CN108568320A - microfluidic device, biochemical detection system and method - Google Patents

Abstract

The application discloses a micro-fluid device, a biochemical detection system and a method, wherein the biochemical detection system comprises a probe card and the micro-fluid device. The probe card is provided with a plurality of probes and an opening, and the probes are used for contacting a plurality of electrode pads of at least one chip on a substrate so as to detect an electrical signal of at least one biochemical sensor of the at least one chip. The microfluid device is clamped in the opening and is provided with a chamber, and the chamber is used for receiving a solution to be detected and enabling the solution to be detected to be contacted with the biochemical sensor.

Description

Microfluidic device, biochemical detection system and method

technical field

Embodiments of the present invention relate to a microfluidic device, a biochemical detection system and a method.

Background technique

A biochemical sensor (also called a biosensor) is a device that can sense and detect biochemical substances by operating on the basis of electrical, electrochemical, optical and/or mechanical detection principles.

Biological field-effect transistors (BioFETs) are biochemical sensors containing transistors, which can sense and detect biochemical molecules or biological entities through electrical means. This detection action can be achieved through direct detection and sensing, or through the reaction or interaction of specific reactants with biochemical molecules/biological entities. Specifically, when the target biochemical molecule or biological entity is combined with the gate of the biofield effect transistor or the acceptor molecule fixed on the gate, the drain current of the biofield effect transistor will change due to the gate voltage, and depends on The type and number of target bonds generated vary. This change in drain current can be measured and used to determine the type and/or amount of binding of the receptor to a target biochemical molecule or biological entity.

In addition, a wide variety of acceptors may be used to functionalize the gate of biofield effect transistors. For example, for the detection of single-stranded deoxyribonucleic acid (ssDNA), biofield effect transistors The gate can be functionalized with immobilized complementary single-stranded DNA. In order to detect different proteins, such as tumor markers, the gates of biofield effect transistors can be functionalized with monoclonal antibodies.

Biofield effect transistors can be manufactured using semiconductor processes and can convert electronic signals quickly, so they have been widely used in integrated circuits. Usually, a semiconductor wafer includes tens to hundreds of integrated circuit chips. In electrical measurement, in order to avoid possible short circuit caused by the solution and damage to nearby integrated circuit chips, the integrated circuit chips are generally separated along the wafer dicing line, and then the solution to be tested is carefully dropped on each of the IC chips manually. The location of the biofield effect transistor on the chip, and then use the probe to measure and obtain the electrical signal (such as the drain current) of the biofield effect transistor to determine the type and/or quantity of the target biochemical substance in the solution to be tested.

However, this detection method is very difficult to control the consistency of the test conditions (such as detection time, reaction temperature and liquid evaporation, etc.), causing the accuracy and quality of the detection results to be questioned, and the efficiency is extremely poor (that is, the detection time is too long). long). Therefore, it is necessary to provide an improved scheme of a biochemical detection system and method.

Contents of the invention

Some embodiments of the present invention provide a microfluidic device, comprising: a body; a flexible pad disposed on the bottom of the body; a chamber formed in the body and the flexible pad, and the chamber is formed on the bottom of the microfluidic device There is an opening; and a drain valve is movably arranged in the chamber for blocking or allowing a solution injected into the chamber to flow to the opening.

Some embodiments of the present invention provide a biochemical detection system, including: a probe card with a plurality of probes and an opening, the probes are used to contact a plurality of electrode pads of at least one chip on a substrate to detect the at least one The electrical signal of at least one biochemical sensor of the chip; and a microfluidic device, which is engaged in the opening and has a chamber, the chamber is used to receive a solution to be tested, and make the solution to be tested and the biochemical sensor touch.

Some embodiments of the present invention provide a biochemical detection method, including: setting a substrate on a carrier platform, having at least one chip on the substrate, the chip has at least a biochemical sensor and a plurality of electrode pads; providing a probe card and A microfluidic device, wherein the probe card has a plurality of probes and an opening, the microfluidic device is engaged in the opening and has a chamber; the microfluidic device and the probe card are moved so that the chamber of the microfluidic device and the probe The positions of the probes of the needle card correspond to the positions of the biochemical sensors and the electrode pads of the chip respectively; the carrier platform is moved to combine the microfluidic device with the substrate; a solution to be tested is injected into the chamber of the microfluidic device to make the tested The solution is in contact with the biochemical sensor of the chip for a certain period of time; and the probe of the probe card is used to measure the electrical properties of the biochemical sensor of the chip, and according to the electrical measurement results, the type and type of the target biochemical substance in the solution to be tested are determined. /or quantity.

Description of drawings

FIG. 1 shows a schematic plan view of a wafer and an enlarged view of a chip on the wafer according to some embodiments.

Figure 2 shows a block diagram of a biochemical detection system according to some embodiments.

FIG. 3 shows a schematic plan view of the positional relationship between the probe card and the microfluidic device in FIG. 2 .

Figure 4A shows a schematic top view of a microfluidic device according to some embodiments.

FIG. 4B shows a schematic cross-sectional view along line A-A in FIG. 4A.

5 shows a schematic diagram of a leak-proof design and an automatic drain valve of a microfluidic device according to some embodiments.

Figure 6A shows a schematic diagram of a microfluidic device tightly bonded to a wafer.

FIG. 6B shows a schematic diagram of the separation of the microfluidic device and the wafer.

