TW201833023A - Microfludic device, biochemical detection system and method - Google Patents

Abstract

A biochemical detection system includes 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 the electrical signal of at least one biochemical sensor of the at least one chip. The microfluidic device is engaged in the opening and has a chamber. The chamber is used to receive a test solution such that the test solution is in contact with the biochemical sensor.

Description

 Microfluidic device, biochemical detection system and method  

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

Biochemical sensors (also known as biosensors) are devices that operate on the basis of electrical, electrochemical, optical, and/or mechanical detection principles to sense and detect biochemical materials.

A biological field-effect transistor (BioFET) is a biochemical sensor containing a transistor that electrically senses and detects biochemical molecules or biological entities. This detection behavior can be achieved by direct detection of induction, or by reaction or interaction with specific biochemical molecules/biological entities via specific reactants. Specifically, when the target biochemical molecule or biological entity is combined with the gate of the bio-effect transistor or the receptor molecule fixed on the gate, the gate current of the bio-effect transistor changes due to the gate voltage, and It varies depending on the type and number of target bonds generated. This change in the buckling current can be measured and used to determine the type and/or amount of bonds that the receptor generates with the target biochemical molecule or biological entity.

In addition, a wide variety of receptors may be used to functionalize the gate of a bio-field effect transistor, for example, to detect single-stranded deoxyribonucleic acid (ssDNA), biological field effect The gate of the transistor can be functionalized with an immobilized complementary single-stranded deoxyribonucleic acid. In order to detect different proteins, such as tumor markers, the gate of a bio-field effect transistor can be functionalized with a monoclonal antibody.

Bio-field-effect transistors can be fabricated by semiconductor processes and can quickly convert electronic signals, so they have been widely used in integrated circuits. Generally, a semiconductor wafer includes tens to hundreds of integrated circuit chips. In the electrical measurement, in order to avoid damage to the nearby integrated circuit wafer caused by the solution may cause a short circuit, the integrated circuit wafer is generally separated first along the wafer cutting line, and then the solution to be tested is manually carefully Dropping on the position of the bio-effect transistor of each wafer, and then using the probe to measure the electrical signal of the bio-effect transistor (such as the drain current) to determine the type of target biochemical in the solution to be tested and/or Or quantity.

However, such a detection method is very difficult to control the consistency of test conditions (such as detection time, reaction temperature, and liquid evaporation), resulting in the accuracy and quality of the test results being questioned, and the efficiency is extremely poor (that is, the detection time is too long). Therefore, there is a need to provide an improved solution for biochemical detection systems and methods.

Some embodiments of the present invention provide a microfluidic device comprising: a body; a soft pad body disposed on a bottom surface of the body; a cavity formed in the body and the soft pad body, and the cavity is formed on a bottom surface of the microfluidic device An opening; and a drain valve movably disposed within 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 having a plurality of probes and an opening for contacting a plurality of electrode pads of at least one wafer on a substrate to sense the at least one An electrical signal of at least one biosensor of the chip; and a microfluidic device engaged in the opening and having a chamber for receiving a solution to be tested and causing the solution to be tested and the biochemical sensor contact.

Some embodiments of the present invention provide a biochemical detection method, including: disposing a substrate on a carrier having at least one wafer on the substrate, the wafer having at least one biochemical sensor and a plurality of electrode pads; providing a probe card and a 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 to make the chamber and the probe of the microfluidic device The positions of the probes of the card respectively correspond to the positions of the biochemical sensor and the electrode pad of the wafer; the moving stage is such that the microfluidic device is combined with the substrate; and a solution to be tested is injected into the chamber of the microfluidic device, so that the solution to be tested Contacting the biosensor of the wafer for a certain period of time; and electrically measuring the biosensor of the wafer by the probe of the probe card, and determining the type of the target biochemical in the solution to be tested according to the electrical measurement result And / or quantity.

