JP2009254258A - Heat control matrix device and reaction treatment device - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a heater matrix device which can highly accurately control heat, and to provide a reaction treatment device. <P>SOLUTION: In a heater unit 110, switches SW111, SW112 function as receiving portions for taking calorific power information given to data DTL in a state selecting scanning line WSL. A capacitor C111 functions as a holding portion for holding the calorific power information also after the scanning line is not selected. A transistor T111 and a switch SW113 function as driving portions for flowing an electric current on the basis of the read calorific power information and generating the calorie in response to the electric current. <P>COPYRIGHT: (C)2010,JPO&amp;INPIT

Description

  The present invention relates to a heater matrix device and a reaction processing device applicable to a PCR method for performing gene amplification. More specifically, the present invention relates to a thermal control matrix device and a reaction processing device capable of highly accurate temperature control.

  When it is necessary to control the reaction based on the temperature condition, it is desired that the temperature condition can be controlled with higher accuracy. It is desired that the temperature can be controlled with high accuracy in a reaction processing apparatus that performs a reaction regardless of liquid, solid, or gas. For example, there is such a request in the technical field such as gene analysis.

  As an example, a PCR method (polymerase chain reaction) that performs gene amplification is used. The PCR method can be said to be a standard method for quantitative analysis of a small amount of nucleic acid.

In the PCR method, DNA and the like can be amplified several hundred thousand times by continuously performing an amplification cycle of “thermal denaturation → annealing with a primer → polymerase extension reaction”.
The PCR amplification product thus obtained can be monitored in real time for quantitative analysis of the trace nucleic acid.

However, in the PCR method, it is necessary to accurately control the amplification cycle. For this purpose, highly accurate temperature control is required.
If the temperature control is insufficient, irrelevant DNA sequences may be amplified or no amplification may be observed.

General real-time PCR has the following problems.
1. The number of samples that can be analyzed at one time is small, and exhaustive analysis is not possible.
2. Since the temperature control of the thermal cycler currently commercialized is a gradient mechanism, the temperature control of each sample cannot be performed individually. Furthermore, time control during amplification cannot be performed individually. As a result, the amplification amount of each sample cannot be made constant, and a by-product may be generated.

As described above, it is important that the above-described apparatuses and the like can be controlled with high accuracy as a reaction processing apparatus. As techniques related to this, Patent Documents 1 and 2 disclose techniques related to temperature control of the reaction processing apparatus.
In the techniques disclosed in these documents, a semiconductor element or the like is also used for heat generation control in a minute region. Specifically, a MOS transistor is used as a current drive element for heat generation, and it can be applied to heat generation control in a minute region.

JP 2003-298068 A JP 2004-025426 A

  Even when temperature control is performed using a semiconductor element or the like in the proposed reaction processing apparatus, there are the following disadvantages.

  Since semiconductor devices generally have manufacturing variations, even if the same temperature control is performed in each reaction region, the heating amount varies from substrate to substrate or from heating unit to component even on the same substrate. It will occur. As a result, highly accurate temperature control as a reaction processing apparatus becomes difficult.

In addition, semiconductor elements generally have a property that their characteristics change with temperature. For example, a MOS transistor using single crystal silicon has negative temperature characteristics, and even when the same voltage value is applied, the flowing current decreases as the temperature increases.
Therefore, even if the voltage value is the same, the heating amount varies depending on the temperature, and high-precision temperature control is difficult.

  An object of the present invention is to provide a thermal control matrix device and a reaction processing device that can perform temperature control with high accuracy.

  A first aspect of the present invention is a thermal control matrix device in a reaction processing apparatus that performs a DNA amplification reaction, a plurality of heater units arranged in a matrix, and a scanning line for selecting each of the heater units. And a data line for giving calorific value information to the heater unit, each heater unit receiving a calorific value information given to the data line in a state where the scanning line is selected; And a holding unit that holds the calorific value information even after the scanning line is not selected, and a drive unit that generates current according to the calorific value information and generates a corresponding amount of heat.

  Preferably, each of the heater units temporarily converts the signal current indicating the calorific value information given in the form of current level from the data line into the form of voltage level, and holds the converted voltage level. The holding unit, and the driving unit that converts the held voltage level into a current level and drives it.

  Preferably, the holding unit includes at least one capacitor, and the driving unit includes a switch connected in series between a power supply potential and a reference potential, and at least one field effect transistor having the gate connected to the capacitor. The receiving unit includes a switch for transferring heat generation amount information of the data line to the capacitor and storing electric charge, and the switch of the driving unit and the switch of the receiving unit are complementarily turned on and off.

  A second aspect of the present invention is a thermal control matrix device in a reaction processing apparatus that performs a DNA amplification reaction, and a plurality of temperature detection units arranged in a matrix and scanning for selecting each of the temperature detection units. A current drive line for supplying a current to the temperature detection unit, and a detection line for detecting a current of the temperature detection unit, and each temperature detection unit receives a current from the current drive line. A PIN diode that is supplied and in which a forward current flows; and a transfer unit that supplies a current of the current drive line to the PIN diode and transfers a current flowing through the PIN diode to the detection line.

  Preferably, the transfer unit includes a switch held in an on state when temperature is detected.

  A third aspect of the present invention is a thermal control matrix device in a reaction processing apparatus that performs a DNA amplification reaction, and supplies a plurality of fluorescence detection units arranged in a matrix and a reverse voltage to each of the fluorescence detection units. A reverse voltage line and a detection line for detecting a reverse current of the fluorescence detection unit, and each fluorescence detection unit includes a PIN diode to which a reverse voltage is applied by the reverse voltage line And a transfer unit that supplies a reverse voltage of the reverse voltage line to the PIN diode and transfers a reverse current flowing through the PIN diode to the detection line.

  A fourth aspect of the present invention is a thermal control matrix device in a reaction processing apparatus for performing a DNA amplification reaction, wherein a plurality of heater units are arranged in a matrix and are arranged in a matrix corresponding to each of the heater units. A plurality of temperature detection units for detecting the temperature heated by the heater unit; a first scanning line for selecting each of the heater units; and a data line for giving heat generation amount information to the heater unit; A second scanning line for selecting each temperature detection unit, a current drive line for supplying a current to the temperature detection unit, and a detection line for detecting a current of the temperature detection unit. The heater units each include a receiving unit that captures calorific value information given to the data line when the scanning line is selected, and the scanning line. Each of the temperature detection units includes: a holding unit that holds heat generation amount information even after being unselected; and a drive unit that generates a heat amount according to the current flow based on the heat generation amount information. A PIN diode through which a current from a current drive line is supplied and a forward current flows; and a transfer unit that supplies the current of the current drive line to the PIN diode and transfers the current flowing through the PIN diode to the detection line. .

  Preferably, the heat generation amount of the heater unit is controlled by the heat generation amount information based on information detected by the detection line.

  A fifth aspect of the present invention is a thermal control matrix device in a reaction processing apparatus for performing a DNA amplification reaction, wherein a plurality of temperature detection units arranged in a matrix and a matrix corresponding to the temperature detection units are arranged. A plurality of arranged fluorescence detection units, at least one scanning line for selecting each temperature detection unit and the fluorescence detection unit, a current drive line for supplying a current to the temperature detection unit, and the temperature A first detection line for detecting a current of the detection unit; a reverse voltage line for supplying a reverse voltage to each of the fluorescence detection units; and a second detection line for detecting a reverse current of the fluorescence detection unit; Each temperature detection unit includes a PIN diode to which a current from the current drive line is supplied and a forward current flows, and a current in the current drive line A first transfer unit that supplies the PIN diode and transfers a current flowing through the PIN diode to the detection line, and each fluorescence detection unit is supplied with a reverse voltage from the reverse voltage line. A PIN diode; and a second transfer unit that supplies a reverse voltage of the reverse voltage line to the PIN diode and transfers a reverse current flowing through the PIN diode to the detection line.

  Preferably, the temperature detection unit and the fluorescence detection unit share the PIN diode.

  Preferably, a temperature control correction is performed by sensing a dark current with the PIN diode, and a function of detecting an amplification reaction by sensing a light reception current generated during fluorescence reception.

  A sixth aspect of the present invention is a thermal control matrix device in a reaction processing apparatus for performing a DNA amplification reaction, wherein a plurality of heater units are arranged in a matrix and are arranged in a matrix corresponding to each of the heater units. A plurality of temperature detection units for detecting the temperature heated by the heater unit; a plurality of fluorescence detection units arranged in a matrix corresponding to the temperature detection unit; and for selecting each of the heater units A first scanning line; a data line for providing calorific value information to the heater unit; at least one second scanning line for selecting each of the temperature detection units and the fluorescence detection unit; and the temperature detection. A current drive line for supplying a current to the unit, a first detection line for detecting a current of the temperature detection unit, A reverse voltage line for supplying a reverse voltage to the light detection unit, and a second detection line for detecting a reverse current of the fluorescence detection unit, and each heater unit is selected by the scanning line A receiving unit that captures the calorific value information given to the data line in the generated state, a holding unit that retains the calorific value information even after the scanning line is deselected, and a current based on the calorific value information. Each of the temperature detection units is supplied with a current from the current drive line and a forward current flows, and a current of the current drive line is supplied to the PIN. A first transfer unit that supplies a diode and transfers a current flowing through the PIN diode to the detection line, and each fluorescence detection unit receives a reverse voltage from the reverse voltage line. Including a PIN diode to be fed, a second transfer unit for transferring the reverse voltage of the reverse voltage line is supplied to the PIN diode, the reverse current flowing through the PIN diode to the detection line, the.

