JPH0646190B2 - Semiconductor multi-biosensor - Google Patents

Description

TECHNICAL FIELD The present invention relates to a semiconductor multi-biosensor, and more particularly to a semiconductor multi-biosensor obtained by integrating a semiconductor field effect ion sensor having an enzyme-immobilized film on the surface thereof. It is a thing.

[Conventional technology]

Conventionally, semiconductor field effect ion sensor (Ion Sensitive Fitld Effect Traction) has been used as a kind of specific biosensor in solution.
It is known that an enzyme-immobilized membrane is provided on the surface of an nsistor (hereinafter abbreviated as ISFET) (Yuji Miyahara, Shoko Shiokawa, Toyoe Morizumi, Hideaki Matsuoka, Masao Karube, Shuichi Suzuki: "Use of semiconductor technology" Biosensor ", IEICE, Electronic Components and Materials Research Society, Material CPM 81-93, 61 (198
1)). This ISFET biosensor detects the concentration of a specific organic substance in an enzyme-immobilized membrane by detecting the change in ion concentration in the membrane that occurs when the specific organic substance in the solution is changed by the catalytic action of the enzyme. It is something to measure. As an example of the enzyme-immobilized membrane having this selectivity, for example, a urease-immobilized membrane for urea detection and a glucose oxidase-immobilized membrane for glucose detection are known. In addition, by measuring the output difference between the ISFET with and without the enzyme-immobilized membrane, the effect of potential change in the solution can be canceled, and a metal electrode such as platinum or gold can be used as a reference electrode. It has been reported recently to use (Y. Hanazato) and Shiono (S. Shi).
ono): “Bioelectrode Using Two Hydrogen Ion Sens
itive Transistor and a Platinum Wire Pseudo Refere
nce Electrode ”, Proc. of the International meeting on Chemica
Sensors, P513 (1983)).

The inventors formed ISFET provided with an enzyme immobilization film and ISFET provided with a deactivated enzyme immobilization film on the same chip by using island-shaped silicon provided on a sapphire substrate, and the back surface We have developed a single-chip biosensor by providing a gold electrode as a reference electrode (T.Kuriyama, J.Kimura, and Kawana (Y.Kawan).
a): “An Integrated SOS / FET Biosensor”, 198
4 International Conference on Solid State Devices and Materials, 1
984 International Conterence on Solid State De
vices and Materials, Late News Abstracts, LC-12
3, pp. 66-67, (1984)). Since this single-chip biosensor uses a substrate with excellent insulation properties, the ISFET is surrounded by an insulator except for the electrodes in the wafer state, and the biosensor can be simply cut by cutting the wafer. The sensor element could be obtained. Furthermore, width 1
Since it is a minute sensor with a thickness of 0.5 mm or less and a thickness of 0.5 mm or less, it requires a small amount of sample for measurement.
Due to the IC manufacturing method, mass production was possible and the price was low.

[Problems to be solved by the invention]

However, multiple ISFETs with different types of enzyme-immobilized membranes on the surface are required to realize a multi-biosensor capable of simultaneously measuring multi-component organic matter in a solution. The number of ISFETs formed on one chip has increased, and the size of the chip, especially its width, has been increased, making it difficult to realize minute sensors. This increase in the chip size has been a serious problem when the semiconductor biosensor is placed in a blood vessel for measurement or when it is used as a device inside an injection needle.

[Means for solving problems]

The present invention relates to a semiconductor field effect type ion sensor having a plurality of biological substances on the surface at one end of an insulating substrate having an elongated planar shape or an insulating substrate having an island-shaped semiconductor layer, and an insulated gate field effect. Transistors are provided in pairs, the source region of each semiconductor field effect ion sensor is electrically connected to the drain region of the corresponding insulated gate field effect transistor, and the plurality of semiconductor field effect ion sensors are also provided. Have a common drain region, the drain region is extended to the other end of the substrate to provide an electrode, and the plurality of insulated gate field effect transistors have a common source region, and the source region is the substrate. An electrode is provided extending to the other end on the top,
Further, the semiconductor biosensor is characterized in that the gate electrodes of the plurality of insulated gate type electrode effect transistors are covered with an insulator and extended to the other end of the substrate to provide electrodes.

