Microfluidic chip with magnetic field control mechanism, microfluidic processing system, and microfluidic processing method

Abstract

To provide a micro fluid chip that allows a target extraction and a biological medical examination to be done in one apparatus.SOLUTION: Each micro electrode device 1 of a micro fluid chip includes: a micro fluid electrode 11 below an upper plate; a multifunctional electrode 13 below the micro fluid electrode 11; and a control circuit below the multifunctional electrode 13. Each control circuit includes a first storage circuit, a second storage circuit, a micro fluid control and position detection circuit 151, and a temperature and magnetism control circuit 153. Each first control circuit reads a sample operation setting. Each second storage circuit reads a magnetic field control setting. Each micro fluid control and position detection circuit is in a sample control state which corresponds to a sample operation setting. Each temperature and magnetism control circuit is in a magnetism control state which corresponds to a magnetic field control setting.SELECTED DRAWING: Figure 1D

Description

Priority

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 338,185, filed May 4, 2022, which is incorporated herein by reference in its entirety. [Technical field] The present invention relates to a microfluidic chip, a microfluidic processing system, and a microfluidic processing method, and more particularly to a microfluidic chip, a microfluidic processing system, and a microfluidic processing method having a magnetic field control mechanism. [Background technology]

[0002] Compared with conventional biomedical devices, the adoption of digital microfluidic biochips (DMFBs) in biomedical testing (e.g., protein analysis, disease diagnosis) offers several advantages, including device miniaturization, reduced reaction volume, reduced sample and reagent consumption, low cost, and clinical laboratory automation. Specifically, DMFBs with electrode arrays are powerful analytical platforms for biomedical testing, such as nucleic acid-based tests and drug screening applications.

[0003] Conventional DMFBs typically use electrowetting on dielectric (EWOD) technology to perform microfluidic processing, providing opportunities for clinical laboratory automation. However, because the electrodes of conventional DMFBs are arranged in a specific pattern for a specific target biomedical test, once configured, they cannot be used for other biomedical tests. Therefore, there remains an urgent need for digital microfluidic testing devices that are adaptable to various biomedical tests, and microfluidic testing technologies that provide adaptive control for various biomedical tests.

[0004] Furthermore, to obtain more accurate test results for samples containing trace amounts of targets (e.g., nucleic acids), it is usually necessary to extract the targets from the samples before performing biomedical tests. A conventional method for target extraction is to use magnetic beads to separate the targets from others, and one example of such a method comprises the following major steps: That is, (1) mixing the original sample with a lysis buffer in a container to disrupt cells in the original sample and expose and / or suspend the desired target, (2) adding magnetic beads (the surface of which is coated with a specific material for capturing the desired target) and a specific binding buffer into the container to capture the desired target with the magnetic beads, (3) applying an external magnetic field to the outer edge of the container to attract the magnetic beads (i.e., immobilize the magnetic beads) and adding a wash buffer to wash away unnecessary parts, (4) adding an elution buffer into the container to separate the magnetic beads carrying the desired target, and (5) applying an external magnetic field to the outer edge of the container to attract the magnetic beads (i.e., immobilize the magnetic beads) and extract the desired target. Next, a biomedical test is applied to the extracted target.

[0005] While applying biomedical testing to extracted targets can result in more accurate test results, target extraction is tedious. Furthermore, if target extraction and biomedical testing are performed using different instruments, transferring the extracted targets from one instrument to another can result in contamination of the extracted targets. Therefore, there is a need for a technology that allows for easier target extraction and for target extraction and biomedical testing to be performed using the same instrument. Summary of the Invention

[0006] An object of the present invention is to provide a microfluidic chip. The microfluidic chip includes a top plate and a microelectrode dot array disposed below the top plate. The microelectrode dot array includes a plurality of microelectrode devices connected in series. Each of the microelectrode devices includes a microfluidic electrode disposed below the top plate, a multifunction electrode disposed below the microfluidic electrode, and a control circuit disposed below the multifunction electrode. Each of the control circuits includes a first storage circuit, a second storage circuit, a microfluidic control and position detection circuit coupled to the corresponding microfluidic electrode, and a temperature and magnetic control circuit coupled to the corresponding multifunction electrode. Each of the first storage circuits is configured to read a sample operation setting during a sub-time interval of a first time interval in accordance with a first clock signal. Each of the second storage circuits is configured to read a magnetic field control setting during a sub-time interval of a second time interval in accordance with a second clock signal. Each of the microfluidic control and position detection circuits is configured to enter a sample control state corresponding to the corresponding sample operation setting during a third time period in accordance with a sample control signal. Each of the temperature and magnetic control circuits is configured to assume a magnetic control state corresponding to a corresponding magnetic field control setting during a fourth time interval in accordance with the magnetic field control signal.

[0007] In some embodiments, for each microelectrode device, the second memory circuit is further configured to read a heating control setting during a sub-time interval of the fifth time interval in accordance with the second clock signal, and the temperature and magnetic control circuit is configured to assume a heating control state corresponding to the heating control setting during a sixth time interval in accordance with the heating control signal.

[0008] Another object of the present invention is to provide a microfluidic processing system. The microfluidic processing system includes a control device and a microfluidic chip. The microfluidic chip includes an upper plate and a microelectrode dot array disposed below the upper plate. The microelectrode dot array includes a plurality of microelectrode devices connected in series. Each of the microelectrode devices includes a microfluidic electrode disposed below the upper plate, a multifunction electrode disposed below the microfluidic electrode, and a control circuit disposed below the multifunction electrode. Each of the control circuits includes a first memory circuit, a second memory circuit, a microfluidic control and position detection circuit coupled to the corresponding microfluidic electrode, and a temperature and magnetic control circuit coupled to the corresponding multifunction electrode.

[0009] The controller is configured to provide a first clock signal, a second clock signal, a plurality of sample operation settings, a plurality of magnetic field control settings, a sample control signal, and a magnetic field control signal. Each of the first storage circuits is configured to read one of the sample operation settings during a sub-time interval of the first time interval in accordance with the first clock signal. Each of the second storage circuits is configured to read one of the magnetic field control settings during a sub-time interval of the second time interval in accordance with the second clock signal. Each of the microfluidic control and position detection circuits is configured to assume a sample control state corresponding to one of the sample operation settings during a third time interval in accordance with the sample control signal. Each of the temperature and magnetic control circuits is configured to assume a magnetic control state corresponding to one of the magnetic field control settings during a fourth time interval in accordance with the magnetic field control signal.

[0010] In some embodiments, the controller is further configured to provide a plurality of heating control settings and a heating control signal. Each of the second memory circuits is further configured to load one of the heating control settings during a sub-time interval of the fifth time interval in accordance with the second clock signal. Each of the temperature and magnetic control circuits is configured to enter a heating control state corresponding to one of the heating control settings during a sixth time interval in accordance with the heating control signal.

[0011] Another object of the present invention is to provide a microfluidic processing method for use in a controller of a microfluidic processing system to control a microfluidic chip. The microfluidic chip includes an upper plate and a microelectrode dot array disposed below the upper plate, the microelectrode dot array including a plurality of microelectrode devices connected in series. Each of the microelectrode devices includes a microfluidic electrode disposed below the upper plate, a multifunction electrode disposed below the microfluidic electrode, and a control circuit disposed below the multifunction electrode. Each of the control circuits includes a first memory circuit, a second memory circuit, a microfluidic control and position detection circuit coupled to the corresponding microfluidic electrode, and a temperature and magnetic control circuit coupled to the corresponding multifunction electrode. The microfluidic processing method includes the steps of: (a) providing a first clock signal to the microfluidic chip; (b) providing a second clock signal to the microfluidic chip; (c) providing multiple sample operation settings to the microfluidic chip; (d) providing multiple magnetic field control settings to the microfluidic chip; (e) providing a sample control signal to the microfluidic chip; and (f) providing a magnetic field control signal to the microfluidic chip.

[0012] Each of the first storage circuits is configured to load one of the sample operation settings during a sub-time interval of the first time interval in accordance with the first clock signal. Each of the second storage circuits is configured to load one of the magnetic field control settings during a sub-time interval of the second time interval in accordance with the second clock signal. Each of the microfluidic control and position detection circuits is configured to assume a sample control state corresponding to one of the sample operation settings during a third time interval in accordance with the sample control signal. Each of the temperature and magnetic control circuits is configured to assume a magnetic control state corresponding to one of the magnetic field control settings during a fourth time interval in accordance with the magnetic field control signal.

[0013] In some embodiments, the microfluidic processing method further comprises providing a plurality of heating control settings to the microfluidic chip and providing a heating control signal to the microfluidic chip. Each of the second memory circuits is further configured to read one of the heating control settings during a sub-time interval of the fifth time interval in accordance with the second clock signal. Each of the temperature and magnetic control circuits is configured to enter a heating control state corresponding to one of the heating control settings during a sixth time interval in accordance with the heating control signal.