  Preferably, at the stage where the heat generation control is fed back to the temperature detection unit in real time based on the detection result, fluorescence detection is performed as a signal of reaction amplification detection using a PIN diode which is a temperature detection device, and the amplification reaction is performed with the amount of fluorescence. Perform detection in real time.

  A seventh aspect of the present invention is a reaction processing apparatus having a plurality of reaction regions, comprising a thermal control matrix device for performing thermal control, wherein the thermal control matrix device corresponds to the reaction region. Corresponding to a plurality of heater units arranged in a matrix, a plurality of temperature detection units arranged in a matrix corresponding to each of the heater units, and detecting the temperature heated by the heater unit, and the temperature detection unit A plurality of fluorescence detection units arranged in a matrix, a first scanning line for selecting each of the heater units, a data line for giving heat generation amount information to the heater unit, and each temperature detection At least one second scanning line for selecting a unit and the fluorescence detection unit, and a power for supplying a current to the temperature detection unit. A drive line, a first detection line for detecting a current of the temperature detection unit, a reverse voltage line for supplying a reverse voltage to each of the fluorescence detection units, and a reverse current of the fluorescence detection unit are detected. A second detection line, wherein each heater unit receives a calorific value information given to the data line in a state where the scanning line is selected, and the scanning line is not selected. A holding unit that holds the calorific value information, and a drive unit that generates current according to the calorific value information and generates a heat amount corresponding to the current, and each of the temperature detection units is connected to the current drive line. A PIN diode through which a forward current is supplied and a current is supplied to the PIN diode, and a first transfer unit is configured to supply the current through the PIN diode to the PIN diode and to transfer the current through the PIN diode to the detection line; Each of the fluorescence detection units includes a PIN diode to which a reverse voltage is supplied by the reverse voltage line, a reverse voltage of the reverse voltage line to the PIN diode, and a reverse current that flows through the PIN diode. And a second transfer unit that transfers current to the detection line.

  According to the present invention, temperature control can be performed with high accuracy.

Hereinafter, embodiments of the present invention will be described with reference to the accompanying drawings.
Each embodiment shown in an accompanying drawing shows an example of typical embodiment concerning the present invention, and, thereby, the scope of the present invention is not interpreted narrowly.

In the present embodiment, a thermal control matrix device that can be applied to a reaction processing apparatus that employs the PCR method will be described.
An example of a reaction processing apparatus that employs the PCR method is a real-time PCR apparatus that detects a gene expression level.

  FIG. 1 is a conceptual diagram illustrating a configuration example of a real-time PCR apparatus as a reaction processing apparatus according to an embodiment of the present invention.

  As shown in FIG. 1, the PCR device 1 includes a well substrate 11 having a plurality of reaction regions A1, a light source 12, and an excitation light scanning plate 13 that guides excitation light L1 and L2 emitted from the light source 12. Yes. A filter 14, a fluorescence detection unit 15 that detects fluorescence L 3, and a heating unit 16 that heats the reaction region A 1 are provided on the measurement substrate 17.

  In the PCR device 1, the excitation light L1 emitted from the light source 12 passes through the excitation light scanning plate 13 and is irradiated to each reaction region A1 as the excitation light L2. Then, the fluorescence L3 emitted from within the reaction region A1 is detected and measured by the fluorescence detection unit 15.

In the PCR apparatus 1, in particular, a heating unit 16 is provided for each reaction region A1, and a temperature detection unit that detects a temperature in the vicinity of the heat source of the heating unit 16 and converts the temperature into an electrical signal is provided. By having the function of determining the heating amount based on the correlation between the heating amount and the heating amount of the heat source, the temperature of each reaction region A1 can be controlled individually and with high accuracy.
The PCR device 1 will be further described in detail after the description of the thermal control matrix device according to the present embodiment.

In the PCR device, when detecting a signal as a reaction signal in another functional unit that is stacked in the vicinity of the upper or lower portion of the TFT substrate that is a heating unit, in detecting fluorescence as a reaction signal, In the case of direct detection, it is desirable to form a heater matrix on a relatively large transparent insulating substrate (for example, glass) that has a light-transmitting property that does not adversely block fluorescence detection.
In this case, it is preferable to use a thin film transistor (hereinafter sometimes referred to as TFT) as a semiconductor element in terms of cost, manufacturing process, and the like.
However, it is generally known that TFTs have larger manufacturing variations and changes over time than single crystal semiconductor elements.

More specifically, as the heater in the PCR apparatus, it is preferable to use a low-temperature polysilicon process capable of forming a TFT having a relatively high current driving capability on a large glass substrate. In the low-temperature polysilicon process, after forming an amorphous silicon film on a glass substrate, crystallization is usually performed by a laser annealing method in order to avoid thermal deformation of the substrate.
However, it is not easy to uniformly irradiate a large glass substrate with laser energy, and it is inevitable that the crystallization state of polysilicon varies depending on the location in the substrate. As a result, even if TFTs are formed on the same substrate, it is not uncommon for the Vth (threshold value) to vary from several hundred mV depending on the location, and sometimes 1 V or more. When such a TFT is used, it is difficult to construct a highly accurate and highly reliable PCR reaction apparatus with existing technology.
Therefore, in the present embodiment, a thermal control matrix device for realizing a PCR device capable of high-precision temperature control using a thin film transistor formed on a transparent insulating substrate is realized.

  Specifically, in the embodiment described below, a heater unit is configured by a current copy or current mirror using TFTs, thereby enabling highly accurate temperature control, and further, a so-called PIN diode is used as a temperature sensor. Thus, by performing feedback and realizing fluorescence detection as an amplification reaction signal with a parallel PIN diode, high-accuracy comprehensive analysis is enabled.

The thermal control matrix device according to the present embodiment can be applied as, for example, the heating unit 16, the temperature detection unit, and the fluorescence detection unit 15 of the PCR 1 described above.
Hereinafter, as an embodiment of the thermal control matrix device, a heater matrix device applicable as a heating unit (heat generation unit) capable of controlling the amount of heat generation, a temperature detection matrix applicable as a temperature detection unit, and fluorescence applicable as a fluorescence detection unit Detection matrix device, temperature fluorescence detection matrix device having both functions of temperature detection matrix device and fluorescence detection unit, heater temperature detection matrix device having both functions of heater matrix device and function of temperature detection matrix device, and heater matrix device A heater temperature fluorescence detection matrix device having both the above functions and a function as a temperature fluorescence matrix device will be described in order.

  First, the heater matrix device will be described.

<Heater matrix device>
FIG. 2 is a diagram illustrating a configuration example of the heater matrix device according to the embodiment of the present invention.

  As shown in FIG. 2, the heater matrix device 100 includes a cell array unit 101 in which heater units 110 are arranged in an m × n matrix, a data line driving circuit (DTDRV) 102, a scanning line driving circuit (WSDRV) 103, Scan lines WSL101 to WSL10m for selecting data lines DTL101 to DTL10m for giving heat generation amount information to heater unit 110 and heater unit 110, writing heat generation power information, and flowing current according to the written heat generation amount information. Have

The data line driving circuit 102 applies a signal current to each of the data lines DTL101 to DTL10n in synchronization with the driving timing of the scanning lines WSL101 to WSL10m of the scanning line driving circuit 103, whereby the heater unit 110 as each heating unit is applied. On the other hand, calorific value information is written in units of lines.
The scanning line drive circuit 103 sequentially selects and scans the scanning lines WSL101 to WSL10m. The scanning line driving circuit 103 controls the timing at which the heater unit 110 acquires heat generation amount information by driving the scanning lines WSL101 to WSL10m.
The scanning line driving circuit 103 deselects the scanning lines WSL101 to WSL10m after completing the writing of the heat generation amount information in the heater unit 110, so that a driving current having the same current value as the signal current is supplied to each heating unit (heater unit). Can continue to flow.
In this manner, a current having a desired magnitude can be supplied to each heater unit 110, and as a result, a desired amount of heat can be generated.

The data line driving circuit 102 transfers heat generation information corresponding to a control signal CTL supplied by a temperature detection control system (not shown) to each of the data lines DTL101 to DTL10n as a signal current, thereby generating heat from each heater unit 110. The amount can be controlled.
In other words, the heat generation amount of the heater unit 110 is controlled by the written heat generation amount information.

  Next, a specific configuration example of the heater unit 110 will be described.