2‧‧‧Biochemical detection system

10‧‧‧ wafer

11‧‧‧ wafer

21‧‧‧Loading station

22‧‧‧Control device

23‧‧‧ Probe Card

23A‧‧‧Probe

23B‧‧‧ openings

24‧‧‧Clamping mechanism

25‧‧‧Microscope

26‧‧‧Microfluidic device

27A‧‧‧solution injection unit

27B‧‧‧Fluid extraction unit

28‧‧‧ Positioning agency

40‧‧‧ body

41‧‧‧Soft mat

41A‧‧‧First layer structure

41B‧‧‧Second layer structure

42‧‧‧Water storage space

42A‧‧‧ openings

43‧‧‧First microchannel

44‧‧‧Second microchannel

45‧‧‧Liquid channel

46‧‧‧Air passage

51‧‧‧Discharge valve

51A‧‧‧ Rod

51B‧‧‧Capillary structure

52‧‧‧Leak detection element

101‧‧‧Biochemical Sensor

102‧‧‧electrode pads

700‧‧‧Biochemical test methods

701~706‧‧‧Steps

C‧‧‧室

C1‧‧‧ Shrinkage

C2‧‧‧stop structure

E‧‧‧solution outlet

I‧‧‧ solution inlet

O1‧‧‧ openings

O2‧‧‧ openings

S1‧‧‧ active surface

S2‧‧‧ bottom

S3‧‧‧ top surface

T‧‧‧Test solution

1 shows a schematic plan view of a wafer and an enlarged view of a wafer on a wafer in accordance with some embodiments.

Figure 2 shows a block diagram of a biochemical detection system in accordance with some embodiments.

Fig. 3 is a plan view showing the positional relationship between the probe card and the microfluidic device in Fig. 2.

Figure 4A shows a top schematic view of a microfluidic device in accordance with some embodiments.

Fig. 4B is a schematic cross-sectional view taken along line A-A of Fig. 4A.

Figure 5 shows a schematic diagram of a leak proof design and an automatic drain valve for a microfluidic device in accordance with some embodiments.

Figure 6A shows a schematic view of the microfluidic device intimately coupled to the wafer.

Figure 6B shows a schematic diagram of the separation of the microfluidic device from the wafer.

Figure 7 shows a flow chart of a biochemical detection method in accordance with some embodiments.

The following disclosure provides many different embodiments or examples to implement various features of the present invention. The following disclosure sets forth specific examples of various components and their arrangement to simplify the description. Of course, these specific examples are not intended to be limiting. For example, if a first feature is formed on or above a second feature, it may mean that the first feature is directly in contact with the second feature, and may include additional features. Formed between the first feature and the second feature described above such that the first feature and the second feature are not in direct contact with each other.

Spatially related terms used in the following, such as "below", "below", "lower", "above", "higher" and the like, are used to facilitate the description in the drawings. The relationship between one element or feature and another element or feature(s). In addition to the orientation depicted in the drawings, these spatially relative terms are also meant to refer to devices that may be used in different orientations or in operation.

The same component numbers and/or characters may be repeated in the following various embodiments, which are for the purpose of simplicity and clarity, and are not intended to limit the specific relationship between the various embodiments and/or structures discussed.

The vocabulary of the first and second terms used hereinafter is for illustrative purposes only and is not intended to limit or limit the scope of the patent. Further, the terms such as the first feature and the second feature are not limited to the same or different features.

In the drawings, the shape or thickness of the structure may be enlarged to simplify or facilitate the marking. It is to be understood that elements not specifically described or illustrated may be in various forms well known to those skilled in the art.

It should be noted that, in order to overcome the above-mentioned technical problems, the embodiment of the present invention provides an improved automatic biochemical detection system, which can directly utilize the biochemical sensor of a plurality of wafers on a wafer (or substrate) for sensing and detecting. The target biochemical substance in the solution to be tested, without cutting the wafer and separately operating each wafer (including dropping the solution to be tested on each wafer separately, and mounting the probe on each wafer for electrical measurement, etc.) Therefore, the detection time can be greatly shortened and the detection efficiency can be improved.

Please refer to FIG. 1 , which shows a schematic plan view of a wafer 10 and an enlarged view of a wafer 11 on the wafer 10 in accordance with some embodiments of the present invention. The wafer 10 is a semiconductor wafer (for example, a germanium wafer) having a plurality of integrated circuit wafers 11 (hereinafter referred to as wafers 11) manufactured by a semiconductor process. Each of the wafers 11 has an active surface S1, a biochemical sensor 101 and a plurality of electrode pads 102. The biochemical sensor 101 and the electrode pads 102 can be exposed on the active surface S1. In some embodiments, each wafer 11 can also have a plurality of biochemical sensors 101. The biochemical sensor 101 can be a bioFET (BioFET), and the electrode pads 102 are electrically connected to the gate, the drain and the source of the bio-effect transistor, respectively. Furthermore, the biofield effect transistors of each wafer 11 may be the same or different. It should be noted that the wafer 10 is only for convenience of description of the embodiment, but the wafer 10 may also have a substrate (for example, a glass substrate, a plastic substrate, etc.) having or provided with a plurality of wafers 11.

