Microfluidic chip and apparatus and method for detecting biomolecules

Abstract

Microfluidic chips and apparatuses and methods for detecting biomolecules are provided. According to an example embodiment, a microfluidic chip includes a first reservoir configured to hold a sample, the sample including a target material; a plurality of second reservoirs connected to the first reservoir, the plurality of second reservoirs including a reactant for the target material; and a plurality of well arrays respectively connected to the plurality of second reservoirs and configured to hold a solution of the sample in which the reactant for the target material is dissolved.

Description

[0001] This application claims priority to Korean Patent Application No. 10-2020-0079882, filed on June 30, 2020, and Korean Patent Application No. 10-2021-0028301, filed on March 3, 2021, the entire contents of which are incorporated herein by reference for all purposes. Technical Field

[0002] The disclosure relates to microfluidic chips and devices and methods for detecting biomolecules. Background Technology

[0003] Clinical or environmental samples are analyzed through a series of biochemical, chemical, and mechanical processes. Recently, the development of technologies for diagnosing or monitoring biological samples has received considerable attention. Nucleic acid-based molecular diagnostics, with its excellent accuracy and sensitivity, is increasingly used in various applications (such as the diagnosis of infectious diseases or cancer, pharmacogenomics, and the development of new drugs). Microfluidic devices are widely used for convenient and accurate sample analysis for a variety of purposes. Summary of the Invention

[0004] According to one aspect of the disclosure, a microfluidic chip is provided, the microfluidic chip comprising: a first reservoir configured to contain a sample including a target material; a plurality of second reservoirs connected to the first reservoir, the plurality of second reservoirs including reactants against the target material; and a plurality of trap arrays respectively connected to the plurality of second reservoirs and configured to contain a solution therein of the sample in which the reactants against the target material are dissolved.

[0005] The number of the plurality of second reservoirs may correspond to the amount of target material and is in the range of 1 to 20.

[0006] The number of the plurality of well arrays may be greater than or equal to the number of the plurality of second memories.

[0007] The size of the wells in each of the plurality of well arrays may be less than or equal to 1 nL.

[0008] The number of wells in each of the plurality of well arrays may range from ten thousand to one million.

[0009] The bottom and walls of the wells in each of the plurality of well arrays may have different surface properties.

[0010] At least one of the multiple well arrays or the first memory includes at least one of a field-effect transistor (FET), a silicon photonic structure, a two-dimensional (2D) micromaterial, a 2D nanomaterial, a 2D microstructure, or a 2D nanostructure.

[0011] The microfluidic chip may also include a filter located on a channel connecting the first reservoir and the plurality of second reservoirs.

[0012] The microfluidic chip may also include a mixer disposed inside the second reservoir or at the outlet of the second reservoir among the plurality of second reservoirs.

[0013] The microfluidic chip may also include a valve located on each channel, which respectively connects the plurality of second reservoirs and the plurality of trap arrays.

[0014] The microfluidic chip may also include an absorbent pad connected to the plurality of trap arrays.

[0015] The microfluidic chip may also include a valve located on each channel, which connects the plurality of trap arrays and absorbent pads respectively.

[0016] The microfluidic chip may also include at least one of a slider, centrifuge, or punch configured to inject a solution of the sample from the plurality of second reservoirs into the plurality of trap arrays or to fix the solution of the sample into the plurality of trap arrays.

[0017] The microfluidic chip may also include at least one of a bubble trap, a bubble removal material, or a gas-permeable material disposed inside the trap array or at the inlet of the trap array.

[0018] According to one aspect of the disclosure, a microfluidic chip is provided, the microfluidic chip comprising: a reservoir configured to contain a sample including a target material, the reservoir including a reactant against the target material; a mixer disposed between the reservoir and a trap array, the mixer being configured to mix a solution of the sample in which the reactant against the target material is dissolved; and a trap array in which an enzymatic reaction of a solution of the sample injected through the mixer occurs.

[0019] At least one of the memory or well array may include at least one of field-effect transistors (FETs), silicon photonic structures, 2D micromaterials, 2D nanomaterials, 2D microstructures, and 2D nanostructures.

[0020] The microfluidic chip may also include a filter located at the outlet of the reservoir.

[0021] According to one aspect of the disclosure, an apparatus for detecting biomolecules is provided, the apparatus comprising: a first reservoir configured to contain a sample including a target material; a plurality of second reservoirs, each of the plurality of second reservoirs including a reactant against the target material; a plurality of trap arrays in which an enzymatic reaction of a solution of the sample containing the reactant against the target material occurs; an optical unit including a light source and a detector, the optical unit being configured to emit first light onto the solution of the sample in the plurality of trap arrays during the occurrence of the enzymatic reaction and being configured to measure an optical signal reflected from the solution of the sample; and a processor configured to detect biomolecules based on the optical signal.

[0022] Target materials may include one or more duplexes of one or more of the following: ribonucleic acid (RNA), deoxyribonucleic acid (DNA), peptide nucleic acid (PNA), locked nucleic acid (LNA), oligopeptides, proteins, and toxins.

