JP2003035611A - Reaction heat detector and reaction heat detector - Google Patents

Abstract

(57) [Summary] [PROBLEMS] To provide a reaction heat detector suitable for detecting minute heat of reaction accompanying a biochemical reaction or the like in a minute space. SOLUTION: A plurality of thin-film temperature sensors 4a and 4b are provided on a thin-film membrane (bridge) 3 formed so as to be thermally insulated from a semiconductor substrate 1, and a plurality of thin-film temperature sensors are guided to the respective thin-film temperature sensors. Micro channels 5a, 5
b is formed on the semiconductor substrate via the membrane (bridge). Then, a fluid is caused to flow through each microchannel via inlets 6a and 6b and outlets 7a and 7b. For example, a fluid to be detected and its reaction reagent are mixed in one channel, and the fluid to be detected is mixed in the other channel. A dummy fluid instead of the above-mentioned reaction reagent is mixed and allowed to flow, and its temperature is detected, particularly its temperature difference, through each thin-film temperature sensor.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a reaction heat detector and a reaction heat detection device suitable for detecting a minute reaction heat associated with a biochemical reaction in a minute space.

[0002]

[Related Background Art] When analyzing the properties of a substance or detecting a specific substance in a sample, generally, a chemical separation technique such as chromatography is used, or a physical separation such as centrifugation is performed. Method is used. The presence or absence of the reaction is also detected by using a reagent that selectively reacts with a specific substance to be detected.

[0003]

However, in such a conventional general analysis method, there is a problem that the equipment is likely to be large-scale and the analysis accuracy is easily influenced by the surrounding environment. Moreover, there is a problem in how to detect the reaction with the reagent with high accuracy. Further, such an analysis method is generally unsuitable for analysis of biochemical reactions in a minute space.

The present invention has been made in consideration of such circumstances, and an object thereof is to detect a minute reaction heat associated with a biochemical reaction in a minute space with high sensitivity and to detect a specific substance. It is an object of the present invention to provide a reaction heat detector and a reaction heat detection device suitable for detection and analysis of a chemical reaction mechanism in a micro region.

[0005]

In order to achieve the above-mentioned object, a reaction heat detector according to the present invention is realized by using a micromachining technique, and a semiconductor substrate is thermally coupled with the semiconductor substrate. Providing multiple thin film temperature sensors on a thin film membrane or bridge formed by insulation,
A plurality of microchannels for guiding a fluid are formed on each of these thin film temperature sensors on the semiconductor substrate via the membrane or bridge, and inlets and outlets for allowing fluids to flow through the respective microchannels. Is provided, for example, a fluid to be detected is allowed to flow in one of the channels, and a fluid obtained by mixing the fluid to be detected and a reaction reagent thereof is allowed to flow through the other channel to cause each of the microchannels to flow. The temperature of the fluid flowing therethrough, in particular the temperature difference, is detected via each of the thin film temperature sensors.

Preferably, the inlet and the outlet are provided on the back surface side of the semiconductor substrate so as to communicate with the respective microchannels, thereby facilitating the supply and discharge of the fluid to the respective microchannels. . Further, the thin film membrane or bridge is provided so as to straddle the recess formed in the semiconductor substrate to be thermally insulated from the semiconductor substrate, thereby thermally isolating the plurality of thin film temperature sensors from the outside thereof. It is desirable to do.

Further preferably, a cover body is further provided for covering the surface side of the semiconductor substrate on which the plurality of microchannels are formed, thereby isolating the internal space from the external environment, and the cover body is provided with the internal space and the external ( It is desirable that a structure is provided in which a communication portion that connects to the outside world is provided, and the pressure between the inside of the cover body (internal space of the detector) and the outside (outside world) is balanced through the communication portion.

More specifically, the inlet comprises a first inlet into which the fluid to be detected is introduced and a second inlet into which a reaction reagent for the fluid to be detected is introduced, and the first and second inlets are provided. A mixed fluid of the fluid to be detected and its reaction reagent introduced from the inlets is guided to one of a plurality of microchannels, and only the fluid to be detected introduced from the first inlet is guided to the other microchannel. Is composed of.

