CN108568320B

CN108568320B - Microfluidic device, biochemical detection system and method

Info

Publication number: CN108568320B
Application number: CN201710138281.0A
Authority: CN
Inventors: 黄睿政; 姜慧如; 刘佩雯; 李维; 苏哿暐
Original assignee: Taiwan Semiconductor Manufacturing Co TSMC Ltd
Current assignee: Taiwan Semiconductor Manufacturing Co TSMC Ltd
Priority date: 2017-03-09
Filing date: 2017-03-09
Publication date: 2021-03-26
Anticipated expiration: 2037-03-09
Also published as: CN108568320A

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

The embodiment of the invention relates to a micro-fluid device, a biochemical detection system and a method.

Background

A biosensor (also referred to as a biosensor) is a device that can operate on the basis of electrical, electrochemical, optical and/or mechanical detection principles for sensing and detecting biochemical substances.

BioFETs are biochemical sensors that contain transistors that electrically sense and detect biochemical molecules or biological entities. This detection may be achieved by direct detection sensing, or by reaction or interaction of specific reactants with biochemical molecules/biological entities. Specifically, when a target biochemical molecule or biological entity binds to a gate of a bio-field effect transistor or a receptor molecule fixed on the gate, the drain current of the bio-field effect transistor varies due to the gate voltage, and varies according to the type and amount of target bonds generated. The change in drain current can be measured and used to determine the type and/or amount of binding between the receptor and the target biochemical molecule or biological entity.

In addition, a variety of receptors may be used to functionalize the gate of a bio-field effect transistor, for example, to detect single-stranded helical deoxyribonucleic acid (ssDNA), the gate of a bio-field effect transistor may be functionalized with immobilized complementary single-stranded helical deoxyribonucleic acid. For the detection of different proteins, such as tumor markers, the gate of the biofet may be functionalized with monoclonal antibodies.

The bio-field effect transistor can be manufactured by a semiconductor process and can rapidly convert an electronic signal, and thus has been widely used in an integrated circuit. Typically, a semiconductor wafer includes tens to hundreds of integrated circuit chips. In electrical measurement, in order to avoid damage to nearby integrated circuit chips due to short circuit caused by solution, the integrated circuit chips are generally separated along a dicing line, then a solution to be measured is manually dropped on the position of the bio-field effect transistor of each chip, and then an electrical signal (e.g., drain current) of the bio-field effect transistor is obtained by probe measurement to determine the type and/or amount of a target biochemical substance in the solution to be measured.

However, the consistency of the testing conditions (such as testing time, reaction temperature, and evaporation amount of liquid) is very difficult to control, and the accuracy and quality of the testing results are questioned and the efficiency is very poor (i.e. the testing time is too long). Accordingly, there is a need for an improved biochemical detection system and method.

Disclosure of Invention

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

Some embodiments of the invention provide a biochemical detection system, comprising: 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; and a microfluid device which is clamped in the opening and is provided with a chamber, wherein 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.

Some embodiments of the invention provide a biochemical detection method, comprising: arranging a substrate on a bearing table, wherein the substrate is provided with at least one chip, and the chip is provided with at least one biochemical sensor and a plurality of electrode pads; providing a probe card and a micro-fluid device, wherein the probe card is provided with a plurality of probes and an opening, and the micro-fluid device is clamped in the opening and is provided with a chamber; moving the micro-fluid device and the probe card to enable the positions of a cavity of the micro-fluid device and the position of a probe of the probe card to respectively correspond to the positions of a biochemical sensor and an electrode pad of the chip; moving the carrier to bond the microfluidic device to the substrate; injecting a solution to be detected into a chamber of the microfluid device, so that the solution to be detected is contacted with a biochemical sensor of the chip for a certain time; and carrying out electrical measurement on the biochemical sensor of the chip through the probe of the probe card, and judging the type and/or the quantity of the target biochemical substance in the solution to be measured according to the electrical measurement result.

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.

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

FIG. 3 is a schematic plan view showing the probe card of FIG. 2 in relation to the micro-fluidic device.

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

Fig. 4B shows a schematic cross-sectional view along the line a-a in fig. 4A.

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

FIG. 6A shows a schematic view of the microfluidic device in close association with a wafer.

FIG. 6B shows the microfluidic device and the wafer separated from each other.

FIG. 7 shows a flow diagram of a biochemical detection method according to some embodiments.

