DETECTION SYSTEM

A detection system applied to detection of microfluidic chips, includes: a detection chip including a base substrate, an electrode layer and a microfluidic channel layer for accommodating a sample solution having magnetic beads, the base substrate is provided with a bearing surface, the electrode layer is on the bearing surface, the microfluidic channel layer is on the side of the electrode layer away from the base substrate, the electrode layer includes electrodes including at least one strong magnetic electrode and driving electrodes; a magnetic field device being on the side of the base substrate away from the electrode layer, and having a strong magnetic region corresponding one to one to the strong magnetic electrode; a driving mechanism being connected to the magnetic field device, and driving the magnetic field device to approach or move away from the detection chip in a direction that is perpendicular to the bearing surface.

TECHNICAL FIELD

The disclosure relates to the technical field of biomedical technology, particularly to a detection system applied to a microfluidic chip.

BACKGROUND

Research on microfluidic chips began in the early 1990s, presenting a potential technology for lab-on-a-chip. Microfluidic chips integrate the sample solution preparation, reaction, separation, and detection processes of biological, chemical, and medical analyses into a single chip at the micrometer scale. The microchannels form a network, allowing controlled fluid flow throughout the system, replacing various functions of conventional biological or chemical laboratories and automating the entire analysis process.

Digital microfluidics (DMF) is a powerful technology used for the precise manipulation of microscale droplets. Based on the dielectric wetting principle, DMF enables the electrical control of individual discrete liquid droplets. In biological analyses based on digital microfluidics, such as library preparation and gene sequencing, precise manipulation of various particles in droplets, including purification, separation, size selection, and enrichment, is often required.

SUMMARY

The disclosure provides the following technical solution.

A detection system for microfluidic chip detection, includes a detection chip. The detection chip includes a base substrate, an electrode layer, and a microfluidic channel layer for accommodating a sample solution with magnetic beads; the base substrate has a bearing surface, and the electrode layer is formed on the bearing surface; the microfluidic channel layer is disposed on a side of the electrode layer away from the base substrate; the electrode layer includes a plurality of electrodes, and the plurality of electrodes comprises at least one strong magnetic electrode and multiple driving electrodes. The detection system further includes a magnetic field device. The magnetic field device is disposed on a side of the base substrate away from the electrode layer and has a strong magnetic zone corresponding to the strong magnetic electrode. The detection system further includes a drive mechanism. The drive mechanism is connected with the magnetic field device and drives the magnetic field device to move towards or away from the bearing surface of the base substrate. In response to the magnetic field device being in a working position close to the detection chip, for each corresponding pair of strong magnetic zone and strong magnetic electrode, the strong magnetic zone is configured for causing magnetic beads in the sample solution on a side of the strong magnetic electrode away from the base substrate to gather; in response to the magnetic field device being in a working position away from the detection chip, causing the magnetic beads in the sample solution on a side of the strong magnetic electrode away from the base substrate to disperse.

Optionally, the magnetic field device includes a fixing body and a plurality of permanent magnets. The fixing body has a side-open mounting groove, including a bottom wall, a first side wall, a second side wall, a third side wall, and a fourth side wall. The first side wall and the second side wall are opposite, and the first side wall is located at a side of the second side wall facing the base substrate. The third side wall and the fourth side wall are opposite and arranged along the first direction, where the first direction is parallel to the bearing surface of the base substrate. The first side wall has a first opening corresponding to the strong magnetic electrode in a one-to-one manner, allowing a magnetic field to pass through to form the strong magnetic zone. The plurality of permanent magnets are installed in the mounting groove, and arranged along the first direction.

Optionally, the detection system further includes a pressing component. At least one of the third side wall and the fourth side wall has a second opening that passes through its own thickness along the first direction. At least a portion of the pressing component enters into the mounting groove through the second opening, and an entered part of the pressing component abuts against the permanent magnet adjacent to the second opening among the plurality of permanent magnets in the mounting groove, allowing each pair of adjacent permanent magnets to abut against each other.