More preferably, as the inlet, a first inlet into which a fluid to be detected is introduced, a reaction reagent for the fluid to be detected and a fluid reagent having the same fluid characteristics as the reaction reagent and reacting with the fluid to be detected. And two second inlets into which dummy fluids are introduced respectively, and one of the microchannels is a mixed fluid of the fluid to be detected introduced from the first and second inlets and its reaction reagent. It is desirable to introduce a mixed fluid of the fluid to be detected introduced from the first inlet and the dummy fluid into the other microchannel.

Further, the reaction heat detecting apparatus according to the present invention comprises a reaction heat detector having the above-mentioned structure, and control means for controlling on / off control of introduction of the fluid to be detected into the first inlet. And In particular, a means for periodically turning on / off the introduction of the fluid to be detected is provided. And based on the temperature detected by the thin film temperature sensor when the introduction of the fluid to be detected to the first inlet is stopped,
Compensation means for compensating the temperature detected by the thin film temperature sensor at the time of introducing the fluid to be detected is provided to correct the temperature difference between the reaction reagent and the dummy fluid and the variation in the temperature measurement characteristics of the plurality of thin film temperature sensors. The heat of reaction between the fluid to be detected and the reaction reagent is detected with high accuracy.

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION A reaction heat detector according to an embodiment of the present invention will be described below with reference to the drawings. This reaction heat detector is manufactured by using a micromachining technique, and as shown in FIG.
A thin film-shaped membrane (bridge) 3 having a thickness of, for example, about 1 μm, which is formed by being thermally insulated from the semiconductor substrate 1 by straddling the concave portion 2 provided in the semiconductor substrate 1, etc. ), The thin film temperature sensors 4a, 4b are embedded and formed, and a plurality of (two) microchannels 5 for guiding the fluid onto the thin film temperature sensors 4a, 4b, respectively.
It has a structure in which a and 5b are formed.

Incidentally, the thin film temperature sensors 4a and 4b.
2 are provided symmetrically at a predetermined distance in the width direction and thermally insulated from each other on a membrane (bridge) 3 formed across the recess 2 as shown in the plane arrangement structure in FIG. To be And each of the micro channels 5a, 5
Reference numeral b denotes a membrane (bridge) 3 which forms a flow path that passes through the thin film temperature sensors 4a and 4b and forms a minute space having a cross-sectional area of about 200 μm ² having a width of 20 μm and a height of 10 μm. It is installed in parallel on the top.

Incidentally, these micro channels 5a, 5b
Are formed so as to extend from above the membrane (bridge) 3 to a region sandwiching the recess 2 on the semiconductor substrate 1. And each of these micro channels 5a,
5b are respectively connected to an inlet 6 and an outlet 7 each having a through hole formed in the semiconductor substrate 1 as shown in the sectional structure of FIG. Forming a path. The inlet 6 and the outlet 7 are preferably formed in a tapered shape as schematically shown in FIG. 3 in consideration of the pressure loss and the alignment property with respect to the microchannels 5a and 5b. In order to process the inlet 6 and the outlet 7 into a tapered shape, for example, the Si substrate on which the inlet 6 and the outlet 7 are formed may be partially anisotropically etched.

By the way, in this embodiment, as shown in FIG. 2, the semiconductor substrate 1 is provided with three inlets 6.
a, 6b, 6c and one outlet 7 are provided, and the two microchannels 5a, 5b are connected to the outlet 7 by being combined into one flow path via a merging portion on the downstream side thereof. There is. Further, the two microchannels 5a and 5b are commonly connected to the first inlet 6a on the upstream side via a flow dividing portion, and
The inlets 6b and 6c are connected to the microchannel 5a on the downstream side of the flow dividing portion via the joining portions.

