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Description  |
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The present invention relates to a thermostatting device for adjusting the
temperature of at least one sample to any value within a predetermined
temperature range, comprising an elongated main body of good
heat-conducting properties which has its first end thermally connected to
a first thermostat means that can be set to a first temperature, and has
its second end thermally connected to a second thermostat means that can
be set to a second temperature, and which is sized in such a way that a
temperature gradient develops along the main body, between these two ends,
and comprising further a heat-conductive sample holder body that can be
brought into contact with the main body, for thermal coupling, at any
point between its thermostatted ends.
A thermostatting device of the type described above has been known from
DE-OS 2 063 607.
It is a requirement in many chemical and biochemical processes to bring
solutions to different temperatures in the course of one and the same
experiment. The required temperatures may be in the range of below
0.degree. Centigrade and up to more than 100.degree. Centigrade, and the
specific temperatures used in any experiment differ largely within that
range. Enzymatic reactions, for example, require temperatures of between
30.degree. Centigrade and 70.degree. Centigrade, depending on the
particular enzyme. For heat denaturation of nucleic acids, temperatures of
up to 120.degree. Centigrade are used, depending on their chain length and
sequence. For stopping reactions, temperatures of around 0.degree.
Centigrade are required. The temperatures used for storing samples are
considerably below 0.degree. Centigrade. In addition, most of the
experiments require quick changes of the solution temperature. Similar
requirements have to be met in other fields of science and technology.
There have been known in laboratory practice thermostats and metal-block
thermostats that can be adjusted to different temperatures. In the case of
liquid thermostats, the reaction vessels are thermostatted by circulating
liquid around them. Metal-block thermostats are provided with bores for
the reaction vessels, the latter being thermostatted by their contact with
the walls of such bores. Heat transmission can be improved by filling the
bores with water or oil. The temperature of metal-block thermostats can be
adjusted, for example, with the aid of heating cartridges, which are
controlled against a constantly operating water or convection cooling
system. Further, Peltier elements can be used for heating and cooling
metal-block thermostats. Any change in temperature of the samples is
effected in the case of the two before-described types of thermostats by
heating up or cooling down the whole thermostat.
It is an advantage of the before-described thermostats that a single
thermostat is required only for the different temperatures. However, due
to the considerable heat storage capacity and thermal inertia of these
thermostats, the process of changing the temperature is too slow and too
time-consuming for many types of reactions.
Another possibility of adjusting the temperature of samples to different
values consists in providing a separate liquid-bath thermostat for each
temperature. For a desired temperature of 0.degree., this may be an ice
bath, for example. One then introduces the reaction vessels into the
thermostat which is set to the particular desired temperature, which in
most cases is effected manually. However, there are also known set-ups
where the samples are manipulated with the aid of a robot arm.
It is an advantage of this approach that shorter temperature-changing times
can be achieved than in the case of the before-mentioned types of
thermostats, the time constant for temperature changes being determined,
in the case of well agitated liquid-bath thermostats, by the heat
transmission between the liquid and the sample, rather than by the
temperature response time of the respective thermostat. However, this
solution is expensive and space-consuming given the fact that a separate
thermostat is required for each temperature.
The before-mentioned DE-OS-2 063 607 describes a vibrator which is intended
for cultivating simultaneously, at different temperatures, a plurality of
cultures of microorganisms. In the case of the known vibrator, an
aluminium block, which is set into vibrating movement, is heated on its
one end and cooled on its other end so that a temperature gradient
develops along the aluminium block. The aluminium block is further
provided with grooves extending in parallel to its longitudinal direction,
and a plurality of bores which serve to receive steel Petri dishes or
glass flasks containing the microorganisms to be cultivated.
The known vibrator is intended for incubating simultaneously a plurality of
cultures at different temperatures. Changes in temperature of the
individual cultures during the many hours or even days of the incubation
period are neither envisaged, nor are they necessary. Instead, the
cultures--as generally required for the cultivation of microorganism--are
are maintained at a constant temperature for the whole incubation period.
The broad temperature spectrum of the aluminium block provides the
possibility to examine the conditions of growth of different cultures, at
different temperatures, on a single vibrator and during one and the same
incubation period.