  FIG. 3 is a circuit diagram showing a first configuration example of the heater unit in the heater matrix device according to the present embodiment. FIG. 4 is a circuit diagram showing one state of the circuit operation of FIG. FIG. 5 is a circuit diagram showing another state of the circuit operation of FIG.

The heater unit 110 of FIG. 3 includes a transistor T111 formed of an n-channel insulated gate transistor, switches SW111, SW112, SW113, a capacitor C111, and nodes ND111, ND112, ND113.
In the figure, symbol g indicates the gate of the transistor, symbol d indicates the drain, and symbol s indicates the source. A symbol Cs indicates the capacitance of the capacitor C111.

In the heater unit 110, the drain d of the transistor T111 functioning as a driving transistor is connected to the node ND111, the gate g is connected to the node ND112, and the source s is connected to the node ND113. The node ND113 is connected to the ground potential GND.
The switch SW111 is connected between the data line DTL through which the signal current Isig is propagated and the node ND113. A switch SW112 is connected between the node ND111 and the node ND112. A switch SW113 is connected between the node ND111 and the power supply potential VDD.
Capacitor C111 has a first electrode connected to node ND112 and a second electrode connected to node ND113 (or ground potential GND).

In the heater unit 110, the switches SW111 and SW112 are turned on and off in the same phase according to the levels of the scanning lines WSL101 to WSL10m.
The switch SW113 is turned on and off complementarily with the switches SW111 and SW112 according to the levels of the scanning lines WSL101 to WSL10m.

Among these components, the switches SW111 and SW112 function as a receiving unit that captures heat generation amount information given to the data line DTL in a state where the scanning line WSL is selected.
The capacitor C111 functions as a holding unit that holds heat generation amount information even after the scanning line is not selected.
Then, the transistor T111 and the switch SW113 function as a drive unit that causes a current to flow based on the written heat generation amount information and generates a heat amount corresponding thereto.

In the heater unit 110, the drive current flows between the power supply potential VDD and the ground potential GND via the transistor T111 and the switch SW113.
The Joule heat generated by the resistance component of the transistor T111 and the switch SW113 can be used as a heat source.
Note that the transistor T111 is an n-channel, and a p-channel transistor can be used as appropriate in the present invention.

  In the present embodiment, the heating amount information transmitted from the data line DTL is a signal current Isig, and it is desirable to have a circuit configuration in which this signal current is converted into a signal voltage and thermally controlled. Hereinafter, the operation of the circuit of FIG. 3 will be described with reference to FIG. 4 and FIG.

  FIG. 4 shows an operation of writing heating amount information (that is, a signal current) in the form of a current level in the heater unit 110. In this write operation, the switches SW111 and SW112 are on and the switch SW113 is off.

The transistor T111 is in a state where the drain d and the gate g are short-circuited by the switch SW2, and the signal current I _sig flows (see FIG. 4).
As a result, a gate-source signal voltage V _gs corresponding to the value of the signal current I _sig is generated.

If the transistor T111 is an enhancement type transistor (that is, the threshold value V _th > 0), the transistor T111 operates in a saturation region, and a well-known expression between the signal current I _sig and the signal voltage V _gs (1) is established.

[Equation 1]
Isig = μ · Cox · W / L / 2 · (Vgs−Vth) ² (1)

Here, μ represents carrier mobility, C _OX represents gate capacitance per unit area, W represents channel width, and L represents channel length.

When the switch SW112 is turned off when the circuit is stabilized, the gate-source voltage _Vgs is held in the capacitor C111. Therefore, the signal write operation is completed by turning the switch SW111 off.

After that, when the switch SW113 is turned on at an arbitrary timing as shown in FIG. 5, a current flows from the power supply voltage VDD toward the ground potential GND. At this time, as the transistor T111 is operated in the saturation region, sufficiently high power supply voltage VDD, is set sufficiently low on-resistance of the switch SW 113, the drive current _{I drv} flowing through the transistor T111, the drain-source voltage It is given by the following formula (2) without depending on V _ds . The drive current I _drv matches the signal current I _sig .

[Equation 2]
Idrv = μ · Cox · W / L / 2 · (Vgs−Vth) ² (2)

That is, each parameter appearing on the right side of the equations (1) and (2) generally varies from one board to another or from place to place even within the same board, but the driving shown in FIGS. 4 and 5 is performed. Thus, the signal current I _sig and the drive current I _drv match regardless of the values of these parameters.

Since the signal current I _sig can be generated with an accurate value by a control circuit or the like outside the heater matrix device, the Joule heat generated from the heater unit circuit in FIG. It is possible to obtain an accurate value determined by the product of the power supply voltage VDD and the signal current I _sig (VDD × I _sig ).

  FIG. 6 is a circuit diagram showing a modification of the circuit configuration shown in FIG.

The circuit shown in FIG. 6 is different from FIG. 3 in the connection relationship between the switch SW112 and the like. Specifically, the switch SW112 is connected not between the node ND111 and the node ND112 but between the data line DTL and the node ND112.
In the case of the circuit of FIG. 6, the connection relationship between the node ND112 and the data line DTL is equivalent to that of FIG. 3 in terms of circuit operation depending on whether or not the connection is made through the switch SW111 and the node ND111.
As in the circuit shown in FIG. 3, the circuit shown in FIG. 6 turns on the switch SW111 and the switch SW112 and turns off the switch SW113 during signal writing.
During the heat generation operation, the switches SW111 and SW112 are turned off and the switch SW113 is turned on.
The circuit of FIG. 6 can also exhibit the same function as the circuit of FIG.

  FIG. 7 is a circuit diagram showing another modification of the circuit configuration shown in FIG.

7 differs from the circuit of FIG. 3 in that a p-channel transistor is used as the transistor T111 and the direction of current is reversed.
In the case of the circuit of FIG. 7, the source s of the transistor T111 is connected to the power supply potential VDD (node ND113), the drain d is connected to the node ND111, and the switch SW113 is connected between the node ND111 and the ground potential GND. .
The circuit in FIG. 7 is in principle common to the circuit in FIG. 3 and can exhibit the same function.

  In the present invention, a p-channel insulated gate transistor (PMOS) is preferably used for the low-temperature polysilicon thin film transistor (low-temperature polysilicon TFT). In the low-temperature polysilicon TFT, the PMOS is preferable because the characteristics are stable.

  FIG. 8 is a circuit diagram showing still another modification of the circuit configuration shown in FIG.

In the circuit of FIG. 8, the control of each switch SW111, SW112, SW113 is the same as that of the circuit of FIG. 3, but differs in that the signal current I _sig is drawn from the source side of the transistor T111.
In the case of the circuit in FIG. 8, the transistor T111 is an n-channel transistor, but the drain d of the transistor T111 is connected to the power supply potential VDD, the drain d is connected to the node ND111, and the switch SW113 is connected between the node ND111 and the ground potential GND. Connected between.
The circuit of FIG. 8 is operated in the same manner as the circuit of FIG. 3 in that the signal current I _sig flows in a state where the gate and drain are short-circuited, and the gate-source voltage V _gs generated accordingly is held in the capacitor C111. They are common and can perform the same function.

  FIG. 9 is a circuit diagram showing still another modification of the circuit configuration shown in FIG.

The circuit of FIG. 9 is different in that a transistor T112, a switch SW114, and a capacitor 112 are added to the circuit configuration of FIG. The switch SW114 is controlled to be turned on and off in the same manner as the switch SW112.
The gate of the transistor T114 is connected to the node ND114, the drain is connected to the node ND113, and the source is connected to the ground potential GND. The switch SW114 is connected between the node ND113 and the node ND114, the first electrode of the capacitor C112 is connected to the node ND114, and the second electrode is connected to the ground potential GND.
The operation of this circuit will be described below.

In the circuit of FIG. 3, the signal current I _sig is given by the equation (1), the drive current I _drv is given by the equation (2), and it has already been described that the signal current I _sig and the drive current I _drv coincide. This is, for example, the current flowing through the MOS transistor, irrespective of the voltage V _ds between the drain and the source in the saturation region operation, is in line with the basic operation of being determined only by the gate-source voltage V _gs .

However, in an actual transistor, when the drain-source voltage V _ds increases, the drain-source current I _ds generally increases somewhat. This phenomenon includes the back gate effect in which the drain potential affects the channel conduction state, the short channel effect in which the effective channel length L is shortened by the depletion layer (depletion layer) at the drain end extending to the source side, and the like. Is considered to be the cause.

Referring to the circuit of FIG. 3 as an example, when a relatively small signal current I _sig is written, the gate-source voltage V _gs generated by the equation (1) becomes a relatively small value, and the drain-source voltage V _ds is a small value equal to the gate-source voltage V _gs .

On the other hand, at the time of driving, the drive current _{I drv} voltage drop across the switch SW113 to small small, the drain-source voltage _{V ds} of the transistor T111 becomes greater than the time of writing. Thus, the drain-source voltage V _ds of the transistor T111 in the time of driving at the time of writing does not generally match. Therefore, the signal current I _sig and the drive current I _drv do not exactly match. This may cause the desired amount of heating not to be obtained.