The fluid introduced through the first inlet 6a is divided into the two microchannels 5a and 5b to flow therethrough, and the fluid is introduced into the second inlet 6a.
Fluid introduced via b and 6c (reaction reagent)
Are introduced into the microchannels 5a and 5b, respectively. The fluid to be detected is introduced into the inlet 6a, the reaction reagent to be reacted with the fluid to be detected is introduced into the inlet 6b, and the inlet 6c has fluid characteristics close to those of the reaction reagent. A fluid that does not react (dummy fluid) is introduced at the same flow rate.

As a result, the fluids (the fluid to be detected and the reaction reagent) introduced through the two inlets 6a and 6b are mixed into one of the microchannels 5a and flow in a state where a predetermined reaction is promoted. The fluids (the fluid to be detected and the dummy fluid) introduced through the two inlets 6a and 6c are mixed and flow through the other microchannel 5b. And the thin film temperature sensor 4a,
Reference numeral 4b denotes the temperature of the fluid flowing in each of the microchannels 5a and 5b, that is, the first thin film temperature sensor 4a detects the reaction temperature associated with the reaction between the fluid to be detected and the reaction reagent, and the second thin film temperature. The sensor 4b detects a temperature that does not cause a reaction between the fluid to be detected and the dummy fluid.

As described above, the semiconductor substrate in which the two thin film temperature sensors 4a and 4b are formed on the membrane (bridge) 3 and the microchannels 5a and 5b are formed on the thin film temperature sensors 4a and 4b, respectively. The surface side of 1 is covered with a cover body 8 having a predetermined recessed space 8a as shown in FIG. The cover body 8 forms an internal space 8a surrounding the sensing portion mainly composed of the thin film temperature sensors 4a and 4b and is isolated from the outside thereof to mechanically protect the above-mentioned microchannels 5a and 5b and the like. The thin film temperature sensors 4a and 4b play a role of making the thin film temperature sensors 4a and 4b less likely to be affected by changes in the external environment. Further, the cover body 8
A communication portion 9 including a minute groove or the like is provided on the peripheral portion of the. The communication portion 9 has a size capable of preventing the ingress of water and the like, and the air is passed between the internal space 8a formed by the cover body 8 and the outside (outside) of the internal space 8a, so that the inside thereof is It plays a role of pressure-balancing the space 8a and the outside.

Further, a third thin film temperature sensor 4c is provided on the peripheral portion of the semiconductor substrate 1 independently of the above-mentioned thin film temperature sensors 4a and 4b. The third thin film temperature sensor 4c detects the temperature of the external environment through the semiconductor substrate 1, and for example, the thin film temperature sensors 4a, 4 described above are used.
It is used to correct the temperature detected by b (the reaction temperature between the fluid to be detected and the reaction reagent) according to the external environment.

By the way, since the reaction reagent and the dummy fluid are introduced into the reaction heat detector from different systems, their respective temperatures themselves may be different. Moreover, the thin film temperature sensor 4 provided in each of the micro channels 5a and 5b
The temperature measurement characteristics of a and 4b may also vary. Therefore, practically, for example, in the state where the fluid to be detected (sample) is not introduced from the inlet 6a, the reaction reagent and the dummy fluid are caused to flow at the same flow rate from the inlets 6b and 6c, respectively, and the introduction of the fluid to be detected from the inlet 6a is turned on.・ Off control. When the introduction of the fluid to be detected is turned on / off, the thin film temperature sensors 4a, 4b are
The temperature difference between the reaction reagent and the dummy fluid and the variations in the temperature measurement characteristics of the thin film temperature sensors 4a and 4b may be corrected based on the temperatures respectively detected in.

Incidentally, the temperature sensing circuit incorporated in this reaction heat detector is formed in a membrane (bridge) 3 and has channels 5a and 5b as shown in FIG. 4, for example.
A differential amplifier 11 is provided which determines the difference between the outputs of the first and second thin film temperature sensors 4a and 4b, which detect the temperature of the fluid flowing therethrough, as the temperature difference. Then, the output (temperature difference) of the differential amplifier 11 is detected by using the first sample-hold circuit 12a in the state where the fluid to be detected (sample) is introduced, and the fluid to be detected (sample) is not introduced. In, the detection is performed using the second sample hold circuit 12b. Then, in the temperature correction circuit 13, the output of the first sample hold circuit 12a is corrected by the output of the second sample hold circuit 12b, and further according to the environmental temperature detected by the third thin film temperature sensor 4c. It is configured to obtain the detected output (temperature difference) by performing the correction. Then, minute reaction heat of, for example, mK order or less, which accompanies the reaction between the fluid to be detected and the reaction reagent generated in the microchannel 5a, is highly accurate as a temperature difference detected by the thin film temperature sensors 4a and 4b. Is to be detected.