[0014] Detailed techniques implemented for the present invention and preferred embodiments are described in the following paragraphs accompanied by the attached drawings to enable those skilled in the art to understand the features of the present invention as recited in the claims. [Brief explanation of the drawings]

[0015] [Figure 1A] FIG. 1A is a schematic diagram of a system configuration of a microfluidic processing system according to some embodiments.

[0016] [Figure 1B] FIG. 1B is a side view of the microfluidic chip.

[0017] [Figure 1C] FIG. 1C is a top view of the microfluidic chip.

[0018] [Figure 1D] FIG. 1D is a circuit block diagram of the microelectrode device.

[0019] [Figure 1E] FIG. 1E is a schematic diagram of a semiconductor structure having four metal layers.

[0020] [Figure 1F] FIG. 1F shows a spiral multi-function electrode employed in some embodiments.

[0021] [Figure 2A] FIG. 2A is an exemplary timing diagram for determining the position of a droplet and applying one or more sample operations to the droplet.

[0022] [Figure 2B] FIG. 2B shows an example of determining droplet size and position based on capacitance values.

[0023] [Figure 2C] FIG. 2C shows an exemplary sample control pattern.

[0024] [Figure 3A] FIG. 3A is an exemplary timing diagram for determining the position of a droplet and applying a magnetic field to the droplet.

[0025] [Figure 3B] FIG. 3B shows an exemplary magnetic field pattern.

[0026] [Figure 4A] FIG. 4A is an exemplary timing diagram for determining the position of a droplet and heating the droplet.

[0027] [Figure 4B] FIG. 4B shows an exemplary heating control pattern.

[0028] [Figure 4C] FIG. 4C shows another exemplary heating control pattern.

[0029] [Figure 5] FIG. 5 is an exemplary timing diagram for applying sample manipulation and a magnetic field together to a droplet.

[0030] [Figures 6A-6F] 6A-6F show droplets in the microfluidic chip 2 after various stages of DNA extraction have been performed.

[0031] [Figure 7] FIG. 7 is a circuit diagram showing a specific example of the control circuit.

[0032] [Figure 8] FIG. 8 shows a main flow chart of a microfluidic processing method according to some embodiments of the present invention.

[0033] [Figure 9] FIG. 9 shows a main flow chart of a microfluidic processing method according to some embodiments of the present invention.

[0034] [Figure 10] FIG. 10 shows a main flow chart of a microfluidic processing method according to some embodiments of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0035] In the following description, the microfluidic chip with a magnetic field control mechanism, the microfluidic processing system, and the microfluidic processing method of the present invention will be described with reference to specific embodiments thereof. However, these embodiments are not intended to limit the present invention to any specific environment, application, or implementation described in these embodiments. Therefore, the description of these embodiments is for illustrative purposes only and does not limit the scope of the present invention. Note that elements unrelated to the present invention are not shown in the following embodiments and accompanying drawings. Furthermore, in the accompanying drawings, the dimensions of each element and the dimensions between each element are provided for ease of illustration and description and do not limit the scope of the present invention.

[0036] 1A is a schematic diagram of a microfluidic processing system 100 according to some embodiments of the present invention. The microfluidic processing system 100 includes a microfluidic chip 2 and a controller 3, which cooperate to perform one or more biomedical processes (e.g., target extraction, biomedical testing). In the following description, the hardware configuration of the microfluidic chip 2 and the controller 3 will be first described, and the operation of the microfluidic chip 2 and the controller 3 will be described later.

[0037] Microfluidic chip configuration

[0038] 1B and 1C are side and top views, respectively, of the microfluidic chip 2. The microfluidic chip 2 includes an upper plate 10 and a microelectrode dot array 21, which is disposed below the upper plate 10. The upper plate 10 may be formed of a conductive material, such as indium tin oxide (ITO) glass. A space SP is formed below the upper plate 10 and above the microelectrode dot array 21. At least one droplet LO can be positioned and moved within the space SP under the control of a control device 3 (described in detail below). In some embodiments, the droplet may be a test sample (i.e., a sample to be tested), a reagent, or a buffer solution (e.g., a lysis buffer, binding buffer, wash buffer, or elution buffer used in DNA extraction).

[0039] In some embodiments, the microfluidic chip 2 may further include two hydrophobic layers 22 and 24. The hydrophobic layer 22 is disposed below the upper plate 10 and is in direct contact with the upper plate 10, while the hydrophobic layer 24 is disposed above the microelectrode dot array 21. A space SP for droplets to be moved therein may be defined by the hydrophobic layers 22 and 24. Each of the hydrophobic layers 22 and 24 may be formed from a hydrophobic material.

[0040] The microelectrode dot array 21 includes a plurality of microelectrode devices 1 connected in series. The microelectrode devices 1 are arranged in a two-dimensional array of size p×q, where p and q are both positive integers greater than 1. The control device 3 recognizes that the microelectrode devices 1 are arranged in a two-dimensional array of size p×q. Each microelectrode device 1 includes a microfluidic electrode 11, a multifunctional electrode 13 (which can be used as a heating electrode, an insulating layer, or a magnetic field supply layer depending on the operation to be performed, as described in detail below), and a control circuit 15. Each microfluidic electrode 11 is disposed below the upper plate 10, each multifunctional electrode 13 is disposed below the corresponding microfluidic electrode 11 (i.e., the microfluidic electrode 11 belonging to the same microelectrode device 1), and each control circuit 15 is disposed below the corresponding multifunctional electrode 13 (i.e., the multifunctional electrode 13 belonging to the same microelectrode device 1). In some embodiments, the microelectrode dot array 21 may further include a microelectrode junction layer 20 disposed above the microelectrode device 1 and below the hydrophobic layer 24. The microelectrode contact layer 20 is used to contact the hydrophobic layer 24 and can be a SiO2 insulating layer.

[0041] The size of each microelectrode device 1 is not limited to any particular size in the present invention. However, in some embodiments, the area of ​​the top surface of each microelectrode device 1 is 2500 μm 2 Furthermore, the distance between any two adjacent microelectrode devices 1 is not limited to any particular distance in the present invention. In some embodiments, the distance between one microelectrode device 1 and its adjacent microelectrode device 1 may be 1 μm.

[0042] In FIG. 1C , each square represents a microelectrode device 1, each of which has two input terminals (i.e., a first input terminal and a second input terminal) and two output terminals (i.e., a first output terminal and a second output terminal). The microelectrode devices 1 are connected in series by having a first input / output chain and a second input / output chain. For each microelectrode device 1 except the first, the first input terminal is coupled to the first output terminal of the immediately preceding microelectrode device 1 to form the first input / output chain. In this way, each microelectrode device 1 except the first receives an input signal DI1 (e.g., sample manipulation settings) through the preceding microelectrode device 1, and each microelectrode device 1 except the last provides an output signal DO1 (e.g., a stored capacitance value) through the preceding microelectrode device 1. Similarly, for each of the microelectrode devices 1 except the first microelectrode device 1, the second input terminal is coupled to the second output terminal of the immediately preceding microelectrode device 1 to form a second input / output chain. In this way, each of the microelectrode devices 1 except the first microelectrode device 1 receives an input signal DI2 (e.g., heating control setting, magnetic field control setting) through the preceding microelectrode device 1, and each of the microelectrode devices 1 except the last microelectrode device 1 provides an output signal DO2 (e.g., stored capacitance value) through the preceding microelectrode device 1.

[0043] 1D is a circuit block diagram of each microelectrode device 1 of the microelectrode dot array 21. Each microelectrode device 1 includes a microfluidic electrode 11, a multifunctional electrode 13, and a control circuit 15. The control circuit 15 of each microelectrode device 1 includes a microfluidic control and position detection circuit 151, a temperature and magnetic control circuit 153, and two memory circuits 155 and 157. In each microelectrode device 1, the microfluidic control and position detection circuit 151 is coupled to the microfluidic electrode 11 and the memory circuit 155, and the temperature and magnetic control circuit 153 is coupled to the multifunctional electrode 13 and the memory circuit 157. For each microelectrode device 1, the first input terminal and the first output terminal belong to the memory circuit 155, and the second input terminal and the second output terminal belong to the memory circuit 157. That is, the first input / output chain is formed by connecting the storage circuits 155, and the second input / output chain is formed by connecting the storage circuits 157.

[0044] Each of the microfluidic control and position detection circuits 151 can receive a sample control signal EN_F and a position detection signal EN_S. Each of the memory circuits 155 can receive a clock signal CLK1, receive and store an input signal DI1 (e.g., sample operation settings), and provide an output signal DO1 (e.g., a stored capacitance value). Each of the temperature and magnetic control circuits 153 can receive a heating control signal EN_T and a magnetic field control signal EN_M. Each of the memory circuits 157 can receive a clock signal CLK2, receive and store an input signal DI2 (e.g., heating control settings, magnetic field control settings), and provide an output signal DO2 (e.g., a stored capacitance value). Furthermore, a voltage signal VS (e.g., a 1 kHz, 50 Vp-p square wave) can be supplied to the upper surface of the upper plate 10 to generate sufficient driving force by EWOD technology to move a droplet within the space SP between the upper plate 10 and the microelectrode dot array 21.