Optionally, a surface of at least one of the third side wall and the fourth side wall, facing the mounting groove, is provided with an avoidance slot for placing and retrieving the permanent magnets.

Optionally, the second side wall includes a placement slot with an embedded magnet, where the fixing body is magnetically connected to the drive mechanism through the embedded magnet.

Optionally, the second side wall includes multiple placement slots arranged along the first direction on the second side wall.

Optionally, along the first direction, every two adjacent ones among the plurality of permanent magnets have their N pole orientations perpendicular to each other, and the N pole orientations of every two adjacent permanent magnets23rotate 90° in a same direction around a rotation axis parallel to the second direction. Here, the second direction is perpendicular to the first direction and parallel to the bearing surface.

Optionally, for each corresponding pair of strong magnetic electrode and the first opening, an orthographic projection of the first opening on the bearing surface is smaller than an orthographic projection of the strong magnetic electrode on the bearing surface, and the orthographic projection of the first opening on the bearing surface is within the orthographic projection of the strong magnetic electrode on the bearing surface.

Optionally, for each corresponding pair of strong magnetic electrode and the first opening, an axis of the first opening is perpendicular to the bearing surface, and the axis of the first opening passes through a center of the strong magnetic electrode.

Optionally, the plurality of electrodes are arranged in an array; and for multiple electrodes along the first direction, each pair of adjacent strong magnetic electrodes has at least one driving electrode.

Optionally, a diameter of the first opening is in a range of 1 mm to 3 mm.

Optionally, the detection system further includes a frame and a pressing structure connected to the frame, where the detection chip is fixed to the frame via the pressing structure.

Optionally, the drive mechanism includes a fixing part, an expansion part, and a support platform. The fixing part is fixed relative to the frame. The expansion part is movably installed on the fixing part along a third direction perpendicular to the bearing surface. The support platform is installed on the expansion part, and the magnetic field device is installed on the support platform.

Optionally, the drive mechanism includes a fixing structure, an expansion component, and a support platform. The fixing structure includes a base and two connection parts, where the base and the two connection parts cooperatively form a U-shaped structure; the two connection parts are fixedly connected to the base and the frame, and the base comprises a through-hole that passes through its thickness along a third direction perpendicular to the bearing surface. The expansion component includes a fixing part and an expansion part, where the fixing part is located at a side of the base away from the support platform and is fixedly connected to the base; the expansion part is movably installed on the fixing part along the third direction, and a free end of the expansion part passes through the through-hole into a space enclosed by the base and the two connection parts. The support platform is located in a space enclosed by the U-shaped structure and is fixedly connected to the free end of the expansion part.

DETAILED DESCRIPTION

The technical solutions of the embodiments of the disclosure will be clearly and completely described below in conjunction with the accompanying drawings in the embodiments of the disclosure. It is evident that the described embodiment is only a part not all of the embodiments disclosed herein. Based on the embodiments disclosed herein, all other embodiments obtained by those skilled in the art without inventive labor are within the scope of protection of this disclosure.

Digital Microfluidics (DMF) is a powerful technology for the simple and precise manipulation of micro-scale droplets. Digital microfluidics technology is based on the principles of dielectric wetting and allows for the electrical manipulation of individual discrete droplets. By sequentially applying voltage to different electrodes, operations such as movement, separation, and mixing of droplets can be performed on the chip. In contrast to traditional microfluidics technology, the use of electrical driving eliminates the need for external components such as micro-pumps and micro-valves to provide the power for fluid movement. Traditional purification, separation, and enrichment methods for microfluidic chips typically involve handling sample solutions outside the chip using reagents, tubes, centrifuge tubes, etc. Traditional methods consume large amounts of reagents, and the sample solution concentration is often too low for processing and detection on a microfluidic chip without prior purification, separation, and concentration. Performing purification, separation, and concentration of reagents outside the microfluidic chip for each independent sample solution is time-consuming, labor-intensive, and prone to sample solution contamination.

The following is a detailed description of the operation of sample solution B using digital microfluidic technology.