[0023] Reactants targeting the material may include one or more of the following: reverse transcriptase, polymerase, ligase, peroxidase, primer, and probe.

[0024] Primers may include oligonucleotides.

[0025] The probe may include at least one of oligonucleotides, fluorescent materials, or quenchers.

[0026] Reactants targeting the material can be freeze-dried.

[0027] The device may further include a pretreatment unit configured to pretreat a sample contained in a first reservoir, the pretreatment unit including at least one of a heater, a chemical treatment zone, magnetic beads, a solid-phase extractor, or an ultrasonic source.

[0028] The device may further include a temperature controller configured to control the temperature of a sample contained in a first reservoir.

[0029] The temperature controller may include at least one of an optical heater, an electric heater, or a temperature sensor. The optical heater includes a light source configured to emit second light onto a first storage device and a heating material configured to respond to the second light. The electric heater includes one of a heating element and a Peltier element.

[0030] Enzymatic reactions may include at least one of nucleic acid amplification reactions, redox reactions, or hydrolysis reactions, with nucleic acid amplification reactions including at least one of polymerase chain reaction (PCR) amplification or isothermal amplification.

[0031] Optical signals may include at least one of fluorescence, phosphorescence, absorbance, and surface plasmon resonance.

[0032] According to one aspect of the disclosure, a method for detecting biomolecules is provided, the method comprising: loading a sample into a first reservoir of a microfluidic chip; providing the sample loaded in the first reservoir to a plurality of second reservoirs, each of the plurality of second reservoirs including a reactant for a target material; injecting a solution of the sample in which the reactant is dissolved from the plurality of second reservoirs into a trap array; measuring an optical signal during an enzymatic reaction occurring in the solution of the sample injected into the trap array; and detecting biomolecules based on the measured optical signal.

[0033] The method may further include performing pretreatment on the sample loaded in the first reservoir, the pretreatment including at least one of heating, chemical treatment, magnetic bead treatment, solid phase extraction or ultrasonic treatment.

[0034] The target material may include RNA, and the reactants against the target material may include reverse transcriptase.

[0035] Enzymatic reactions may include at least one of nucleic acid amplification reactions, redox reactions, or hydrolysis reactions, with nucleic acid amplification reactions including at least one of polymerase chain reaction amplification (PCR) or isothermal amplification. Attached Figure Description

[0036] The above and other aspects, features and advantages disclosed will become clearer from the following detailed description taken in conjunction with the accompanying drawings.

[0037] Figure 1 This is a diagram illustrating a microfluidic chip according to an example embodiment.

[0038] Figure 2 yes Figure 1 Side view of the microfluidic chip.

[0039] Figure 3 This is a diagram illustrating a microfluidic chip according to an example embodiment.

[0040] Figure 4 This is a diagram illustrating a microfluidic chip according to an example embodiment.

[0041] Figure 5 yes Figure 4 Side view of the microfluidic chip.

[0042] Figure 6A and Figure 6B This is a diagram illustrating an example arrangement of a microfluidic chip according to an exemplary embodiment.

[0043] Figure 7 , Figure 8 , Figure 9 and Figure 10 This is a block diagram illustrating a device for detecting biomolecules according to an example embodiment.

[0044] Figure 11 This is a flowchart illustrating a method for detecting biomolecules according to an example embodiment. Detailed Implementation

[0045] Details of the exemplary embodiments are included in the following detailed description and accompanying drawings. The advantages and features of the disclosure, as well as the methods for implementing the disclosure, will become clearer from the exemplary embodiments described in detail below with reference to the accompanying drawings. Throughout the drawings and detailed description, unless otherwise described, the same reference numerals will be understood to denote the same elements, features, and structures. For clarity, illustration, and convenience, the relative dimensions and depictions of these elements may be exaggerated.

[0046] It will be understood that although the terms first, second, etc., may be used herein to describe various elements, these elements should not be limited by these terms. These terms are used only to distinguish one element from another. Unless otherwise expressly stated, any reference to the singular may include the plural. Furthermore, unless explicitly stated otherwise, expressions such as “comprising” or “including” will be understood to imply inclusion of the stated element but not exclusion of any other element. Moreover, terms such as “unit” or “module” should be understood as a unit that performs at least one function or operation and can be implemented as hardware, software, or a combination thereof. Expressions such as “at least one of…” modify the entire list of elements when following a list of elements, without modifying any individual element in the list. For example, the expression “at least one of a, b, and c” should be understood to include only a, only b, only c, both a and b, both a and c, both b and c, or all of a, b, and c.

[0047] In the following sections, various exemplary embodiments of microfluidic chips and devices and methods for detecting biomolecules will be described in detail with reference to the accompanying drawings.

[0048] Figure 1 This is a diagram illustrating a microfluidic chip according to an example embodiment. Figure 2 yes Figure 1 Side view of the microfluidic chip.