As described above, the bio-field effect transistor can electrically sense and detect a target biochemical substance in a solution to be tested, such as deoxyribonucleic acid (DNA), ribonucleic acid (RNA), protein. Or other organic and inorganic small molecules. Specifically, when the target biochemical molecules or biological entities are combined with the gate of the bio-effect transistor or the receptor molecule fixed on the gate, the gate current of the bio-effect transistor changes due to the gate voltage. It varies depending on the type and number of target bonds generated. The change in the buckling current can be measured and used to determine the type and/or amount of bonding between the acceptor and the target biochemical molecule or biological entity, as well as to sense and detect the target biochemical in the solution to be tested. Since the structure and detection mechanism of various biological field effect transistors are well known and are not the technical focus of the present invention, they are not described here. The biochemical sensor 101 referred to herein includes various known bio-field effect transistors, such as ion-sensing field-effect transistors (ISFETs) and enzyme field-effect transistors (ENFETs). Or immuno field effect transistor (ImmunoFET).

2 is a block diagram of a biochemical detection system 2 according to some embodiments, wherein the biochemical detection system 2 is an automated biochemical detection system, and the biochemical sensor 101 of the plurality of wafers 11 on the wafer 10 can be utilized ( Figure 1) Sensing and detecting the target biochemical in a solution to be tested. As can be seen from FIG. 2, the biochemical detection system 2 includes a carrier 21 for carrying the wafer 10. In some embodiments, the carrier 21 can hold the wafer 10 thereon by vacuum adsorption, but some other means of clamping the wafer 10 (eg, electrostatic chucks) can be utilized. The carrier 21 can also carry the wafer 10 to move in the horizontal direction (the X-axis and the Y-axis directions 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 (for example, a computer), and the control device 22 can control the above movement of the loading platform 21.

The biochemical detection system 2 also includes a probe card 23 (please refer to FIG. 3 together), and has a plurality of probes 23A underneath for contacting the electrode pads 102 of each wafer 11 on the wafer 10 (FIG. 1). The electrical signal of the biochemical sensor 101 is obtained by measurement. The probe card 23 can be a Micro-Electrical-Mechanical Systems (MEMS) probe card or other optional 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 signal of the biochemical sensor 101, and measure the power of the biochemical sensor 101. Sexual signals are processed, analyzed, stored, and displayed.

The biochemical detection system 2 also includes a clamping mechanism 24 for holding the probe card 23 and moving in a horizontal direction (X-axis and Y-axis directions as shown). Specifically, the clamping mechanism 24 can be coupled 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 such that the clamping mechanism 24 and the upper portion thereof The probe card 23 is moved in the horizontal direction to achieve alignment between the probe 23A of the probe card 23 and the electrode pad 102 (Fig. 1) of a wafer 11 on the underlying wafer 10. Although not shown, the arrangement of the probes 23A of the probe card 23 corresponds to the arrangement of the electrode pads 102 of the wafers 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 wafer 11 on the wafer 10 below. In some embodiments, the microscope 25 can be electrically coupled to the control device 22.

When the control device 22 controls the positioning mechanism, the clamping mechanism 24 and the probe card 23 thereon are moved in the horizontal direction, and the position of the probe 23A of the probe card 23 and the wafer 10 are observed by the microscope 25. When the position of the electrode pad 102 of the wafer 11 is aligned, the stage 21 can be further controlled to move upward in the Z-axis direction until the electrode pad 102 of the wafer 11 contacts the probe 23A of the probe card 23. Then, the control device 22 can control the probe card 23 to measure the electrical signal of the biochemical sensor 101 of the wafer 11, and perform subsequent processing such as calculation and analysis on the measured electrical signal.

Furthermore, when the control device 22 receives the electrical signal measured from the probe card 23, it can be determined that the electrical measurement of the wafer 11 has ended. Thereafter, the control device 22 can further control the carrier 21 to move downward in the Z-axis direction (so that the electrode pad 102 of the wafer 11 is separated from the probe 23A of the probe card 23) and move horizontally to the next wafer 11 to reach the probe. The position below the probe 23A of the card 23 is then moved upward so that the electrode pad 102 of the next wafer 11 contacts the probe 23A of the probe card 23 to perform electrical measurement of the next wafer 11. It should be understood that since the control device 22 can pre-set and record the positions of the wafers 11 on the wafer 10, the carrier 21 can be controlled to sequentially move the wafers 11 on the wafer 10 to the probes corresponding to the probe cards 23. 23A location. By repeating the above electrical measurement operation, the electrical measurement of all the wafers 11 on the wafer 10 can be completed.