The rapid changes of the temperature of the samples, which are required for
the chemical and biochemical methods mentioned at the outset, are not
possible with the known vibrator.
EP-A-0 094 458 describes a device where a temperature gradient can be set
and varied in an oblong sample holder consisting of a thermally conductive
material. There is provided for this purpose a transport means which moves
the sample holder a greater or lesser distance along the longitudinal axis
of a furnace, into the latter's heating zone, whereby for monitoring the
developing temperature gradient, two temperature sensors are arranged
separately in the longitudinal direction of the sample holder. The
temperature sensor intended for picking up the upper temperature value of
the temperature gradient is arranged at the end of the sample holder
projecting into the heating zone and is connected to the temperature
control of the heating of the furnace, while the temperature sensor
assigned to the lower temperature value is connected to the control of the
transport means.
The end of the sample holder which is located in the heating zone is heated
up to the pre-set furnace temperature by the heat radiation of the
furnace, while the end located outside the furnace is cooled by heat
dissipation to the surrounding air. The length of the temperature gradient
in the longitudinal direction of the sample holder, and the lower
temperature value, are determined by the position of the sample holder
relative to the heating zone. The shape of the temperature gradient is
determined either by means of temperature sensors arranged along the
sample holder or by means of temperature sensors which can be displaced
along the sample holder. For linearizing the shape of the temperature
gradient, an additional intermediate heating zone may be provided upstream
of the heating zone whose heating may be controlled by means of another
temperature sensor arranged on the sample holder between the two
first-mentioned temperature sensors.
The temperature of the samples, which are arranged on the sample holder in
fixed relationship, is varied by varying the shape of the temperature
gradient in the sample holder. This is effected on the one hand by
displacing the sample holder relative to the heating zone and, on the
other hand, by adjusting the heating of the furnace to different
temperature values. The time required for varying the temperature gradient
is a function of the time required for heating up and/or cooling down the
sample holder by radiation. In any case, acceptable times can be achieved
in this respect only for temperatures far above room temperature. Given
the fact, however, that the process of heat exchange by radiation is
basically very slow, the process of building up a new temperature gradient
always takes a very long time, even at high temperatures.
Further, a method for adjusting the temperature of liquid samples in an
automatically operating analyzer has been known from EP-A-0 151 781. This
device comprises a rack consisting of a material offering good thermal
conductivity and intended to receive the vessels and/or cells containing
the liquid samples. The rack is moved back and forth intermittently
between the different processing and measuring stations of the analyzer.
In its stationary condition, the rack is clamped between two lateral walls
of which one at least is heated in order to adjust the rack and, thus, the
liquid sample in the vessels to a given temperature.
The known device is intended for carrying out analyses in clinical
laboratories, and to prevent disturbing temperature variations from
occurring during the analysis processes. This is particularly important
for enzyme-kinetic measurements which are highly temperature-responsive
and which have to be carried out at exactly defined and reproducible
temperatures if comparable results are to be obtained. The samples,
therefore, are heated up to a predetermined temperature which is then
exactly maintained during the subsequent procedures.
The known device, therefore, only allows the samples to be heated up to a
single temperature, while no temperature change can be effected during the
further procedures. The known device does not permit to effect the rapid
temperature changes in the samples, which are required for the chemical
and biochemical methods described at the outset.
Further, a device for the gradual cooling-down and heating-up of biological
samples in a time-controlled manner has been known from WO-A1-87/02122.
This device comprises a thermally insulated box equipped with a lid and
with a basket holding the samples, and further a feeding mechanism by
means of which the basket can be lowered and lifted inside the box. A
supply of liquid nitrogen is provided on the bottom of the box so that a
temperature gradient from -192.degree. Centigrade to room temperature
develops between the bottom and the lid. By lowering the basket and
closing the lid one then causes the samples to freeze gradually while the
temperature gradient disappears by the time due to the closed lid. When
the lid is opened and the basket is raised, the temperature gradient
builds up again so that the samples thaw gradually.
A comparable device for the controlled and slow freezing-up and thawing of
biological samples has been known from U.S. Pat. No. 4,388,814. It
distinguishes itself from the before-described device only by the
different design of its feeding mechanism.