In contrast, consider the operation of the circuit configuration shown in FIG.
For example, the transistors T111, similar to the circuit of Figure 3, the drain-source voltage V _ds of the transistor T111 in the time of driving and the time of writing does not generally match.
However, for example, when the drain-source voltage V _ds during driving is large, the driving current I _drv is larger than the signal current I _sig , but if the transistor T112 operates in a saturated state (in other words, If it is operating close to a constant current source), its differential resistance is very large.

As a result, the source potential of the transistor T111 greatly increases even if the drive current _Idrv slightly increases. This acts in the direction of decreasing the gate-source voltage _Vgs of the transistor T111 and decreasing the drive current _Idrv . As a result, the drive current _{I drv} can not be increased too much with respect to the signal current _{I sig,} consistent with the signal current _{I sig} and the drive current _{I drv} becomes better than the example of FIG.

  FIG. 10 is a circuit diagram showing a specific configuration example of FIG.

In the circuit of FIG. 10, three switches SW111 and 112 are formed by p-channel transistors T113 and 114, and the switch SW113 is formed by an n-channel transistor T115.
The gates of these three transistors T113 to T115 are commonly connected to the scanning line WSL. A signal writing operation can be performed when the scanning line WSL is at a low level, and a driving operation can be performed when the scanning line WSL is at a high level.
As will be described later, in the present invention, the gates of the transistors T113, T114, and T115 may not be connected in common, but the circuit diagram of FIG. 10 is preferable because the structure is simple.

  FIG. 11 is a circuit diagram showing another modification of the circuit configuration of FIG.

  The circuit configuration shown in FIG. 11 is different from the circuit configuration shown in FIG. 10 in that transistors T114a and T114b are included.

In general, a TFT is likely to be defective in a manufacturing process, and for example, a problem that a minute leak current flows when the switch transistor is in an off state occurs stochastically.
In the circuit of FIG. 10, when a leak current occurs in the transistor T4, the voltage held in the capacitor C111 changes due to the leak current. For this reason, a situation in which a correct heat generation state cannot be maintained may occur.

On the other hand, in the circuit shown in FIG. 11, one transistor T114 used in FIG. 10 is composed of two transistors T114a and T114b connected in series. As a result, leakage current can be suppressed.
Similarly, three or more transistors can be connected in series, or a plurality of transistors can be connected to the transistors T113 and T115.

FIG. 12 is a circuit diagram showing still another modification of the circuit configuration of FIG.
FIG. 13 is a diagram showing a configuration example of a heater matrix device having the heater unit of FIG.

The circuit diagram shown in FIG. 12 is a configuration example in which the control of the transistor T115 is independent from the control of the transistors T113 and T114.
The heater matrix device 100A includes drive scanning lines DSL101 to DSL10m and a drive line drive circuit 104 for driving the transistor T115 in addition to the configuration of FIG.

In this case, at the time of signal writing, the write scanning lines WSL101 to WSL10m and the drive scanning line DSL101 to SL10m are both set to a low level.
After the writing is completed (that is, after the writing scanning line is set to the high level), the driving scanning lines DSL101 to DSL10m are set to the high level at an arbitrary timing, so that the heating operation can be performed.

On the other hand, if the drive scanning lines DSL101 to DSL10m are set to a low level, the heat generation operation can be easily stopped, which is preferable when it is desired to quickly lower the temperature. In addition, since the heat generation operation time can be adjusted, for example, even when it is difficult for the signal current source to accurately generate a small current, an accurate minute heat generation operation can be performed.
If you want to avoid intermittent heat generation due to such an operation, stop the heat generation and heat generation multiple times within the period from when the heat generation amount information is written until the next heat generation amount information is written. If repeated, more stable heat generation is possible in time.

  FIG. 14 is a circuit diagram showing still another modification of the circuit configuration of FIG.

14 is characterized in that the power supply potential line LVDD is arranged in parallel with the scanning line WSL and the switch SW113 in FIG. 3 is formed by a diode D111.
At the time of signal writing, if the power supply voltage VDD is set to a low level, the diode D111 is turned off, and at the time of driving, if the power supply voltage VDD is set to a high level, the diode D111 is turned on, so that the diode D111 can be operated as a switch. it can.
Therefore, the circuit configuration illustrated in FIG. 14 can have the same function as the circuit configuration illustrated in FIG.

  FIG. 15 is a circuit diagram showing still another modification of the circuit configuration of FIG.

The circuit shown in FIG. 15 differs from the circuit configuration shown in FIG. 3 in that a transistor T116 for converting the signal current I _sig into a voltage form and a transistor T111 for supplying a current for heat generation are provided separately.
The drain and gate of the transistor T116 are connected to each other, the connection point is connected to the nodes ND111 and ND112, and the source of the transistor T116 is connected to the ground potential GND.

At the time of signal writing, the switches SW111 and SW112 are turned on, and the signal current I _sig is passed through the transistor T116. At this time, the following expression (3) is established.

[Equation 3]
Isig = μ · Cox · W1 / L / 2 · (Vgs−Vth) ² (3)

Further, in the equation (3), the meaning of each parameter is equivalent to the equation (1), the channel width of the transistor T116 and the _{W 1.} At the time of driving, the two switches SW111 and SW112 are turned off.
On the other hand, the capacitor C111, since the gate-source voltage _{V gs} generated in the write operation is held, the following equation (4) is satisfied for the drive current _{I drv} flowing through the transistor T111.

[Equation 4]
Idrv = μ · Cox · W2 / L / 2 · (Vgs−Vth) ² (4)

Here, the channel width of the transistor T111 is _{W 2,} the transistor T116, T111 is considered to be formed in small heating portion, the parameters _μ, C OX, _{V th} is assumed virtually equal for the transistors T116, T111 . The channel length L can be designed to be equal. As a result, the following equation (5) can be derived from the equations (3) and (4).

[Equation 5]
Idrv / Isig = W2 / W1 (5)

Each parameter appearing on the right side of the equations (3) and (4) may generally vary from substrate to substrate or from place to location even within the same substrate, but the signal current I _{sig is independent} of the values of these parameters. It can be seen that the ratio of the drive current I _drv matches the ratio of the channel widths of the transistors T111 and T116.

The feature of this circuit is that, unlike the circuit of FIG. 3, the ratio of the signal current I _sig to the drive current I _drv can be adjusted arbitrarily. For example, when it is desired to generate a small amount of heat, if it is difficult for the external circuit to generate a small amount of current, the channel width may be designed so that the right side of Equation (5) becomes small. On the contrary, it is easy to design so that a large drive current _Idrv can be controlled by a small signal current I _sig .

The heater matrix device has been described above.
Next, the temperature detection matrix device will be described.

<Temperature detection matrix device>
FIG. 16 is a diagram illustrating a configuration example of the temperature detection matrix device according to the embodiment of the present invention.

  As shown in FIG. 16, this temperature detection matrix device 200 includes a cell array unit 201 in which temperature detection units 210 are arranged in an m × n matrix, a current drive circuit (IDRV) 202, and a scanning line drive circuit (WSDRV) 203. , Voltage detectors (V) 204-1 to 204-n, current drive lines IDL201 to IDL20m, temperature detection lines TSL (Temperature Sense Line) 201 to TSL20m, and detection unit 210 are selected, and a detection signal of temperature detection unit 210 is selected. Are transferred to temperature detection lines TSL201 to TSL20m, scanning lines SSL201 to SSL20m are provided.

  FIG. 17 is a circuit diagram illustrating a configuration example of the temperature detection unit according to the present embodiment.

  As shown in FIG. 17, the temperature detection unit 210 includes a PIN diode D211, n-channel transistors T211 and T212 as switches, and a node ND211.

The anode side of the PIN diode 211 is connected to the node ND211 and the cathode side is connected to the ground potential GND.
The source and drain of the transistor T211 are connected to the node ND211 and the current drive line IDL. The source and drain of the transistor T212 are connected to the node ND211 and the temperature detection line TSL.
The gates of the transistors T211 and T212 are connected in common to the scanning line SSL.

  In this example, the transistors T211 and T212 are turned on when the scanning line SSL is at a high level, and the transistors T211 and T212 are turned off when the scanning line SSL is at a low level.

Here, the basic operation of the temperature detection unit 210 will be described.
When the current source I211 that supplies the current Idet is connected to the current drive line IDL and the scanning line SSL is at a high level, the forward current Idet flows from the current source I211 connected to the current drive line IDL to the PIN diode D211. .
In parallel with this, the forward voltage generated in the PIN diode D211 can be detected by connecting the voltage detector 204 to the temperature detection line TSL. As the voltage detector 204, for example, an analog-digital converter or the like can be applied.

  In the temperature detection unit 210, temperature detection is performed by sensing dark current with the PIN diode D211, and the temperature, for example, the amount of heat generated by each heater unit in the heater matrix device is controlled according to the detected temperature.

FIG. 18 shows the temperature dependence of the dark current.
Using this characteristic, it becomes possible to recognize the temperature from the detected current.