Continuing to refer to FIG. 2, the probe card 23 also has an opening 23B extending through the upper and lower surfaces. Furthermore, as shown in Figures 2 and 3, the biochemical detection system 2 also includes a microfluidic device 26 that is engageable within the opening 23B. Wherein, the microfluidic device 26 has a chamber C (as indicated by a broken line in FIG. 3) for receiving a solution T to be tested, and the solution T to be tested (in the chamber C) and the wafer below The biochemical sensor 101 (Fig. 1) of the previous wafer 11 is contacted and reacted. In this way, the probe card 23 can measure the electrical signal of the biochemical sensor 101 by the foregoing method 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 coupled 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 and a solenoid valve, wherein a plurality of solutions to be tested may be injected into the microfluidic device 26 via an electric pump, and the solenoid valve is used to selectively Only one test solution can be injected into the microfluidic device 26 at a time. The solution injection unit 27A is also electrically connected to the control device 22, and the control device 22 can control the procedure and speed at which the solution injection unit 27A injects the solution to be tested.

Further, the biochemical detection system 2 also includes a fluid extraction unit 27B coupled to the microfluidic device 26 and configured to withdraw the solution to be tested in the chamber C (Fig. 3) and exit the microfluidic device 26. Specifically, although not shown, the fluid extracting unit 27B may include, for example, an electric pump and a solenoid valve, wherein the electric pump is used to extract the solution to be tested in the chamber C (through the pumping method), and the electromagnetic The valve is used to control the communication between the electric pump and the chamber C. In other words, when the solenoid valve is opened, the electric pump can extract the solution to be tested in the chamber C, and when the solenoid valve is closed, the electric pump does not extract the solution to be tested in the chamber C. In addition, the fluid extracting unit 27B is also electrically connected to the control device 22, and the control device 22 can control the program and speed of the fluid extracting unit 27B to extract the solution to be tested.

Referring to FIG. 2, the biochemical detection system 2 also includes a positioning mechanism 28 in which 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. Additionally, the positioning mechanism 28 can be electrically coupled to the control device 22, and the control device 22 can control the positioning mechanism 28 to move the microfluidic device 26 and cause the microfluidic device 26 to be positioned and engaged within the opening 23B of the probe card 23. When the microfluidic device 26 is snapped into 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 may follow the probe card 23 Move in the horizontal direction. At this time, the positioning mechanism 28 is also interlocked with the microfluidic device 26.

Further, when the control device 22 controls the loading stage 21 to move upward, the wafer 10 is combined with the microfluidic device 26 (to make the solution to be tested in the chamber C of the microfluidic device 26 and the biochemical sensor 101 of the wafer 11 (the first In the case of contact and reaction, the positioning mechanism 28 can also be controlled by the control device 22 to press the microfluidic device 26 downwardly, which facilitates the tight coupling of the microfluidic device 26 to the wafer 10 (with respect to the microfluidic device 26). The manner of bonding with the wafer 10 will be further explained in the following paragraphs).

As described above, since the microfluidic device 26 is engaged with the opening 23B in the horizontal direction, the microfluidic device 26 can also move in the horizontal direction with the probe card 23 when the probe card 23 is moved in the horizontal direction. . 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 the wafer 11 of the wafer 10 below, the position of the chamber C of the microfluidic device 26 can also be aligned. The position of the biochemical sensor 101 of the wafer 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 the position of the electrode pad 102 of the next wafer 11, the chamber C of the microfluidic device 26 The position can also be aligned to the position of the biochemical sensor 101 of the next wafer 11.

In this way, the simultaneous positioning of the probe card 23 and the microfluidic device 26 (corresponding to each wafer 11 of the wafer 10) can be achieved, and the loading device 21 and the wafer 10 thereon can be automatically controlled by the upper control device 22. The mechanism for moving the probes 23 relative to the probe card 23 to electrically measure the wafers 11 on the wafer 10, that is, the biochemical sensor 101 of each wafer 11 on the wafer 10 can be used to sense and detect biochemistry in the solution to be tested. substance. Since the operations of the various components (or mechanisms) of the above 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 traditional manual operation with an automatic mechanical action, thereby reducing errors that may occur in manual operations and improving the consistency of test conditions (such as detection time, reaction temperature, and liquid evaporation). Sex.

Next, the design of the microfluidic device 26 of the embodiment of the present invention will be further described. Referring to FIGS. 4A and 4B , in some embodiments, the microfluidic device 26 includes a body 40 and a soft 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 (Figs. 1 and 2), and the soft pad 41 is used to prevent the body 40 from contacting or striking the crystal. The surface of the circle 10 and the solution to be tested are prevented from leaking from 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 material, and the soft pad 41 is made of, for example, polydimethylsiloxane (PDMS) or other optional soft material. to make.