Description of reference numerals:

2-biochemical detection system;

10-wafer;

11-chip;

21-a bearing table;

22-a control device;

23-a probe card;

23A-probe;

23B-opening;

24-a clamping mechanism;

25-microscope;

26-a microfluidic device;

27A-a solution injection unit;

27B-a fluid extraction unit;

28-positioning mechanism;

40 to the body;

41-flexible cushion body;

41A-a first layer structure;

41B-a second layer structure;

42-water storage space;

42A-opening;

43-a first microchannel;

44-a second micro-channel;

45-liquid channel;

46-an air flow channel;

51-a water release valve;

51A-a rod part;

51B-capillary structure;

52-leakage detection element;

101-a biochemical sensor;

102-electrode pad;

700-biochemical detection method;

701-706 step(s);

c, a chamber;

c1-constriction;

c2-stop structure;

e, a solution outlet;

i, a solution inlet;

o1-opening;

o2-opening;

s1, an active surface;

s2-bottom surface;

s3-top surface;

t-solution to be measured.

Detailed Description

The following disclosure provides many different embodiments, or examples, for implementing different features of the disclosure. The following disclosure describes specific examples of components and arrangements thereof to simplify the description. Of course, these specific examples are not intended to be limiting. For example, if embodiments describe a first feature formed over or on a second feature, that may include the first feature being in direct contact with the second feature, embodiments may also include additional features formed between the first and second features such that the first and second features are not in direct contact.

Spatially relative terms, such as "below," "lower," "above," "upper," and the like, may be used hereinafter with respect to elements or features in the figures to facilitate describing relationships between one element or feature and another element(s) or feature(s) in the figures. These spatially relative terms are intended to encompass the possible use or operation of the device in the figures in addition to the orientation depicted in the figures.

The same reference numbers and/or letters may be repeated in the various embodiments below for simplicity and clarity, and are not intended to limit the particular relationships between the various embodiments and/or structures discussed.

The terms first and second, etc. are used hereinafter for clarity of explanation only and are not intended to correspond or limit the claims. The terms first feature and second feature are not intended to be limited to the same or different features.

In the drawings, the shape or thickness of the structures may be exaggerated to simplify or facilitate labeling. It is to 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 above-mentioned problems of the prior art, embodiments of the present invention provide an improved automatic biochemical detection system, which can directly use biochemical sensors of a plurality of chips on a wafer (or substrate) to sense and detect target biochemical substances in a solution to be detected, without cutting the wafer and separately operating each chip (including dropping the solution to be detected on each chip and mounting probes on each chip for electrical measurement, etc.), thereby greatly shortening the detection time and improving the detection efficiency.

Referring first to fig. 1, a plan view of a wafer 10 and an enlarged view of a chip 11 on the wafer 10 according to some embodiments of the invention are shown. The wafer 10 is a semiconductor wafer (e.g., a silicon wafer) having a plurality of integrated circuit chips 11 (hereinafter referred to as chips 11) fabricated by a semiconductor process. Each chip 11 has an active surface S1, a biosensor 101 and a plurality of electrode pads 102, wherein the biosensor 101 and the electrode pads 102 are exposed on the active surface S1. In some embodiments, each chip 11 may also have a plurality of biosensors 101. The biosensor 101 may be a bio-field effect transistor (BioFET), and the electrode pads 102 are electrically connected to the gate, the drain and the source of the BioFET, respectively. In addition, the biological field effect transistors of the chips 11 may be the same or different. It should be noted that the wafer 10 is only for convenience of describing the embodiment, but the wafer 10 may be replaced by a substrate (e.g., a glass substrate, a plastic substrate, etc.) having or provided with a plurality of chips 11.

As mentioned above, the fefets can electrically sense and detect target biochemical substances in a solution to be tested, such as deoxyribonucleic acid (DNA), ribonucleic acid (RNA), proteins, or other small organic and inorganic molecules. Specifically, when these target biochemical molecules or biological entities are bound to the gate of the fefet or the receptor molecules immobilized on the gate, the drain current of the fefet changes due to the gate voltage, and varies according to the type and amount of target bonds generated. The change in drain current can be measured and used to determine the type and/or amount of binding between the receptor and the target biochemical molecule or biological entity, i.e., to sense and detect the target biochemical in the test solution. Since the structures and detection mechanisms of various biological field effect transistors are conventional and are not the technical focus of the present invention, they are not described herein again. The biochemical sensor 101 mentioned herein includes various known biological field effect transistors such as Ion-sensing field effect transistors (ISFETs), Enzyme field effect transistors (ENFETs), or immune field effect transistors (immunofets). .