Figure 7 shows a flowchart of a biochemical detection method according to some embodiments.

Explanation of reference signs:

2～biochemical detection system;

10 ~ wafer;

11～chip;

21～carrying platform;

22 ~ control device;

23～probe card;

23A～probe;

23B～opening;

24 ~ clamping mechanism;

25 ~ Microscope;

26～microfluidic device;

27A～solution injection unit;

27B～fluid extraction unit;

28～positioning mechanism;

40～body;

41～flexible cushion body;

41A～first floor structure;

41B～Second layer structure;

42～water storage space;

42A～opening;

43 ~ the first micro channel;

44～the second microchannel;

45 ~ liquid channel;

46 ~ air flow channel;

51～drain valve;

51A～rod;

51B～capillary structure;

52～Leakage detection element;

101～biochemical sensor;

102～electrode pad;

700～biochemical detection methods;

701～706～steps;

C ~ chamber;

C1～shrink mouth;

C2～stop structure;

E～solution outlet;

I ~ solution inlet;

O1～opening;

O2～opening;

S1～Active surface;

S2～bottom surface;

S3～top surface;

T ~ the solution to be tested.

Detailed ways

The following disclosure provides many different embodiments, or examples, for implementing different features of the disclosure. The following disclosure describes specific examples of various components and their arrangements to simplify the description. Of course, these specific examples are not intended to be limiting. For example, if it is described in the embodiment that a first feature is formed on or above a second feature, it may include the situation that the above-mentioned first feature is in direct contact with the above-mentioned second feature, and may also include additional features Formed between the above-mentioned first feature and the above-mentioned second feature, so that the above-mentioned first feature and the second feature are not in direct contact.

Spatial terms used hereinafter, such as "below", "beneath", "lower", "above", "higher" and similar terms, are for the convenience of describing an element or The relationship between a feature and another element(s) or feature. These spatially relative terms are also intended to potentially encompass use or operation of the device in the figures in different orientations in addition to the orientation shown in the figures.

The same component numbers and/or words may be used repeatedly in the following different embodiments. These repetitions are for the purpose of simplification and clarity, and are not intended to limit the specific relationship between the different embodiments and/or structures discussed.

Words such as first and second used in the following are only for the purpose of explaining them clearly, and are not used to correspond to or limit the claims. In addition, terms such as first feature and second feature are not limited to the same or different features.

In the drawings, the shape or thickness of structures may be exaggerated for simplicity or ease of labeling. It must be understood that elements not specifically described or illustrated may exist in various forms well known to those skilled in the art.

It should be noted that, in order to overcome the aforementioned problems in the prior art, an embodiment of the present invention provides an improved automatic biochemical detection system, which can directly use the biochemical sensors of multiple chips on the wafer (or substrate) to sense and Detect the target biochemical substances in the solution to be tested without cutting the wafer and operating each chip separately (including dripping the solution to be tested on each chip, and erecting the probes on each chip for electrical measurement, etc.) , so the detection time can be greatly shortened and the detection efficiency can be improved.

Please refer to FIG. 1 first, which shows a schematic plan view of a wafer 10 and an enlarged view of a chip 11 on the wafer 10 according to some embodiments of the present invention. The wafer 10 is a semiconductor wafer (such as a silicon wafer) on which a plurality of integrated circuit chips 11 (hereinafter referred to as chips 11 ) are produced through semiconductor manufacturing process. Each chip 11 has an active surface S1, a biochemical sensor 101 and a plurality of electrode pads 102, and the biochemical sensor 101 and the electrode pads 102 can be exposed on the active surface S1. In some embodiments, each chip 11 may also have a plurality of biochemical sensors 101 . The biochemical sensor 101 can be a bio-field effect transistor (BioFET), and the aforementioned electrode pads 102 are electrically connected to the gate, drain and source of the bio-field effect transistor, respectively. In addition, the biofield effect transistors of each chip 11 may be the same or different. It is worth mentioning that the above-mentioned wafer 10 is only for the convenience of describing the embodiment, but the wafer 10 may also be changed into a substrate (such as a glass substrate, a plastic substrate, etc.) with or provided with a plurality of chips 11 .

As mentioned above, the biofield effect transistor can electrically sense and detect target biochemical substances in a solution to be tested, such as deoxyribonucleic acid (DNA), ribonucleic acid (RNA), protein or Other organic and inorganic small molecules. Specifically, when these target biochemical molecules or biological entities are combined with the gate of the biofield effect transistor or the acceptor molecules fixed on the gate, the drain current of the biofield effect transistor will change due to the gate voltage, and Varies depending on the type and number of target bonds generated. The change of the drain current can be measured and used to determine the type and/or quantity of the bond between the receptor and the target biochemical molecule or biological entity, that is, to achieve the purpose of sensing and detecting the target biochemical substance in the solution to be tested. Since the structures and detection mechanisms of various biofield effect transistors already belong to the existing ones and are not the technical focus of the invention of the present application, they will not be repeated here. The biochemical sensor 101 mentioned herein includes various known bio-field-effect transistors, such as ion-sensitive field-effect transistor (Ion-sensitive FET, ISFET), enzyme field-effect transistor (Enzyme FET, ENFET) or immune Field Effect Transistor (ImmunoFET). .