As shown in Figures 4A and 4B, in some embodiments, the body 40 has a cylindrical structure projecting outwardly from a side wall and a water storage space 42 is formed in the cylindrical structure. A solution inlet I is formed in one side wall of the cylindrical structure and communicates with the water storage space 42. Although not shown, the solution inlet I can be connected to the solution injection unit 27A by a conduit (Fig. 2). In addition, the microfluidic device 26 has a chamber C (formed in the body 40 and the soft pad 41) extending substantially from the top of the microfluidic device 26 to the bottom (high aspect ratio structure) at its center, and the chamber C An opening O1 is formed in 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 FIGS. 4A and 4B), the position of the chamber C may correspond to the biochemical sensor 101 of a wafer 11 on the wafer 10. 1 picture) location. In addition, a first micro flow channel 43 is formed in the body 40, and communicates with the chamber C and the water storage space 42 , and a second micro flow channel 44 is formed in the body 40 , and communicates with the chamber C and is formed on the body 40 . Solution outlet E on one of the side walls. Although not shown, the solution outlet E can be connected to the fluid extracting unit 27B by a catheter (Fig. 2).

With the above structure, when the microfluidic device 26 is tightly coupled to 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 after filling the water storage space 42, A microchannel 43 then flows to chamber C. The solution T to be injected into the chamber C can be in contact with the biochemical sensor 101 (not shown) on the wafer 10 via 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 injected into the chamber C does not pass through the first The second microchannel 44 flows toward the solution outlet E, and only gradually accumulates in the chamber C.

In some embodiments, the control device 22 stops the injection after the injection of the solution T to be tested for a certain period of time according to the setting controllable solution injection unit 27A, and causes the solution T to be tested in the chamber C to be accumulated to a certain amount or height (eg, As shown in FIG. 4B, this helps the test solution T to remain stable with the biochemical sensor 101 for a certain period of time in contact with and reacting with the biochemical sensor 101 (not shown) on the wafer 10. The amount of the T solution to be tested which is in contact with and reacts with the biochemical sensor 101 due to the evaporation phenomenon is unstable or too small.

In addition, the water storage space 42 is also designed to fill the solution T to be tested in the chamber C through capillary action in the case where the solution T to be tested in the chamber C is excessively evaporated, so that the chamber C is filled. The amount of T in the solution to be tested remains stable.

After the solution T to be tested in the chamber C reacts with the biochemical sensor 101 on the wafer 10 for a certain time, the control device 22 controls the fluid extraction unit 27B to be within the chamber C and within the microfluidic device 26 according to the setting. The solution T to be tested is taken out. It is worth mentioning that in some embodiments, a small opening 42A may be formed at the top of the water storage space 42, whereby the solution T to be tested in the microfluidic device 26 may be extracted by the fluid under the action of atmospheric pressure. Unit 27B is smoothly withdrawn and solution residue is avoided. In addition, the second microchannel 44 is disposed adjacent to the bottom surface of the body 40 (as shown in FIG. 4B), which also serves to allow the solution T to be tested in the microfluidic device 26 to be smoothly withdrawn.

It should be understood that the microfluidic device 26 described above in Figures 4A and 4B is merely exemplary and is not intended to define the structure of the microfluidic device of the present invention. The structure of the microfluidic device 26 of the above embodiment is focused on providing a chamber having a high aspect ratio structure to facilitate stable contact and reaction of the solution to be tested with the biochemical sensor on the wafer, and to provide fluid injection and Structural guidance such as the introduction of the chamber, as for some structure and shape design can be modified and changed.

In addition, in some embodiments, an opening O2 (Figs. 4A and 4B) may be formed at the top of the chamber C for allowing at least one test condition sensor (for example, a temperature sensor, a pH sense) The detector and/or the water level sensor (not shown) enters the chamber C and contacts the solution T to be tested to sense the test conditions of the solution T to be tested, such as temperature, pH value 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 the operation of some components in the system according to the result of the test condition sensor sensing, and make the solution T to be tested. Test conditions are consistent.

For example, as shown in FIG. 4A, the body 40 can also have a liquid passage 45 disposed around the chamber C and allowing a liquid (eg, 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 of the sensing of the test condition sensor, it can control a water supply device (not shown) to be injected. A suitable temperature of water is introduced into the liquid passage 45 to change and cause the temperature of the solution T to be tested to reach a standard test temperature. It should be understood that, in some embodiments, the at least one test condition sensor may be directly buried in the wall surface of the chamber C, and the opening O2 may be omitted.

