Note: Descriptions are shown in the official language in which they were submitted.
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METHOD OF HEATING A SPECIMEN CARRIER
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
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sheet and applying a heating current to said sheet.
In some aspects, there is provided a method of heating a
specimen carrier of the kind comprising a plurality of
specimen sites, which carrier is in the form of a metallic
sheet and said sheet is one of a thin metal tray coated with a
bio-compatible polymer or a metallised plastic tray, the
method comprising applying a current to said sheet so as to
heat specimens carried by said carrier.
In some aspects, there is provided an apparatus comprising a
specimen carrier of the kind carrying a plurality of specimen
sites, which carrier is in the form of a metallic electrically
conductive sheet, said sheet being one of a thin metal tray
coated with a bio-compatible polymer or a metallised plastic
t ray ;
power supply means, and a transformer having aprimary winding
connected to said power supply means, and a secondary winding
directly connected to said conductive sheet, thereby providing
resistive heating of the sheet to heat the specimens carried
in the carrier.
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.
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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 biocompatible 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
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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
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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).
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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
5 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
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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
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controlled since the block becomes part of a heavy
secondary circuit of the transformer. The cross-
w
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 JDe 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.
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