Thus, according to the reaction heat detector (reaction heat detection device) configured as described above, the two thin film temperature sensors 4a and 4b are formed so as to straddle the recess 2 formed in the semiconductor substrate 1. It is formed on a membrane (bridge) 3 which is thermally insulated from the semiconductor substrate 1, and these thin film temperature sensors 4a and 4b are provided thermally and separated symmetrically. And the above-mentioned two channels 5a, 5
Since b is provided above each of the thin film temperature sensors 4a and 4b, the thin film temperature sensors 4a and 4b are provided.
The a and 4b respectively detect only the temperature of the fluid flowing through the two channels 5a and 5b. Therefore, as described above, the fluid in which the fluid to be detected and the reaction reagent are mixed is allowed to flow through one of the microchannels 5a, and the fluid to be detected and the dummy fluid are allowed to flow through the fluid in the other microchannel 5b. The thin film temperature sensors 4a and 4b can detect the minute reaction heat accompanying the reaction between the fluid to be detected and the reaction reagent, the temperature of the fluid to be detected and the dummy fluid, and consequently the temperature difference thereof with high accuracy. .

In particular, the sensing portion mainly composed of the thin film temperature sensors 4a and 4b is covered with the cover body 8 and is isolated from the external environment, and is provided on the membrane (bridge) 3 as described above. Since it is in a state of being thermally insulated from the outside, even if the reaction heat caused by the reaction between the fluid to be detected and the reaction reagent generated in the minute space in the microchannel 5a is minute, the reaction heat is affected by the disturbance factor. It is possible to detect with high accuracy without being performed. Particularly, since the heat of reaction between the fluid to be detected and the reaction reagent is detected as the temperature difference with the temperature of the fluid to be detected and the dummy fluid flowing in the microchannel 5b as a reference, it is possible to sufficiently enhance the detection accuracy. And so on. Therefore, it becomes possible to detect the minute reaction heat generated by the reaction between the fluid to be detected and the reaction reagent generated in the minute space with high accuracy, which greatly contributes to various fluid analysis.

Incidentally, when manufacturing the reaction heat detector having the above-mentioned structure, for example, as shown in FIG.
Silicon nitride (SiNx) film 20 on semiconductor substrate 1 such as i
Then, a Pt thin film 21 forming the first and second thin film temperature sensors 4a and 4b is formed by vapor deposition on the insulating thin film 20 as shown in FIG. 5B. The Pt thin film 21 is patterned into a membrane (bridge) 3
It is provided, for example, in the central part of the portion where After that, as shown in FIG. 5C, the entire surface is covered and the SiNx film 22 is further formed.
To form.

Then, as shown in FIG. 5 (d), channels 5a, 5 having a predetermined flow passage cross-sectional area are formed on the SiNx film 22.
An Al layer 23 is formed as a sacrificial layer for forming b.
The Al layer 23 is formed on the Pt thin film 21 at a position where the membrane (bridge) 3 is formed by forming the pattern shown in FIG. 2 so as to pass through the membrane (bridge) 3. It is provided. Thereafter, as shown in FIG. 5E, a SiNx film 24 is formed so as to cover the entire Al layer 23 and form the channels 5a and 5b. At this stage, an opening (not shown) for etching is formed in the SiNx films 20 and 22 for forming a membrane (bridge) 3 by forming a recess 2 in the lower portion of the channels 5a and 5b as described later. It is formed on the side part of the part where the (bridge) 3 is formed.