FIG. 2 is 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 sense and detect a target biochemical substance in a solution to be detected by the biochemical sensors 101 (FIG. 1) of the plurality of chips 11 on the wafer 10. As can be seen in fig. 2, the biochemical detection system 2 includes a carrier 21 for carrying the wafer 10. In some embodiments, the susceptor 21 may hold the wafer 10 thereon by vacuum suction, but other alternative means of holding the wafer 10 (e.g., electrostatic chuck) may be used. The susceptor 21 may also support the wafer 10 for movement in a horizontal direction (e.g., X-axis and Y-axis directions) and a vertical direction (e.g., Z-axis direction). In addition, the supporting platform 21 is electrically connected to a control device 22 (e.g., a computer), and the control device 22 can control the movement of the supporting platform 21.

The bio-chemical detection system 2 also includes a probe card 23 (see also fig. 3) having a plurality of probes 23A disposed thereunder for contacting the electrode pads 102 (fig. 1) of the chips 11 on the wafer 10 to measure and obtain electrical signals of the bio-chemical sensor 101. Probe card 23 can be a Micro-electro-Mechanical Systems (MEMS) probe card or other alternative type of probe card. 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 signals of the biochemical sensor 101, and perform the processing such as calculation, analysis, storage and display on the measured electrical signals of the biochemical sensor 101.

The biochemical detection system 2 also includes a clamping mechanism 24 for clamping the probe card 23 and moving along the horizontal direction (such as the X-axis and Y-axis directions in the figure). Specifically, the clamping mechanism 24 can be connected to a positioning mechanism (not shown) electrically connected to the control device 22, wherein the control device 22 can control the positioning mechanism to move the clamping mechanism 24 and the probe card 23 thereon along the horizontal direction, so as to achieve the position 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, the probes 23A of the probe card 23 are arranged in a manner corresponding 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 may be electrically connected to the control device 22.

When the control device 22 controls the positioning mechanism to move the clamping mechanism 24 and the probe card 23 thereon along the horizontal direction and observe through the microscope 25 that the position of the probe 23A of the probe card 23 is aligned with the position of the electrode pad 102 of a chip 11 on the wafer 10, the stage 21 can be further controlled to move upward along the Z-axis direction until the electrode pad 102 of the chip 11 contacts the probe 23A of the probe card 23. Then, the control device 22 controls the probe card 23 to measure the electrical signals of the biochemical sensors 101 of the chip 11, and then the measured electrical signals are processed by computation, analysis, and the like.

Furthermore, when the control device 22 receives the electrical signal measured by the probe card 23, it can determine that the electrical measurement of the chip 11 has been completed. Thereafter, the control device 22 can further control the carrier 21 to move downward along the Z-axis (so as to separate the electrode pads 102 of the chip 11 from the probes 23A of the probe card 23), move horizontally to a position where the next chip 11 reaches below the probes 23A of the probe card 23, and then move upward so that the electrode pads 102 of the next chip 11 contact the probes 23A of the probe card 23, so as to perform electrical measurement on the next chip 11. It should be understood that, since the control device 22 can preset and record the position of each chip 11 on the wafer 10, the stage 21 can be controlled to move each chip 11 on the wafer 10 to the position corresponding to the probe 23A of the probe card 23 in sequence. By repeating the electrical measurement operation, the electrical measurement of all the chips 11 on the wafer 10 can be completed.

Referring to fig. 2, the probe card 23 also has an opening 23B penetrating the upper and lower surfaces. In addition, as shown in fig. 2 and 3, the biochemical detection system 2 also includes a micro-fluid device 26 that can be engaged in the opening 23B. The micro-fluid device 26 has a chamber C (shown as a dotted line in fig. 3) for receiving a solution T to be tested, and the solution T to be tested (in the chamber C) is contacted and reacted with the biosensor 101 (fig. 1) of a chip 11 on the wafer 10 below. In this way, the probe card 23 can measure the electrical signal of the biochemical sensor 101 in the above-mentioned manner to determine the type and/or amount of the target biochemical in the solution T.

In addition, the biochemical detection system 2 also includes a solution injection unit 27A connected to the microfluidic device 26 and configured to inject 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 through which a plurality of solutions to be tested can be injected into the microfluidic device 26, and a solenoid valve for selectively controlling that only one solution to be tested can be injected into the microfluidic device 26 at a time. The solution injecting unit 27A is also electrically connected to the control device 22, and the control device 22 can control the process and speed of injecting the solution to be tested by the solution injecting unit 27A.