As shown inFIGS.1and2, embodiments of the disclosure provide a detection system for microfluidic chip testing. The detection system includes:a detection chip1, including a base substrate11, an electrode layer12, a hydrophobic layer14, and a microfluidic channel layer13for accommodating a sample solution B with magnetic beads A; here, the base substrate11has a bearing surface, and the electrode layer12is formed on the bearing surface of base substrate11; the microfluidic channel layer13is disposed on a side facing away from base substrate11, of electrode layer12; the hydrophobic layer14is located between the microfluidic channel layer13and the electrode layer12; the electrode layer12includes a plurality of electrodes121, and the plurality of electrodes121includes at least one strong magnetic electrode1211and multiple driving electrodes1212; preferably, the plurality of electrodes121can be arranged in an array; the electrodes121are arranged in the X and Y directions, and the sample solution B with magnetic beads A can move along the X and Y directions through the interaction between electrodes121;a magnetic field device2on a side away from electrode layer12, of base substrate11and has a strong magnetic zone corresponding to the strong magnetic electrode1211in a one-to-one manner; anda drive mechanism3connected with the magnetic field device2, here the drive mechanism3drives the magnetic field device2to move towards or away from the bearing surface of base substrate11in a direction perpendicular to the base substrate11;where in response to the magnetic field device2being in the working position close to the detection chip1, between each corresponding pair of the strong magnetic zone and the strong magnetic electrode1211, the strong magnetic zone is used to gather the magnetic beads A in the sample solution B on a side of base substrate11away from the strong magnetic electrode1211;in response to the magnetic field device2being in the working position far away from the detection chip1, the strong magnetic zone releases the magnetic control of the magnetic beads A in the sample solution B on the side of base substrate11away from the strong magnetic electrode1211, causing the magnetic beads A to disperse.

In the use of the detection system described above, firstly, a sample solution B containing a target substance is provided. The sample solution B contains a target substance such as DNA, RNA, etc. The sample solution B is mixed uniformly with magnetic beads A, causing the target substance in the sample solution B to covalently bind to the functional groups on the surface of magnetic beads A, forming a magnetic bead-target substance complex C. The sample solution B mixed with magnetic beads A is injected into the detection chip1and fills the microfluidic channel layer13. When the drive mechanism3drives the magnetic field device2to move to the position away from the detection chip1, and controls the driving electrodes1212according to the set drive timing, the droplets containing the magnetic bead-target substance complex move in the direction parallel to the base substrate11, toward the strong magnetic electrode1211on the side of the base substrate11away from the base substrate11. Subsequently, the drive mechanism3drives the magnetic field device2to move to the position close to the detection chip1, the magnetic beads A in the droplets are fixed on the surface of the strong magnetic electrode1211of the detection chip1and gather at the strongest magnetic field position, due to the magnetic field of the strong magnetic zone. Then, by controlling the driving electrodes1212with the timing of the driving circuit, the sample solution B moves in the direction parallel to the bearing surface of the base substrate11, allowing the magnetic beads A in the sample solution B that are free from the magnetic field to move to a specific position for fixation, reducing the loss of magnetic beads A in the sample solution B. After fixing the magnetic beads A, continue to control the electrodes1212with the timing of the driving circuit, allowing the sample solution B to move in the direction away from the magnetic beads A. The electrode-driven method of manipulating sample solution B can be done with droplet precision, reducing the consumption of the corresponding reagents during the sample solution B and the detection process. After fixing the magnetic beads A, continue to control the electrodes1212with the timing of the driving circuit, allowing the sample solution B to move in the direction away from the magnetic beads A. Since the dielectric wetting force in the sample solution B is greater than the resistance of the magnetic beads A fixed on the chip to the droplets, the magnetic bead-target substance complex C is separated from the sample solution B. This achieves the purification, separation, and enrichment of the target sample solution adsorbed on magnetic beads A. This system and method can handle and analyze various sample solutions and find wide applications in the field of biological analysis.