[0045] In some embodiments, a semiconductor process (e.g., 0.35 μm 2P4M complementary metal-oxide semiconductor (CMOS) technology from Taiwan Semiconductor Manufacturing Company) capable of forming a semiconductor structure such as that shown in FIG. 1E can be employed to fabricate the microelectrode device 1. The semiconductor structure shown in FIG. 1E includes a substrate S and four metal layers on a top surface of the substrate S, the four metal layers comprising, from bottom to top, a first metal layer M1, a second metal layer M2, a third metal layer M3, and a fourth metal layer M4. In these embodiments, the control circuitry 15 of the microelectrode device 1 can be formed on the first metal layer M1 and the second metal layer M2, the multifunctional electrode 13 of the microelectrode device 1 can be formed on the third metal layer M3, and the microfluidic electrode 11 of the microelectrode device 1 can be formed on the fourth metal layer M4. In some embodiments, in order for the multifunctional electrodes 13 to provide a magnetic field, each of the multifunctional electrodes 13 has a spiral shape, as shown in FIG. 1F.

[0046] Control device configuration

[0047] FIG. 1A also shows the hardware configuration of the control device 3. The control device 3 includes a storage device 31, at least one transmission interface 33, and a processor 35. The processor 35 is electrically connected to the storage device 31 and the at least one transmission interface 33. The storage device 31 can be a memory, a Universal Serial Bus (USB) disk, a portable disk, a hard disk drive (HDD), or any other non-transitory storage medium, device, or circuit having the same function and known to those skilled in the art. Each of the transmission interfaces 33 can be a digital input / output interface card capable of communicating with a biochip and known to those skilled in the art. The processor 35 can be one of various processors, central processing units (CPUs), microprocessor units (MPUs), digital signal processors (DSPs), or other computing devices known to those skilled in the art. In some embodiments, the control device 3 can be a desktop computer, a notebook computer, or a mobile device (e.g., a tablet computer or a smartphone). The processor 35 is configured to generate various control signals and settings for controlling the microfluidic chip 2, and the at least one transmission interface 33 is configured to transmit these control signals and settings to the microfluidic chip 2.

[0048] Operations performed by the microfluidic chip and controller

[0049] Operations that can be performed by the microfluidic chip 2 and the controller 3 include precisely determining the position of one or more droplets, applying sample operations to one or more droplets (e.g., moving one or more droplets, cutting droplets, mixing droplets), applying a magnetic field to one or more droplets, heating one or more droplets, etc. The above-mentioned operations can be performed individually or in combination. In some embodiments, the above-mentioned operations can be organized in various ways to perform different biomedical processes. Operations that can be performed by the microfluidic chip 2 and the controller 3 are described in more detail below.

[0050] Droplet position determination

[0051] The microfluidic processing system 100 can detect all droplets within the microfluidic chip 2 (specifically within the space SP of the microfluidic chip 2) and determine the positions of all droplets within the microfluidic chip 2 (i.e., determine the size and position of all droplets within the microfluidic chip 2).

[0052] See the exemplary timing diagram in FIG. 2A , which is not intended to limit the scope of the present invention. The control device 3 supplies a position detection signal EN_S to the microfluidic chip 2 via the transmission interface 33. At this time, the position detection signal EN_S is enabled within a time interval T1 (e.g., the voltage level of the position detection signal EN_S can be set high within the time interval T1). Because the position detection signal EN_S is enabled within the time interval T1, the microfluidic control and position detection circuit 151 of each microelectrode device 1 detects a capacitance value between the top plate 10 and the corresponding microfluidic electrode 11 during the time interval T1 and stores the capacitance value in the corresponding storage circuit 155. Each capacitance value C1 reflects whether or not any liquid exists between the top plate 10 and the corresponding microfluidic electrode 11. If the numbers "0" and "1" are used to indicate the detected capacitance value, the number "1" can be used to indicate that there is liquid between the top plate 10 and the microfluidic electrode 11, and the number "0" can be used to indicate that there is no liquid between the top plate 10 and the microfluidic electrode 11.

[0053] Furthermore, the control device 3 supplies a clock signal CLK1 to the microfluidic chip 2 via the transmission interface 33. At this time, the clock signal CLK1 is enabled within a plurality of divided time intervals of the time interval T2 (for example, the voltage level of the clock signal CLK1 can be set high within the divided time intervals of the time interval T2). The time interval T2 follows the time interval T1. The divided time intervals of the time interval T2 correspond one-to-one to the memory circuits 155 of the microelectrode devices 1. If the microelectrode dot array 21 includes N microelectrode devices 1, the time interval T2 has N divided time intervals, where N is a positive integer. Since the clock signal CLK1 is enabled within the divided time intervals of the time interval T2, the memory circuits 155 output capacitance values ​​C1 during each divided time interval of the time interval T2. The present invention does not limit the clock rate of the clock signal CLK1 to a specific rate. For example, the storage circuit 155 may output the capacitance value C1 with the clock rate of the clock signal CLK1 set to 100 kHz.

[0054] The control device 3 receives the capacitance value C1 from the microfluidic chip 2 via the transmission interface 33. The control device 3 knows that the microelectrode devices 1 are arranged in a two-dimensional array of size p×q, and that the capacitance value C1 corresponds one-to-one with the microelectrode devices 1. Therefore, the processor 35 of the control device 3 can detect all droplets in the microfluidic chip 2 based on the capacitance value C1, and determine the size and position of all droplets based on the capacitance value C1.

[0055] For a better understanding, please refer to the specific example shown in FIG. 2B. This is not intended to limit the scope of the present invention. FIG. 2B shows capacitance values ​​C1 arranged in a two-dimensional array of size p×q. In FIG. 2B, N squares represent the capacitance values ​​C1 of the N microelectrode devices 1, respectively, with each white square indicating that the corresponding capacitance value is the value "0" and each gray square indicating that the corresponding capacitance value is the value "1." Recognizing that the microelectrode devices 1 are arranged in a two-dimensional array of size p×q, the processor 35 of the control device 3 can determine, based on the capacitance value C1, that there is one droplet LO in the microfluidic chip 2, and can determine the size and position of the droplet LO in the microfluidic chip 2 based on the capacitance value C1.

[0056] It should be noted that if the control device 3 knows the size and position of the droplet to be processed, the above-described operation for determining the position of the droplet can be omitted.

[0057] Applying sample operations

[0058] It is assumed that the controller 3 already knows the size and position of the droplets (e.g., the controller 3 has determined the position of the droplets within the microfluidic chip 2 at time intervals T1 and T2). The controller 3 can control the microfluidic chip 2 to apply sample operations to one or more droplets within the microfluidic chip 2 (e.g., moving one or more droplets, cutting droplets, mixing droplets).

[0059] The controller 3 generates a plurality of sample operation settings according to sample operation requirements (e.g., moving a droplet to a specified position, cutting a droplet, mixing droplets) and the size and position of at least one droplet in the microfluidic chip 2, where the sample operation settings correspond one-to-one to the microelectrode device 1. Each sample operation setting is used to instruct the corresponding microfluidic control and position detection circuit 151 to be in a sample control state (i.e., activated or deactivated) corresponding to the sample operation setting during the sample operation time interval.

[0060] In some embodiments, the processor 35 of the control device 3 can generate a sample control pattern according to sample operation requirements and the size and position of at least one droplet, and then generate sample operation settings according to the sample control pattern. See the exemplary sample control pattern CP shown in FIG. 2C . This is not intended to limit the scope of the present invention. The sample control pattern CP is used to cut the droplet LO into two smaller droplets. In FIG. 2C , N squares correspond to N sample operation settings read by the N memory circuits 155, with each gray square representing "ON" and each white square representing "OFF." The processor 35 of the control device 3 generates sample operation settings according to the sample control pattern CP. For example, the sample operation settings corresponding to the white squares may be assigned a value of "0," and the sample operation settings corresponding to the gray squares may be assigned a value of "1."

[0061] The control device 3 supplies the sample operation setting S2 to the microfluidic chip 2 via the transmission interface 33. See the exemplary timing diagram in FIG. 2A. The clock signal CLK1 supplied by the control device 3 to the microfluidic chip 2 is enabled within multiple divided time intervals of the time interval T3 (e.g., the voltage level of the clock signal CLK1 can be high within the divided time intervals of the time interval T3). The time interval T3 comes after the time interval T2. The divided time intervals of the time interval T3 correspond one-to-one to the memory circuit 155 of the microelectrode device 1. Thus, the memory circuit 155 reads the sample operation setting S2 during each divided time interval of the time interval T3.