[0049] Reference Figure 1 The microfluidic chip 100 includes structures such as a first reservoir 110, a plurality of second reservoirs 120, a well array 130 having a plurality of wells, and channels 111, 121, and 131. In the microfluidic chip 100, the first reservoir 110, the second reservoirs 120, and the well array 130 are arranged sequentially, and may also include an absorbent pad 140 disposed at the end of the microfluidic chip 100 and used to absorb a sample solution, allowing the sample solution to move via capillary action.

[0050] The microfluidic chip 100 may include a substrate 10 on which microfluidic structures are disposed. For example... Figure 2 As shown, the base 10 may have a two-layer structure in which an upper plate 11 and a lower plate 12 are joined together. Figure 2 As shown, a first reservoir 110, a second reservoir 120, a trap array 130, and an absorbent pad 140 may be disposed on an upper plate 11 or a lower plate 12, and channels 111, 121, and 131 through which fluid passes may be formed between the upper plate 11 and the lower plate 12. The substrate 10 may comprise inorganic materials (such as glass, silicon, ceramics, graphite, etc.) or materials such as acrylic materials, polyethylene terephthalate (PET), polycarbonate, polystyrene, polypropylene, etc. The microfluidic structure may be formed on the substrate 10 by etching, milling, drilling, etc.

[0051] Additionally, the microfluidic chip 100 may also include structures (not shown) for the flow of microfluidics (such as active and / or passive drive devices, capillaries, or electrowetting devices). Active and / or passive drive devices may include, but are not limited to, passive vacuum gap pumps, syringe pumps, vacuum pumps, pneumatic pumps, etc.

[0052] The sample is loaded and received in the first storage 110, and can be dispersed into multiple second storages 120 via the first channel 111. For example... Figure 1 As shown, the first channel 111 may have an inlet formed therein that connects to an outlet disposed in the first reservoir 110, and may have a plurality of outlets that are respectively connected to a plurality of second reservoirs 120. However, the first reservoir 110 is not limited thereto, and may have outlets formed at a plurality of portions of the first reservoir 110 such that a plurality of first channels 111 may be connected to the first reservoir 110.

[0053] Samples may include respiratory secretions, or a biological fluid containing at least one of blood, urine, sweat, tears, saliva, etc., or a swab sample from the upper respiratory tract, or a solution of a biological fluid or swab sample dispersed in other media. In this case, other media may include, but are not limited to, water, saline solution, alcohol, phosphate buffered saline solution, vital transport media, etc. The sample volume may range from 1 μL to 1000 μL, and may be, for example, 20 μL.

[0054] The sample loaded in the first reservoir 110 can be pretreated before being dispersed and received in the second reservoir 120. For example, the sample can be pretreated by heating, chemical treatment, magnetic bead treatment, solid phase extraction, ultrasonic treatment, etc. The material or structure used for pretreatment can be formed inside or outside the first reservoir 110.

[0055] Furthermore, the first memory 110 may include a field-effect transistor (FET), a silicon photonic structure, a two-dimensional (2D) micro / nano (or micro and / or nano) material, a 2D micro / nano structure, etc. Additionally, the first memory 110 may include materials and / or structures with optical or electrothermal properties for controlling the temperature of the sample. For example, the first memory 110 may include optically heated materials and / or structures that respond to a light source (such as a light-emitting diode (LED), a laser, a vertical-cavity surface-emitting laser (VCSEL), etc.), or may include an electrothermal element such as a Peltier element.

[0056] One or more second reservoirs 120 may be provided for each target material. The number of second reservoirs 120 may be determined according to the amount of target material, the size of the microfluidic chip 100, etc., and may be, for example, in the range of 1 to 20, or for example, 10. Target materials may include, but are not limited to, one or more duplexes of ribonucleic acid (RNA), deoxyribonucleic acid (DNA), peptide nucleic acid (PNA), locked nucleic acid (LNA), oligopeptides, proteins, toxins, etc.

[0057] The second reservoir 120 may include at least one reactant for each target material, and the corresponding second reservoir 120 may include reactants for different target materials. For example... Figure 2 As shown, the reactant RS for the target material can be freeze-dried to immobilize it in the second reservoir 120. Reactants for each target material may include, but are not limited to, reverse transcriptase, polymerase, ligase, peroxidase, primer, probe, etc. Primers may include oligonucleotides (e.g., target-specific single-strand oligonucleotides). Furthermore, probes may include oligonucleotides (e.g., target-specific single-strand oligonucleotides, fluorescent materials, quenchers, etc.). Probes can exhibit fluorescent signals by interacting with specific target materials in a solution in which different types of materials are dissolved. This characteristic signal can be tracked, detected, and processed over a predetermined time period by the optical unit and / or processor of a device for detecting biomolecules for the purpose of biomolecule detection.

[0058] The sample loaded and / or pretreated in the first reservoir 110 can be dispersed and received in the second reservoir 120. In this case, structures such as active and / or passive actuation devices, capillaries, or electrowetting devices can be used for the flow of microfluidic samples. When the sample is introduced into the second reservoir 120, the freeze-dried and immobilized reactants against the target material in the second reservoir 120 are dissolved in the sample.