The detection system provided in embodiments of the disclosure uses magnetic beads A and magnetic field device2in combination to achieve solid-liquid separation. Specifically, the process involves coating purified sample solution B on the surface of nanoscale biological magnetic beads A. By adsorbing the sample solution B (such as nucleic acids, i.e., DNA or RNA, etc.) onto the surface of magnetic beads A and applying the magnetic field from magnetic field device2, the nano-magnetic beads A with adsorbed nucleic acids are separated from the liquid, realizing the solid-liquid separation, and realizing the purification, separation, and enrichment of nucleic acids. The described method is simple to operate, provides high extraction purity, is non-toxic, non-polluting, and is suitable for automation and high-throughput operations.

On the basis of the specific embodiments mentioned above, the magnetic field device in the detection system can be configured in various ways, and the specific structure can be set according to practical needs. In one specific embodiment, as shown inFIGS.4,5, and6, the magnetic field device in the detection system includes a fixing body21and multiple permanent magnets23.

The fixing body21has an open-sided mounting groove22, including a bottom wall225, a first side wall221, a second side wall222, a third side wall223, and a fourth side wall224. The first side wall221and the second side wall222are opposite, and the first side wall221is located at a side of the second side wall222facing the base substrate11. The third side wall223and the fourth side wall224are opposite and arranged along a first direction parallel to the bearing surface of base substrate11. The first side wall221has first openings2211corresponding to the strong magnetic electrodes1211in a one-to-one manner, allowing the magnetic field to pass through to form the strong magnetic zone.

The multiple permanent magnets23are installed in the mounting groove22, and the permanent magnets23are arranged along the first direction.

In this magnetic field device2, each permanent magnet23is installed in the mounting groove22of the fixing body21, improving the stability of the relative positions between the permanent magnets23. Further, strong magnetic zones corresponding to the strong magnetic electrodes1211can be formed via the first openings2211on the first side wall221, ensuring good structural stability and stable control of the magnetic field direction in the strong magnetic zones.

To further enhance the stability of the structure of the magnetic field device2provided by the technical solution, the permanent magnets23can be adhered to each other. The adhered structure of the permanent magnets23is then embedded in the mounting groove22.

Furthermore, to ensure the stability of the connection between the permanent magnets23and the fixing body21, the magnetic field device2includes a pressing component. At least one of the third side wall223and the fourth side wall224has at least one second opening that traverses its own thickness along the first direction. For example, as shown inFIG.6, the third side wall223has a second opening2231, and the fourth side wall has a second opening2241. Taking the second opening2231in the third side wall223as an example, a portion of the pressing component enters into the mounting groove22through the second opening2231and an entered part of the pressing component abuts against the permanent magnet23adjacent to the second opening among the plurality of permanent magnets in the mounting groove22, allowing each pair of adjacent permanent magnets23to abut against each other.

Of course, to facilitate the assembly between the permanent magnets23and the fixing body21, and to ensure a more secure fixation of the permanent magnets23, in another embodiment, a pressing component is not included. Only the third side wall223has a second opening2231, and/or the fourth side wall224has a second opening2241. When installing the permanent magnets23, a push rod can be used to push the permanent magnets23in the mounting groove22tight along the first direction through the second opening2231and/or the second opening2241.

To facilitate the assembly or disassembly of the permanent magnets23in the mounting groove22, in some embodiments, as shown inFIG.6, a surface of at least one of the third side wall223and the fourth side wall224has an avoidance slot on a surface facing the mounting groove22. As shown inFIG.6, the third side wall223has an avoidance slot2232, and the fourth side wall224has an avoidance slot2242. The avoidance slot facilitates the insertion of magnetic fixtures or hands into the mounting groove22to assemble or disassemble the permanent magnets23.

On the basis of the various embodiments mentioned above, to facilitate the assembly or disassembly between the magnetic field device2and the drive mechanism3, in some embodiments, as shown inFIG.6, the second side wall222of the mounting groove22has placement slots2221. The placement slots2221contain magnets (not shown in the figure), and the fixing body21is magnetically connected to the drive mechanism3based on the magnetic force of the magnets. Further, based on the magnetic connection between the fixing body21and the drive mechanism3, the specific position of the magnetic field device2can be changed flexibly, thus enabling a wider application.