Here, when a constant forward current Idet is passed through the PIN diode D211, the relationship shown in FIG. 19 is obtained between the forward voltage (FORWARD VOLTAGE) of the PIN diode D211 and the temperature.
That is, the forward voltage changes linearly with temperature, and temperature information can be obtained by detecting the forward voltage of the temperature detection line TSL connected to the PIN diode D211.

  Next, the fluorescence detection matrix device will be described.

<Fluorescence detection matrix device>
FIG. 20 is a diagram illustrating a configuration example of the fluorescence detection matrix device according to the embodiment of the present invention.

  As shown in FIG. 20, the fluorescence detection matrix device 300 includes a cell array unit 301 in which fluorescence detection units 310 are arranged in an m × n matrix, a scanning line drive circuit (WSDRV) 303, a reverse voltage line (Reverse Voltage). line) RVL301, fluorescence detection lines LSL301 to TSL30m, and detection unit 310 are selected, and scanning lines SSL301 to SSL30m for transferring detection signals of fluorescence detection unit 310 to fluorescence detection lines LSL301 to LSL30m are provided.

  FIG. 21 is a circuit diagram illustrating a configuration example of the fluorescence detection unit according to the present embodiment.

  As shown in FIG. 21, the fluorescence detection unit 310 includes a PIN diode D311, p-channel transistors T311 and T312 as switches, and a node ND311.

The anode side of the PIN diode 311 is connected to the node ND311 and the cathode side is connected to the ground potential GND.
The source and drain of the transistor T311 are connected to the node ND311 and the reverse voltage line RVL. The source and drain of the transistor T312 are connected to the node ND311 and the fluorescence detection line LSL.
The gates of the transistors T311 and T312 are commonly connected to the scanning line SSL.

  In this example, the transistors T311 and T312 are turned on when the scanning line SSL is at a low level, and the transistors T311 and T312 are turned off when the scanning line SSL is at a high level.

Here, the basic operation of the fluorescence detection unit 310 will be described.
When a negative voltage source is connected to the reverse voltage line RVL and the scanning line SSL is at a low level, the PIN diode D311 is biased in the reverse direction by the negative voltage applied to the reverse voltage line RVL, and the reverse current IR Flows.
Fluorescence can be detected by detecting the reverse current Iout via the fluorescence detection line LSL.

  Next, the heater temperature detection matrix device will be described.

<Heater temperature detection matrix device>
FIG. 22 is a diagram illustrating a configuration example of the heater temperature detection matrix device according to the embodiment of the present invention.

  The heater temperature detection matrix device 400 in FIG. 22 has a configuration in which the heater matrix device 100 in FIG. 2 and the temperature detection matrix device 200 in FIG. 16 are combined. Therefore, in FIG. 22, the same components as those in FIGS. 2 and 16 are denoted by the same reference numerals for easy understanding.

  As shown in FIG. 22, the heater temperature detection matrix device 400 includes a cell array unit 401 in which heater temperature detection units 410 are arranged in an m × n matrix, a data line driving circuit (DTDRV) 102, a scanning line driving circuit ( (WSDRV) 103, data lines DTL101 to DTL10m for giving the heat generation amount information to the heater unit 110, the heater unit 110 are selected, the heat generation amount information is written, and a scanning line for flowing a current according to the written heat generation amount information WSL101 to WSL10m, current drive circuit (IDRV) 202, scan line drive circuit (WSDRV) 203, voltage detectors (V) 204-1 to 204-n, current drive lines IDL201 to IDL20m, temperature detection line TSL (Temperature Sense Line) ) 201-TSL20m, and Select temperature detection unit 210 has a scanning line SSL201~SSL20m for transferring a detection signal of the temperature detection unit 210 to the temperature detection line TSL201～TSL20m.

  FIG. 23 is a circuit diagram illustrating a configuration example of the heater temperature detection unit according to the present embodiment.

The heater temperature detection unit 410 in FIG. 23 is formed by using the heater unit 110 in FIG. 10 and the temperature detection unit 210 in FIG.
Therefore, in FIG. 23, the same components as those in FIGS. 2 and 17 are denoted by the same reference numerals for easy understanding.

  According to the heater temperature detection matrix device 400 of FIG. 22, by sensing actual generated heat after being written as heat generation amount information at the current copier, the current copier is compared with the amount of heat generation information written. The temperature control can be corrected by sensing dark current with a PIN diode.

  In this case, temperature detection by the PIN diode D211 can be performed from the relationship between the heater current of the heater unit 110 and the detection voltage corresponding to the current of the PIN diode D211 of the temperature detection unit 210.

FIG. 24 is a diagram showing the relationship between the heater current of the heater unit and the detection voltage according to the current of the PIN diode of the temperature detection unit.
In FIG. 24, the horizontal axis represents the heater current, and the vertical axis represents the diode voltage.
In the figure, IF1 represents a voltage value with a diode current of 10 μA, and IF2 represents a voltage value with a diode current of 100 μA.

  When the diode current is 10 μA and 100 μA, it can be converted into a temperature from the difference (ΔV) between the voltage values given by the following equation.

[Equation 6]
ΔV = η (kT / q) ln (IF1 / IF2) (6)
Temp (C) = 5.00072 × ΔV + 273.15

  Next, the temperature fluorescence detection matrix device will be described.

<Temperature fluorescence detection matrix device>
FIG. 25 is a diagram illustrating a configuration example of the temperature fluorescence detection matrix device according to the embodiment of the present invention.

  25 has a configuration in which the temperature detection matrix device 200 of FIG. 16 and the fluorescence detection matrix device 300 of FIG. 20 are combined. Therefore, in FIG. 25, the same components as those in FIGS. 16 and 20 are denoted by the same reference numerals for easy understanding.

  As shown in FIG. 25, the temperature fluorescence detection matrix device 500 includes a cell array unit 501 in which temperature fluorescence detection units 510 are arranged in an m × n matrix, a current drive circuit (IDRV) 202, a scan line drive circuit (WSDRV). ) 203, voltage detectors (V) 204-1 to 204-n, current drive lines IDL201 to IDL20m, temperature detection lines TSL (Temperature Sense Line) 201 to TSL20m, and detection unit 210 are selected and detected by temperature detection unit 210 Scan lines SSL201 to SSL20m for transferring signals to the temperature detection lines TSL201 to TSL20m, scan lines SSL301 to SSL30n for selecting the fluorescence detection unit 210, a scan line drive circuit (WSDRV) 303, a reverse voltage line (Reverse Volta) Having e line) RVL301, and fluorescence detection line LSL301～TSL30m.

  FIG. 26 is a circuit diagram illustrating a configuration example of the temperature fluorescence detection unit according to the present embodiment.

26 is configured to share the PIN diode D211 and the node ND211 of the temperature detection unit 210 of FIG. 17 and the PIN diode D311 and the node ND311 of the fluorescence detection unit 310 of FIG.
Therefore, in FIG. 26, the same components as those in FIGS. 17 and 21 are denoted by the same reference numerals for easy understanding.

  The temperature fluorescence detection unit 510 includes one PIN diode D211 (D311), two n-channel transistors T211 and T212, and two p-channel transistors T311 and T312.

  FIG. 27 is a diagram showing the state of each transistor as a switch at the time of temperature detection and fluorescence detection in the temperature fluorescence detection unit according to the present embodiment.

A switch signal that periodically changes between a high level and a low level is applied to the scanning line SSL. The gates of the n-channel transistors T211 and T212 and the p-channel transistors T311 and T312 are commonly connected to the scanning line SSL.
Accordingly, when the scanning line SSL is at a high level, the transistors T211 and T212 are turned on, and the transistors T311 and T312 are turned off.
On the other hand, when the scanning line SSL is at a low level, the transistors T211 and T212 are turned off, and the transistors T311 and T312 are turned on.

  FIG. 28 is a diagram for explaining the temperature detection operation of the temperature fluorescence detection unit according to this embodiment. FIG. 29 is a diagram for explaining the fluorescence detection operation of the temperature fluorescence detection unit according to this embodiment.

At the time of temperature detection, the current source I211 for supplying the current Idet is connected to the current drive line IDL. When the scanning line SSL is at the high level, as shown in FIG. 28, the current source I211 connected to the current drive line IDL is PIN-connected. A forward current Idet flows through the diode D211.
In parallel with this, the forward voltage generated in the PIN diode D211 can be detected by connecting the voltage detector 204 to the temperature detection line TSL.

Here, when a constant forward current Idet is passed through the PIN diode D211, the relationship shown in FIG. 19 is obtained between the forward voltage (FORWARD VOLTAGE) of the PIN diode D211 and the temperature.
That is, the forward voltage changes linearly with temperature, and temperature information can be obtained by detecting the forward voltage of the temperature detection line TSL connected to the PIN diode D211.

When detecting fluorescence, a negative voltage source is connected to the reverse voltage line RVL. When the scanning line SSL is at a low level, the negative voltage applied to the reverse voltage line RVL biases the PIN diode D311 in the reverse direction. As shown in FIG. 29, a reverse current IR flows.
Fluorescence can be detected by detecting the reverse current Iout via the fluorescence detection line LSL.