2 shows a block diagram of a biochemical detection system 2 according to some embodiments, wherein the biochemical detection system 2 is an automatic biochemical detection system, and can utilize the biochemical sensors 101 of the plurality of chips 11 on the aforementioned wafer 10 (FIG. 1 ) sensing and detecting a target biochemical substance in a solution to be tested. As can be seen from FIG. 2 , the biochemical detection system 2 includes a carrying platform 21 for carrying the wafer 10 . In some embodiments, the stage 21 can hold the wafer 10 thereon by vacuum suction, but some optional other ways of holding the wafer 10 (such as an electrostatic chuck) can also be used. The carrier table 21 can also carry the wafer 10 to move along the horizontal direction (the X axis and the Y axis direction in the figure) and the vertical direction (the Z axis direction in the figure). In addition, the carrying platform 21 is electrically connected to a control device 22 (such as a computer), and the control device 22 can control the above-mentioned movement of the carrying platform 21 .

The biochemical detection system 2 also includes a probe card 23 (please also refer to FIG. 3 ), below which there are a plurality of probes 23A for contacting the electrode pads 102 ( FIG. 1 ) of each chip 11 on the wafer 10 to measure The electrical signal of the biochemical sensor 101 is obtained. The probe card 23 can be a Micro-Electrical-Mechanical Systems (MEMS) probe card or other optional types of probe cards. The probe card 23 is also electrically connected to the control device 22, and the control device 22 can control the probe card 23 to measure the electrical signal of the biochemical sensor 101, and the measured electrical signal of the biochemical sensor 101 Perform calculation, analysis, storage and display.

The biochemical detection system 2 also includes a clamping mechanism 24 for clamping the probe card 23 and can move along the horizontal direction (X-axis and Y-axis in the figure). Specifically, the clamping mechanism 24 can be connected to a positioning mechanism (not shown), and the positioning mechanism is electrically connected to the control device 22, wherein the control device 22 can control the positioning mechanism, so that the clamping mechanism 24 and its upper The probe card 23 moves along the horizontal direction, so as to achieve the alignment between the probes 23A of the probe card 23 and the electrode pads 102 ( FIG. 1 ) of a chip 11 on the wafer 10 below. Although not shown in the figure, the arrangement of the probes 23A of the probe card 23 corresponds to the arrangement of the electrode pads 102 of the chips 11 on the wafer 10 .

The biochemical detection system 2 also includes a microscope 25 for observing whether the position of the probe 23A of the probe card 23 is aligned with the position of the electrode pad 102 ( FIG. 1 ) of a chip 11 on the wafer 10 below. In some embodiments, the microscope 25 can be electrically connected to the control device 22 .

When the control device 22 controls the aforementioned positioning mechanism so that the clamping mechanism 24 and the probe card 23 on it move along the horizontal direction, and observe the position of the probe 23A of the probe card 23 and a chip on the wafer 10 through the microscope 25 When the positions of the electrode pads 102 of the chip 11 are aligned, the stage 21 can be further controlled to move upward along the Z-axis until the electrode pads 102 of the chip 11 contact the probes 23A of the probe card 23 . Next, the control device 22 can control the probe card 23 to measure the electrical signal of the biochemical sensor 101 of the chip 11 , and perform subsequent processing such as calculation and analysis on the measured electrical signal.

Moreover, when the control device 22 receives the aforementioned electrical signal measured from the probe card 23 , it can be judged that the aforementioned electrical property measurement of the chip 11 has ended. Afterwards, the control device 22 can further control the carrying table 21 to move downward along the Z-axis direction (so that the electrode pads 102 of the chip 11 are separated from the probes 23A of the probe card 23), and move horizontally until the next chip 11 reaches the probes. The position below the probes 23A of the card 23 is then moved upwards, so that the electrode pads 102 of the next chip 11 contact the probes 23A of the probe card 23 for electrical measurement of the next chip 11 . It should be understood that since the control device 22 can pre-set and record the positions of the chips 11 on the wafer 10, it can control the stage 21 to move the chips 11 on the wafer 10 to the corresponding probes of the probe card 23 in sequence. Position of needle 23A. By repeating the above electrical measurement operation, the electrical measurement of all the chips 11 on the wafer 10 can be completed.

Please continue to refer to FIG. 2 , the probe card 23 also has an opening 23B passing through the upper and lower surfaces. In addition, as shown in FIG. 2 and FIG. 3 , the biochemical detection system 2 also includes a microfluidic device 26 that can be engaged in the opening 23B. Wherein, the microfluidic device 26 has a chamber C (the part indicated by the dotted line among Fig. 3), is used to receive a test solution T, and makes the test solution T (in the chamber C) and the wafer 10 below The biochemical sensor 101 ( FIG. 1 ) of the previous chip 11 contacts and reacts. In this way, the probe card 23 can measure the electrical signal of the biochemical sensor 101 in the aforementioned manner to determine the type and/or quantity of the target biochemical substance in the solution T to be tested.

In addition, the biochemical detection system 2 also includes a solution injection unit 27A connected to the microfluidic device 26 and used for injecting at least one solution to be tested into the microfluidic device 26 and the chamber C ( FIG. 3 ). Specifically, although not shown, the solution injection unit 27A may include, for example, an electric pump and a solenoid valve, wherein various solutions to be tested can be injected into the microfluidic device 26 through the electric pump, and the solenoid valve is used for selectively Only one solution to be tested can be injected into the microfluidic device 26 at a time under strict control. The solution injection unit 27A is also electrically connected to the control device 22, and the control device 22 can control the program and speed of the solution injection unit 27A injecting the solution to be tested.