[0062] The control device 3 supplies a sample control signal EN_F to the microfluidic chip 2 via the transmission interface. This sample control signal EN_F is enabled during time interval T4 (e.g., the voltage level of the sample control signal EN_F can be high during time interval T4). Furthermore, during time interval T4, the voltage level of the voltage signal VS supplied to the upper surface of the upper plate 10 is high, while during other time intervals, the voltage level of the voltage signal VS supplied to the upper surface of the upper plate 10 is low. Time interval T4 is the aforementioned sample operation time interval. During time interval T4, the sample control signal EN_F is enabled, and the voltage level of the voltage signal VS is high. Therefore, during time interval T4, the microfluidic control and position detection circuit 155 of each microelectrode device 1 is in a sample control state (i.e., activated or deactivated) according to the corresponding sample operation setting. In this way, the required sample operation (e.g., droplet movement, droplet cutting, droplet mixing) is achieved during time interval T4. It should be noted that during the sample operation time interval (eg, time interval T4), each of the multi-function electrodes 13 is an insulating layer (eg, connected to a low voltage level).

[0063] Applying a magnetic field to a droplet

[0064] It is assumed that the controller 3 already knows the size and position of the droplet (e.g., the controller 3 has determined the position of the droplet within the microfluidic chip 2 during time intervals T1 and T2). The controller 3 can control the microfluidic chip 2 to apply a magnetic field to the droplet within the microfluidic chip 2. For the following explanation, please refer to the exemplary timing diagram shown in FIG. 3A and the exemplary magnetic field pattern shown in FIG. 3B.

[0065] The control device 3 generates a plurality of magnetic field control settings according to magnetic field requirements (e.g., magnetic field strength) and the size and position of at least one droplet in the microfluidic chip 2, where the magnetic field control settings correspond one-to-one to the microelectrode device 1. Each magnetic field control setting is used to instruct the corresponding temperature and magnetic control circuit 153 to be in a magnetic control state (i.e., whether or not to perform magnetic control) corresponding to the magnetic field control setting during a magnetic control time interval. In some embodiments, performing magnetic control involves turning on a switch provided in the temperature and magnetic control circuit 153 and supplying an AC voltage to the temperature and magnetic control circuit 153.

[0066] In some embodiments, the processor 35 of the control device 3 can generate a magnetic field pattern according to the magnetic field requirements and the size and position of at least one droplet, and then generate magnetic field control settings according to this magnetic field pattern. In the exemplary magnetic field pattern MP shown in FIG. 3B , N squares correspond to N magnetic field control settings loaded by the N memory circuits 157, respectively, with each gray square representing "magnetic control enabled" and each white square representing "magnetic control disabled." The processor 35 of the control device 3 then generates magnetic field control settings according to the magnetic field pattern MP. For example, the magnetic field control settings corresponding to the white squares may be assigned a numerical value of "0," and the magnetic field control settings corresponding to the gray squares may be assigned a numerical value of "1."

[0067] The control device 3 supplies the magnetic field control setting S3 to the microfluidic chip 2 via the transmission interface 33 to apply a corresponding magnetic field. Specifically, the control device 3 supplies a clock signal CLK2 to the microfluidic chip 2 via the transmission interface 33, and the clock signal CLK2 is enabled within multiple divided time intervals of the time interval T5 (for example, the voltage level of the clock signal CLK2 can be set high within the divided time intervals of the time interval T5). The time interval T5 comes after the time interval T2. The divided time intervals of the time interval T5 correspond one-to-one to the memory circuit 157 of the microelectrode device 1. Thus, the memory circuit 157 reads the magnetic field control setting S3 during each divided time interval of the time interval T5.

[0068] The control device 3 supplies a magnetic field control signal EN_M to the microfluidic chip 2 via the transmission interface, and this magnetic field control signal EN_M is enabled within time interval T6 (for example, the voltage level of the magnetic field control signal EN_M can be set high within time interval T6). Time interval T6 comes after time interval T5. Time interval T6 is the aforementioned magnetic control time interval. Because the magnetic field control signal EN_M is enabled within time interval T6, the temperature and magnetic control circuit 153 of each microelectrode device 1 is in a magnetic control state (i.e., whether to perform magnetic control) according to the corresponding magnetic field control setting during time interval T6.

[0069] In some embodiments, performing magnetic control involves turning on a switch provided in the temperature and magnetic control circuit 153 and supplying an AC voltage to the temperature and magnetic control circuit 153. In these embodiments, if the magnetic field control setting instructs the corresponding temperature and magnetic control circuit 153 to perform magnetic control (e.g., the magnetic field control setting is the value "1"), the temperature and magnetic control circuit 153 turns on its switch during time interval T6, and an AC voltage is supplied to the temperature and magnetic control circuit 153 during time interval T6, causing the corresponding multifunction electrode 13 to supply a magnetic field (i.e., the multifunction electrode 13 can be considered to be a magnetic field in use). On the other hand, if the magnetic field control setting instructs the corresponding temperature and magnetic control circuit 153 not to perform magnetic control (e.g., the magnetic field control setting is the value "0"), the temperature and magnetic control circuit 153 turns off its switch during time interval T16, causing the corresponding multifunction electrode 13 not to perform magnetic control (i.e., the multifunction electrode 13 can be considered to be a magnetic field not in use). In this way, the required magnetic field is applied to the droplet in the microfluidic chip 2 during the time interval T6.

[0070] Droplet heating

[0071] It is assumed that the controller 3 already knows the size and position of the droplet (e.g., the controller 3 has determined the position of the droplet within the microfluidic chip 2 during time intervals T1 and T2). The controller 3 can control the microfluidic chip 2 to heat the droplet within the microfluidic chip 2. For the following explanation, please refer to the exemplary timing diagram shown in FIG. 4A and two exemplary heating control patterns shown in FIGS. 4B and 4C.

[0072] The control device 3 generates a plurality of heating control settings according to temperature requirements (e.g., the test environment must be 95°C) and the size and position of at least one droplet in the microfluidic chip 2, where the heating control settings correspond one-to-one to the microelectrode device 1. Each heating control setting is used to instruct the corresponding temperature and magnetic control circuit 153 to be in a heating control state (i.e., whether to perform heating) corresponding to the heating control setting during a heating time interval. In some embodiments, performing heating means turning on a switch provided in the temperature and magnetic control circuit 153 and supplying a DC voltage to the temperature and magnetic control circuit 153 to perform heating.

[0073] In some embodiments, the processor 35 of the control device 3 can generate a heating control pattern according to the temperature requirements and the size and position of at least one droplet, and then generate heating control settings according to this heating control pattern. For the exemplary heating control pattern HP1 shown in FIG. 4B , N squares correspond to N heating control settings loaded by the N memory circuits 157, respectively, with each gray square representing "execute heating" and each white square representing "do not execute heating." The processor 35 of the control device 3 generates heating control settings according to the heating control pattern HP1. For example, the heating control settings corresponding to the white squares may be assigned a numerical value of "0," and the heating control settings corresponding to the gray squares may be assigned a numerical value of "1."

[0074] In some embodiments, the heating control pattern generated by the control device 3 may include a heated area and an annular non-heated area, where the annular non-heated area surrounds the heated area and the position of the droplet LO corresponds to the center of the heated area. The annular non-heated area can be referred to as a guard ring. By having a guard ring surrounding the heated area, the heating effect within the heated area is not affected by the external environmental temperature. Therefore, the target temperature can be reached with a better temperature change rate and less energy consumption.

[0075] The heating control pattern HP1 shown in FIG. 4B has a guard ring. More specifically, the heating control pattern HP1 includes a heated area A1 (i.e., a gray square covering the droplet LO in FIG. 4B), an annular non-heated area A2 (i.e., a white square surrounding the aforementioned gray square in FIG. 4B), another heated area A3 (i.e., a gray square surrounding the aforementioned white square in FIG. 4B), and another non-heated area A6. The location of the droplet LO corresponds to the center of the heated area A1. The annular non-heated area A2 surrounds the heated area A1, the other heated area A3 surrounds the annular non-heated area A2, and the remaining area is the non-heated area A6. The number of multi-function electrodes (used as heating electrodes) in the heated areas A1 and A3 depends on the temperature requirements (i.e., the specific temperature to be reached) specified in the test protocol. The higher the required temperature, the greater the number of multi-function electrodes in the heated areas A1 and A3. The present invention does not limit the number of annular unheated regions (i.e., the number of guard rings) in a heating control pattern to any particular number. Another example in Figure 4C shows a heating control pattern HP2 having two guard rings (i.e., annular unheated regions A4 and A5).

[0076] The control device 3 supplies the heating control setting S1 to the microfluidic chip 2 via the transmission interface 33. Specifically, the clock signal CLK2 supplied by the control device 3 to the microfluidic chip 2 is enabled within multiple divided time intervals of the time interval T7 (for example, the voltage level of the clock signal CLK2 can be set high within the divided time intervals of the time interval T7). The time interval T7 comes after the time interval T2. The divided time intervals of the time interval T7 correspond one-to-one to the memory circuit 157 of the microelectrode device 1. Thus, the memory circuit 157 reads the heating control setting S1 during each divided time interval of the time interval T7.