Then, Si is formed on the lower surface of the semiconductor substrate 1.
An Nx film 25 is formed, and the SiNx film 25 is patterned to form an opening for selectively etching the semiconductor substrate 1. Then, as shown in FIG. 5 (f), the semiconductor substrate 1 is etched from the lower surface side using the SiNx film 25 as a mask to form holes for forming the inlets 6a, 6b, 6c and the outlet 7 in the semiconductor substrate 1, respectively. 26 are formed respectively. Next, the semiconductor substrate 1 made of Si
5G, the SiNx films 20 and 22 described above are sequentially etched until the Al layer 23 is reached from the back surface side of the semiconductor substrate 1, and the hole 26 is dug down, as shown in FIG. The inlets 6a, 6b, 6c and the outlet 7 are formed, respectively.

After that, S provided on the front surface side of the semiconductor substrate 1
Using the iNx films 20 and 22 as a mask, the semiconductor substrate 1 is anisotropically etched through the openings provided in the SiNx films 20 and 22, and the first and second thin films are formed as shown in FIG. Below the Pt thin film 21 forming the temperature sensors 4a and 4b, the recess 2 forming the membrane (bridge) 3 is formed. Then, through the holes 26 forming the inlets 6a, 6b, 6c and the outlet 7, respectively, the above-mentioned A
The I layer 23 is removed by etching to form channels 5a and 5b surrounded by the SiNx film 24 on the membrane (bridge) 3 as shown in FIG.

When the cover body 8 is provided so as to cover the channels 5a and 5b, the electrode molding is performed so that the electrode leads (not shown) of the thin film temperature sensors 4a and 4b are taken out from the back surface side of the semiconductor substrate 1. I'll do it. After that, in another step, another semiconductor substrate is processed by etching, and the cover body 8 having the through holes 9 described above is bonded to the upper surface of the semiconductor substrate 1 to detect the reaction heat having the cross-sectional structure shown in FIG. Complete the vessel. Regarding the bonding between the semiconductor substrate 1 and the cover body 8, for example, an Au film may be provided on each bonding surface and these Au films may be bonded to each other.

As described above, the reaction heat detector according to the present invention is
Etching processing for semiconductor substrates and CVD (chemic
It can be manufactured relatively easily using a micromachining technique using thin film growth such as al vapor deposition). Moreover, the membrane (bridge) 3 on which the thin film temperature sensors 4a and 4b are formed is attached to the semiconductor substrate 1 and the cover 8
Since it can be embedded in the internal space formed by, there is an advantage that it can be made structurally excellent without being affected by external force.

The present invention is not limited to the above embodiment. For example, here, a bridge 3 that straddles the recess 2 is formed, and the thin film temperature sensor 4a,
Although 4b is formed, it is also possible to form a thin film diaphragm in the central portion of the semiconductor substrate 1 and form the thin film temperature sensors 4a and 4b on this diaphragm. Further, not only the resistance temperature detector made of Pt described above may be formed as the thin film temperature sensors 4a and 4b, but also the thin and thin film temperature sensors 4a and 4b may be formed as the thermopile (thermocouple) hot junction and cold junction. It is possible. Further, the inlets 6a, 6b and the outlet 7 communicating with the microchannels 5a, 5b may be provided on the cover body 8 side. Further, the extraction of electrodes from the thin film temperature sensors 4a and 4b is not particularly limited, and may be adjusted according to various specifications.

Also here two microchannels 5
a, 5b are formed, and the temperature of the fluid flowing through each microchannel 5a, 5b is measured, but three or more microchannels are formed in parallel and the temperature of the fluid flowing through each microchannel is measured. It is also possible to configure the reaction heat detector to measure. When the dummy fluid is not used, the mixed fluid of the fluid to be detected and its reaction reagent is allowed to flow through one of the two microchannels 5a and 5b, and only the fluid to be detected is allowed to flow through the other microchannel. Alternatively, the temperature difference may be detected. In addition, the present invention can be variously modified and implemented without departing from the scope of the invention.