Referring to Figures 4A, 5 and 6A, in some embodiments, the microfluidic device 26 also has a plurality of airflow channels 46 that communicate with the bottom surface S2 of the microfluidic device 26 (i.e., the bottom surface of the soft pad 41) and Top surface S3 (top surface of body 40). It will be appreciated that a portion of the structure of the microfluidic device 26 shown in Figure 5 is viewed along the direction of line B-B in Figure 4A. In addition, an electric pump (not shown) may be connected to the air flow passage 46 via an opening formed in the top surface S3 via the air flow passage 46. Thereby, when the carrying platform 21 moves upwards, so that the surface of the wafer 10 (ie, the active surface S1) is connected to the bottom surface S2 of the microfluidic device 26 (FIG. 6A), the electric pump can be connected to the microfluid via the airflow passage 46. The space between the bottom of the device 26 and the wafer 10 is evacuated or evacuated (as indicated by the arrows in Figure 6A) to cause the microfluidic device 26 to be tightly coupled to the wafer 10.

It is worth mentioning that when the electric pump is pumping, it can be known whether the microfluidic device 26 and the wafer 10 are tightly coupled by interpreting the pressure gauge thereon. For example, when the value of the pressure gauge is below a certain value, it can be said that the microfluidic device 26 is tightly coupled to the wafer 10, and when the value of the pressure gauge is never reduced, the microfluidic device 26 and the wafer 10 can be represented. 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 determine whether the microfluidic device 26 and the wafer 10 are tightly combined according to the value of the pressure value, thereby determining whether to control the solution. The injection unit 27A (Fig. 2) injects the solution to be tested into the microfluidic device 26. In other words, this method can confirm whether the microfluidic device 26 and the wafer 10 are tightly coupled before injecting the solution to be tested into the microfluidic device 26.

As shown in Figures 5 and 6A, in some embodiments, a drain valve 51 is movably disposed at an upper position within the chamber C. As can be seen from the figure, the drain valve 51 has a stem portion 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 the shrinkage port C1 at the upper position in the chamber C, and block the solution to be tested from flowing to the chamber. The bottom of C (ie, opening O1). When the microfluidic device 26 is tightly coupled to the wafer 10, the soft pad 41 can be crushed and deformed in the vertical direction, and the wafer 10 will top the drain valve 51 and its stem portion 51A (as shown in FIG. 6A). The arrow in the middle) causes the drain valve 51 to leave the shrink port C1. As such, 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 (ie, to the wafer 10). As can be seen from Figures 5 and 6A, the upper position within the chamber C can have a stop stop structure C2 for limiting the extent to which the drain valve 51 is moved upward. In addition, a capillary structure 51B is formed on the top of the drain valve 51 for guiding the solution to be tested smoothly and gently to the bottom of the chamber C.

In particular, the stem 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). Thereby, when the wafer 10 tops the rod portion 51A (that is, the microfluidic device 26 is tightly coupled to the wafer 10), the control device 22 can receive the signal from the touch sensor and confirm the microfluidic device 26 In close contact with the wafer 10, the 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 to automatically supply the solution to be tested can be realized.

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

As shown in FIGS. 5 and 6A, in some embodiments, a liquid leakage detecting element 52 is also disposed at the bottom of the outer side wall of the microfluidic device 26 for detecting whether the solution to be tested is from the microfluidic device 26 and the wafer 10. Leak between. Specifically, the liquid leakage detecting element 52 includes a metal material (for example, copper) or a wire, which is circumferentially fixed to the bottom side of the outer wall of the body 40 and electrically connected to a detector (not shown). When the solution to be tested leaks from the microfluidic device 26 and the wafer 10 and contacts the liquid leakage detecting element 52, the detector can detect the change in resistance, thereby detecting the occurrence of liquid leakage. In addition, the liquid leakage detecting component 52 can also be electrically connected to the control device 22 ( FIG. 2 ), and the control device 22 can determine whether there is a solution to be tested from the microfluidic device 26 according to the resistance value detected by the detector. Leakage with the wafer 10 to determine whether to stop the operation of the entire system.

Next, referring to FIG. 6B, when the inspection of a wafer 11 on the wafer 10 is completed, the carrier 21 (Fig. 2) will start to move downward to separate the probe 10A of the wafer 10 and the probe card 23 ( Figure 2). At this time, the control device 22 (Fig. 2) can control the positioning mechanism 28 (Fig. 2) to raise the microfluidic device 26 upward to the original position, and can also control the electric pump to the microfluidic device 26 that connects the airflow passage 46. The space between the bottom and the wafer 10 is inflated (as indicated by the arrows in Figure 6B) to enable the microfluidic device 26 to be smoothly separated from the wafer 10.