[0077] The control device 3 supplies a heating control signal EN_T to the microfluidic chip 2 via the transmission interface, and the heating control signal EN_T is enabled within time interval T8 (for example, the voltage level of the heating control signal EN_T can be high within time interval T8). Time interval T8 comes after time interval T7. Time interval T8 is the aforementioned heating time interval. Because the heating control signal EN_T is enabled within time interval T8, the temperature and magnetic control circuit 153 of each microelectrode device 1 is in a heating control state (i.e., whether to perform heating) according to the corresponding heating control setting during time interval T8.

[0078] In some embodiments, performing heating means turning on a switch provided in the temperature and magnetic control circuit 153 and supplying a DC voltage to the temperature and magnetic control circuit 153. In these embodiments, if the heating control setting instructs the corresponding temperature and magnetic control circuit 153 to perform heating (e.g., the heating control setting is the value "1"), the temperature and magnetic control circuit 153 turns on its switch during time interval T8 (i.e., the heating time interval) and supplies a DC voltage to the temperature and magnetic control circuit 153, causing the corresponding multifunction electrode 13 to perform heating (i.e., the multifunction electrode 13 can be considered to be a heating electrode in use). On the other hand, if the heating control setting instructs the corresponding temperature and magnetic control circuit 153 not to perform heating (e.g., the heating control setting is the value "0"), the temperature and magnetic control circuit 153 turns off its switch during time interval T8 (i.e., the heating time interval) and prevents the corresponding multifunction electrode 13 from functioning (i.e., heating is not performed, and the multifunction electrode 13 can be considered to be a heating electrode not in use). In this way, the droplet in the microfluidic chip 2 can be heated to the required temperature during the time interval T8.

[0079] Both sample manipulation and magnetic field applied to droplets

[0080] It is assumed that the controller 3 already knows the size and position of the droplet (e.g., the controller 3 has determined the position of the droplet within the microfluidic chip 2 at time intervals T1 and T2). The controller 3 can control the microfluidic chip 2 to apply sample manipulations and apply magnetic fields to one or more droplets within the microfluidic chip 2. For the following discussion, please refer to the exemplary timing diagram shown in FIG. 5.

[0081] The controller 3 generates a plurality of sample manipulation settings according to the sample manipulation requirements and the size and position of at least one droplet in the microfluidic chip 2, as described in the "Application of Sample Manipulation" section. Furthermore, the controller 3 generates a plurality of magnetic field control settings according to the magnetic field requirements and the size and position of at least one droplet in the microfluidic chip 2, as described in the "Application of a Magnetic Field to a Droplet" section.

[0082] The control device 3 supplies the sample operation setting S2 and the magnetic field control setting S3 to the microfluidic chip 2 via the transmission interface 33. As shown in FIG. 5, the clock signal CLK1 and the clock signal CLK2 are enabled within a plurality of divided time intervals of the time interval T9 (for example, the voltage level of the clock signal CLK1 and the voltage level of the clock signal CLK2 can be high within the divided time intervals of the time interval T9). The time interval T9 occurs after the time interval T2. The divided time intervals of the time interval T9 correspond one-to-one to the memory circuit 155 of the microelectrode device 1 and correspond one-to-one to the memory circuit 157 of the microelectrode device 1. Because the clock signal CLK1 is enabled within the divided time intervals of the time interval T9 and the divided time intervals of the time interval T9 correspond one-to-one to the memory circuit 155, the memory circuit 155 reads the sample operation setting S2 during each divided time interval of the time interval T9. Similarly, clock signal CLK2 is enabled within the divided time intervals of time interval T9, and since the divided time intervals of time interval T9 correspond one-to-one to memory circuit 157, memory circuit 157 reads magnetic field control setting S3 during each divided time interval of time interval T9.

[0083] During time interval T10 (the time interval after time interval T9), the sample control signal EN_F is enabled, the magnetic field control signal EN_M is enabled, and the voltage level of the voltage signal VS supplied to the upper surface of the top plate 10 is set to high. Because the sample control signal EN_F is enabled and the voltage level of the voltage signal VS is set to high during time interval T10, the microfluidic control and position detection circuit 155 of each microelectrode device 1 is set to a sample control state according to the corresponding sample operation setting during time interval T10. Furthermore, because the magnetic field control signal EN_M is enabled during time interval T10, the temperature and magnetic control circuit 153 of each microelectrode device 1 is set to a magnetic control state according to the corresponding magnetic field control setting during time interval T10. In this way, both the desired sample operation and the desired magnetic field can be applied to the droplet during time interval T10.

[0084] Target extraction with a microfluidic processing system

[0085] As described above, the operations that can be performed by microfluidic processing system 100 (including precisely determining the location of one or more droplets, applying sample operations to one or more droplets, applying a magnetic field to one or more droplets, heating one or more droplets, etc.) can be organized in various ways to perform various biomedical processes.

[0086] In some embodiments, by appropriately adjusting sample manipulation requirements and magnetic field requirements, the microfluidic processing system 100 can perform specific operations to achieve target (e.g., nucleic acid) extraction. Specific examples are provided below with reference to Figures 6A-6F, but the present invention is not limited thereto.

[0087] In this example, the microelectrode device 1 is divided into six groups, and the microfluidic chip 2 is divided into six regions G1, G2, G3, G4, G5, and G6. Furthermore, the target extraction comprises six stages, including an initiation stage, a lysis stage, a binding stage, a washing stage, an elution stage, and a removal stage.

[0088] The objective of the start stage is to place required droplets within the microfluidic chip 2. Specifically, sample operation requirements include moving the test sample TS to the center of region G4, moving lysis buffer LB to the center of region G1, moving magnetic bead-containing binding buffer BMB to the center of region G1, and moving elution buffer EB to the center of region G5. Note that the test sample TS, lysis buffer LB, magnetic bead-containing binding buffer BMB, and elution buffer EB are each droplets. The control device 3 generates multiple sample operation settings according to the above sample operation requirements and transmits these sample operation settings to the microfluidic chip 2. The memory circuit 155 reads each sample operation setting, and then the microfluidic control and position detection circuit 151 of each microelectrode device 1 enters a sample control state according to the corresponding sample operation setting. Based on the description in the "Application of Sample Operation" section, those skilled in the art should understand the operations performed by the microfluidic processing system 100 to achieve the start stage. After the initiation step, the sizes and positions of the test sample TS, lysis buffer LB, magnetic bead-containing binding buffer BMB, and elution buffer EB are as shown in Figure 6A.

[0089] The purpose of the lysis step is to destroy cells in the test sample TS so that the desired target is exposed and / or suspended. Specifically, there is a sample operation requirement to move the test sample TS to the center of region G1 and mix the test sample TS with the lysis buffer LB. The control device 3 generates multiple sample operation settings according to the sample operation requirement, the size and position of the test sample TS, and the size and position of the lysis buffer LB, and transmits these sample operation settings to the microfluidic chip 2. The memory circuit 155 reads each sample operation setting, and then the microfluidic control and position detection circuit 151 of each microelectrode device 1 enters a sample control state according to the corresponding sample operation setting. Based on the description in the "Application of Sample Operation" section, those skilled in the art will understand the operations performed by the microfluidic processing system 100 to achieve the lysis step. After the lysis step, the test sample TS and the lysis buffer LB are mixed to form a mixed buffer TL, as shown in FIG. 6B. The desired target is exposed and / or suspended in the mixed buffer TL. Note that the mixed buffer TL is considered to be a droplet.

[0090] The purpose of the binding step is to capture the desired target with magnetic beads, each of which is coated with a specific material for capturing the desired target. Specifically, there is a sample manipulation requirement to move the mixed buffer solution TL to the center of region G2 and mix the mixed buffer solution TL with the magnetic bead-containing binding buffer solution BMB. The control device 3 generates multiple sample manipulation settings according to the sample manipulation requirement, the size and position of the mixed buffer solution TL, and the size and position of the magnetic bead-containing binding buffer solution BMB. The control device 3 transmits these sample manipulation settings to the microfluidic chip 2. The memory circuit 155 reads each sample manipulation setting, and then the microfluidic control and position detection circuit 151 of each microelectrode device 1 enters a sample control state according to the corresponding sample manipulation setting. Based on the description in the "Application of Sample Manipulation" section, those skilled in the art will understand the operations performed by the microfluidic processing system 100 to achieve the binding step. After the binding step, the test sample TS and lysis buffer solution LB are mixed to form a mixed buffer solution TB, as shown in FIG. 6C. The desired targets are captured by the magnetic beads in the mixed buffer TB, which is considered a droplet.