[0059] The well array 130 may include multiple wells having micron / nanostructures, wherein a sample solution containing a reactant of the target material is introduced from a corresponding second reservoir 120 into a well corresponding to the second reservoir 120. The number of well arrays 130 is determined by the amount of target material and may be, for example, in the range of 1 to 20, and may be greater than or equal to the number of second reservoirs 120. The size of the wells included in each well array 130 may be, for example, 1 nL (1 nanoliter) or smaller. Furthermore, the number of wells included in each well array 130 may be in the range of ten thousand to one million, and may be, for example, twenty thousand.

[0060] The bottoms and walls of each well may have different properties (e.g., different wettability). Furthermore, structures for bubble removal (not shown) (e.g., bubble traps, bubble removal materials, and / or chambers and / or gas-permeable materials) may be disposed inside each well array 130 or at the entrance of the well array 130. Each well of the well array 130 may include field-effect transistors (FETs), silicon photonic structures, 2D micro / nano materials, etc. Additionally, each well of the well array 130 may include an optically heating material and / or structure that reacts to an external light source (such as a light-emitting diode (LED), laser, vertical-cavity surface-emitting laser (VCSEL), etc.) to have optically heating properties, or each well of the well array 130 may include an electrically heating element (such as a Peltier element, etc.) to have electrically heating properties.

[0061] The sample solution containing the reactant of the target material is introduced into each corresponding well array 130 through the second channel 121 from the corresponding second reservoir 120. In this case, in order to fill the wells of each well array 130 with sample fluid or fix the sample fluid to the wells of each well array 130, a sliding device (or slide), a centrifugal device (or centrifuge), or a stamping device (or stamper) provided in the microfluidic chip 100 can be used.

[0062] The sample solution introduced into each trap array 130 can undergo an enzymatic reaction within a predetermined time period to detect biomolecules. In this case, reverse transcription using reverse transcriptase can be performed on the RNA sample in each trap array 130. The enzymatic reaction may include, for example, a nucleic acid amplification reaction including at least one of polymerase chain reaction amplification (PCR) and isothermal amplification, or a redox reaction, hydrolysis reaction, etc. When the enzymatic reaction is performed in each trap array 130, an optical signal is measured by an optical unit and / or processor of a device for detecting biomolecules, and the biomolecule can be detected based on the measured optical signal. The optical signal may include fluorescence, phosphorescence, absorbance, surface plasmon resonance, etc. As described above, the microfluidic chip 100 can be used to detect the presence, quantification information, etc. of the target DNA template during the replication process of polymerase.

[0063] like Figure 1 As shown, an absorbent pad 140 is disposed at the rear end of the trap array 130 and connected to the trap array 130 via a third channel 131, allowing the sample solution to move and drain. As described above, the rate of sample inflow or transfer can be easily controlled by providing the absorbent pad 140. However, the absorbent pad 140 is not limited to this, and the flow rate and volume of the sample solution through the trap can be controlled by changing the position, size, and type of the absorbent pad 140. For example, during an enzyme reaction, the sample can move slowly, while during washing, the sample can move rapidly, thereby improving reaction sensitivity.

[0064] Figure 3 This is a diagram illustrating a microfluidic chip according to another example embodiment.

[0065] Reference Figure 3 According to an example embodiment, the microfluidic chip 300 may include a first channel 111 connecting a first reservoir 110 and a second reservoir 120, and a filter 310 formed on the outlet side of the first reservoir 110.

[0066] Filter 310 can block biomolecules in the sample loaded and pretreated in the first reservoir 110 and can only allow fluid to pass through. Filter 310 can be a single-layer or multi-layer filter having micropores and formed as a membrane, and depending on the pore size, filter 310 can block biomolecules of a desired size. Filter 310 may include, but is not limited to, materials such as silicon, polyvinylidene fluoride (PVDF), polyethersulfone, polycarbonate, glass fiber, polypropylene, cellulose, mixed cellulose esters, polytetrafluoroethylene (PTFE), polyethylene terephthalate, polyvinyl chloride (PVC), nylon, cellulose phosphate, diethylaminoethyl cellulose (DEAE), etc. The pores can have various shapes (such as circular, square, slit, irregular shapes made of glass fiber, etc.).

[0067] Additionally, the microfluidic chip 300 may also include a mixer 321 for mixing a sample solution in the second reservoir 120 in which the reactant containing the target material is dissolved. Figure 3 As shown, mixer 321 may be disposed on the outlet side of second reservoir 120, which is connected to trap array 130 via a second channel. However, mixer 321 is not limited thereto and may be disposed inside second reservoir 120.