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

With continued reference to FIG. 2, the biochemical detection system 2 also includes a positioning mechanism 28, wherein the microfluidic device 26 can be secured to the positioning mechanism 28 by, for example, locking or snapping. In some embodiments, the positioning mechanism 28 is a conventional six-axis 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 micro fluid device 26 is engaged in the opening 23B of the probe card 23 (more specifically, the micro fluid device 26 is engaged with the opening 23B in the horizontal direction), it can move along the horizontal direction along with the probe card 23. At this time, the positioning mechanism 28 is also interlocked with the micro-fluid device 26.

Further, when the control device 22 controls the carrier 21 to move upward 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 contact and react with the biochemical sensor 101 (fig. 1) of the chip 11), the positioning mechanism 28 can also be controlled by the control device 22 to press the microfluidic device 26 downward, which facilitates the tight combination of the microfluidic device 26 and the wafer 10 (the combination of the microfluidic device 26 and the wafer 10 will be further described in the following paragraphs).

As described above, since the microfluidic device 26 is engaged with the opening 23B in the horizontal direction, when the probe card 23 is moved in the horizontal direction, the microfluidic device 26 can also be moved in the horizontal direction along with the probe card 23. In addition, when the probe card 23 is moved to a position where the position of 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 may 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 where the probes 23A of the probe card 23 are aligned with the electrode pads 102 of the next chip 11, the position of the chamber C of the micro-fluid device 26 may also be aligned with the position of the bio-chemical sensor 101 of the next chip 11.

In this way, the probe card 23 and the micro-fluid device 26 (corresponding to each chip 11 of the wafer 10) can be simultaneously positioned, and the control device 22 can automatically control the carrying stage 21 and the wafer 10 thereon to move relative to the probe card 23 to perform the electrical measurement on each chip 11 on the wafer 10, so that 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 measured. Since the operation of the above-described components (or mechanisms) of the 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 the conventional manual operation with an automatic mechanical operation, so that the errors possibly generated by the manual operation can be reduced, and the consistency of the test conditions (such as detection time, reaction temperature, liquid evaporation amount, etc.) can be improved.

The design of the microfluidic device 26 of the present embodiment is further described next. Referring first to fig. 4A and 4B, in some embodiments, the microfluidic device 26 includes a body 40 and a flexible pad 41 disposed on a bottom surface of the body 40. The body 40 is mainly used to define a reaction space of the solution to be tested from the solution injection unit 27A (fig. 2) on the wafer 10 (fig. 1 and 2), and the flexible pad 41 is used to prevent the body 40 from contacting or striking the surface of the wafer 10 and to prevent the solution to be tested from leaking between the body 40 (the microfluidic device 26) and the wafer 10. In some embodiments, the body 40 is made of, for example, acrylic or other optional hard material, and the flexible pad 41 is made of, for example, Polydimethylsiloxane (PDMS) or other optional flexible material.

As shown in fig. 4A and 4B, in some embodiments, the body 40 has a cylindrical structure protruding outward from a sidewall, and a water storage space 42 is formed in the cylindrical structure. A solution inlet I is formed in a sidewall 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 pipe. In addition, the microfluidic device 26 has a chamber C (formed within the body 40 and the flexible pad 41) at the center thereof that extends substantially from the top to the bottom (high aspect ratio configuration) of the microfluidic device 26, and the chamber C forms an opening O1 at the bottom surface of the microfluidic device 26. As described above, when the microfluidic device 26 is combined with the wafer 10 (not shown in fig. 4A and 4B), the position of the chamber C may correspond to the position of the biochemical sensor 101 (fig. 1) of a chip 11 on the wafer 10. In addition, a first micro flow channel 43 is formed in the body 40 and communicates the chamber C with the water storage space 42, and a second micro flow channel 44 is formed in the body 40 and communicates the chamber C with a solution outlet E formed on a side wall of the body 40. Although not shown, the solution outlet E may be connected to the fluid pumping unit 27B (fig. 2) through a pipe.

With the above structure, when the micro fluid device 26 is tightly 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. 2), and flows to the chamber C through the first micro channel 43 after the water storage space 42 is filled. The solution T to be tested injected into the chamber C can contact the biosensor 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 measured, the solenoid valve in the fluid extraction unit 27B (fig. 2) is closed, so that the solution T to be measured flowing into the chamber C does not flow to the solution outlet E through the second microchannel 44, but 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 solution T after a certain period of time after starting to inject the solution T, and to accumulate the solution T in the chamber C to a certain amount or height (as shown in fig. 4B), which helps the solution T to be tested to keep stable contact with the biosensor 101 during a certain period of time when the solution T is in contact with and reacts with the biosensor 101 (not shown) on the wafer 10, and the amount of the solution T to be tested that is in contact with and reacts with the biosensor 101 is not unstable or too small due to evaporation.