[0091] The purpose of the washing step is to immobilize the magnetic beads and wash away any unwanted particles. Specifically, there is a magnetic field requirement to attract the magnetic beads in the mixed buffer solution TB and keep them in the center of region G2 (i.e., the first region in space SP), and a sample manipulation requirement to move a portion of the mixed buffer solution TB to the center of region G3 (i.e., the second region in space SP). The controller 3 generates multiple magnetic field control settings according to the magnetic field requirement and the size and position of the mixed buffer solution TB. The controller 3 also generates multiple sample manipulation settings according to the sample manipulation requirement and the center of region G3. The controller 3 transmits these magnetic field control settings and sample manipulation settings to the microfluidic chip 2. The temperature and magnetic control circuit 153 of each microelectrode device 1 then enters a magnetic control state according to the corresponding magnetic field control setting. Meanwhile, the microfluidic control and position detection circuit 151 of each microelectrode device 1 enters a sample control state according to the corresponding sample manipulation setting. Based on the descriptions in the sections "Application of Sample Manipulation" and "Application of Magnetic Field to Droplets," those skilled in the art will understand the operations performed by the microfluidic processing system 100 to achieve the washing step. After the washing step, as shown in FIG. 6D , droplet TB1 (i.e., magnetic beads and a very small portion of mixed buffer solution TB) remains within the central portion of region G2, and another droplet TB2 (i.e., an unnecessary portion of mixed buffer solution TB) has been moved to the center of region G3. In some embodiments, droplet TB2 may be removed from the microfluidic chip 2.

[0092] The objective of the elution stage is to separate the magnetic beads from the desired targets. Specifically, there are sample manipulation requirements for mixing the droplet TB1 with the elution buffer EB (e.g., moving the droplet TB1 to the center of region G5) and magnetic field requirements for attracting the magnetic beads. The controller 3 generates multiple sample manipulation settings according to the sample manipulation requirements, the size and position of the droplet TB1, and the size and position of the elution buffer EB. The controller 3 further generates multiple magnetic field control settings according to the magnetic field requirements and the size and position of the elution buffer EB. The controller 3 transmits these magnetic field control settings and sample manipulation settings to the microfluidic chip 2. Next, the microfluidic control and position detection circuit 151 of each microelectrode device 1 enters a sample control state according to the corresponding sample manipulation setting. Meanwhile, the temperature and magnetic control circuit 153 of each microelectrode device 1 enters a magnetic control state according to the corresponding magnetic field control setting. Based on the descriptions in the sections "Application of Sample Manipulation" and "Application of a Magnetic Field to Droplets," those skilled in the art will understand the operations performed by the microfluidic processing system 100 to achieve the elution stage. After the elution step, droplet TB1 and elution buffer EB are combined into another droplet TE, as shown in Figure 6E, in which the desired target is separated from the magnetic beads.

[0093] The objective of the extraction phase is to extract the desired target from the droplet TE. Specifically, there is a magnetic field requirement to attract the magnetic beads in the droplet TE and keep them within the center of region G5 (i.e., the third region within the space SP), and a sample manipulation requirement to move a portion of the droplet TE to the center of region G6 (i.e., the fourth region within the space SP). The controller 3 generates multiple magnetic field control settings according to the magnetic field requirement and the size and position of the droplet TE. The controller 3 further generates multiple sample manipulation settings according to the sample manipulation requirement, the size and position of the droplet TE, and the center of region G6. The controller 3 transmits these magnetic field control settings and sample manipulation settings to the microfluidic chip 2. The temperature and magnetic control circuit 153 of each microelectrode device 1 then enters a magnetic control state according to the corresponding magnetic field control setting. Meanwhile, the microfluidic control and position detection circuit 151 of each microelectrode device 1 enters a sample control state according to the corresponding sample manipulation setting. Based on the explanations in the sections "Application of Sample Manipulation" and "Application of a Magnetic Field to Droplets," one skilled in the art would understand the operations performed by microfluidic processing system 100 to achieve the removal step. After the removal step, as shown in Figure 6F, droplet TE1 (i.e., the magnetic beads and only a very small portion of droplet TE) remains within the central portion of region G5, and another droplet TE2 (i.e., the portion containing the desired target) has been moved to the center of region G6.

[0094] In some alternative embodiments, the microfluidic processing system 100 can determine the position of the droplet within the microfluidic chip 2 before each step of target extraction to achieve more accurate results. Those skilled in the art will understand how to achieve this based on the description in the "Determining Droplet Position" section, and therefore will not be repeated in detail here.

[0095] In some other embodiments, microfluidic processing system 100 may further perform other biomedical tests on droplet TE2. For example, microfluidic processing system 100 may heat droplet TE2 to a particular degree Celsius based on temperature requirements. Those skilled in the art will understand how to accomplish this based on the description in the "Heating a Droplet" section.

[0096] BioProtocol

[0097] In some embodiments, the storage device 31 may store multiple protocols Pa, Pb, ..., Pc, each of which corresponds to a biomedical process (e.g., target extraction, biomedical test). Because every biomedical process performed must follow the corresponding protocol to achieve accurate results, the protocol for a biomedical process may be referred to as a bioprotocol. Specifically, a protocol for a biomedical process may include a sample volume, at least one temperature requirement (e.g., reaching a specific temperature), at least one sample manipulation requirement (e.g., moving, sorting, cutting, or mixing the sample for testing), at least one magnetic field requirement (e.g., magnetic field strength), and / or other requirements that the biomedical test must follow.

[0098] For example, if protocol Pa is for polymerase chain reaction (PCR) testing for a particular disease, protocol Pa may include the sample volume of the test sample, temperature requirements and corresponding time intervals for a deoxyribonucleic acid (DNA) denaturation step, temperature requirements and corresponding time intervals for an annealing step, and temperature requirements and corresponding time intervals for an extension step.

[0099] As another example, if the test protocol Pc is for target (e.g., nucleic acid) extraction, the test protocol Pc may include sample manipulation requirements and magnetic field requirements for the initiation, lysis, binding, washing, elution, and removal stages, as described in the section "Target Extraction Using a Microfluidic Processing System."

[0100] In accordance with the present invention, there is no limit to the number of protocols that may be stored in the storage device 31 of the controller 3. It is understood that the more protocols that are stored in the storage device 31 of the controller 3, the more biomedical processes that may be performed by the microfluidic testing system 100.

[0101] Control circuit example

[0102] An exemplary circuit diagram of the control circuit 15 of the microelectrode device 1 of the present invention is shown in Figure 7. It should be noted that the circuit diagram shown in Figure 7 is not intended to limit the scope of the present invention.

[0103] In this specific example, when attempting to perform the sample manipulation requirements specified in the protocol, the control signal EN act The value of is 0 (corresponding to the sample control signal EN_F being enabled), and the data signal Q n The value of is the sample manipulation setting read by the microelectrode device 1, and the clock rate of the clock signal CLK1 (which can be set to, for example, 1 kHz to 10 kHz) can be slower than the clock rates set for other operations. The microfluidic control and position detection circuit 151 generates a tensile force to achieve sample manipulation on the droplet LO.

[0104] In this example, if the capacitance value between the upper plate 10 and the microfluidic electrode 11 is to be detected, the control signal EN actThe value of CLK_S becomes 1 (corresponding to the position detection signal EN_S being enabled), and the clock rate of the clock signal CLK1 (which can be set, for example, to 1 MHz to 10 MHz) can be faster than the clock rate set for the sample operation. The microfluidic control and position detection circuit 151 converts the detected capacitance value (i.e., the capacitance discharge result) into the detection result D. sen The detection result D sen , the data signal D n As described above, the microelectrode devices 1 provided in the microelectrode dot array 21 are connected in series, so the memory circuit 155 receives the data signal Q of the memory circuit 155 of another microelectrode device 1 that is disposed before it and outputs a data signal. 1,1 ,...,Q 1,n-1 will be received.

[0105] In this example, when the temperature requirements specified in the protocol are to be implemented, the control signal EN temp / EN magnetic The value of the data signal Q becomes 1 (corresponding to the heating control signal EN_T being enabled). 2,n The value of EN_T is the heating control setting read by the microelectrode device 1 (e.g., a value of "0" indicates that heating is not performed, and a value of "1" indicates that heating is performed). A multiplexer in the temperature and magnetic control circuit 153 multiplexes the heating control signal EN_T and the data signal Q 2,n According to this, the switch in the circuit is turned on to generate a DC voltage V DD_HEAT When the switch of the temperature and magnetic control circuit 153 is turned on, the DC voltage V DD_HEAT is supplied to the temperature and magnetic control circuit 153, and the current flows through the resistor R HEAT and passes through the multifunctional electrode 13, thereby achieving a heating result.

