Heating specimen carriers

Details Heating specimen carriers Heating specimen carriers

2001-03-23

2003-10-21

Ludlow, Jan (Department: 1743)

Chemistry: analytical and immunological testing

Including sample preparation

C219S435000, C219S670000, C219S672000, C219S674000, C366S146000, C366S273000, C422S091000, C422S105000, C435S287200, C435S288400, C435S809000

Reexamination Certificate

active

06635492

ABSTRACT:

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 sheets which may have a multiplicity of wells or impressed sample sites, are used for various processes where small samples are heated or 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. It is important that the temperature of the whole of the sheet or more particularly the temperature in each well be as uniform as possible.
The individual samples are normally liquid solutions, typically between 1 &mgr;l and 200 &mgr;l in volume, contained within individual sample tubes or arrays of sample tubes that may be part of a monolithic plate. It is desirable to minimize temperature differentials within the volume of an individual sample, during thermal processing. The temperature differentials that may be measured within a liquid sample increase with increasing rate of change of temperature and may limit the maximum rate of change of temperature that may be practically employed.
Previous methods of heating such specimen carriers have involved the use of attached heating devices such as wire, strip and film elements and Peltier effect thermoelectric devices, or the use of indirect methods where separately heated fluids are directed into or around the carrier
The previous methods of heating suffer from the disadvantage that heat is generated in a heater that is separate from the specimen carrier that is required to be heated.
The thermal energy must then be transferred from the heater to the carrier sheet, which in the case of an attached heater element occurs, through an insulating barrier and in the case of a fluid transfer mechanism occurs by physically moving fluid from the heater to the sheet.
The separation of the heater from the block introduces a time delay or “lag” in the temperature control loop. That is to say that the application of power to the heating elements does not produce an instantaneous or near instantaneous increase in the temperature of the block. The presence of a thermal gap or barrier between the heater and the block requires the heater to be hotter than the block if heat energy is to be transferred from the heater to the block. Therefore, there is a further difficulty that cessation of power application to the heater does not instantaneously stop the block from increasing in temperature.
The lag in the temperature control loop will increase as the rate of temperature change of the block is increased. This can lead to inaccuracies in temperature control and limit the practical rates of change of temperature that may be used.
Inaccuracies in terms of thermal uniformity and further lag may be produced when attached heating elements are used, as the elements are attached at particular locations on the block and the heat produced by the elements must be conducted from those particular locations to the bulk of the block. For heat transfer to occur from one pan of the block to another, the first part of the block must be hotter than the other.
Another problem with attaching a thermal element, particularly a Peltier effect device, is that the interface between the block and the thermal device will be subject to mechanical stresses due to differences in the thermal expansion coefficients of the materials involved. Thermal cycling will lead to cyclic stresses that will tend to compromise the reliability of the thermal element and the integrity of the thermal interface.
The present invention aims to solve at least some of these problems by applying direct electrical resistance heating to a metallic specimen carrier. Thus the invention provides a method of heating a specimen carrier in the form of a metallic sheet by applying a heating current to said sheet.
The electric current passing through it directly heats the sheet; this removes lags in the temperature control loop. The whole of the sheet can be substantially instantaneously heated.
Preferably the metallic sheet will be of a metal having high thermal conductivity such as copper or silver. Small variations in metal thickness or thermal loading over the area of the sheet may be tolerated if the thermal conductivity of the sheet is high enough to equalise the temperature differences between any localised high or low temperature regions. The level of temperature variation that may be tolerated will depend upon the application, for PCR, applications more than 0.5 C is not tolerable.
Silver is preferred over copper in some circumstances, for example when rapid thermal cycling is to be used, as silver has a lower specific heat capacity than copper and will therefore require less energy to produce any particular temperature change.
The sheet will generally have a thin section in the region of 0.3 mm thickness, say in the range of 0.2-0.5 mm.
The sheet may be in a form where a matrix of sample wells is incorporated in the sheet.
The sheet may have an impressed regular array of wells to form a block and a basal grid or perforated sheet may be attached to link the tips of the wells at their closed ends to form an extremely rigid three-dimensional structure. In some applications the mechanical stiffness of the block is an important requirement. Where a basal grid is used, heating current is also passed through the metal of the grid. The basal grid is preferably made of the same metal as the block.
While the metallic sheet may be a solid sheet 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 if 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 alternating current supplied by a transformer system wherein the heating power is controlled by regulating the power supplied to the primary winding of the transformer. The sheet to be heated may be made part of the transformer secondary circuit. The secondary winding may be a single or multiple loop of metal that is connected in series with the sheet. By these means, the high current, low voltage power that is required to heat the highly conductive sheet may be simply controlled by regulating the high voltage, low current power supplied to the primary winding of the transformer.
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.
When heating samples in sample wells of a carrier in the way described above it is sometimes desirable to provide agitation or

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