Moreover, for increased stability in the magnetic connection between the fixing body21and the drive mechanism3, multiple placement slots2221along the first direction are arranged.

As the embodiments of the disclosure provides a detection chip1as a digital microfluidic chip, which is relatively small in size, using multiple independent permanent magnets23in combination may result in cross-interference of magnetic fields when handling multiple sample solutions B. In the embodiments, radial and parallel arrangements of multiple permanent magnets23are combined. Specifically, as shown inFIGS.3,4, and5, several permanent magnets23are installed in the mounting groove22along the length direction of the mounting groove22. Preferably, as shown inFIG.3, along the first direction, every two adjacent ones among the several permanent magnets23have their N pole orientations perpendicular to each other, and the N pole orientations of every two adjacent permanent magnets23rotate 90° in the same direction around a rotation axis parallel to the second direction. The second direction is perpendicular to the first direction and parallel to the bearing surface of the base substrate11. When arranged in this way, the magnetic lines of the permanent magnets23converge at a side facing the electrodes121, resulting in significantly enhanced magnetic force at this side and weakened magnetic force on the other side, thereby obtaining a strong one-sided magnetic field.

Further, for each pair of corresponding strong magnetic electrode1211and the first opening2211, an orthographic projection of the first opening2211on the bearing surface of the base substrate11is smaller than an orthographic projection of the strong magnetic electrode1211on the bearing surface, and the orthographic projection of the first opening2211on the bearing surface is located within the orthographic projection of the strong magnetic electrode1211. In this case, the setting of the first opening2211is conducive to further focusing the magnetic field in the strong magnetic zone corresponding to the strong magnetic electrode1211and prevents mutual interference of magnetic fields in the strong magnetic zones corresponding to different strong magnetic electrodes1211.

Specifically, the diameter of the first opening2211is in the range of 1 mm-3 mm.

Preferably, to ensure that the magnetic field device2can better gather the magnetic beads A, between each pair of corresponding strong magnetic electrode1211and the first opening2211, an axis of the first opening2211is perpendicular to the bearing surface, and the axis of the first opening2211passes through a center of the strong magnetic electrode1211.

Referring toFIG.1again, the detection system provided in embodiments of the disclosure further includes a frame5and a pressing structure4connected with the frame5, where the pressing structure4fixes the detection chip1to the frame5. When the detection chip1is to be fixed or removed, only the pressing structure4needs to be opened, the detection chip1is inserted into the pressing structure4. In order to ensure the stability of the detection chip1in the pressing structure4, the pressing structure4is fixed to the detection platform on the frame5by a fixing piece41.

As shown inFIGS.7and8, regarding the drive mechanism3, there are multiple options, including the following.

Option 1: as shown inFIG.7, the drive mechanism3includes a fixing part32, an expansion part31, and a support platform33.

The fixing part32is fixed relative to the frame5.

The expansion part31is movably installed along a third direction on the fixing part32, where the third direction is perpendicular to the bearing surface.

The support platform33is installed on the expansion part31, and the magnetic field device (not shown in the figure) is installed on the support platform33. The magnets placed in the placement slots2221on the second side wall222of the magnetic field device2are magnetically connected to the support platform33. When it is necessary to gather magnetic beads A in the detection chip1, the movement of the expansion part31drives the magnetic field device2closer to the detection chip1, thereby aggregating the magnetic beads A on the detection chip1. When it is necessary to disperse the magnetic beads A, the movement of the expansion part31drives the magnetic field device2away from the detection chip1. The specific expansion part and fixing part can be an electric push rod or a cylinder, thus achieving the effect of expansion and contraction.

Option 2: the drive mechanism3includes a fixing structure34, an expansion component, and a support platform33.

The fixing structure34includes a base341and two connection parts342. The base341, in cooperation with the two connection parts342, forms a U-shaped structure. The two connection parts342are fixedly connected to the base341and the frame (here the frame refers to the operating platform of the detection system, which is not shown in the figure), and the base341has a through-hole running through its thickness along a third direction perpendicular to the bearing surface.