In addition, the biochemical detection system 2 also includes a fluid extraction unit 27B connected to the microfluidic device 26 and used to extract the solution to be tested in the chamber C ( FIG. 3 ) and leave the microfluidic device 26 . Specifically, although not shown, the fluid pumping unit 27B may include, for example, an electric pump and a solenoid valve, wherein the electric pump is used to pump out the solution to be tested in the chamber C (by means of pumping air), and the electromagnetic valve A valve is used to control the communication between the electric pump and chamber C. In other words, when the solenoid valve is open, the electric pump can pump out the solution to be tested in the chamber C, but when the solenoid valve is closed, the electric pump cannot pump out the solution to be tested in the chamber C. In addition, the fluid extraction unit 27B is also electrically connected to the control device 22, and the control device 22 can control the procedure and speed of the fluid extraction unit 27B to extract the solution to be tested.

Please continue to refer to FIG. 2 , the biochemical detection system 2 also includes a positioning mechanism 28 , wherein the microfluidic device 26 can be fixed to the positioning mechanism 28 by means such as locking or engaging. In some embodiments, the positioning mechanism 28 is a conventional 6-axes positioner. In addition, the positioning mechanism 28 can be electrically connected to the control device 22 , and the control device 22 can control the positioning mechanism 28 to move the microfluidic device 26 so that the microfluidic device 26 is positioned and engaged in the opening 23B of the probe card 23 . When the microfluidic device 26 is engaged in the opening 23B of the probe card 23 (more specifically, the microfluidic device 26 is engaged with the opening 23B in the horizontal direction), it can follow the probe card 23 along the Move in the horizontal direction. At this time, the positioning mechanism 28 is also linked with the microfluidic device 26 .

Further, when the control device 22 controls the carrier table 21 to move upwards so that the wafer 10 is combined with the microfluidic device 26 (in order to make the solution to be tested in the chamber C of the microfluidic device 26 and the biochemical sensor 101 of the chip 11 (Fig. 1) During contact and reaction), the positioning mechanism 28 can also be controlled by the control device 22 to press the microfluidic device 26 downward, which helps the microfluidic device 26 and the wafer 10 to be tightly combined (about the microfluidic device 26 and the wafer 10). The bonding method of the wafer 10 will be further described in the following paragraphs).

As mentioned above, since the microfluidic device 26 engages with the opening 23B in the horizontal direction, when the probe card 23 moves in the horizontal direction, the microfluidic device 26 can also move along with the probe card 23 in the horizontal direction. . In addition, when the probe card 23 moves to the position where the probe 23A is aligned with the electrode pad 102 of a chip 11 of the wafer 10 below, the position of the chamber C of the microfluidic device 26 can also be aligned with The position of the biochemical sensor 101 of the chip 11 . Further, when the control device 22 controls the stage 21 to move the wafer 10 to the position of the probe 23A of the probe card 23 to align with the position of the electrode pad 102 of the next chip 11, the chamber C of the microfluidic device 26 The position of can also be aligned with the position of the biochemical sensor 101 of the next chip 11.

In this way, the simultaneous positioning of the probe card 23 and the microfluidic device 26 (corresponding to each chip 11 of the wafer 10) can be achieved, and the upper control device 22 can automatically control the carrier 21 and the wafer 10 on it. The mechanism of moving relative to the probe card 23 to measure the electrical properties of each chip 11 on the wafer 10, that is, the biochemical sensor 101 of each chip 11 on the wafer 10 can be used to sense and detect the biochemical substances in the solution to be tested . Since the operation of each component (or mechanism) of the above-mentioned biochemical detection system 2 can be automated (automatically controlled by the control device 22), the efficiency of biochemical detection can be greatly improved. In addition, the biochemical detection system of the above embodiment replaces traditional manual operations with automated mechanical actions, which can also reduce possible errors caused by manual operations and improve the consistency of test conditions (such as detection time, reaction temperature, and liquid evaporation, etc.) sex.

Next, the design of the microfluidic device 26 according to the embodiment of the present invention will be further introduced. Please refer to FIG. 4A and FIG. 4B first. In some embodiments, the microfluidic device 26 includes a body 40 and a flexible pad 41 disposed on the bottom surface of the body 40 . The body 40 is mainly used to define the reaction space of the solution to be measured from the solution injection unit 27A ( FIG. 2 ) on the wafer 10 ( FIGS. 1 and 2 ), and the flexible pad 41 is used to prevent the body 40 from contacting or impacting the wafer. 10 and prevent the solution to be tested from leaking between the body 40 (microfluidic device 26 ) and the wafer 10 . In some embodiments, the body 40 is made of, for example, acrylic or other optional hard materials, and the flexible pad body 41 is made of, for example, polydimethylsiloxane (Polydimethylsiloxane, PDMS) or other optional flexible materials. .

As shown in FIG. 4A and FIG. 4B , in some embodiments, the body 40 has a cylindrical structure protruding outward from a side wall, and a water storage space 42 is formed in the cylindrical structure. A solution inlet I is formed on the side wall of the cylindrical structure and communicates with the water storage space 42 . Although not shown, the solution inlet I may be connected to the solution injection unit 27A (FIG. 2) through a conduit. In addition, the microfluidic device 26 has a chamber C (formed in the body 40 and the flexible pad 41 ) extending approximately from the top to the bottom (high aspect ratio structure) of the microfluidic device 26 at its center, and the chamber C An opening O1 is formed on the bottom surface of the microfluidic device 26 . As mentioned above, when the microfluidic device 26 is combined with the wafer 10 (not shown in FIGS. 1) The location. In addition, a first micro-channel 43 is formed in the body 40, and communicates with the chamber C and the water storage space 42, and a second micro-channel 44 is formed in the body 40, and communicates with the chamber C and formed in the body 40 The solution outlet E on the side wall of the Although not shown, the solution outlet E may be connected to the fluid extraction unit 27B (FIG. 2) through a conduit.

