 7 or 8, comprising temperature control means connected to regulate flow of heating current through said secondary winding at a rate which maintains a controlled heating temperature within said specimen carrier.
10. Apparatus according to Claim 9 comprises fan cooling means arranged to direct cooling air to a rear side of said specimen carrier and operatively connected to said temperature control means .
11. Apparatus according to any of Claims 7 to 10 in which said metallic sheet is a solid block of silver.
12. Apparatus according to any of Claims 7 to 10 in which said metallic sheet is a metallised plastic tray.
13. Apparatus according to any of Claims 7 to 10 in which said metallic sheet is an electro-formed thin metal tray.
EP97901166A 1996-01-25 1997-01-23 Heating of a specimen carrier Expired - Lifetime EP0876218B1 (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
GB9601471 1996-01-25
GBGB9601471.7A GB9601471D0 (en) 1996-01-25 1996-01-25 Heating
GB9603717 1996-02-22
GBGB9603717.1A GB9603717D0 (en) 1996-02-22 1996-02-22 Heating
PCT/GB1997/000195 WO1997026993A1 (en) 1996-01-25 1997-01-23 Heating

Publications (2)

Publication Number Publication Date
EP0876218A1 true EP0876218A1 (en) 1998-11-11
EP0876218B1 EP0876218B1 (en) 2000-10-25

Family

ID=26308521

Family Applications (1)

Application Number Title Priority Date Filing Date
EP97901166A Expired - Lifetime EP0876218B1 (en) 1996-01-25 1997-01-23 Heating of a specimen carrier

Country Status (11)

Country Link
EP (1) EP0876218B1 (en)
JP (1) JP3705606B2 (en)
AT (1) ATE197129T1 (en)
AU (1) AU1451097A (en)
CA (1) CA2244178C (en)
DE (1) DE69703381T2 (en)
DK (1) DK0876218T3 (en)
ES (1) ES2151241T3 (en)
GR (1) GR3034671T3 (en)
PT (1) PT876218E (en)
WO (1) WO1997026993A1 (en)

Families Citing this family (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0007219D0 (en) * 2000-03-24 2000-05-17 Bjs Company Ltd Heating specimen carriers
US6635492B2 (en) 1996-01-25 2003-10-21 Bjs Company Ltd. Heating specimen carriers
EP1000661A1 (en) * 1998-10-29 2000-05-17 Hans-Knöll-Institut für Naturstoff-Forschung e.v. Ultrathin-walled multiwell plate for heat block thermocycling
DE10028323A1 (en) * 2000-06-07 2001-12-20 Evotec Biosystems Ag Microtiter plate or chip for containing biological or chemical samples, comprises a flat plastic sheet containing wells, a supporting core made from high melting point material surrounding each well being embedded in plastic sheet
GB2370112A (en) * 2000-12-15 2002-06-19 Hybaid Ltd Multiwell sample plates
DE20101734U1 (en) * 2001-02-01 2002-06-13 Evotec Biosystems Ag sample carrier
AU2002310629A1 (en) * 2001-06-21 2003-01-08 Hybaid Limited Sample well plate
GB0121827D0 (en) 2001-09-10 2001-10-31 Bjs Company Ltd Zone heating of specimen carriers
JP4574328B2 (en) * 2004-11-10 2010-11-04 キヤノン株式会社 Sample temperature controller
US7632464B2 (en) * 2006-06-29 2009-12-15 Bio-Rad Laboratories, Inc. Low-mass sample block with rapid response to temperature change
CN103476498B (en) 2010-12-17 2016-09-28 Bjsip有限公司 Method and system for fast PCR heating
EP2855019A1 (en) 2012-05-24 2015-04-08 BJS IP Limited Clamp for fast pcr heating
US20140302562A1 (en) 2013-03-15 2014-10-09 Bjs Ip Ltd. Fast pcr heating

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3266735D1 (en) * 1981-02-18 1985-11-14 Eisai Co Ltd An enzyme immuno-assay for simultaneously measuring a plurality of samples and test vessel for carrying out this method
WO1994001529A1 (en) * 1992-07-01 1994-01-20 Keiichi Katoh Ceramic heating/cooling device
EP0706646B1 (en) * 1993-07-02 1998-03-25 Institut Für Molekulare Biologie E.V. Sample holder and its use
US5410130A (en) * 1994-04-20 1995-04-25 Ericomp, Inc. Heating and temperature cycling

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9726993A1 *

Also Published As

Publication number Publication date
ATE197129T1 (en) 2000-11-15
GR3034671T3 (en) 2001-01-31
PT876218E (en) 2001-03-30
AU1451097A (en) 1997-08-20
CA2244178C (en) 2008-10-14
CA2244178A1 (en) 1997-07-31
EP0876218B1 (en) 2000-10-25
JP2000505889A (en) 2000-05-16
WO1997026993A1 (en) 1997-07-31
ES2151241T3 (en) 2000-12-16
DE69703381D1 (en) 2000-11-30
JP3705606B2 (en) 2005-10-12
DK0876218T3 (en) 2001-01-08
DE69703381T2 (en) 2001-04-12

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