It is to be understood that the microfluidic device 26 of the above embodiment can be well bonded and separated from the wafer 10, and has a plurality of active or passive detections for preventing leakage of the solution to be tested from between the microfluidic device 26 and the wafer 10. The design can avoid the possibility that the solution to be tested may leak during the detection process, causing short circuit or damage to the nearby wafer. In addition, by providing at least one test condition sensor in the chamber C of the microfluidic device 26, the test conditions of the solution to be tested can also be monitored, and then some components in the system can be controlled by the control device 22 to be tested. The test conditions of the solution are consistent, which improves the accuracy and quality of the test results.

FIG. 7 shows a flow chart of a biochemical detection method 700 in accordance with some embodiments. In step 701, a substrate is disposed on a carrier having at least one wafer on the substrate, the wafer having at least one biochemical sensor 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 chamber. In step 703, the microfluidic device and the probe card are moved such that the positions of the chamber of the microfluidic device and the probe of the probe card correspond to the positions of the biochemical sensor and the electrode pad of the wafer, respectively. In step 704, the carrier is moved such that the microfluidic device is coupled 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 is in contact with the biosensor of the wafer for a certain period of time. In step 706, the biosensor of the wafer is electrically measured by the probe of the probe card, and the type and/or quantity of the target biochemical in the solution to be tested 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 examples, and in some embodiments, the biochemical detection method may also include other steps and sequence of steps.

For example, in some embodiments, the biochemical detection method described above may further include a step of moving the stage to move the substrate relative to the microfluidic device and the probe card to perform biochemical detection using another wafer on the substrate. In some embodiments, in the step of moving the carrier, such that the microfluidic device is combined with the substrate, the pump may also include evacuating a space between the bottom of the microfluidic device and the substrate by a pump to make the microfluidic device. The step of tightly bonding to the substrate. In some embodiments, before moving the carrier to move the substrate relative to the microfluidic device and the probe card, the device may also include inflating a space between the bottom of the microfluidic device and the substrate by a pump. The step of separating the microfluidic device from the substrate. In some embodiments, the biochemical detection method may further include setting at least one test condition sensor in a chamber of the microfluidic device to sense a test condition of the solution to be tested, and using the control device according to the test condition sensor The result of the sensing controls the operation of at least one component of the biochemical detection system such that the test conditions of the solution to be tested are maintained, wherein the test conditions include temperature, pH, and/or water level. In some embodiments, after the step of electrically measuring the biosensor of the wafer by the probe of the probe card, the step of extracting the solution to be tested out of the microfluidic device may also be included. In some embodiments, after the step of extracting the solution to be tested out of the microfluidic device, the step of injecting the same or different solution to be tested into the chamber of the microfluidic device and performing biochemical detection using the same wafer may also be included.

In summary, the embodiments of the present invention provide an automatic biochemical detection system and method, which can directly sense and detect a target biochemical substance in a solution to be tested by using a biochemical sensor of a plurality of wafers on a wafer (or a substrate). There is no need to cut the wafer and operate each wafer 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 the errors that can be caused by manual operations, and improve the consistency of test conditions (such as detection time, reaction temperature and liquid evaporation), thereby improving the test results. Accuracy and quality.

According to some embodiments, a microfluidic device is provided comprising a body, a soft pad, a chamber, and a drain valve. The soft pad body is disposed on the bottom surface of the body. The chamber is formed in the body and the soft cushion body, and the chamber is formed with an opening on the bottom surface of the microfluidic device. A drain valve is operatively disposed within 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 that extends toward the bottom surface of the microfluidic device and protrudes from the bottom surface of the body.

According to some embodiments, the microfluidic device further includes a plurality of airflow passages connecting the bottom surface of the soft cushion body and the top surface of the body.

According to some embodiments, the soft pad has a plurality of layers in the direction from the chamber to the 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 has a plurality of probes and an opening for contacting a plurality of electrode pads contacting at least one of the wafers on the substrate to sense electrical signals of the at least one biochemical sensor of the at least one wafer. The microfluidic device is engaged in the opening and has a chamber for receiving a solution to be tested and contacting the solution to be tested with the biochemical sensor.