In the temperature fluorescent matrix device 500 of FIG. 25, the scanning line driving circuit 203 sequentially sets the scanning lines SSL201 to SSL20m to a high level, and the current driving line driving circuit 202 supplies constant currents to the current driving lines IDL201 to IDL20n in synchronization therewith. By applying the voltage and monitoring the voltage of the temperature detection lines TSL201 to TSL20n, it is possible to detect temperature information for each PIN diode D211 in units of rows.
If the scanning line is sequentially lowered to a low level after the temperature detection is completed, a reverse voltage is applied to each PIN diode D211 and fluorescence information can be detected for each PIN diode D211 in rows.
In this way, each unit can detect temperature and fluorescence alternately.

In the fluorescence detection process, for example, as shown in FIG. 30, first, the dark current of the PIN diode D211 (D311) is detected and binarized to obtain V1. V1 is scanned 2 to 3 times to obtain an average value (ST101).
Next, the above-described fluorescence detection is performed to binarize the detection current to obtain V2. V2 is scanned 2 to 3 times to obtain an average value (ST102).
Then, the difference between V2 and V1 is taken (ST103).
By performing such processing, highly accurate fluorescence detection can be realized.

  Next, the heater temperature fluorescence detection matrix device will be described.

<Heater temperature fluorescence detection matrix device>
FIG. 31 is a diagram illustrating a configuration example of the heater temperature detection matrix device according to the embodiment of the present invention.

  A heater temperature fluorescence detection matrix device 600 in FIG. 31 has a configuration in which the heater matrix device 100 in FIG. 2, the temperature detection matrix device 200 in FIG. 16, and the fluorescence detection matrix device 300 in FIG. 20 are combined. Therefore, in FIG. 31, in order to facilitate understanding, the same components as those in FIGS. 2, 16, and 20 are denoted by the same reference numerals.

  As shown in FIG. 31, the heater temperature detection matrix device 600 includes a cell array unit 601 in which heater temperature fluorescence detection units 610 are arranged in an m × n matrix, a data line driving circuit (DTDRV) 102, and a scanning line driving circuit. (WSDRV) 103, data lines DTL101 to DTL10m for providing the heat generation amount information to the heater unit 110, the heater unit 110 are selected, the heat generation power information is written, and the current is applied according to the written heat generation amount information. Lines WSL101 to WSL10m, current drive circuit (IDRV) 202, scanning line drive circuit (WSDRV) 203, voltage detectors (V) 204-1 to 204-n, current drive lines IDL201 to IDL20m, temperature detection line TSL (Temperature Sense) Line) 201-TSL20m, Scan line SSL201 to SSL20n, current drive circuit (IDTC) 302, scan line drive circuit (WSDRV) 303 for selecting the degree detection unit 210 and transferring the detection signal of the temperature detection unit 210 to the temperature detection lines TSL201 to TSL20n, It has a reverse voltage line (Reverse Voltage line) RVL301 and fluorescence detection lines LSL301 to TSL30m.

However, the data line driving circuit 102 and the current driving circuit 202 can be shared.
In this case, the data line DTL and the temperature detection line TSL can be shared.

  FIG. 32 is a circuit diagram illustrating a configuration example of the heater temperature fluorescence detection unit according to the present embodiment.

In the heater temperature fluorescence detection unit 600 of FIG. 32, the heater temperature fluorescence detection unit 610 is formed using the heater unit 110 of FIG. 10 and the temperature fluorescence detection unit 510 of FIG.
Therefore, in FIG. 32, the same components as those in FIGS. 10 and 26 are denoted by the same reference numerals for easy understanding.
In this example, the data line DTL and the temperature detection line TSL are shared.

According to the heater temperature fluorescence detection matrix device 600 of FIG. 31, by sensing actual generated heat after being written as heat generation amount information at the current copier, the current copier with respect to the heat generation amount information write amount. Thus, temperature control can be corrected by sensing dark current with a PIN diode.
Then, the amplification reaction can be detected by sensing the light receiving current generated when the fluorescence is received.
More specifically, at the stage where the heat generation control is fed back in real time by the circuit configuration of the current copier (heater unit) and the temperature detection unit, fluorescence detection is performed on the PIN diode D211 which is a temperature detection device as a reaction amplification detection signal. Thus, the amplification reaction can be detected in real time by the amount of fluorescence.

  As described above, the thermal control matrix device applicable to the reaction processing apparatus that performs the DNA amplification reaction can obtain the following effects.

By performing active matrix control, individual temperature control for each well is possible, and as a result, gene expression levels can be comprehensively analyzed in a short time.
Even if there are variations in the characteristics of the semiconductor elements and temperature characteristics, it is possible to obtain an accurate amount of heat generation by the feedback configuration by having the temperature detection circuit configuration, and as a result, efficient PCR control is possible.
By having a temperature detection circuit configuration even when the characteristics of the semiconductor element change with time, an accurate heat generation amount can be obtained by a feedback configuration, and a highly reliable PCR control device can be provided.
By having the function of stopping the heat generation operation in units of scanning lines, it is possible to easily and quickly lower the temperature, and since the heat generation time can be controlled, minute heat generation control is easy.
With respect to the written heat generation information, it is possible to provide a highly accurate heat generation amount by sensing the actual heat generation amount with high accuracy and correcting the heat generation writing amount.
In parallel with the temperature detection circuit configuration that performs temperature sensing, it is possible to realize fluorescence detection that is a signal of an amplification reaction with the same configuration.

  Thus, according to this embodiment, it can be set as the reaction processing apparatus which can carry out heat control with high precision and individually. This reaction processing apparatus can be used for a wide range of applications as an apparatus used for reactions requiring precise heat control. Among them, for example, it can be suitably used as a PCR apparatus for performing a gene amplification reaction or the like. Hereinafter, the case where it uses as a PCR apparatus is demonstrated.

  In a general PCR apparatus, the temperature control of the thermal cycler is certainly performed, but because of the gradient mechanism, individual temperature control for each sample is difficult. In addition, the temperature control during the gene amplification reaction cannot be performed individually. As a result, the problem that the amount of gene amplification of each sample cannot be made constant was remarkable.

  By applying the reaction processing apparatus according to the present invention to such a PCR apparatus, it is possible to obtain a PCR apparatus that can solve the above-described problems and the like and can perform comprehensive analysis. Hereinafter, the form of the PCR apparatus of the present invention will be described with reference to FIG. 1 and FIG.

FIG. 1 is a conceptual diagram illustrating a configuration example of a real-time PCR apparatus as a reaction processing apparatus according to an embodiment of the present invention.
In the drawings used below, for the convenience of explanation, the configuration of the apparatus and the like are simplified.

  The PCR device 1 includes a well substrate 11 having a plurality of reaction regions A1, a light source 12, and an excitation light scanning plate 13 that guides excitation light L1 and L2 emitted from the light source 12. A filter 14, a fluorescence detection unit 15 that detects fluorescence L 3, and a heating unit 16 that heats the reaction region A 1 are provided on the measurement substrate 17. Of course, the circuit configuration described above can be used for the heating unit 16.

  In the PCR device 1, the excitation light L1 emitted from the light source 12 passes through the excitation light scanning plate 13 and is irradiated to each reaction region A1 as the excitation light L2. Then, the fluorescence L3 emitted from within the reaction region A1 is detected and measured by the fluorescence detection unit 15.

  In the PCR apparatus 1, in particular, the heating unit 16 is provided for each reaction region A1, and temperature detection means for detecting the temperature in the vicinity of the heat source of the heating unit 16 and converting it into an electrical signal is provided. By providing means for determining the heating amount based on the correlation between the signal and the heating amount of the heat source, the temperature of each reaction region A1 can be controlled individually and with high accuracy.

  By setting the heating amount information in consideration of the temperature information of each reaction region A1, temperature control with higher accuracy can be performed. As a result, the gene expression level can be analyzed with high accuracy. Hereinafter, each component of the PCR apparatus 1 will be described in detail.

  The well substrate 11 includes a plurality of reaction regions (wells) A1. A predetermined reaction is performed in this reaction region A1. For example, the well substrate 11 can be formed of a low fluorescent light-emitting plastic material or glass, and a number of reaction regions A1 equal to the number of human genes can be arranged in a matrix.

  In the present embodiment, the reaction region (well) A1 for the PCR reaction is desirably a micro space. For example, if the wells are 300 μm × 300 μm × 300 μm (capacity of about 30 nL) and about 40,000 wells are arranged, a device having an area of about 6 cm square is obtained.

  Here, the shape of each reaction region A1 is not particularly limited, and may be any shape as long as it can hold the reaction solution. A suitable shape can be appropriately selected in consideration of an optical path for irradiating / introducing the excitation lights L1 and L2, an optical path for detecting the fluorescence L3, and the like. In the PCR device 1, the reaction region A1 has a curved surface portion in order to reflect the fluorescence L3 in the reaction region A1.