[0106] In this example, if the magnetic field requirements specified in the protocol are to be implemented, the control signal EN temp / EN magnetic The value of becomes 1 (corresponding to the magnetic control signal EN_M being enabled), and the data signal Q 2,n The value of EN_M is the magnetic field control setting read by the microelectrode device 1 (e.g., a value "0" indicates that no magnetic field is provided, and a value "1" indicates that a magnetic field is provided). A multiplexer within the temperature and magnetic control circuit 153 multiplexes the magnetic control signal EN_M and the data signal Q 2,n According to this, the switch in the circuit is turned on to generate an AC voltage V AC The switch of the temperature and magnetic control circuit 153 is turned on, and the AC voltage V AC is supplied to the temperature and magnetic control circuit 153, a magnetic field is generated.

[0107] Microfluidic Processing Methods

[0108] The present invention also provides a microfluidic processing method used in a control device of a microfluidic processing system (for example, the control device 3 described in the above embodiment) to control the microfluidic chip 2.

[0109] 8 shows a main flowchart of a microfluidic processing method according to some embodiments of the present invention. In these embodiments, the microfluidic processing method includes steps S801 to S807 for determining the position of a droplet in the microfluidic chip 2, and steps S809 to S813 for applying a sample operation to the droplet.

[0110] Step S801 is executed to supply a position detection signal EN_S to the microfluidic chip 2. The position detection signal EN_S is enabled within a time interval T1, and each of the microfluidic control and position detection circuits 151 detects a capacitance value between the upper plate 10 and a corresponding microfluidic electrode 11 according to the position detection signal during the time interval T1, and stores the capacitance in a corresponding storage circuit 155.

[0111] Step S803 is executed to supply a clock signal CLK1 (first clock signal) to the microfluidic chip 2. The clock signal CLK1 is enabled within a plurality of divided time intervals of the time interval T2, and each of the storage circuits 155 outputs a corresponding capacitance value during the corresponding divided time interval of the time interval T2.

[0112] Step S805 is performed to receive capacitance values ​​from the microfluidic chip 2. Step S807 is performed to determine the size and position of each droplet between the top plate 10 and the microelectrode dot array 21 based on the capacitance values. In some embodiments, the size and position of the droplet to be processed may already be known by the controller. In such embodiments, steps S801, S805, and S807 are omitted, and clock signal CLK1 is not enabled within a sub-time interval of time interval T2.

[0113] Step S809 is performed to provide multiple sample operation settings to the microfluidic chip 2. Specifically, clock signal CLK1 is enabled within multiple divided time intervals of time interval T3, and each of memory circuits 155 reads a corresponding sample operation setting within the corresponding divided time interval. In some embodiments, the microfluidic processing method performs another step before step S809 to generate sample operation settings according to sample operation requirements and the size and position of droplets to be processed.

[0114] Step S811 is executed to supply a sample control signal EN_F to the microfluidic chip 2. Step S813 is executed to supply a voltage signal VS to the upper surface of the upper plate 10. During time interval T4, the sample control signal EN_F is enabled and the voltage level of the voltage signal VS becomes high, so that each of the microfluidic control and position detection circuits 151 is in a sample control state according to the corresponding sample operation setting during time interval T4. In this manner, the sample operation is applied to the droplet.

[0115] The present invention does not limit the execution order of steps S801, S803, S811, and S813. However, time interval T2 comes after time interval T1, time interval T3 comes after time interval T2, and time interval T4 comes after time interval T3.

[0116] 9 shows a main flowchart of a microfluidic processing method according to some embodiments of the present invention. In these embodiments, the microfluidic processing method includes steps S801 to S807 for determining the position of a droplet in the microfluidic chip 2, and steps S909 to S913 for applying a magnetic field to the droplet. Note that the details of steps S801 to S807 have been described above, so they will not be repeated here.

[0117] Step S909 is executed to supply a clock signal CLK2 (second clock signal) to the microfluidic chip 2, and this clock signal CLK2 is enabled within multiple divided time intervals of the time interval T5. Step S911 is executed to supply multiple magnetic field control settings to the microfluidic chip 2. Each of the memory circuits 157 reads a corresponding magnetic field control setting during a corresponding divided time interval of the time interval T5. Step S913 is executed to supply a magnetic field control signal EN_M to the microfluidic chip 2. The magnetic field control signal EN_M is enabled within the time interval T6, so that each of the temperature and magnetic control circuits 153 is in a magnetic control state according to the corresponding magnetic field control setting during the time interval T6. In this manner, a magnetic field is applied to the droplet.

[0118] The present invention does not limit the execution order of steps S801, S803, and S909, except that time interval T2 comes after time interval T1, time interval T5 comes after time interval T2, and time interval T6 comes after time interval T5.

[0119] 10 shows a main flowchart of a microfluidic processing method according to some embodiments of the present invention. In these embodiments, the microfluidic processing method includes steps S801 to S807 for determining the position of a droplet in the microfluidic chip 2, and steps S109 to S113 for heating the droplet. Note that the details of steps S801 to S807 have been described above, and will not be repeated here.

[0120] Step S109 is executed to supply a clock signal CLK2 (second clock signal) to the microfluidic chip 2, and this clock signal CLK2 is enabled within multiple divided time intervals of the time interval T7. Step S111 is executed to supply multiple heating control settings to the microfluidic chip 2. Each of the memory circuits 157 reads a corresponding heating control setting during a corresponding divided time interval of the time interval T7. Step S113 is executed to supply a heating control signal EN_T to the microfluidic chip 2. The heating control signal EN_T is enabled within the time interval T8, so that each of the temperature and magnetic control circuits 153 is in a heating control state according to the corresponding heating control setting during the time interval T8. In this manner, the droplet is heated.

[0121] The present invention does not limit the execution order of steps S801, S803, and S109, except that time interval T2 comes after time interval T1, time interval T7 comes after time interval T2, and time interval T8 comes after time interval T7.

[0122] The steps of determining the location of the droplet, applying a sample manipulation to the droplet, applying a magnetic field to the droplet, and heating the droplet described above can be performed individually or in combination. In some embodiments, the steps described above can be organized in various ways to perform various biomedical processes.

[0123] In addition to the steps described above, the microfluidic processing method provided by the present invention may perform other steps, so that the control device 3 can control the microfluidic chip 2 to have similar functions and achieve similar technical effects as those described in the various embodiments above. How the microfluidic processing method provided by the present invention performs these operations and steps, has similar functions, and achieves similar technical effects should be easily understood by those skilled in the art based on the above description of the previously shown embodiments, and therefore will not be further described herein.

[0124] In the present specification and claims, some terms (including time intervals, capacitance values, and sampling times) may be preceded by the terms "first," "second," ..., or "eighth." These terms "first," "second," ..., and "eighth" are used solely to distinguish between different terms. When the order of these terms is not specified or cannot be derived from the context, the order of these terms is not limited by the preceding "first," "second," ..., or "eighth."

[0125] According to the above description, the microfluidic processing technology provided by the present invention can determine the position of a droplet, apply a sample manipulation to the droplet, apply a magnetic field to the droplet, and heat the droplet. By properly configuring the timing diagram, the sample manipulation and the magnetic field can be applied together (i.e., within the same time interval). Therefore, by properly configuring the sample manipulation requirements, magnetic field requirements, and / or temperature requirements and generating the necessary sample manipulation settings, necessary magnetic field control settings, and / or necessary heating control settings according to the current size and position of the droplet to be processed, various types of biomedical processing (e.g., target extraction, biomedical testing) can be accurately performed in the same device. Compared to conventional technologies, performing biomedical processing using the microfluidic processing technology provided by the present invention is much more convenient because all operations can be performed in the same device. Furthermore, since all operations can be performed in the same device, droplets will not be contaminated.

[0126] The above disclosure relates to detailed technical contents and features of the invention. Those skilled in the art can continue to make various modifications and substitutions based on the disclosure and suggestions of the present invention described without departing from its features. However, although such modifications and substitutions are not fully disclosed in the above description, they are substantially covered in the scope of the appended claims.

Claims

1. An upper plate; a microelectrode dot array disposed below the top plate and comprising a plurality of serially connected microelectrode devices; A microfluidic chip comprising: at least one droplet can be positioned and moved within the space below the top plate and above the microelectrode dot array; Each of the microelectrode devices comprises: a microfluidic electrode disposed below the top plate; a multifunctional electrode disposed below the microfluidic electrode; a control circuit disposed below the multifunction electrode; The control circuit a first storage circuit configured to perform, during a fractional time interval of the first time interval in accordance with a first clock signal, (a) an operation of reading a sample operation configuration; a second storage circuit configured to read one of the magnetic field control setting and the heating control setting during a fractional time interval of the second time interval according to a second clock signal; a microfluidic control and position detection circuit coupled to the microfluidic electrode and configured to perform one of the following operations during a third time interval: (c) upon entering a sample control state corresponding to the sample manipulation setting in accordance with a sample control signal affecting the at least one droplet, (d) detecting a capacitance value between the top plate and the microfluidic electrode in response to a position detection signal, and storing the capacitance value in the first storage circuit; a temperature and magnetic control circuit coupled to the multifunction electrode and configured to perform, during a fourth time interval, one of the following operations: (e) entering a magnetic control state corresponding to the magnetic field control setting in accordance with a magnetic field control signal affecting the at least one droplet; and (f) entering a heating control state corresponding to a heating control setting in accordance with a heating control signal affecting the at least one droplet; the first storage circuit is further configured to (b) output the capacitance value during a fractional time interval of a fifth time interval in accordance with the first clock signal; the first clock signal, the second clock signal, the sample control signal, the position detection signal, the magnetic field control signal, the heating control signal, the sample manipulation setting, the magnetic field control setting, and the heating control setting are provided by a controller, and the sample control signal, the heating control signal, and the magnetic field control signal are associated with a protocol corresponding to a biomedical process; Microfluidic chip.