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

According to some embodiments, the microfluidic device further has a liquid leakage detecting element disposed at the bottom of the outer side wall 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, including: disposing a substrate on a carrier having at least one wafer on the substrate, the wafer having at least one biochemical sensor and a plurality of electrode pads; providing a probe card and a 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 to make the chamber and the probe of the microfluidic device The positions of the probes of the card respectively correspond to the positions of the biochemical sensor and the electrode pad of the wafer; the moving stage is such that the microfluidic device is combined with the substrate; and a solution to be tested is injected into the chamber of the microfluidic device, so that the solution to be tested Contacting the biosensor of the wafer for a certain period of time; and electrically measuring the biosensor of the wafer by the probe of the probe card, and determining the type of the target biochemical in the solution to be tested according to the electrical measurement result And / or quantity.

According to some embodiments, the biochemical detection method further comprises moving the carrier such that the substrate moves relative to the microfluidic device and the probe card, thereby performing biochemical detection using another wafer on the substrate, wherein the substrate is moved relative to the micro Before the step of moving the fluid device and the probe card, the method further comprises inflating a space between the bottom of the microfluidic device and the substrate by a pump to separate the microfluidic device from the substrate.

According to some embodiments, the biochemical detection method further comprises: 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 sensing by the control device according to the test condition sensor As a result, at least one component of the biochemical detection system is controlled to operate, and the test conditions of the solution to be tested are maintained, wherein the test conditions include temperature, pH, and/or water level.

Although the present invention has been disclosed above in the foregoing embodiments, it is not intended to limit the invention. Those skilled in the art having the ordinary skill in the art can make some modifications and refinements without departing from the spirit and scope of the invention. Therefore, the scope of the invention is defined by the scope of the appended claims.

Claims (10)

 A microfluidic device comprising: a body; a soft pad body disposed on a bottom surface of the body; a chamber formed in the body and the soft pad body, and the cavity forming an opening in a bottom surface of the microfluidic device And a drain valve movably disposed within the chamber for blocking or allowing a solution injected into the chamber to flow to the opening.    The microfluidic device of claim 1, wherein the drain valve has a stem extending toward a bottom surface of the microfluidic device and protruding from a bottom surface of the body.    The microfluidic device according to claim 1 or 2, further comprising a plurality of airflow passages connecting the bottom surface of the soft cushion body and the top surface of the body.    The microfluidic device of claim 1 or 2, wherein the soft pad has a plurality of layers in a direction from the chamber to a sidewall of the microfluidic device.    A biochemical detection system includes: a probe card having a plurality of probes and an opening for contacting a plurality of electrode pads of at least one wafer on a substrate to sense at least one of the at least one wafer An electrical signal of the biochemical sensor; and a microfluidic device engaged in the opening and having a chamber for receiving a solution to be tested and causing the solution to be tested and the biochemical sensor contact.    The biochemical detection system of claim 5, wherein the microfluidic device further has a plurality of gas flow channels connected to the bottom surface of the microfluidic device, and the biochemical detection system further comprises a pump connecting the gas flow channels. Wherein the pump is used to evacuate and/or inflate the space between the bottom of the microfluidic device and the substrate, and to cause the microfluidic device to be tightly coupled to the substrate and/or separated from each other.    The biochemical detection system of claim 5 or 6, wherein the microfluidic device further has a liquid leakage detecting element disposed at a bottom of the outer side wall of the microfluidic device for detecting whether the solution to be tested is from The microfluidic device leaks between the substrate.    A biochemical detection method includes: disposing a substrate on a loading platform, the substrate having at least one wafer, the wafer having 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; moving the microfluidic device and the probe card such that the chamber of the microfluidic device The positions of the probes corresponding to the probe card respectively correspond to the positions of the biochemical sensor and the electrode pads of the wafer; moving the carrier to enable the microfluidic device to be combined with the substrate; The solution is injected into the chamber of the microfluidic device such that the solution to be tested is in contact with the biosensor of the wafer for a certain period of time; and the biochemical sensor of the wafer is performed by the probes of the probe card The electrical measurement is performed, 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.    The biochemical detection method of claim 8, further comprising moving the carrying platform to move the substrate relative to the microfluidic device and the probe card, and then performing biochemical detection using another wafer on the substrate. Before moving the loading platform to move the substrate relative to the microfluidic device and the probe card, the method further comprises: inflating a space between the bottom of the microfluidic device and the substrate by a pump, The microfluidic device is separated from the substrate.    The biochemical detection method according to claim 8 or 9, further comprising: setting at least one test condition sensor in the chamber of the microfluidic device to sense a test condition of the test solution, and by using The control device controls the operation of at least one component in the biochemical detection system according to the result of the sensing condition sensor sensing, so that the test conditions of the solution to be tested are maintained, wherein the test conditions include temperature, pH value and/or Water level height.