[0068] Furthermore, the microfluidic chip 300 may also include a first valve 322 and / or a second valve 331. The first valve 322 is disposed at a second channel connecting the second reservoir 120 and the trap array 130 and is configured to control fluid flow from the second reservoir 120 to the trap array 130. The second valve 331 is disposed at a third channel connecting the trap array 130 and the absorbent pad 140 and is configured to control fluid flow from the trap array 130 to the absorbent pad 140. Figure 3 As shown, the first valve 322 may be located at the outlet of the second reservoir 120, or at the outlet of the mixer 321 when a mixer 321 is provided. The first valve 322 and the second valve 331 may be various types of microvalves that open and close the microfluidic channel. For example, the microvalves may include active microvalves (such as pneumatic and / or thermopneumatic actuated valves, electrostatic actuated valves, piezoelectric actuated valves, electromagnetic actuated valves) or passive microvalves that open and close by using fluid flow or interfacial tension differences without manual external operation, but the microvalves are not particularly limited to these.

[0069] Figure 4 This is a diagram illustrating a microfluidic chip according to yet another example embodiment. Figure 5 yes Figure 4 Side view of the microfluidic chip.

[0070] Reference Figure 4 and Figure 5The microfluidic chip 400 according to an example embodiment may include: a reservoir 410 in which a sample is loaded and, if necessary, pretreated in the reservoir 410; a trap array 430 in which an enzymatic reaction of the sample solution is performed; and a microfluidic mover 440 for moving microfluidics. Furthermore, a mixer 420 may be disposed in a channel connecting the reservoir 410 and the trap array 430. Additionally, a filter 450 may be disposed in a channel between the reservoir 410 and the mixer 420. As described above, the microfluidic chip 400 may include a substrate 10 having a two-layer structure in which an upper plate 11 and a lower plate 12 are bonded to each other, and each microfluidic structure may be disposed on the upper plate 11 or the lower plate 12. The substrate 10 may include a breathable polymer, polydimethylsiloxane (PDMS), etc.

[0071] Reservoir 410 may perform the same or similar functions as the first reservoir 110 described above; therefore, a detailed description of reservoir 410 will be omitted. In one example embodiment, reservoir 410 may include reactants of the target material. For example, reactants of the target material may be freeze-dried and fixed. When a sample is loaded into reservoir 410, the freeze-dried reactants may dissolve in the sample. As described above, a pretreatment process for the loaded sample may be performed in reservoir 410. The sample solution in reservoir 410 in which the reactants of the target material are dissolved may be mixed by mixer 420 and injected into trap array 430. Filter 450 may be disposed before or after mixer 420 on substrate 10 to filter biomolecules.

[0072] The trap array 430 may have a nanostructure and may include materials and / or structures with electrothermal or optical heating properties. Various enzymatic reactions can occur in the trap array 430, and biomolecules can be detected by measuring optical signals using an external optical unit during the enzymatic reaction. The trap array 430 may perform the same or similar functions as the trap array 130 described above; therefore, a detailed description of the trap array 430 will be omitted.

[0073] The microfluidic mover 440 may be, for example, a vacuum cell for moving a sample loaded in the reservoir 410 to the trap array 430 by a vacuum method, but is not limited thereto.

[0074] Figure 6A and Figure 6B These are diagrams illustrating various examples of the arrangement of a microfluidic chip according to an exemplary embodiment.

[0075] Reference Figure 6AThe microfluidic chip can be divided into a first region 610 and a second region 620. The first region 610 may include a first reservoir 110 in which a sample is loaded and / or pretreated, and the second region 620 may include structures 120, 130, and 140 for dispersing and processing samples introduced from the first reservoir 110. (See reference...) Figure 6A A second region 620 of the microfluidic chip according to an example embodiment may be connected to an outlet formed in the first reservoir 110. (Refer to...) Figure 6B Multiple outlets are formed in the first region 610 to connect to multiple second regions 621, 622, 623, 624, 625, and 626. The number of second regions may vary depending on the amount of target material or the size of the microfluidic chip.

[0076] Figures 7 to 10 This is a block diagram illustrating a device for detecting biomolecules according to an example embodiment.

[0077] Reference Figure 7 The device 700 for detecting biomolecules includes a microfluidic chip 710, an optical unit 720, and a processor 730. (See above for reference.) Figures 1 to 6B The microfluidic chip 710 has been described in detail, therefore, the microfluidic chip 710 will be briefly described below.

[0078] The sample is loaded into a first reservoir of the microfluidic chip 710, and the loaded sample can be dispersed into one or more second reservoirs using manual and / or automatic actuation devices, capillaries, or electrowetting devices. The sample may include respiratory secretions, or a biological fluid containing at least one of blood, urine, sweat, tears, saliva, etc., or a swab sample from the upper respiratory tract, or a solution of a biological fluid or swab sample dispersed in other media (such as water, saline solution, alcohol, phosphate buffered saline solution, active transport medium, etc.). The sample volume can range from 1 μL to 1000 μL, and may be, for example, 20 μL.