2. each of the microelectrode devices having an input terminal and an output terminal; for each of the microelectrode devices except a first microelectrode device, the input terminal is coupled to the output terminal of the immediately preceding microelectrode device; The microfluidic chip of claim 1 .

3. the at least one droplet comprises a first droplet, the first droplet being a buffer solution containing a plurality of magnetic beads; the magnetic field control setting is used to attract and retain the magnetic beads within a first region within the space, and the sample manipulation setting is used to move a portion of the buffer solution to a second region within the space; The microfluidic chip of claim 1 .

4. the at least one droplet includes a first droplet and a second droplet, the first droplet being a first buffer solution containing a plurality of magnetic beads, and the second droplet being a second buffer solution; the sample manipulation setting is used to mix the first droplet and the second droplet, and the magnetic field control setting is used to attract the magnetic beads; The microfluidic chip of claim 1 .

5. a control device; Microfluidic chips and 1. A microfluidic processing system comprising: The microfluidic chip comprises: An upper plate; a microelectrode dot array disposed below the top plate and comprising a plurality of microelectrode devices connected in series; at least one droplet can be positioned and moved within a space below the top plate and above the microelectrode dot array; Each of the microelectrode devices comprises: a microfluidic electrode disposed below the top plate; a multifunctional electrode disposed below the microfluidic electrode; a control circuit disposed below the multifunction electrode; The control circuit a first memory circuit, a second memory circuit, a microfluidic control and position detection circuit coupled to the microfluidic electrode, and a temperature and magnetic control circuit coupled to the multifunction electrode; the controller is configured to provide a first clock signal, a second clock signal, a plurality of sample manipulation settings, a plurality of magnetic field control settings, a plurality of heating control settings, a position detection signal, a sample control signal, a magnetic field control signal, and a heating control signal, the sample control signal, the heating control signal, and the magnetic field control signal being associated with a protocol corresponding to a biomedical process; each of the first storage circuits configured to perform, during a sub-time interval of a first time interval in accordance with the first clock signal, (a) an operation of reading one of the sample operation configurations; each of the second storage circuits is configured to read one of the magnetic field control settings or one of the heating control settings during a fractional time interval of a second time interval in accordance with the second clock signal; each of the microfluidic control and position detection circuits is configured to perform one of the following operations during a third time interval: (c) upon entering a sample control state corresponding to one of the sample manipulation settings in accordance with the sample control signal affecting the at least one droplet; and (d) detecting a capacitance value between the top plate and the microfluidic electrode in response to the position detection signal and storing the capacitance value in the first storage circuit; each of the temperature and magnetic control circuits is configured to perform one of the following operations during a fourth time interval: (e) assuming a magnetic control state corresponding to one of the magnetic field control settings in accordance with the magnetic field control signal affecting the at least one droplet; and (f) assuming a heating control state corresponding to the heating control setting in accordance with the heating control signal affecting the at least one droplet; Each of the first storage circuits is further configured to (b) output the capacitance value during a fractional time interval of a fifth time interval in accordance with the first clock signal; Microfluidic processing systems.

6. each of the microelectrode devices having an input terminal and an output terminal; for each of the microelectrode devices except a first of the microelectrode devices, the input terminal is coupled to the output terminal of the immediately preceding microelectrode device; The microfluidic processing system of claim 5 .

7. 7. The microfluidic processing system of claim 6, wherein the controller is further configured to receive the capacitance values ​​and determine a size and a position of each of the at least one droplet between the top plate and the microelectrode dot array according to the capacitance values.

8. 8. The microfluidic processing system of claim 7, wherein the sample manipulation settings are provided by a sample manipulation requirement, one of the at least one size, and one of the at least one location, and the magnetic field control settings are provided by a magnetic field requirement, one of the at least one size, and one of the at least one location.

9. the at least one droplet comprises a first droplet, the first droplet being a buffer solution containing a plurality of magnetic beads; the magnetic field control setting is used to attract and retain the magnetic beads and a first portion of the buffer solution in a first region within the space; the sample manipulation setup is used to move a second portion of the buffer solution to a second region within the space; The microfluidic processing system of claim 5 .

10. the at least one droplet includes a first droplet and a second droplet, the first droplet being a first buffer solution containing a plurality of magnetic beads, and the second droplet being a second buffer solution; the sample manipulation setting is used to mix the first droplet and the second droplet, and the magnetic field control setting is used to attract the magnetic beads; The microfluidic processing system of claim 5 .

11. 1. A microfluidic processing method used in a controller of a microfluidic processing system to control a microfluidic chip, the controller storing a protocol corresponding to a biomedical process, the microfluidic chip comprising: an upper plate; and a microelectrode dot array, the microelectrode dot array comprising a plurality of serially connected microelectrode devices disposed below the upper plate, capable of displacing and moving at least one droplet within a space below the upper plate and above the microelectrode dot array, each of the microelectrode devices comprising: a microfluidic electrode disposed below the upper plate; a multifunction electrode disposed below the microfluidic electrode; and control circuitry disposed below the multifunction electrode, each of the control circuits comprising: a first memory circuit; a second memory circuit; a microfluidic control and position detection circuit coupled to a corresponding one of the microfluidic electrodes; and a temperature and magnetic control circuit coupled to a corresponding one of the multifunction electrodes. The microfluidic processing method includes: providing a first clock signal to the microfluidic chip; providing a second clock signal to the microfluidic chip; providing a plurality of sample manipulation configurations to the microfluidic chip; providing a plurality of magnetic field control settings to the microfluidic chip; providing a plurality of heating control settings to the microfluidic chip; providing a position detection signal to the microfluidic chip; providing a sample control signal to the microfluidic chip; providing a magnetic field control signal to the microfluidic chip; and providing a heating control signal to the microfluidic chip; the sample control signal, the heating control signal, and the magnetic field control signal are associated with the protocol, and each of the first storage circuits is configured to perform, during a sub-time interval of a first time interval in accordance with the first clock signal, (a) an operation of loading one of the sample operation settings; each of the second storage circuits is configured to read one of the magnetic field control settings or one of the heating control settings during a fractional time interval of a second time interval in accordance with the second clock signal; each of the microfluidic control and position detection circuits is configured to perform one of the following operations during a third time interval: (c) upon entering a sample control state corresponding to one of the sample manipulation settings in accordance with the sample control signal affecting the at least one droplet; and (d) detecting a capacitance value between the top plate and the microfluidic electrode in response to the position detection signal and storing the capacitance value in the first storage circuit; each of the temperature and magnetic control circuits is configured to perform one of the following operations during a fourth time interval: (e) assuming a magnetic control state corresponding to one of the magnetic field control settings in accordance with the magnetic field control signal affecting the at least one droplet; and (f) assuming a heating control state corresponding to the heating control setting in accordance with the heating control signal affecting the at least one droplet; Each of the first storage circuits is further configured to (b) output the capacitance value during a fractional time interval of a fifth time interval in accordance with the first clock signal; Microfluidic processing methods.

12. each of the microelectrode devices having an input terminal and an output terminal; for each of the microelectrode devices except a first of the microelectrode devices, the input terminal is coupled to the output terminal of the immediately preceding microelectrode device; The microfluidic processing method of claim 11.

13. receiving the capacitance value from the microfluidic chip; and determining a size and a position of each of the at least one droplet between the top plate and the microelectrode dot array based on the capacitance value.

13. The microfluidic processing method of claim 12.

14. the sample manipulation configuration is provided by a sample manipulation requirement, one of the at least one size, and one of the at least one location; the magnetic field control setting is provided by a magnetic field requirement, one of the at least one size, and one of the at least one location; 14. The microfluidic processing method of claim 13.

15. the at least one droplet comprises a first droplet, the first droplet being a buffer solution containing a plurality of magnetic beads; the magnetic field control setting is used to attract and retain the magnetic beads and a first portion of the buffer solution in a first region within the space, and the sample manipulation setting is used to move a second portion of the buffer solution to a second region within the space; The microfluidic processing method of claim 11.

16. the at least one droplet includes a first droplet and a second droplet, the first droplet being a first buffer solution containing a plurality of magnetic beads, and the second droplet being a second buffer solution; the sample manipulation setting is used to mix the first droplet and the second droplet, and the magnetic field control setting is used to attract the magnetic beads; The microfluidic processing method of claim 11.

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