  In order to suppress a decrease in detection sensitivity due to the influence of light scattering or external light, the reaction region A1 is preferably coated with a light shielding material (for example, diamond-like carbon).

  In this embodiment, the light source 12 and the excitation light scanning plate 13 for introducing the excitation light L1 into each reaction area A1 are used as optical means capable of irradiating all of the plurality of reaction areas A1 with excitation light having a specific wavelength. be able to.

  The light source 12 is not particularly limited as long as it emits light of a specific wavelength, and it is preferable to use a white or monochromatic light emitting diode (LED). By using a light emitting diode, light that does not contain unnecessary ultraviolet rays and infrared rays can be easily obtained.

In the present embodiment, the installation location of the light source 12 and the number of light sources are not particularly limited. Although not shown, a plurality of light sources 12 may be provided so as to correspond to each reaction region A1, and each light source 12 may directly irradiate excitation light toward each corresponding reaction region A1.
Thereby, since each reaction area A1 can be directly irradiated with the light source 12, more excitation light quantity can be extract | collected, the light quantity of excitation light L1, L2 can be controlled separately, and excitation light is uniformly distributed to each reaction area A1. L1 and L2 can be irradiated.

The excitation light scanning plate 13 guides the excitation light L1 emitted from the light source 12 to each reaction region A1 in the well substrate 11. Excitation light L <b> 1 emitted from the light source 12 is introduced into the spacer 131 inside the excitation light scanning plate 13.
A reflection film 132 is provided on the bottom of the excitation light scanning plate 13, and the excitation light L <b> 2 can be introduced into the well substrate 11. Thereby, the fluorescent substance in the reaction solution in each reaction region A1 can be excited with a uniform amount of light. The material of the reflection film 132 is not particularly limited, but it is preferable to use a dichroic mirror.

Further, in the present embodiment, it is desirable to provide a filter 133 that transmits only the wavelength light of the excitation light L1 and L2 above the excitation light scanning plate 13.
Thereby, the excitation light L2 can be efficiently extracted from the light emitted from the light source 12 and guided to the reaction region A1. As this filter 133, a polarizing filter etc. can be used, for example.

  The excitation light L2 irradiated to the reaction region A1 emits fluorescence L3 when irradiated to the fluorescent substance of the probe in the reaction solution in the reaction region A1. The fluorescence L3 is reflected by the wall surface in the reaction region A1, and is detected and measured by the fluorescence detection unit 15 provided below the reaction region A1.

  In the present embodiment, the filter 14 can also be disposed between the reaction region A1 and the fluorescence detection unit 15 so that light with a specific wavelength can be extracted. The filter 14 only needs to be able to extract light of a specific wavelength (fluorescence L3 or the like), and the material thereof is not limited, but, for example, a dichroic mirror can be used.

  The fluorescence detection unit 15 detects and measures the fluorescence emitted by the excitation of the fluorescent dye in the intercalated probe in response to the excitation light L2 irradiated to the reaction region A1.

  In the PCR apparatus 1, the heating unit 16 is provided in each reaction region A1. The heating unit 16 includes a temperature control mechanism, and thereby controls the temperature of the reaction region A1 of the heating unit 16. Thereby, for example, when performing a PCR cycle, it is possible to perform temperature control with higher accuracy in the steps of thermal denaturation → annealing → extension reaction.

FIG. 33 is a conceptual diagram showing another configuration example of the real-time PCR apparatus as the reaction processing apparatus according to the embodiment of the present invention.
Hereinafter, description will be made centering on differences from the embodiment shown in FIG. 1, and description of common parts will be omitted.

  This PCR device 2 is common to the first embodiment in that the fluorescence detection unit 25 and the heating unit 26 are provided on the measurement substrate 27 for each reaction region (well) A2. However, the difference is that, for example, the fluorescence L3 transmitted through the reaction region A2 is detected by irradiating the excitation light L2 from above the well substrate 21.

  In the PCR device 2, the excitation light L <b> 1 emitted from the light source 22 is guided to the reaction region A <b> 2 by the excitation light scanning plate 23. In the excitation light scanning plate 23, the excitation light L 1 passes through the spacer 231, and the excitation light L 2 is introduced into the well substrate 21 by the reflective film 232 and the filter 233.

  Then, the excitation light L2 emits fluorescence L3 by irradiating the fluorescent material or the like of the probe in the reaction solution in the reaction region A2. This fluorescence L3 is detected and measured by a fluorescence detection unit 25 provided below the reaction region A1.

  Moreover, temperature control is performed by the heating part 26 provided under reaction region A2, and temperature control, such as a heating cycle, can be performed by the Peltier element 28 grade | etc.,.

In a general PCR apparatus, a reaction time of 25 to 30 minutes is required to perform about 30 cycles consisting of “thermal denaturation → annealing → extension reaction”. At that time, the temperature is controlled at about 2 ° C./second.
On the other hand, the PCR apparatus of this embodiment can control the temperature at 20 ° C. or more / second, so the time can be shortened by about 40 seconds per cycle, and the reaction of about 25 minutes or less in the entire 30 cycles. Time can be achieved.

  In addition, since the annealing time and extension reaction time can be controlled according to the design of the primer, the amplification rate can be made constant (for example, 2 times, etc.), so that the detection accuracy of the gene expression level is improved. be able to.

It is a conceptual diagram which shows one structural example of the real-time PCR apparatus as a reaction processing apparatus which concerns on embodiment of this invention. It is a figure which shows one structural example of the heater matrix apparatus which concerns on embodiment of this invention. It is a circuit diagram which shows the 1st structural example of the heater unit in the heater matrix apparatus which concerns on this embodiment. FIG. 4 is a circuit diagram showing one state of the circuit operation of FIG. 3. FIG. 4 is a circuit diagram showing another state of the circuit operation of FIG. 3. FIG. 4 is a circuit diagram showing a modification of the circuit configuration shown in FIG. 3. FIG. 4 is a circuit diagram showing another modification of the circuit configuration shown in FIG. 3. FIG. 5 is a circuit diagram showing still another modification of the circuit configuration shown in FIG. 3. FIG. 5 is a circuit diagram showing still another modification of the circuit configuration shown in FIG. 3. FIG. 4 is a circuit diagram illustrating a specific configuration example of FIG. 3. FIG. 11 is a circuit diagram illustrating another modification of the circuit configuration of FIG. 10. FIG. 10 is a circuit diagram showing still another modification of the circuit configuration of FIG. 3. It is a figure which shows the structural example of the heater matrix apparatus which has a heater unit of FIG. FIG. 10 is a circuit diagram showing still another modification of the circuit configuration of FIG. 3. FIG. 10 is a circuit diagram showing still another modification of the circuit configuration of FIG. 3. It is a figure which shows the example of 1 structure of the temperature detection matrix apparatus which concerns on embodiment of this invention. It is a circuit diagram which shows the structural example of the temperature detection unit which concerns on this embodiment. It is a figure which shows the temperature dependence of dark current. It is a figure which shows the relationship between the forward voltage of PIN diode, and temperature when a fixed forward current is sent through a PIN diode. It is a figure which shows the example of 1 structure of the fluorescence detection matrix apparatus which concerns on embodiment of this invention. It is a circuit diagram which shows the structural example of the fluorescence detection unit which concerns on this embodiment. It is a figure which shows the example of 1 structure of the heater temperature detection matrix apparatus which concerns on embodiment of this invention. It is a circuit diagram which shows the structural example of the heater temperature detection unit which concerns on this embodiment. It is a figure which shows the relationship of the detection voltage according to the heater current of a heater unit, and the current of the PIN diode of a temperature detection unit. It is a figure which shows the example of 1 structure of the temperature fluorescence detection matrix apparatus which concerns on embodiment of this invention. It is a circuit diagram which shows the structural example of the temperature fluorescence detection unit which concerns on this embodiment. It is a figure which shows the state of each transistor as a switch at the time of temperature detection and fluorescence detection in the temperature fluorescence detection unit which concerns on this embodiment. It is a figure for demonstrating the temperature detection operation | movement of the temperature fluorescence detection unit which concerns on this embodiment. It is a figure for demonstrating the fluorescence detection operation | movement of the temperature fluorescence detection unit which concerns on this embodiment. It is a figure for demonstrating an example of a fluorescence detection process. It is a figure which shows the example of 1 structure of the heater temperature detection matrix apparatus which concerns on embodiment of this invention. It is a circuit diagram which shows the structural example of the heater temperature fluorescence detection unit which concerns on this embodiment. It is a conceptual diagram which shows the other structural example of the real-time PCR apparatus as a reaction processing apparatus which concerns on embodiment of this invention.

Explanation of symbols

DESCRIPTION OF SYMBOLS 1, ... PCR apparatus (reaction processing apparatus) 100 ... Heater matrix apparatus 110 ... Heater unit 200 ... Temperature detection matrix apparatus 210 ... Temperature detection unit 200 ... Fluorescence detection matrix device, 310 ... Fluorescence detection unit, 400 ... Heater temperature detection matrix device, 410 ... Heater temperature detection unit, 500 ... Temperature fluorescence detection matrix device, 510 ... Temperature fluorescence detection unit , 600 ... heater temperature detection matrix device, 610 ... heater temperature fluorescence detection unit.