In addition, the water storage space 42 is designed to fill the solution T to be measured in the chamber C by capillary action under the condition that the solution T to be measured in the chamber C is excessively evaporated, so that the amount of the solution T to be measured in the chamber C is kept stable.

After the solution T to be measured in the chamber C reacts with the biochemical sensor 101 on the wafer 10 for a certain time, the control device 22 can control the fluid pumping unit 27B to pump out the solution T to be measured in the chamber C and the microfluidic device 26 according to the setting. It should be noted that, in some embodiments, the top of the water storage space 42 may be formed with a small opening 42A, so that the solution T to be tested in the microfluidic device 26 can be smoothly pumped out by the fluid pumping unit 27B under the action of the atmospheric pressure, and the solution residue is avoided. In addition, the second microchannel 44 is disposed near the bottom surface of the body 40 (as shown in fig. 4B), which also allows the solution T to be tested in the microfluidic device 26 to be smoothly pumped out.

It should be understood that the above description of the microfluidic device 26 of fig. 4A and 4B is merely an example, and not intended to limit the structure of the microfluidic device of the present invention. The structure of the microfluidic device 26 of the above embodiment is characterized by providing a chamber with a high aspect ratio structure to facilitate the solution to be tested to stably contact and react with the biochemical sensors on the wafer in the chamber, and providing structural guidance for fluid injection and discharge from the chamber, and some structures and shape designs can be modified and changed.

In addition, in some embodiments, an opening O2 (fig. 4A and 4B) may be formed at the top of the chamber C for allowing at least one test condition sensor (e.g., a temperature sensor, an ph sensor and/or a water level sensor, not shown) to enter the chamber C and contact the solution T to be tested to sense the test conditions of the solution T to be tested, such as temperature, ph and water level. The test condition sensor is also electrically connected to the control device 22 (fig. 2), and the control device 22 can control some components in the system to operate according to the result sensed by the test condition sensor, so as to maintain the test condition of the solution T to be tested to be consistent.

For example, as shown in fig. 4A, the body 40 may also have a liquid passage 45 disposed around the chamber C and allowing a liquid (e.g., 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 or higher than the standard testing temperature according to the result sensed by the testing condition sensor, it may control a water supply device (not shown) to inject water with a proper temperature into the liquid channel 45, so as to change and enable the temperature of the solution T to be tested to reach the standard testing temperature. It should be understood that, in some embodiments, the at least one test condition sensor may also be embedded directly in the wall of the chamber C, and the opening O2 may be omitted.

Referring to fig. 4A, 5 and 6A, in some embodiments, the microfluidic device 26 also has a plurality of air flow channels 46 connecting the bottom surface S2 (i.e., the bottom surface of the flexible pad 41) and the top surface S3 (i.e., the top surface of the body 40) of the microfluidic device 26. 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) may be connected to the airflow passage 46 through an opening of the airflow passage 46 exposed at the top surface S3. Thus, when the stage 21 is moved upward such that the surface (i.e., the active surface S1) of the wafer 10 is connected to the bottom surface S2 of the microfluidic device 26 (fig. 6A), the electric pump can pump or evacuate the space between the bottom of the microfluidic device 26 and the wafer 10 through the air flow channel 46 (as shown by the arrows in fig. 6A) to tightly couple the microfluidic device 26 and the wafer 10.

It should be noted that, when the electric pump is pumping, it can be known whether the micro-fluid device 26 and the wafer 10 are tightly combined by reading the pressure gauge thereon. For example, a pressure gauge value below a certain value may indicate that the microfluidic device 26 is tightly coupled to the wafer 10, and a pressure gauge value that is not reduced may indicate that a gap exists between the microfluidic device 26 and the wafer 10. In addition, the electric pump is also electrically connected to the control device 22 (fig. 2), and the control device 22 can determine whether the microfluidic device 26 is tightly combined with the wafer 10 according to the value of the pressure value, so as to determine whether to control the solution injection unit 27A (fig. 2) to inject the solution to be tested into the microfluidic device 26. In other words, this may be done before injecting the solution to be tested into the microfluidic device 26 to determine whether the microfluidic device 26 is tightly coupled to the wafer 10.