However, these devices are likewise unsuited for carrying out chemical and
biochemical experiments, in particular for varying rapidly the
temperatures of samples.
U.S. Pat. No. 4,584,275 describes an incubator by means of which a
plurality of liquid samples can be incubated simultaneously. The incubator
comprises an outwardly closed heating plate with a peripheral guide
channel of rectangular geometry intended for receiving sample holders in
the form of small flat dishes. The sample holders, which are introduced
into the guide channel via a feed channel, are moved around by steps by
means of five slides until they finally, at the end of a pre-determined
period of time, reach an optical measuring station. On their way to the
measuring station, the samples have been incubated continuously at the
temperature of the heating plate, for the pre-determined period of time,
so that the measurements can be carried out on all samples in succession,
at reproducible conditions. Upon completion of the measurement, the dishes
are ejected from the guide channel, and charged with new samples.
Again, this incubator is not suited for producing the rapid changes in
temperature of solutions which are frequently required in chemical and
biochemical methods.
From DE-PS-815 706 there has been known a heating bed for the thermal
examination of substances, which comprises a metal body built up from a
plurality of superimposed sheet strips. The metal body is heated up on its
one end to a temperature of 300.degree. Centigrade or over, whereby an
approximately linear temperature gradient builds up between the hot end
and the other end which is cooled by the surrounding air. The metal body
is covered by a cover plate of chromium-plated brass which is directly
charged with the substances under examination.
A scale, which is capable of being calibrated, permits to determine the
temperature at the respective position of the heating bed, so that the
melting points, eutectic temperatures, etc., of the substances under
examination can be determined.
The heating bed being cooled by thermal radiation, the temperature range
available is clearly above ambient temperature. Consequently, it is not
possible to carry out chemical and biochemical experiments with the aid of
this heating bed, too.
Now, it is the object of the present invention to improve a thermostatting
device of the before-mentioned type in such a way as to avoid the
disadvantages described above. In particular, the novel thermostatting
device is to make it possible, in connection with the carrying out of
chemical and biochemical processes, to bring solutions to different
temperatures in the course of one and the same experiment, and to bring
about the temperature variation in a quick and simple way.
The invention achieves this object by an arrangement where the sample
holder body is supported on the main body for displacement in the
longitudinal direction, a transport means is provided for displacing the
sample holder body, means are provided for pressing the sample holder body
against the main body, and the heat flow in the main body as well as the
cross-section of the main body are selected in such a way, with a view to
achieving rapid temperature changes in the samples, that the amount of
heat that has to be supplied or carried off as a result of the temperature
variation caused by any displacement of the sample holder body is
transferred from the main body to the sample holder body and absorbed by
the latter within a period of time suited for chemical and biochemical
experiments.
This solves the object underlying the invention. In the case of the
thermostatting device according to the invention it is possible to bring a
sample to any desired temperature within a predetermined temperature range
with the aid of only a single device.
Due to the fact that when varying the sample temperature only the
temperature of the sample holder body, with its relatively small heat
storage value, has to be changed, rather than the temperature of an entire
thermostat, temperature changes can be effected relatively quickly. The
contact pressure means have the effect to press the sample holder body
against the main body in order to ensure efficient thermal contact. The
thermal contact may be further improved by the application of a vacuum,
for example.
In addition, the thermostatting device according to the invention can be
re-fitted very quickly to accommodate different types of sample holders.
Hereafter, a preferred embodiment of the thermostatting device according to
the invention will be described in more detail by reference to the
drawings, in which
FIG. 1 shows a simplified top view of a thermostatting device according to
one embodiment of the invention;
FIG. 2 shows a front view of the thermostatting device according to FIG. 1;
and
FIG. 3 shows a curve illustrating the temperature distribution along a main
body of the thermostatting device according to FIGS. 1 and 2.