[Work]

According to the present invention, even if a plurality of ISFETs are integrated on one chip, the drain regions are common and the ISFEs of the respective ISFEs are integrated.
Since the source region of the MISFET connected to T is common, the element area does not increase significantly. Also, by controlling the gate voltage of each MISFET,
The SFET acts as a switch. For example, the desired ISF
In order to take out the output of ET, the gate voltage of the MISFET connected to this ISFET is set to a value that allows the MISFET to flow a sufficient current, for example, 5 V, and the other IS
MIS gate voltage of MIS connected to FET
It may be set to a value equal to or lower than the threshold voltage of the FET, for example, 5V. In this case, the MISF connected to the desired ISFET
ET is in the on state and the other MISFETs are in the off state. By using the MISFET as a switch in this way, a current can be made to flow only to a desired ISFET and an output can be taken out. Therefore, by switching the switch, the semiconductor multi-biosensor of the present invention can independently control a plurality of components in a solution. Can be measured.

〔Example〕

An embodiment of the present invention will be described in detail below with reference to the drawings. FIG. 1 is a plan view of a semiconductor multi-biosensor showing an embodiment of the present invention, in which an island-shaped single crystal silicon film on an elongated sapphire substrate is covered with an enzyme immobilization film at one end.
Multiple pairs of MOSFETs with FETs and gate electrodes are formed, the source region of the ISFET and the drain region of the MOSFET forming the pair form a common region, and the multiple ISFETs have a common drain region and the drain region is sapphire. A plurality of MOSFETs are formed by extending the other end on the substrate to form a metal electrode 24.
Have a common source region, and this source region is extended to the other end on the sapphire substrate to form a metal electrode 22. Further, the gate electrodes of the MOSFETs are covered with insulators and extended to the other end on the sapphire substrate to extend the metal electrodes 20.
Are formed. 2a, 2b, 2c
The dashed-dotted lines aa ', bb', c- in FIG. 1 respectively.
In the cross-sectional view at c ′, when ISFET and MOSFET are n-channel type, 1 is a sapphire substrate, 2 is a high impurity concentration n-type
ISFET drain region, 3 is a high impurity concentration n-type ISFET source (MOSFET drain) region, 4 is a high impurity concentration n-type MOSFET
Source regions 5, 5 and 6 are p-type semiconductor silicon layers, 7 is conductive polysilicon, 8 is a silicon oxide film, 9 is a silicon nitride film, 10 is a gold electrode, 11 is a polysilicon gate metal electrode, and 12 and 13. Is an enzyme-immobilized membrane, for example 1
2 is a glucose oxidase-immobilized film, 13 is a urease-immobilized film, 14 is a high-impurity-concentration p-type silicon layer for semiconductor ground, ISFET and MOSFET p-type semiconductor silicon layer 5,
6 is electrically connected. A plurality of types of enzyme-immobilized membranes are formed on one chip, and by using this sensor, it is possible to detect a plurality of substrates in a sample.

For example, using three ISFETs provided on a chip with a width of 0.6 mm, a length of 5 mm, and a thickness of 0.4 mm, one of them is used as a reference ISFET, and a film containing no enzyme is formed on the surface, and the other 2 ISFE
Glucose oxidase-immobilized membrane 12 on T,
By forming the urease-immobilized film 13, a one-chip biosensor capable of measuring glucose and urea could be realized. In this case, the three ISFETs are sequentially turned on by changing the voltage of the gate electrode of the corresponding MOSFET, and after measuring the output of each ISFET independently,
It was possible to cancel the potential drift of the sample solution due to the gold electrode on the back surface of the sapphire substrate, by calculating the difference between the output of the ISFET and the output of other ISFETs. This is because when the gold electrode on the back surface of the sapphire substrate is used as a reference electrode that determines the potential of the liquid to be measured, the voltage between the gold electrode and the liquid fluctuates, but the desired ISFET output and reference ISFET output When the difference between the
This is because it acts as the same gate voltage fluctuation on ET and is canceled in the measurement of the differential main force. The semiconductor multi-biosensor according to the present invention is very suitable as a sensor to be placed in a blood vessel or to be installed in an injection needle without changing the width and thickness of the sensor even if the number of ISFETs is increased and the number of items is increased. There is.