[0079] Each second reservoir may include a reactant for each target material, and the reactant for each target material dissolves in the sample when the sample is introduced from the first reservoir. In this case, the reactant for each target material may be freeze-dried. Target materials may include one or more duplexes of ribonucleic acid (RNA), deoxyribonucleic acid (DNA), peptide nucleic acid (PNA), locked nucleic acid (LNA), oligopeptides, proteins, toxins, etc., and may include, but are not limited to, reverse transcriptase, polymerase, ligase, peroxidase, primers, probes, etc.

[0080] When a sample solution containing a reactant in which the target material is dissolved is introduced into a micro / nano trap array, an enzymatic reaction of the sample solution is performed within the micro / nano trap array. The enzymatic reaction may include nucleic acid amplification reactions comprising at least one of polymerase chain reaction (PCR) amplification and isothermal amplification, or redox reactions, hydrolysis reactions, etc.

[0081] When an enzyme reaction is performed in each well of the micro / nano well array, the optical unit 720 can measure optical signals. These optical signals may include fluorescence, phosphorescence, absorbance, surface plasmon resonance, etc. The optical unit 720 may include a light source for emitting light onto a sample solution in the micro / nano well and a detector for detecting optical signals reflected from the sample solution in the micro / nano well. The light source may include, but is not limited to, LEDs, lasers, vertical-cavity surface-emitting lasers (VCSELs), etc. Additionally, the detector may include, but is not limited to, photomultiplier tubes, photodetectors, photomultiplier tube arrays, photodetector arrays, complementary metal-oxide-semiconductor (CMOS) image sensors, etc. Furthermore, the optical unit 720 may also include filters for allowing specific wavelengths to pass through, mirrors for guiding light emitted from the micro / nano well toward the detector, and lenses for collimating light emitted from the micro / nano well.

[0082] The processor 730 is electrically connected to the optical unit 720 and can control the driving of the light source of the optical unit 720. Additionally, the processor 730 can receive and analyze optical signals from the detector, and can detect biomolecules based on the analysis. For example, the processor 730 can use the results of digital nucleic acid amplification detected by the detector based on a Poisson distribution to perform quantitative analysis of biomolecules.

[0083] Reference Figure 8 ,Apart from Figure 7 In addition to the construction of the device 700 for detecting biomolecules, the device 800 for detecting biomolecules according to the example embodiment may also include a preprocessing unit 810.

[0084] The pretreatment unit 810 can perform pretreatment on a sample loaded in the first reservoir, wherein the pretreatment includes, for example, heating, chemical treatment, magnetic bead treatment, solid-phase extraction, ultrasonic treatment, etc. For this purpose, the pretreatment unit 810 may include various materials or structures for pretreatment (such as magnetic beads disposed inside and / or outside the first reservoir, chemical treatment zones, solid-phase extractors, ultrasonic devices (e.g., ultrasonic sources), optical and / or electric heating devices (or heaters), etc.), and the pretreatment unit 810 can control these materials or structures. At least some of the functions of the pretreatment unit 810 can be executed by the processor 730.

[0085] Reference Figure 9 ,Apart from Figure 7 or Figure 8 In addition to the construction of the device 700 or 800 for detecting biomolecules, the device 900 for detecting biomolecules according to the example embodiment may also include a temperature controller 910.

[0086] Temperature controller 910 can control the temperature of samples received in the first reservoir, the second reservoir, and / or the micro / nano trap array. For example, when the sample is loaded in the first reservoir, temperature controller 910 can control the temperature of the sample to be maintained at an isothermal temperature of 95°C or higher. Additionally, when the sample is dispersed in the second reservoir, temperature controller 910 can control the temperature of the sample to be maintained at an isothermal temperature of 30°C to 60°C.

[0087] Temperature controller 910 may include materials or structures for controlling the internal or external temperature of the first reservoir, the second reservoir, and / or the micro / nano well array. For example, an electric heater for electrically heating a sample may be formed inside the first reservoir, the second reservoir, and / or the micro / nano well array. The electric heater may include, for example, heating elements and / or Peltier elements. Optionally, temperature controller 910 may include an optical heater. The optical heater may include: one or more light sources disposed outside the microfluidic chip 710 and emitting light onto the microfluidic chip 710, and heating elements disposed inside the first reservoir, the second reservoir, and / or the micro / nano well of the microfluidic chip 710 and reacting with the light from the light source.

[0088] Additionally, the temperature controller 910 may include a temperature sensor disposed inside or outside the microfluidic chip 710 and measuring the temperature of samples in the first reservoir, the second reservoir, and / or the micro / nano trap. In this case, a thermocouple with a bimetallic junction that generates a temperature-dependent electromotive force (EMF), a resistance thermometer comprising a material having a resistance proportional to temperature, a thermistor, an integrated circuit (IC) temperature sensor, a quartz thermometer, or the like may be used as the temperature sensor.

[0089] Reference Figure 10 ,Apart from Figure 7 , Figure 8 or Figure 9 In addition to the construction of devices 700, 800 or 900, the device 1000 for detecting biomolecules according to the example embodiment may also include an output interface 1010, a storage device 1020 and a communication interface 1030.