The thermostatting device illustrated in FIGS. 1 and 2 comprises a main
body 12 of good heat-conducting properties, in the form of a solid
aluminium rail of U-shaped cross-section comprising two upwardly
projecting legs. Each of the longitudinal ends of the elongated main body
is thermally coupled to a thermostat 14 or 16, respectively, which are
indicated only diagrammatically in the drawing. The thermostats 14, 16 can
be set to different temperatures T.sub.a, T.sub.b which will lead to the
development of a, preferably linear, temperature drop (temperature
gradient) along the main body 12, as indicated by the straight line 18 in
FIG. 3. The main body 12 forms on its upside, between the legs, a
channel-like recessed portion 20, accommodating a sample carrier or sample
holder body 22, which latter consists of a metal of good heat-conducting
properties, such as aluminium, and is mounted for being displaced along
the recessed portion 20. The sample holder body 22 is provided with
recesses 24 adapted for receiving sample or reaction vessels 26, as
indicated diagrammatically in FIG. 2. The main body is equipped with
temperature sensors 22a, 22b near its ends. Another temperature sensor 22c
may be arranged on the sample holder body 22. In order to ensure efficient
thermal contact, the sample holder body 22 may be urged against the main
body 12 by springs 28. The springs 28 are fixed by pins 30 fitted in holes
32 in the legs of the main body 12.
For effecting the displacement of the sample holder body 22 along the main
body 12, the embodiment of the invention illustrated in the drawing is
equipped with transport means comprising two toothed belts 34 running on
guide pulleys 36, one pair of which is coupled with a drive motor 38. The
transport means may comprise a position sensor, for example a
potentiometer coupled with a guide pulley 36, for generating an electric
signal representative of the position of the sample holder body 22 along
the main body 12.
The device is provided with a thermal insulation, which is not shown in the
drawing for the sake of clarity. In particular, in order to avoid heat
losses, the main body 12 may be thermally insulated on all sides by an
expanded plastic layer and may be provided with a thermally insulated lid.
Likewise, the sample holder body 22 may be provided with a lid.
The heat flow generated by the thermostats 14, 16 in the main body 12, and
the cross-section of the main body are determined, on the basis of the
known laws of heat conduction, in such a way as to ensure that the amount
of heat to be supplied to or to be carried off from the sample holder body
22 every time the temperature has to be changed can be given off by the
main body 12 and absorbed by the sample holder body 22 or absorbed by the
main body and given off by the sample holder body, respectively, within a
period of time suitable for the envisaged experiments. The position of the
sample holder body 22 along the main body 12 can be controlled with the
aid of a computer to which is supplied the position signal received from
the position sensor. If the temperature gradient is linear, the
temperature distribution along the main body 12 can then be derived by the
computer from the temperatures T.sub.a and T.sub.b prevailing at the ends
of the main body. If the temperature distribution along the main body 12
is non-linear, then the temperature distribution can be determined for
different values of T.sub.a and T.sub.b, and stored in the computer. In
order to speed up the change of the temperature of the sample, the whole
temperature range available can be utilized. For example, if the
temperature of the samples is to be raised from 30.degree. Centigrade to
70.degree., the sample holder body can be run up initially to the highest
temperature position available, and can then be run back towards the
70.degree. position when the temperature sensor 24 signals that the
temperature of the sample holder body 22 approaches the desired value of
70.degree.. It is an advantage of this way of adjusting the temperature
that one does not have to know exactly the development of the temperature
along the carrier 12 and that one can do with a simple controller which is
supplied with the actual temperature value of the sample holder body, as
supplied by the temperature sensor 24, and further with a temperature
setpoint value, and which then controls the transport means
correspondingly.
The thermostats 14 and 16 may be usual liquid thermostats. Instead,
however, one may also make use of other thermostats, for example such
using heating cartridges, Peltier elements, or the like. At the
low-temperature end, there may also be provided simple cooling fins, if
necessary in combination with a controlled cooling blower, an ice bath, or
the like.
The thermal contact between the sample holder body 22 and the main body 12
may be improved by lubricating agents and/or by the application of a
vacuum for improved contact.
The main body may be equipped, between its two ends, with additional
heating and/or cooling means provided each with a separate temperature
sensor. The additional heating and/or cooling means may serve for
linearizing the temperature gradient, or for generating a predetermined
temperature gradient curve. For example, it is possible in this manner to
produce sections of differently steep temperature gradients along the main
body 12, in order to provide a relatively flat temperature gradient
allowing exact temperature settings in temperature ranges where the
temperature settings are particularly critical, and allowing on the other
hand to produce steeper temperature gradients in other areas where it is
desirable to have available the broadest possible temperature range.
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