The expansion component includes a fixing part32and an expansion part31. The fixing part32is located at a side of the base341away from the support platform (here, the support platform refers to the operating platform of the detection system, not shown in the figure), and is fixedly connected to the base341. The expansion part31can be movably installed along the third direction on the fixing part32, and the free end of the expansion part31passes through the through-hole into the space enclosed by the base32and the two connection parts342.

The support platform33is located in the space enclosed by the U-shaped structure and is fixedly connected to the free end of the expansion part31. To ensure the stability of the support platform33, a U-shaped connector36is set between the free end of the expansion part31and the support platform, and the two ends of the U-shaped connector36are connected to the support platform. Of course, the specific U-shaped connector can have other structures, and there are no specific restrictions here.

The usage process of the detection system provided in embodiments of the disclosure is described in detail below.

As shown inFIGS.9A-9D, first, the sample solution B and magnetic beads A are generated from their respective storage tanks, fused and uniformly mixed, and incubated. This allows the target substance in the sample solution B to bind to the magnetic beads A, forming magnetic bead-target substance complexes C. The sample solution B mixed with magnetic beads A is injected into the detection chip1and fills the microfluidic channel layer13. When the drive mechanism3drives the magnetic field device2away from the detection chip1, the liquid droplets containing the magnetic bead-target substance complexes C, under the control of the drive electrode1212's driving timing, allow the sample solution B with magnetic beads A to move to a specific position along the X and Y directions. This specific position is the strong magnetic position of the magnetic field device2, that is, the position of the strong magnetic electrode1211. At this time, the drive mechanism3drives the magnetic field device2closer to the detection chip1, the magnetic field device2rises and attaches to the detection chip1. The magnetic beads A in the magnetic bead-target substance complexes C are fixed in the strong magnetic zone on the detection chip1under the action of the magnetic field. Then, by controlling the timing of the drive circuit to drive the drive electrode1212, the waste liquid D is moved parallel to the bearing surface of the substrate11to separate the liquid droplets from the magnetic bead-target substance complexes C. The liquid droplets of waste liquid D move to the waste liquid tank. The above process is the separation process of the sample solution B.

Then, the magnetic bead-target substance complexes C remaining on the electrode121are mixed with the washing solution generated in the washing liquid pool. At this point, the drive mechanism3controls the magnetic field device2to descend. Under the action of the drive electrode1212, the mixture is oscillated in the X and Y directions, allowing the magnetic bead-target substance complexes C to be suspended. The washing solution is fully mixed with the magnetic bead-target substance complexes C, and unbound target substances and impurities are removed. The drive mechanism3controls the magnetic field device2to rise, re-fixing the cleaned magnetic bead-target substance complexes C on the chip, and removing the waste liquid D from the mixed solution to the waste liquid tank. This washing step can be repeated 2-3 times. The above process is shown inFIGS.10A-10D.

Finally, the magnetic bead-target substance complexes C fixed on the chip continue to mix with the elution solution generated in the elution liquid pool. At this point, the magnetic field device2descends, and the mixture is oscillated in the X and Y directions to suspend the magnetic beads A in the magnetic bead-target substance complexes. The elution solution is fully mixed with the magnetic bead-target substance complexes C, causing the target substance in the magnetic bead-target substance complexes C to separate from the magnetic bead A and disperse into the elution solution. At this time, the magnetic field device2rises, fixing the magnetic beads A on the chip, moving the elution solution for solid-liquid separation, and collecting the elution solution at the sample outlet. The elution solution is the purified sample solution B obtained through the above series of processes, completing the purification, separation, and enrichment of the sample solution B.

Apparently, those skilled in the art can make various modifications and variations to the embodiments of the disclosure without departing from the spirit and scope of the embodiments of the disclosure. In this way, if these modifications and variations of the embodiments of the disclosure fall within the scope of the claims of the disclosure and their equivalent technologies, the disclosure is also intended to include these modifications and variations.