Through the above structure, when the microfluidic device 26 is closely combined with the wafer 10, a solution T to be tested can be injected into the body 40 by the solution injection unit 27A (FIG. The flow channel 43 flows to the chamber C again. The solution T to be tested injected into the chamber C can contact the biochemical sensor 101 (not shown) on the wafer 10 through the opening O1 . It should be understood that when the solution injection unit 27A injects the solution T to be tested, the solenoid valve in the fluid extraction unit 27B ( FIG. 2 ) is in a closed state, so the solution T to be tested flowing into the chamber C does not pass through the second The micro-channel 44 flows to the solution outlet E, and only gradually accumulates in the chamber C.

In some embodiments, the control device 22 can control the solution injection unit 27A to stop injecting the test solution T after a certain period of time according to the setting, and make the test solution T in the chamber C accumulate to a certain amount or height ( As shown in FIG. 4B ), this helps the solution T to be tested keep stable with the biochemical sensor 101 within a certain period of time when it contacts and reacts with the biochemical sensor 101 (not shown) on the wafer 10 Contact, and the amount of the solution T to be tested that contacts and reacts with the biochemical sensor 101 will not be unstable or too small due to evaporation.

In addition, the design of the water storage space 42 is also to fill the test solution T in the chamber C through capillary action when the test solution T in the chamber C evaporates too much, so that the chamber The amount of the solution T to be tested in C remains stable.

After the solution T to be tested in the chamber C reacts with the biochemical sensor 101 on the aforementioned wafer 10 for a certain period of time, the control device 22 can control the fluid extraction unit 27B to extract the fluid in the chamber C and the microfluidic device 26 according to the setting. The solution T to be tested is drawn out. It is worth mentioning that, in some embodiments, a small opening 42A may be formed on the top of the water storage space 42, whereby under the action of atmospheric pressure, the solution T to be tested in the microfluidic device 26 can be drawn out by the fluid. Unit 27B withdraws smoothly and avoids solution carryover. In addition, the second microchannel 44 is disposed close to the bottom surface of the body 40 (as shown in FIG. 4B ), which is also for the purpose of smoothly pumping out the solution T to be tested in the microfluidic device 26 .

It should be understood that the microfluidic device 26 in FIGS. 4A and 4B described above is only an example, and is not intended to limit the structure of the microfluidic device of the present invention. The structure of the microfluidic device 26 of the above-mentioned embodiment focuses on providing a chamber with a high aspect ratio structure so that the solution to be tested can stably contact and react with the biochemical sensor on the wafer in the chamber, and provide fluid injection and Structural guidance such as exporting chambers, as for some structural and shape designs can be modified and changed.

In addition, in some embodiments, an opening O2 ( FIG. 4A and FIG. 4B ) may also be formed on the top of the chamber C for allowing at least one test condition sensor (such as a temperature sensor, a pH value sensor) Detector and/or water level sensor, not shown in the figure) enters the chamber C, and contacts the solution T to be tested, so as to sense the test conditions of the solution T to be tested, such as temperature, pH value and water level. The aforementioned test condition sensors are also electrically connected to the control device 22 (FIG. 2), and the control device 22 can control the operation of some components in the system according to the results sensed by the test condition sensors, and make the test of the solution T to be tested Conditions remain the same.

For example, as shown in FIG. 4A , the body 40 may also have a liquid channel 45 disposed around the chamber C and allowing a liquid (such as water) to flow therein. When the control device 22 finds that the temperature of the solution T to be tested in the chamber C is lower than or higher than the standard test temperature according to the result sensed by the aforementioned test condition sensor, it can control a water supply device (not shown) to inject Water of an appropriate temperature is fed into the liquid channel 45 to change and make the temperature of the solution T to be tested reach the standard test temperature. It should be understood that, in some embodiments, the aforementioned at least one test condition sensor may also be directly embedded in the wall of the chamber C, and the opening O2 may be omitted.

Then please refer to FIG. 4A, FIG. 5 and FIG. 6A together. In some embodiments, the microfluidic device 26 also has a plurality of airflow channels 46, communicating with the bottom surface S2 of the microfluidic device 26 (that is, the bottom surface of the flexible pad 41). And the top surface S3 (the top surface of the body 40). It should be understood that the partial structure of the microfluidic device 26 shown in FIG. 5 is viewed along the line B-B in FIG. 4A . In addition, an electric pump (not shown in the figure) can be connected to the airflow channel 46 through the opening exposed on the top surface S3 of the airflow channel 46 . Therefore, when the stage 21 moves upwards so that the surface of the wafer 10 (i.e. the active surface S1) connects to the bottom surface S2 of the microfluidic device 26 (FIG. The space between the bottom of the microfluidic device 26 and the wafer 10 is evacuated or evacuated (as shown by the arrow in FIG. 6A ), so that the microfluidic device 26 is closely combined with the wafer 10 .