[0090] The output interface 1010 can output information such as biomolecular detection processing, biomolecular detection results, and / or information about interactions with the user during biomolecular detection processing. The output interface 1010 can provide information to the user through visual, audio, and / or tactile methods using visual output modules (e.g., a display), audio output modules (e.g., a speaker), haptic modules, etc.

[0091] Storage device 1020 can store, for example, various information for detecting biomolecules and / or biomolecule detection results. Storage device 1020 may include at least one storage medium, which includes, but is not limited to, flash memory, hard disk memory, multimedia card micro-memory, card-type memory (e.g., Secure Digital (SD) memory, Extreme Digital (XD) memory, random access memory (RAM), static random access memory (SRAM), read-only memory (ROM), electrically erasable programmable read-only memory (EEPROM), programmable read-only memory (PROM), magnetic storage, magnetic disk, and optical disk.

[0092] The communication interface 1030 can communicate with external devices. For example, the communication interface 1030 can send data generated by the device 1000 for detecting biomolecules (e.g., biomolecule detection results, etc.) to the external device, and can receive data related to the detection of biomolecules from the external device. External devices may include medical devices, printers for printing results, or display devices. Additionally, external devices may include, but are not limited to, digital televisions (TVs), desktop computers, mobile phones, smartphones, tablet PCs (PCs), laptop computers, personal digital assistants (PDAs), portable multimedia players (PMPs), navigation devices, MP3 players, digital cameras, wearable devices, etc.

[0093] The communication interface 1030 can communicate with external devices using, for example, Bluetooth Low Energy (BLE), Near Field Communication (NFC), WLAN, Zigbee, Infrared Data Association (IrDA), Wi-Fi Direct (WFD), Ultra Wideband (UWB), Ant+, Wi-Fi, Radio Frequency Identification (RFID), 3G, 4G, and 5G communication. However, this is merely an example and not intended to be limiting.

[0094] Figure 11 This is a flowchart illustrating a method for detecting biomolecules according to an example embodiment.

[0095] Figure 11 The methods for detecting biomolecules can be described in detail above based on... Figures 7 to 10The example embodiments of the devices 700, 800, 900, and 1000 for detecting biomolecules will be used to perform this, and therefore, they will be briefly described below to minimize redundancy.

[0096] First, in operation 1110, the sample is loaded into the first reservoir of the microfluidic chip, and if necessary, the loaded sample can be pretreated by heating, chemical treatment, magnetic bead treatment, solid phase extraction, ultrasonic treatment, etc.

[0097] Then, in operation 1120, the sample in the first reservoir is dispersed and received in the second reservoir. The sample loaded in the first reservoir can be dispersed into multiple second reservoirs by using manual and / or automatic drive devices, capillary tubes, or electrowetting devices. During this process, particles can be filtered by a filter disposed on the channel connecting the first and second reservoirs.

[0098] Subsequently, when the sample is injected into the second reservoir, in operation 1130, the reactants for each target material included in the second reservoir are dissolved in the sample. In this case, each second reservoir may include reactants for different target materials, and the reactants for the target materials may be freeze-dried and immobilized in the second reservoir.

[0099] Next, in operation 1140, a sample solution in which the reactant against the target material is dissolved is injected from the second reservoir into the micro / nano trap array. In this case, the dissolved sample solution can be thoroughly mixed by using a mixer located at the channel connecting the second reservoir and the trap array or within the second reservoir.

[0100] Then, in operation 1150, an enzymatic reaction of the sample solution is performed in the micro / nano trap array. In this case, if the same solution is an RNA sample, reverse transcription using reverse transcriptase can be performed on the RNA sample. The enzymatic reaction may include, for example, a nucleic acid amplification reaction including at least one of polymerase chain reaction (PCR) amplification and isothermal amplification, or a redox reaction, hydrolysis reaction, etc. In this case, the temperature of the sample in the micro / nano trap can be controlled by using materials or devices for optical heating or electric heating.

[0101] Subsequently, the device for detecting biomolecules can measure the optical signal of the sample solution in the micro / nano trap during the enzyme reaction in operation 1160, and can detect biomolecules in operation 1170 by using the measured optical signal. In this case, by emitting light of a predetermined wavelength onto the micro / nano trap using the light source of the optical unit within a predetermined time period, the device for detecting biomolecules can detect optical signals (such as fluorescence, phosphorescence, absorbance, surface plasmon resonance, etc.), and can obtain quantitative results about the biomolecules by analyzing the detected optical signal based on Poisson distribution.

[0102] The disclosure can be implemented as computer-readable code written on a computer-readable recording medium. A computer-readable recording medium can be any type of recording device that stores data in a computer-readable manner.

[0103] Examples of computer-readable recording media include ROM, RAM, optical disc (CD)-ROM, magnetic tape, floppy disk, optical data storage devices, and carrier waves (e.g., data transmission over the Internet). Computer-readable recording media can be distributed across multiple computer systems connected to a network, allowing computer-readable code to be written into and executed from them in a distributed manner. Programs, code, and code segments used to implement publicly disclosed functions can be readily derived by computer programmers with ordinary skills in the art to which they pertain.

