Active solid-state devices (e.g. – transistors – solid-state diode – Responsive to non-electrical signal – Temperature
Reexamination Certificate
2002-02-12
2003-04-08
Nelms, David (Department: 2818)
Active solid-state devices (e.g., transistors, solid-state diode
Responsive to non-electrical signal
Temperature
C257S468000
Reexamination Certificate
active
06545334
ABSTRACT:
FIELD OF THE INVENTION
The present invention is related to a device which yields an electrical output signal but has an input or intermediate signal of the thermal type. Such a device can be used to characterize chemical and physical processes which are accompanied by changes in heat content or enthalpy. Furthermore a method is disclosed for manufacturing said device by means of micromachining which is a technique closely related to the technique used for the manufacturing of integrated circuits.
BACKGROUND OF THE INVENTION
New approaches in the combinatorial chemistry have resulted in the capability of producing millions of compounds in a short time. Analysis of each compound with respect to multiple parameters is proving to be a significant bottleneck as in e.g. M. A. Shoffner et al., Nucleic Acids Research, 1996, vol. 24, No. 2, pp. 375-9. The number of cells, the test reagent volumes, the throughput rate and the ease of use through automation are all important parameters which should be optimized in order to meet the stringent requirements for modem drug screening. Furthermore a small amount of precious reagent reduces both cost and waste, and increases the number of possible analyses. A candidate for this kind of analysis is a calorimeter. A calorimeter is a device which yields an electrical output signal but has an input or intermediate signal of the thermal type. Calorimetry, more than pH-metry, offers the advantage of generality: all chemical and physical processes are accompanied by changes in heat content, or enthalpy. In fact microcalorimeters can be used for the analysis of the activity of biological cells, chemical reactions in small volumes and other microanalytical applications.
The most frequently used commercially available calorimeters are the Thermometric 2277 Thermal Activity Monitor and the MicroCal MCS Isothermal Titration Calorimeter. They are both based on the use of two or more thermoelectric devices, so called thermopiles, having a common heat sink as reference. A thermopile is at least one thermocouple which is a temperature sensing element and which is connected to identical thermocouples in parallel thermally and in series electrically. Thermocouples do not measure the temperature itself, but rather the temperature difference between two junctions. An advantage of using thermocouples as temperature sensing elements is that there is no offset, i.e. when there is no temperature difference there is no voltage, which makes calibration superfluous. A thermocouple as illustrated in
FIG. 2
, i.e. a combination of two different (semi)conductive materials, converts a thermal difference between its two junctions into a voltage difference by means of the combined Seebeck coefficient S of its two structural thermoelectric materials. In fact a thermocouple comprises a first conductive material (
14
) and a second conductive material (
13
) with an insulating layer (
15
) inbetween. A thermocouple has a so-called hot junction (
11
), where said first material and said second material are short-circuited, and a so-called cold junction (
15
), where said first and said second material are separated one from another by means of said insulating layer. At said cold junction the electrical output signal, representing the temperature difference &Dgr;T between said hot junction and said cold junction, can be measured.
The total generated voltage is the sum of the thermocouple voltages. For n (n being a positive whole number greater than zero) thermocouples, where each thermocouple is identical, it can be written that:
U
tp
=n*S*&Dgr;T.
The temperature difference &Dgr;T is the product of the generated power difference between the two junction sites and the thermal resistance:
&Dgr;T=&Dgr;P
gen
*R
th
Thermopiles are preferred because they are self-generating, easy to integrate and because the temperature changes involved are low frequency signals.
The drawbacks of these state-of-the art devices are the following. These devices have at least two thermopiles and a common heat sink. The cold junctions of each thermopile are thermally coupled to the common heat sink which is at a known temperature. The hot junctions of each thermopile are thermally coupled to a substance under test. So in fact, one tries to perform a kind of absolute measurement by measuring the temperature difference between this substance under test and the heat sink at known temperature. By applying different substances under test to different thermopiles as e.g. for drug screening where the hot junctions of a first thermopile are coupled to reference cells and the hot junctions of a second thermopile are coupled to genetically engineered cells expressing a drug target. When the potential drug candidate is effective, it will activate the genetically engineered cells which results in a heat change. This heat change is determined indirectly by subtracting the measured signals of the first and the second thermopile, where the cold junctions of both thermopiles are coupled to a common heat sink at known temperature. This is a cumbersome approach which lacks accuracy and demands a space consuming design.
SUMMARY OF THE INVENTION
In an aspect of the invention a device is disclosed based on only one thermopile wherein said thermopile is in contact with at least parts of a substrate, e.g. a silicon wafer or the remains thereof. The cold junctions of said thermopile are coupled thermally to a first channel comprising a first substance while the hot junctions of said thermopile are coupled thermally to a second channel comprising a second substance, said first and said second channel are separated and thermally isolated one from another. Said device is capable of handling a very small amount of a substance, typically in the range from 1 microliter to 30 microliter.
In an aspect of the invention a device for monitoring chemical and physical processes which are accompanied by changes in heat content or enthalpy is disclosed, comprising a thermopile, wherein said thermopile is in contact with at least parts of a substrate, e.g. a silicon wafer or the remains thereof, and wherein said thermopile is a set of at least one thermocouple comprising a first conductive material and a second conductive material with an insulating layer inbetween. Said first and said second material are chosen such that their thermoelectric voltages are different. A first substance, i.e. a reference substance, can be thermally coupled to the cold junctions of said thermopile while a second substance, i.e. a test substance, can be thermally coupled to the hot junctions of the same thermopile. Alternatively, a first substance, i.e. a test substance, can be thermally coupled to the cold junctions of said thermopile while a second substance, i.e. a reference substance, can be thermally coupled to the hot junctions of the same thermopile. To speed up measurement time or to test a number of substances at the same time, a modular system comprising an array of devices, each device comprising one thermopile, can be configured on the same substrate. Said device can further comprise a thin insulating layer, e.g. an oxide layer or a nitride layer, on said thermopile in order to prevent a direct contact between the substances and the thermopile to thereby avoid damaging said thermopile. Said device further comprises a membrane to thermally and electrically isolate said thermopile and to mechanically support said thermopile. Silicon oxide and/or silicon nitride can be used as membrane materials. Particularly a liquid rubber, i.e. ELASTOSIL LR3003/10A, B can be used as a membrane material.
In an aspect of the invention a method is disclosed for fabricating a device used to monitor chemical and physical processes which are accompanied by changes in heat content or enthalpy. The device is capable of handling a very small amount of a substance. These requirements can be achieved by micromachining, a technique closely related to integrated circuit fabrication technology. The starting material is a substrate like e.g. a semiconductive wafer, particu
IMEC VZW
Knobbe Martens Olson & Bear LLP
Nguyen Dao H.
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