Claims (18)

A thermal control matrix device in a reaction processing apparatus for performing a DNA amplification reaction,
A plurality of heater units arranged in a matrix;
A scanning line for selecting each heater unit;
A data line for giving heat generation amount information to the heater unit,
Each heater unit is
A receiving unit for capturing heat generation amount information given to the data line in a state where the scanning line is selected;
A holding unit for holding calorific value information even after the scanning line is deselected;
A heat control matrix device including: a drive unit that causes a current to flow based on the heat generation amount information and generates a heat amount corresponding to the current. Each heater unit is
A converter for once converting the signal current indicating the calorific value information given in the form of a current level from the data line into a form of a voltage level;
The holding unit for holding the converted voltage level;
The thermal control matrix device according to claim 1, further comprising: a driving unit that converts and drives the held voltage level into a current level. The holding part is
Including at least one capacitor,
The drive unit is
A switch connected in series between a power supply potential and a reference potential and at least one field effect transistor having the capacitor connected to the gate;
The receiving part is
A switch for transferring heat generation amount information of the data line to the capacitor and storing electric charge;
The thermal control matrix device according to claim 1, wherein the switch of the driving unit and the switch of the receiving unit are turned on and off in a complementary manner. A thermal control matrix device in a reaction processing apparatus for performing a DNA amplification reaction,
A plurality of temperature detection units arranged in a matrix;
A scanning line for selecting each of the temperature detection units;
A current drive line for supplying a current to the temperature detection unit;
A detection line for detecting the current of the temperature detection unit,
Each of the temperature detection units is
A PIN diode that is supplied with current by the current drive line and through which forward current flows;
And a transfer unit that supplies a current of the current drive line to the PIN diode and transfers a current flowing through the PIN diode to the detection line. The transfer unit
The thermal control matrix device according to claim 4, further comprising a switch that is kept in an on state when temperature is detected. A thermal control matrix device in a reaction processing apparatus for performing a DNA amplification reaction,
A plurality of fluorescence detection units arranged in a matrix;
A reverse voltage line for supplying a reverse voltage to each of the fluorescence detection units;

A detection line for detecting a reverse current of the fluorescence detection unit,
Each of the fluorescence detection units is
A PIN diode supplied with a reverse voltage by the reverse voltage line;
And a transfer unit that supplies a reverse voltage of the reverse voltage line to the PIN diode and transfers a reverse current flowing through the PIN diode to the detection line. The transfer unit
The thermal control matrix device according to claim 6, further comprising a switch that is kept in an on state when temperature is detected. A thermal control matrix device in a reaction processing apparatus for performing a DNA amplification reaction,
A plurality of heater units arranged in a matrix;
A plurality of temperature detection units that are arranged in a matrix corresponding to each of the heater units and detect the temperature heated by the heater unit;
A first scanning line for selecting each heater unit;
A data line for giving calorific value information to the heater unit;
A second scanning line for selecting each of the temperature detection units;
A current drive line for supplying a current to the temperature detection unit;
A detection line for detecting the current of the temperature detection unit,
Each heater unit is
A receiving unit for capturing heat generation amount information given to the data line in a state where the scanning line is selected;
A holding unit for holding calorific value information even after the scanning line is deselected;
A drive unit for causing a current to flow based on the heat generation amount information and generating a heat amount corresponding thereto,
Each of the temperature detection units is
A PIN diode that is supplied with current by the current drive line and through which forward current flows;
And a transfer unit that supplies a current of the current drive line to the PIN diode and transfers a current flowing through the PIN diode to the detection line. The heat control matrix device according to claim 8, wherein a heat generation amount of the heater unit is controlled by the heat generation amount information based on information detected by the detection line. A thermal control matrix device in a reaction processing apparatus for performing a DNA amplification reaction,
A plurality of temperature detection units arranged in a matrix;
A plurality of fluorescence detection units arranged in a matrix corresponding to the temperature detection units;
At least one scanning line for selecting each temperature detection unit and the fluorescence detection unit;
A current drive line for supplying a current to the temperature detection unit;
A first detection line for detecting a current of the temperature detection unit;
A reverse voltage line for supplying a reverse voltage to each of the fluorescence detection units;
A second detection line for detecting a reverse current of the fluorescence detection unit,
Each of the temperature detection units is
A PIN diode that is supplied with current by the current drive line and through which forward current flows;
A first transfer unit for supplying a current of the current drive line to the PIN diode and transferring a current flowing through the PIN diode to the detection line;
Each of the fluorescence detection units is
A PIN diode supplied with a reverse voltage by the reverse voltage line;
A thermal control matrix device, comprising: a second transfer unit that supplies a reverse voltage of the reverse voltage line to the PIN diode and transfers a reverse current flowing through the PIN diode to the detection line. The thermal control matrix device according to claim 10, wherein the temperature detection unit and the fluorescence detection unit share the PIN diode. The thermal control matrix device according to claim 11, which has a function of performing temperature control correction by sensing a dark current with the PIN diode, and detecting an amplification reaction by sensing a light reception current generated when receiving fluorescence. A thermal control matrix device in a reaction processing apparatus for performing a DNA amplification reaction,
A plurality of heater units arranged in a matrix;
A plurality of temperature detection units that are arranged in a matrix corresponding to each of the heater units, and that detect temperatures heated by the heater units;
A plurality of fluorescence detection units arranged in a matrix corresponding to the temperature detection units;
A first scanning line for selecting each heater unit;
A data line for giving calorific value information to the heater unit;
At least one second scan line for selecting each temperature detection unit and the fluorescence detection unit;
A current drive line for supplying a current to the temperature detection unit;
A first detection line for detecting a current of the temperature detection unit;
A reverse voltage line for supplying a reverse voltage to each of the fluorescence detection units;
A second detection line for detecting a reverse current of the fluorescence detection unit,
Each heater unit is
A receiving unit for capturing heat generation amount information given to the data line in a state where the scanning line is selected;
A holding unit for holding calorific value information even after the scanning line is deselected;
A drive unit for causing a current to flow based on the heat generation amount information and generating a heat amount corresponding thereto,
Each of the temperature detection units is
A PIN diode that is supplied with current by the current drive line and through which forward current flows;
A first transfer unit for supplying a current of the current drive line to the PIN diode and transferring a current flowing through the PIN diode to the detection line;
Each of the fluorescence detection units is
A PIN diode supplied with a reverse voltage by the reverse voltage line;
And a second transfer unit that supplies a reverse voltage of the reverse voltage line to the PIN diode and transfers a reverse current flowing through the PIN diode to the detection line. The heat control matrix device according to claim 13, wherein the heat generation amount of the heater unit is controlled by the heat generation amount information based on information detected by the first detection line. The thermal control matrix device according to claim 13, wherein the temperature detection unit and the fluorescence detection unit share the PIN diode. The thermal control matrix device according to claim 15, wherein the thermal control matrix device has a function of performing temperature control correction by sensing a dark current with the PIN diode and detecting an amplification reaction by sensing a light reception current generated when receiving fluorescence. At the stage where the heat generation control is fed back to the temperature detection unit in real time based on the detection result, the fluorescence detection is detected in real time as a reaction amplification detection signal using a PIN diode which is a temperature detection device. The thermal control matrix device according to claim 15. A reaction processing apparatus having a plurality of reaction regions,
A thermal control matrix device for performing thermal control;
The thermal control matrix device
A plurality of heater units arranged in a matrix corresponding to the reaction region;
A plurality of temperature detection units that are arranged in a matrix corresponding to each of the heater units and detect the temperature heated by the heater unit;
A plurality of fluorescence detection units arranged in a matrix corresponding to the temperature detection units;
A first scanning line for selecting each heater unit;
A data line for giving calorific value information to the heater unit;
At least one second scan line for selecting each temperature detection unit and the fluorescence detection unit;
A current drive line for supplying a current to the temperature detection unit;
A first detection line for detecting a current of the temperature detection unit;
A reverse voltage line for supplying a reverse voltage to each of the fluorescence detection units;
A second detection line for detecting a reverse current of the fluorescence detection unit,
Each heater unit is
A receiving unit for capturing heat generation amount information given to the data line in a state where the scanning line is selected;
A holding unit for holding calorific value information even after the scanning line is deselected;
A drive unit for causing a current to flow based on the heat generation amount information and generating a heat amount corresponding thereto,
Each of the temperature detection units is
A PIN diode that is supplied with current by the current drive line and through which forward current flows;
A first transfer unit for supplying a current of the current drive line to the PIN diode and transferring a current flowing through the PIN diode to the detection line;
Each of the fluorescence detection units is
A PIN diode supplied with a reverse voltage by the reverse voltage line;
And a second transfer unit for supplying a reverse voltage of the reverse voltage line to the PIN diode and transferring a reverse current flowing through the PIN diode to the detection line.

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