The present invention is not limited to the ISFET and MOSFET formed on the island-shaped silicon layer on the sapphire substrate shown in the embodiment, but uses a silicon layer on another insulating substrate such as spinel or quartz, or uses a bulk silicon wafer. It is also applied to ISFET and MOSFET.

Various enzymes can be used as the biological substance. For example, urease can be used as an enzyme for detecting urea, and this urease is immobilized as an enzyme-immobilized membrane in ISFE by immobilizing it in a membrane of a protein such as albumin using a cross-linking agent such as glutaraldehyde.
It is formed on the surface of the T detection portion. Further, glucose oxidase can be used as an enzyme for glucose detection. Furthermore, the bio-related substance is not limited to the above-mentioned enzymes, and an antibody or an antigen that causes an immune reaction can be used. For example, when detecting a hormone, an antibody that causes a specific immune reaction with the hormone is immobilized on the detection part of the ISFET using a hydrophobic membrane. Conversely, when detecting an antibody, for example, an immunoglobulin (abbreviated as IgG), an antigen that causes a specific immune reaction with IgG is formed in the detection part of the ISFET. It is also possible to provide various ion sensitive films on the ISFET.

Further, when the number of items is increased, the number of gate electrodes increases and the number of lead wires 30 for applying a voltage to the gate electrode 7 from the outside also increases, but as shown in FIG. By incorporating the normal decoder circuit 32, it is possible to control many gate electrodes with a small number of lead wires.

〔The invention's effect〕

According to the present invention, even if the number of ISFETs increases, the area occupied by the drain region and the source region of the ISFET hardly increases, and a minute semiconductor multi-biosensor can be realized.

[Brief description of drawings]

FIG. 1 is a plan view showing an embodiment of a semiconductor multi-biosensor according to the present invention, and FIGS. 2a, 2b, and 2c are the dashed-dotted lines aa ', bb', and FIG. c-
It is sectional drawing in c '. FIG. 3 is a plan view showing another embodiment of the present invention, which is a semiconductor multi-biosensor having a built-in decoder circuit. 1 ... Sapphire substrate, 2 ... High impurity concentration n-type ISFET
Drain region, 3 ... High impurity concentration n-type ISFET source (M
OSFET drain region, 4 ... High impurity concentration n-type MOSFET
Source regions, 5 and 6 ... P-type semiconductor silicon layer, 7 ...
… Conductive polysilicon, 8 …… Silicon oxide film, 9 ……
Silicon nitride film, 10 ... Gold electrode, 20, 22, 24 ...
... metal electrode, 12 ... glucose oxidase-immobilized film, 13 ... urease-immobilized film, 14 ... high impurity concentration p-type silicon layer.

Claims (1)

[Claims] 1. A semiconductor field effect type ion sensor having a plurality of bio-related substances on the surface at one end of an insulating substrate having an elongated planar shape or an insulating substrate having an island-shaped semiconductor layer, and an insulated gate type. The field effect transistors are provided as a pair, the source region of each semiconductor field effect ion sensor is electrically connected to the drain region of the corresponding insulated gate field effect transistor, and the plurality of semiconductor field effect transistors are provided. The ion sensor has a common drain region, the drain region is extended to the other end of the substrate to provide an electrode, and the plurality of insulated gate field effect transistors have a common source region, which is the source region. An electrode is provided so as to extend to the other end of the substrate, and the gate electrodes of the plurality of insulated gate type electrode effect transistors are further provided. It'll be covered with an insulator semiconductor multi biosensor also characterized by the fact that the electrode is extended to the other end on the substrate is provided.