In some embodiments, a drain valve 51 may be movably disposed in an upper position within the chamber C, as shown in fig. 5 and 6A. As can be seen, the drain valve 51 has a stem 51A that extends toward the bottom surface S2 of the microfluidic device 26 and protrudes from the bottom surface of the 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 contraction opening C1 at an upper position in the chamber C and block the solution to be tested from flowing to the bottom of the chamber C (i.e., the opening O1). When the microfluidic device 26 is tightly bonded to the wafer 10, the flexible pad 41 can be deformed by pressing in the vertical direction, and the wafer 10 pushes the drain valve 51 and the rod 51A thereof upward (as shown by the arrow in fig. 6A), so that the drain valve 51 is away from the contraction opening C1. In this way, the drain valve 51 can allow the solution to be tested injected into the chamber C to pass through and flow to the bottom of the chamber C (i.e., onto the wafer 10). As can be seen in fig. 5 and 6A, the upper position in the chamber C may have a stop C2 protruding therefrom for limiting 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 smoothly and gently flow to the bottom of the chamber C.

Specifically, the rod 51A of the drain valve 51 can be provided with a touch sensor and electrically connected to the control device 22 (fig. 2). Therefore, when the wafer 10 pushes the rod 51A up (i.e., the microfluidic device 26 is tightly coupled to the wafer 10), the control device 22 receives the signal from the touch sensor and confirms that the microfluidic device 26 is tightly coupled to the wafer 10, and then controls the solution injection unit 27A (fig. 2) to start injecting the solution to be tested into the microfluidic device 26. In this way, the function of the biochemical detection system 2 to automatically supply the solution to be detected can be realized.

In some embodiments, the flexible pad 41 provided on the bottom surface of the body 40 has a multi-layer structure in a direction (i.e., horizontal direction) from the chamber C to the outer sidewall of the microfluidic device 26. For example, as shown in fig. 5, the flexible pad 41 may have a first layer 41A surrounding the cavity C and a second layer 41B provided at the periphery of the bottom surface of the body 40. The flexible pad 41 having a multi-layer structure design can effectively prevent the solution to be tested from leaking between the body 40 (micro-fluid device 26) and the wafer 10.

As shown in fig. 5 and fig. 6A, in some embodiments, a liquid leakage detecting element 52 is also disposed at the bottom of the outer sidewall of the microfluidic device 26 for detecting whether the solution to be detected leaks from between the microfluidic device 26 and the wafer 10. Specifically, the leakage detecting element 52 includes a thin sheet or line made of metal (e.g., copper), which is circumferentially fixed to the bottom edge of the outer sidewall 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 leak detection element 52, the detector can detect the change in resistance thereof, thereby detecting the occurrence of a leak. In addition, the leakage detecting element 52 may also be electrically connected to the control device 22 (fig. 2), and the control device 22 may determine whether the solution to be detected leaks from between the microfluidic device 26 and the wafer 10 according to the resistance detected by the detector, so as to determine whether to stop the operation of the whole system.

Referring to fig. 6B, after the inspection of a chip 11 on the wafer 10 is completed, the carrier 21 (fig. 2) starts to move downward to separate the wafer 10 from the probes 23A (fig. 2) of the probe card 23. At this time, the control device 22 (fig. 2) may control the positioning mechanism 28 (fig. 2) to lift the microfluidic device 26 to the original position, and also control the electric pump connected to the air flow channel 46 to inflate the space between the bottom of the microfluidic device 26 and the wafer 10 (as shown by the arrow in fig. 6B), so that the microfluidic device 26 and the wafer 10 can be separated smoothly.

It is understood that the microfluidic device 26 of the above embodiment can be well combined with and separated from the wafer 10, and has various active or passive detection designs for preventing the solution to be detected from leaking between the microfluidic device 26 and the wafer 10, so as to avoid the situation that the solution to be detected may leak during the detection process to cause short circuit or damage to the chips nearby. In addition, by disposing at least one testing condition sensor in the chamber C of the microfluidic device 26, the testing condition of the solution to be tested can also be monitored, and further, the control device 22 can control some components in the system to operate, so that the testing condition of the solution to be tested can be kept consistent, thereby improving the accuracy and quality of the testing result.

FIG. 7 shows a flow diagram of a biochemical detection method 700 according to some embodiments. In step 701, a substrate having at least one chip with at least one biochemical sensor and a plurality of electrode pads is disposed on a carrier. In step 702, a probe card having a plurality of probes and an opening and a microfluidic device having a chamber are provided. In step 703, the micro-fluidic device and the probe card are moved such that the positions of the chamber of the micro-fluidic device and the probes of the probe card correspond to the positions of the bio-chemical sensors and the electrode pads of the chip, respectively. In step 704, the carrier stage is moved such that the microfluidic device is bonded to the substrate. In step 705, a solution to be tested is injected into the chamber of the microfluidic device, such that the solution to be tested contacts the biosensor of the chip for a certain time. In step 706, electrical measurement is performed on the biochemical sensors of the chip through the probes of the probe card, and the type and/or amount of the target biochemical substance in the solution to be measured is determined according to the electrical measurement result.