It is worth mentioning that when the aforementioned electric pump pumps air, it can also be known whether the microfluidic device 26 and the wafer 10 are tightly bonded by reading the pressure gauge on it. For example, when the value of the pressure gauge is lower than a certain value, it can indicate that the microfluidic device 26 and the wafer 10 are tightly combined, and when the value of the pressure gauge cannot be lowered all the time, it can indicate that the microfluidic device 26 and the wafer 10 are tightly combined. There is a gap between them. In addition, the electric pump is also electrically connected to the control device 22 ( FIG. 2 ), and the control device 22 can judge whether the microfluidic device 26 is tightly combined with the wafer 10 according to the value of the pressure value, and then determine whether to control the aforementioned solution injection. Unit 27A ( FIG. 2 ) injects the solution to be tested into microfluidic device 26 . In other words, before injecting the solution to be tested into the microfluidic device 26 , it can be confirmed whether the microfluidic device 26 is tightly combined with the wafer 10 .

As shown in FIG. 5 and FIG. 6A , in some embodiments, a drain valve 51 is movably disposed at an upper position in the chamber C. As shown in FIG. It can be seen from the figure that the drain valve 51 has a rod portion 51A extending toward the bottom surface S2 of the microfluidic device 26 and protruding from the bottom surface of the main body 40 . It should be noted that, when the microfluidic device 26 is not combined with the wafer 10, the drain valve 51 can be engaged with a constricted port C1 at an upper position in the chamber C, and prevent the solution to be tested from flowing into the chamber The bottom of C (ie opening O1). And when the microfluidic device 26 is closely combined with the wafer 10, the flexible pad 41 can be squeezed and deformed in the vertical direction, and the wafer 10 will push the drain valve 51 and its rod 51A up (as shown in Figure 6A). As shown by the arrow), so that the drain valve 51 is away from the constriction port C1. In this way, the drain valve 51 allows the solution to be tested injected into the chamber C to pass through and flow to the bottom of the chamber C (that is, to flow onto the wafer 10 ). As can be seen from FIG. 5 and FIG. 6A , a protruding stopper structure C2 may be provided at a higher position in the chamber C to limit the upward movement range of the drain valve 51 . In addition, the top of the drain valve 51 can form a capillary structure 51B for guiding the solution to be tested to flow to the bottom of the chamber C smoothly and gently.

In particular, the rod portion 51A of the drain valve 51 can be provided with a touch sensor and electrically connected to the aforementioned control device 22 ( FIG. 2 ). Therefore, when the wafer 10 pushes the rod portion 51A up (that is, the microfluidic device 26 is tightly combined with the wafer 10), the control device 22 can receive a signal from the touch sensor and confirm that the microfluidic device 26 is in contact with the wafer 10. The wafer 10 is tightly bonded, and then the aforementioned solution injection unit 27A ( FIG. 2 ) can be controlled to start injecting the solution to be tested into the microfluidic device 26 . In this way, the function of the biochemical detection system 2 automatically supplying the solution to be tested can be realized.

In some embodiments, the flexible pad 41 disposed on the bottom of the body 40 has a multi-layer structure along the direction from the chamber C to the outer wall of the microfluidic device 26 (ie, the horizontal direction). For example, as shown in FIG. 5 , the flexible pad 41 may have a first layer structure 41A surrounding the cavity C and a second layer structure 41B disposed around the bottom surface of the body 40 . The flexible pad body 41 has a multi-layer structure design, which can effectively prevent the solution to be tested from leaking from between the body 40 (microfluidic device 26 ) and the wafer 10 .

As shown in FIGS. 5 and 6A , in some embodiments, the bottom of the outer wall of the microfluidic device 26 is also provided with a liquid leakage detection element 52 for detecting whether the solution to be tested is leaked from the microfluidic device 26 and the wafer 10. between leaks. Specifically, the liquid leakage detection element 52 includes a sheet or circuit of metal material (such as copper), which is circumferentially fixed on the bottom edge of the outer wall of the body 40 and electrically connected to a detector (not shown). When the solution to be tested leaks from between the microfluidic device 26 and the wafer 10 and contacts the liquid leakage detection element 52 , the detector can detect a change in its resistance, thereby detecting the occurrence of liquid leakage. In addition, the liquid leakage detection element 52 can also be electrically connected to the control device 22 ( FIG. 2 ), and the control device 22 can judge whether there is a solution to be tested from the microfluidic device 26 and the wafer according to the resistance value detected by the detector. 10 leakage, and then decide whether to stop the operation of the entire system.

Then please refer to FIG. 6B. After the inspection of a chip 11 on the wafer 10 is completed, the carrier table 21 (FIG. 2) will start to move downwards to separate the wafer 10 from the probes 23A of the probe card 23 (FIG. 2). ). At this time, the control device 22 ( FIG. 2 ) can control the positioning mechanism 28 ( FIG. 2 ) to lift the microfluidic device 26 upwards to the original position, and also control the electric pump connected to the air flow channel 46 to the bottom of the microfluidic device 26 . The space between the wafer 10 and the wafer 10 is inflated (as shown by the arrow in FIG. 6B ), so that the microfluidic device 26 and the wafer 10 can be separated smoothly.