[0031]

As described above, according to the present invention, a plurality of thin film temperature sensors are provided on a thin film membrane or bridge formed so as to be thermally insulated from a semiconductor substrate. The temperature of the fluid flowing through each microchannel is detected by forming a plurality of microchannels that guide the fluid to the microchannel, so the minute heat of reaction associated with the reaction between the fluid to be detected and the reaction reagent in the microspace is highly accurate. Moreover, it can be detected easily. Therefore, a great effect can be exerted in applications such as detecting a minute reaction heat associated with a bio-chemical reaction, analyzing its properties, extracting a specific substance, and the like. Moreover, there is an advantage that the reaction heat can be detected with high accuracy without being affected by the external environment.

[Brief description of drawings]

FIG. 1 is a partially sectional perspective view showing a schematic configuration of a main part of a reaction heat detector according to an embodiment of the present invention.

FIG. 2 is a plan view showing an arrangement structure of a thin film temperature sensor and a microchannel in the reaction heat detector shown in FIG.

3 is a sectional view showing a schematic structure of the reaction heat detector shown in FIG.

FIG. 4 is a diagram showing an example of a temperature sensing circuit incorporated in the reaction heat detector shown in FIG.

5 is an exploded view showing an example of a schematic manufacturing process of the reaction heat detector shown in FIG.

[Explanation of symbols]

1 Semiconductor substrate 2 recess 3 Thin film membrane (bridge) 4a, 4b Thin film temperature sensor 5a, 5b Micro Channel 6a, 6b inlet 7 outlets 8 cover body 9 communication section

Claims (9)

[Claims] 1. A thin film membrane or bridge formed on a semiconductor substrate thermally insulated from the semiconductor substrate, a plurality of thin film temperature sensors provided on the membrane or bridge, and via the membrane or bridge. A plurality of microchannels formed on the semiconductor substrate to guide the fluid onto the thin film temperature sensors, and inlets and outlets for allowing the fluids to flow through the microchannels, respectively. A reaction heat detector. 2. The inlet and outlet are
The reaction heat detector according to claim 1, wherein the reaction heat detector is provided on the back surface side of the semiconductor substrate so as to communicate with each of the microchannels. 3. The reaction heat detector according to claim 1, wherein the thin film membrane or bridge is provided so as to straddle a recess formed in the semiconductor substrate. 4. The reaction heat detector according to claim 1, further comprising a cover body that covers a surface side of the semiconductor substrate on which the plurality of microchannels are formed, the cover body including an internal space and an external space. A reaction heat detector comprising a communication part that connects the two. 5. The inlet includes a first inlet into which a fluid to be detected is introduced and a second inlet into which a reaction reagent for the fluid to be detected is introduced, and the microchannel has one of the first and second inlets. A flow path is formed for guiding the mixed fluid of the fluid to be detected and its reaction reagent introduced from the first and second inlets, respectively, and guiding the fluid to be detected introduced from the first inlet to the other microchannel. The reaction heat detector according to claim 1, wherein 6. The inlet has the same fluid characteristics as the first inlet into which the fluid to be detected is introduced and the reaction reagent for the fluid to be detected and the reaction reagent, and does not react with the fluid to be detected. Two second inlets into which dummy fluids are respectively introduced, and the microchannel is a mixed fluid of the fluid to be detected and the reaction reagent thereof introduced into the microchannel from the first and second inlets, respectively. The reaction heat detector according to claim 1, wherein a flow path for guiding the mixed fluid of the fluid to be detected introduced from the first inlet and the dummy fluid is formed in the other microchannel. 7. A reaction heat detector comprising: the reaction heat detector according to claim 5; and a control means for controlling on / off of introduction of the fluid to be detected into the first inlet. Detection device. 8. The reaction heat detection device according to claim 7, further comprising: the fluid to be detected based on a temperature detected by the thin film temperature sensor when the introduction of the fluid to be detected into the first inlet is stopped. A reaction heat detection device, comprising means for correcting the temperature detected by the thin film temperature sensor when the reaction heat is introduced. 9. The reaction heat detection device according to claim 7, wherein the control means turns on / off the introduction of the fluid to be detected into the first inlet at a predetermined cycle.