It is to be understood that the steps of the biochemical detection method described above are merely exemplary, and that the biochemical detection method in some embodiments may include other steps and sequences of steps.

For example, in some embodiments, the biochemical detection method may further include moving the carrier stage to move the substrate relative to the microfluidic device and the probe card, so as to perform biochemical detection by using another chip on the substrate. In some embodiments, the step of moving the carrier to combine the microfluidic device with the substrate may further include a step of pumping the space between the bottom of the microfluidic device and the substrate by a pump to tightly combine the microfluidic device with the substrate. In some embodiments, before the step of moving the carrier stage to move the substrate relative to the microfluidic device and the probe card, a step of inflating a space between a bottom of the microfluidic device and the substrate by a pump to separate the microfluidic device and the substrate from each other may also be included. In some embodiments, the biochemical detection method may further include disposing at least one test condition sensor in the chamber of the microfluidic device to sense a test condition of the solution to be tested, and controlling at least one component in the biochemical detection system by the control device according to the result sensed by the test condition sensor to maintain the test condition of the solution to be tested consistent, wherein the test condition includes a temperature, an pH value and/or a water level. In some embodiments, after the step of electrically measuring the biochemical sensors of the chip by the probes of the probe card, the step of pumping the solution to be measured out of the microfluidic device may also be included. In some embodiments, after the step of pumping the solution to be tested out of the microfluidic device, the step of injecting a same or different solution to be tested into the chamber of the microfluidic device and performing biochemical detection using the same chip may also be included.

In summary, embodiments of the present invention provide an automatic biochemical detection system and method, which can directly use biochemical sensors of multiple chips on a wafer (or substrate) to sense and detect target biochemical substances in a solution to be detected, without cutting the wafer and separately operating each chip, thereby greatly shortening the detection time and improving the detection efficiency. In addition, the conventional manual operation can be replaced by automatic mechanical operation, so that the error possibly generated by the manual operation can be reduced, the consistency of the test conditions (such as detection time, reaction temperature, liquid evaporation amount and the like) is improved, and the accuracy and the quality of the detection result are further improved.

According to some embodiments, a microfluidic device is provided that includes a body, a flexible pad, a chamber, and a drain valve. The flexible cushion body is arranged on the bottom surface of the body. The cavity is formed in the body and the flexible pad, and the cavity 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 and protruding from the bottom surface of the microfluidic device.

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

According to some embodiments, the flexible pad body has a multilayer structure in a direction from the chamber to an outer sidewall of the microfluidic device.

According to some embodiments, a biochemical detection system is provided that includes a probe card and a microfluidic 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.

According to some embodiments, the microfluidic device further comprises a plurality of air flow channels communicating with the bottom surface of the microfluidic device, and the biochemical detection system further comprises a pump connected to the air flow channels, wherein the pump is used for pumping and/or inflating the space between the bottom of the microfluidic device and the substrate, and the microfluidic device and the substrate are tightly combined and/or separated from each other.

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

According to some embodiments, there is provided a biochemical detection method comprising: arranging a substrate on a bearing table, wherein the substrate is provided with at least one chip, and the chip is provided with at least one biochemical sensor and a plurality of electrode pads; providing a probe card and a micro-fluid device, wherein the probe card is provided with a plurality of probes and an opening, and the micro-fluid device is clamped in the opening and is provided with a chamber; moving the micro-fluid device and the probe card to enable the positions of a cavity of the micro-fluid device and the position of a probe of the probe card to respectively correspond to the positions of a biochemical sensor and an electrode pad of the chip; moving the carrier to bond the microfluidic device to the substrate; injecting a solution to be detected into a chamber of the microfluid device, so that the solution to be detected is contacted with a biochemical sensor of the chip for a certain time; and carrying out electrical measurement on the biochemical sensor of the chip through the probe of the probe card, and judging the type and/or the quantity of the target biochemical substance in the solution to be measured according to the electrical measurement result.

According to some embodiments, the biochemical detection method further comprises moving the carrier stage such that the substrate is moved relative to the microfluidic device and the probe card, thereby performing biochemical detection using another chip on the substrate, wherein before the step of moving the carrier stage such that the substrate is moved relative to the microfluidic device and the probe card, the step of inflating a space between a bottom of the microfluidic device and the substrate by a pump is further included, so that the microfluidic device and the substrate are separated from each other.