It should be understood that the microfluidic device 26 of the above-mentioned embodiment can be well combined and separated from the wafer 10, and has multiple active or passive detection methods to prevent the solution to be tested from leaking between the microfluidic device 26 and the wafer 10. Design, so it can avoid the situation that the solution to be tested may leak during the detection process and cause short circuit or damage to nearby chips. In addition, by arranging at least one test condition sensor in the chamber C of the microfluidic device 26, the test condition of the solution to be tested can also be monitored, and then the operation of some components in the system can be controlled by the control device 22, so that the solution to be tested can The test conditions are kept consistent, which can improve the accuracy and quality of the test results.

FIG. 7 shows a flowchart of a biochemical detection method 700 according to some embodiments. In step 701 , a substrate is set on a carrier platform, and at least one chip is provided on the substrate, and the chip has at least one biosensor and a plurality of electrode pads. In step 702, a probe card and a microfluidic device are provided, wherein the probe card has a plurality of probes and an opening, and the microfluidic device is engaged in the opening and has a cavity. In step 703, the microfluidic device and the probe card are moved so that the positions of the chamber of the microfluidic device and the probe of the probe card correspond to the positions of the biochemical sensors and the electrode pads of the chip, respectively. In step 704, the stage is moved such that the microfluidic device is coupled to the substrate. In step 705, a test solution is injected into the chamber of the microfluidic device, so that the test solution is in contact with the biochemical sensor of the chip for a certain period of time. In step 706, the biochemical sensor of the chip is electrically measured by the probe of the probe card, and the type and/or quantity of the target biochemical substance in the solution to be tested is determined according to the electrical measurement result.

It should be understood that the steps of the biochemical detection method described above are only examples, and the biochemical detection method in some embodiments may also include other steps and step sequences.

For example, in some embodiments, the above-mentioned biochemical detection method may also include a step of moving the stage so that the substrate moves relative to the microfluidic device and the probe card, and then uses another chip on the substrate to perform biochemical detection. In some embodiments, in the step of moving the stage to combine the microfluidic device with the substrate, it may also include pumping the space between the bottom of the microfluidic device and the substrate through a pump, so that the microfluidic device and the substrate Substrate bonding step. In some embodiments, before the step of moving the stage so that the substrate moves relative to the microfluidic device and the probe card, it may also include using a pump to inflate the space between the bottom of the microfluidic device and the substrate, so that A step in which the microfluidic device and the substrate are separated from each other. In some embodiments, the above-mentioned biochemical detection method may also include arranging at least one test condition sensor in the chamber of the microfluidic device to sense the test condition of the solution to be tested, and the control device according to the test condition sensor The sensing result controls the operation of at least one component in the biochemical detection system, so that the test conditions of the solution to be tested are kept consistent, wherein the test conditions include temperature, pH value and/or water level. In some embodiments, after the step of measuring the electrical property of the biochemical sensor of the chip through the probe of the probe card, a step of pumping the solution to be tested out of the microfluidic device may also be included. In some embodiments, after the step of pumping the test solution out of the microfluidic device, a step of injecting the same or a different test solution into the chamber of the microfluidic device and using the same chip for biochemical detection may also be included.

To sum up, the embodiments of the present invention provide an automatic biochemical detection system and method, which can directly use the biochemical sensors of multiple chips on the wafer (or substrate) to sense and detect the target biochemical substances in the solution to be tested, There is no need to cut the wafer and operate each chip separately, so the detection time can be greatly shortened and the detection efficiency can be improved. In addition, traditional manual operations can be replaced by automated mechanical actions, which can also reduce possible errors caused by manual operations, and improve the consistency of test conditions (such as detection time, reaction temperature, and liquid evaporation, etc.), thereby improving test results. accuracy and quality.

According to some embodiments, there is provided a microfluidic device comprising a body, a flexible pad, a chamber, and a drain valve. The flexible pad is arranged on the bottom surface of the body. The chamber is formed in the main body and the flexible pad, and the chamber is formed with an opening on the bottom surface of the microfluidic device. The drain valve is movably disposed in the chamber for blocking or allowing a solution injected into the chamber to flow to the opening.

According to some embodiments, the drain valve has a stem extending toward the bottom surface of the microfluidic device and protruding beyond the bottom surface of the body.

According to some embodiments, the microfluidic device further includes a plurality of gas flow channels communicating with the bottom surface of the flexible pad and the top surface of the body.

According to some embodiments, the flexible pad has a multi-layer structure in the direction from the chamber to the outer sidewall of the microfluidic device.

According to some embodiments, a biochemical detection system is provided, including a probe card and a microfluidic device. The probe card has a plurality of probes and an opening. The probes are used to contact a plurality of electrode pads of at least one chip on a substrate to detect electrical signals of at least one biosensor of the at least one chip. The microfluidic device is engaged in the opening and has a chamber for receiving a solution to be tested and making the solution to be tested contact with the biochemical sensor.

According to some embodiments, the microfluidic device further has a plurality of airflow channels connected to the bottom surface of the microfluidic device, and the biochemical detection system further includes a pump connected to the airflow channel, wherein the pump is used for the connection between the bottom of the microfluidic device and the substrate The space between is evacuated and/or inflated, and the microfluidic device and the substrate are closely combined and/or separated from each other.

According to some embodiments, the microfluidic device further has a liquid leakage detection element disposed on the bottom of the outer sidewall of the microfluidic device for detecting whether the solution to be tested leaks from between the microfluidic device and the substrate.