According to some embodiments, the biochemical detection method further includes disposing at least one test condition sensor in the chamber of the microfluidic device to sense a test condition of the solution to be tested, and controlling at least one component in the biochemical detection system by the control device according to the result sensed by the test condition sensor to maintain the test condition of the solution to be tested consistent, wherein the test condition includes temperature, pH and/or water level.

Although the present invention has been described with reference to the above embodiments, it is not intended to limit the invention. Those skilled in the art to which the invention pertains will readily appreciate that numerous modifications and adaptations may be made without departing from the spirit and scope of the invention. Therefore, the protection scope of the present invention should be determined by the appended claims.

Claims

1. A microfluidic device comprising:

a body;

a flexible pad body arranged on the bottom surface of the body;

a chamber formed in the body and the flexible pad, the chamber having an opening formed in a bottom surface of the microfluidic device; and

a drain valve movably disposed in the chamber for blocking or allowing a solution injected into the chamber to flow to the opening;

wherein the drain valve has a stem portion extending toward a bottom surface of the microfluidic device.

2. The microfluidic device of claim 1, wherein the stem of the drain valve protrudes from a bottom surface of the body.

3. The microfluidic device of claim 1 or 2, further comprising a plurality of gas flow channels communicating the bottom surface of the flexible pad and the top surface of the body.

4. The microfluidic device of claim 1 or 2, wherein the flexible pad has a multilayer structure in a direction from the chamber to an outer sidewall of the microfluidic device.

5. A biochemical detection system, comprising:

the probe card is provided with a plurality of probes and an opening, wherein 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; and

and the micro-fluid device is clamped in the opening and is provided with a chamber, 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, the micro-fluid device comprises a water drain valve which is movably arranged in the chamber, and a capillary structure is formed at the top of the water drain valve and used for guiding the solution to be detected to flow to the bottom of the chamber.

6. The biochemical detection system according to claim 5, wherein the microfluidic device further has a plurality of air flow channels communicating with a bottom surface of the microfluidic device, and the biochemical detection system further comprises a pump connected to the air flow channels, wherein the pump is used for pumping and/or inflating a space between the bottom of the microfluidic device and the substrate, and the microfluidic device and the substrate are tightly combined and/or separated from each other.

7. The biochemical detection system according to claim 5 or 6, wherein the microfluidic device further has a leakage detection element disposed at the bottom of the outer sidewall of the microfluidic device for detecting whether the solution to be detected leaks from between the microfluidic device and the substrate.

8. A biochemical detection method, comprising:

arranging a substrate on a bearing table, wherein the substrate is provided with at least one chip, and the chip is provided with at least one biochemical sensor and a plurality of electrode pads;

providing a probe card and a micro-fluid device, wherein the probe card is provided with a plurality of probes and an opening, and the micro-fluid device is clamped in the opening and is provided with a cavity;

moving the micro-fluid device and the probe card to enable the positions of the chamber of the micro-fluid device and the plurality of probes of the probe card to respectively correspond to the positions of the biochemical sensor and the electrode pads of the chip;

moving the carrier to bond the microfluidic device to the substrate;

injecting a solution to be tested into the chamber of the microfluid device, so that the solution to be tested is contacted with the biochemical sensor of the chip for a certain time; and

carrying out electrical measurement on the biochemical sensor of the chip through the probe of the probe card, and judging the type and/or the quantity of the target biochemical substances in the solution to be measured according to the electrical measurement result;

wherein the microfluidic device comprises a drain valve movably arranged in the chamber and used for blocking or allowing the solution to be detected injected into the chamber to flow to the opening;

9. The biochemical detection method according to claim 8, further comprising moving the carrier to move the substrate relative to the microfluidic device and the probe card for biochemical detection using another chip on the substrate, wherein before the step of moving the carrier to move the substrate relative to the microfluidic device and the probe card, the method further comprises inflating a space between a bottom of the microfluidic device and the substrate with a pump to separate the microfluidic device and the substrate from each other.

10. The biochemical detection method according to claim 8, further comprising disposing at least one testing condition sensor in the chamber of the microfluidic device for sensing a testing condition of the solution to be tested, and controlling at least one component in the biochemical sensor to operate according to a result sensed by the testing condition sensor by a control device so as to maintain the testing condition of the solution to be tested consistent, wherein the testing condition includes temperature, pH and/or water level.