According to some embodiments, a biochemical detection method is provided, comprising: setting a substrate on a carrier platform, having at least one chip on the substrate, and the chip has at least one biochemical sensor and a plurality of electrode pads; providing a probe card and A microfluidic device, wherein the probe card has a plurality of probes and an opening, the microfluidic device is engaged in the opening and has a chamber; the microfluidic device and the probe card are moved so that the chamber of the microfluidic device and the probe The positions of the probes of the needle card correspond to the positions of the biochemical sensors and the electrode pads of the chip respectively; the carrier platform is moved to combine the microfluidic device with the substrate; a solution to be tested is injected into the chamber of the microfluidic device to make the tested The solution is in contact with the biochemical sensor of the chip for a certain period of time; and the probe of the probe card is used to measure the electrical properties of the biochemical sensor of the chip, and according to the electrical measurement results, the type and type of the target biochemical substance in the solution to be tested are determined. /or quantity.

According to some embodiments, the biochemical detection method further includes moving the carrier, so that the substrate moves relative to the microfluidic device and the probe card, and then uses another chip on the substrate to perform biochemical detection, wherein the moving carrier makes the substrate move relative to the microfluidic device. Before the step of moving the fluidic device and the probe card, a pump is used to inflate the space between the bottom of the microfluidic device and the substrate, so that the microfluidic device and the substrate are separated from each other.

According to some embodiments, the biochemical detection method further includes arranging at least one test condition sensor in the chamber of the microfluidic device to sense the test condition of the solution to be tested, and controlling the device according to the result sensed by the test condition sensor Control the operation of at least one component in the biochemical detection system to maintain the same test conditions of the solution to be tested, wherein the test conditions include temperature, pH value and/or water level.

Although the present invention is disclosed above with the foregoing embodiments, they are not intended to limit the present invention. Those skilled in the technical field to which the present invention belongs may make some changes and modifications without departing from the concept and scope of the present invention. Therefore, the scope of protection of the present invention should be defined by the appended claims.

Claims (10)

1. A microfluidic device comprising: a body; A flexible pad is arranged on the bottom surface of the body; a chamber formed in the body and the flexible pad, and the chamber forms an opening on the bottom surface of the microfluidic device; and A drain valve is movably arranged in the chamber for blocking or allowing a solution injected into the chamber to flow to the opening. 2. The microfluidic device as claimed in claim 1, wherein the drain valve has a stem extending toward the bottom of the microfluidic device and protruding from the bottom of the body. 3. The microfluidic device according to claim 1 or 2, further comprising a plurality of gas flow channels communicating with the bottom surface of the flexible pad and the top surface of the main body. 4. The microfluidic device according to claim 1 or 2, wherein the flexible pad has a multi-layer structure along the direction from the chamber to the outer sidewall of the microfluidic device. 5. A biochemical detection system comprising: A probe card having a plurality of probes and an opening, the probes are used to contact a plurality of electrode pads of at least one chip on a substrate to detect electrical signals of at least one biosensor of the at least one chip ;as well as A microfluidic device is engaged in the opening and has a chamber for receiving a solution to be tested and making the solution to be tested contact with the biochemical sensor. 6. The biochemical detection system as claimed in claim 5, wherein the microfluidic device also has a plurality of airflow channels, which communicate with the bottom surface of the microfluidic device, and the biochemical detection system also includes a pump, which is connected to the airflow channel, Wherein the pump is used to evacuate and/or inflate the space between the bottom of the microfluidic device and the substrate, and make the microfluidic device and the substrate tightly combined and/or separated from each other. 7. The biochemical detection system as claimed in claim 5 or 6, wherein the microfluidic device also has a liquid leakage detection element, which is arranged on the bottom of the outer side wall of the microfluidic device, and is used to detect whether the solution to be tested is leaked from the microfluidic device. Leakage between the microfluidic device and the substrate. 8. A biochemical detection method, comprising: setting a substrate on a carrier platform, the substrate has at least one chip, and the chip has at least one biosensor and a plurality of electrode pads; A probe card and a microfluidic device are provided, wherein the probe card has a plurality of probes and an opening, and the microfluidic device is engaged in the opening and has a chamber; moving the microfluidic device and the probe card so that the positions of the chamber of the microfluidic device and the plurality of probes of the probe card correspond to the biochemical sensors and the electrode pads of the chip, respectively s position; moving the carrier so that the microfluidic device is combined with the substrate; injecting a solution to be tested into the chamber of the microfluidic device, so that the solution to be tested is in contact with the biochemical sensor of the chip for a certain period of time; and The biochemical sensor of the chip is electrically measured by the probe of the probe card, and the type and/or quantity of the target biochemical substance in the solution to be tested is determined according to the electrical measurement result. 9. The biochemical detection method according to claim 8, further comprising moving the carrier, so that the substrate moves relative to the microfluidic device and the probe card, and then utilizes another chip on the substrate to perform biochemical detection, wherein Before the step of moving the stage so that the substrate moves relative to the microfluidic device and the probe card, it also includes inflating the space between the bottom of the microfluidic device and the substrate through a pump, so that the The microfluidic device is separated from the substrate. 10. The biochemical detection method as claimed in claim 8 or 9, further comprising setting at least one test condition sensor in the chamber of the microfluidic device to sense the test condition of the solution to be tested, and by the control device The operation of at least one component in the biochemical detection system is controlled according to the result sensed by the test condition sensor, so that the test conditions of the solution to be tested are kept consistent, wherein the test conditions include temperature, pH value and/or water level.