[0104] According to exemplary embodiments, at least one of the components, elements, modules, and units described herein can be implemented as various numbers of hardware, software, and / or firmware structures that perform the corresponding functions described above. For example, at least one of these components, elements, and units can use a direct circuit structure (such as a memory, processor, logic circuit, lookup table, etc.) that can perform the corresponding function under the control of one or more microprocessors or other control devices. Furthermore, at least one of these components, elements, and units can be implemented as a portion of a module, program, or code and executed by one or more microprocessors or other control devices, the portion of which contains one or more executable instructions for performing a specific logical function. Additionally, at least one of these components, elements, and units may also include a processor (such as a central processing unit (CPU) performing the corresponding function), a microprocessor, etc., or be implemented by a processor (such as a central processing unit (CPU) performing the corresponding function), a microprocessor, etc. Two or more of these components, elements, or units can be combined into a single component, element, or unit that performs all the operations or functions of the combined two or more components, elements, or units. Furthermore, at least a portion of the function of at least one of these components, elements, and units can be executed by another of these components, elements, or units. Furthermore, although a bus is not shown in the block diagram, communication between components, elements, or units can be performed via a bus. The functional aspects of the above example embodiments can be implemented in algorithms executed by one or more processors. Moreover, the components, elements, or units represented by blocks or processing operations can employ any number of existing technologies for electronic configuration, signal processing and / or control, data processing, etc.

[0105] Although the disclosed exemplary embodiments have been specifically shown and described, those skilled in the art will understand that changes in form and detail may be made therein without departing from the spirit and scope of the appended claims.

Claims

1. A microfluidic chip comprising: a first reservoir configured to contain a sample, the sample including a target material; a plurality of second reservoirs connected to the first reservoir, the plurality of second reservoirs including a reactant for the target material; a plurality of well arrays respectively connected to the plurality of second reservoirs and configured to contain a solution of the sample in which the reactant for the target material is dissolved, and an absorbent pad connected to the plurality of well arrays, wherein a location, a size, and a type of the absorbent pad are varied to control a flow rate and a flow volume of the solution of the sample through a well included in each of the plurality of well arrays.

2. The microfluidic chip of claim 1, wherein, A number of the plurality of second reservoirs is determined by a number of the target material and is in a range of 1 to 20.

3. The microfluidic chip of claim 2, wherein, A number of the plurality of well arrays is greater than or equal to a number of the plurality of second reservoirs.

4. The microfluidic chip of claim 1, wherein, A size of the well included in each of the plurality of well arrays is less than or equal to 1 nL.

5. The microfluidic chip of claim 1, wherein, A number of the well included in each of the plurality of well arrays is in a range of ten thousand to one million.

6. The microfluidic chip of claim 1, wherein, A bottom and a wall of the well included in each of the plurality of well arrays have different surface properties.

7. The microfluidic chip of claim 1, wherein, At least one of the well array of the plurality of well arrays and the first reservoir includes at least one of a field effect transistor, a silicon photonic structure, a two-dimensional micro material, a two-dimensional nano material, a two-dimensional micro structure, and a two-dimensional nano structure. 8.The microfluidic chip of claim 1, further comprising a filter located on a channel connecting the first reservoir and the plurality of second reservoirs. 9.The microfluidic chip of claim 8, further comprising a mixer disposed inside a second reservoir of the plurality of second reservoirs or at an outlet of the second reservoir. 10.The microfluidic chip of claim 1, further comprising a valve located on each channel connecting the plurality of second reservoirs and the plurality of well arrays, respectively. 11.The microfluidic chip of claim 1, further comprising a valve located on each channel connecting the plurality of well arrays and the absorbent pad, respectively. 12.The microfluidic chip of any one of claims 1 to 10, further comprising at least one of a slider, a centrifuge, and a puncher configured to inject a solution of a sample of the plurality of second reservoirs into the plurality of well arrays or to fix the solution of the sample to the plurality of well arrays. 13.The microfluidic chip of any one of claims 1 to 10, further comprising at least one of a bubble catcher, a bubble-removing material, and a gas-permeable material disposed inside a well array of the plurality of well arrays or at an inlet of the well array. 14.A microfluidic chip comprising: a reservoir configured to contain a sample, the sample including a target material, the reservoir including a reactant for the target material; a mixer disposed between the reservoir and the array of traps, the mixer being configured to mix a solution of the sample in which the reactant for the target material is dissolved; the array of traps in which an enzyme reaction of the solution of the sample injected through the mixer occurs; and an absorbent pad connected to the array of traps, wherein a position, a size, and a type of the absorbent pad are changed to control a flow rate and a flow volume of the solution of the sample through the traps included in the array of traps.

15. The microfluidic chip of claim 14, wherein, At least one of the reservoir and the array of traps includes at least one of a field effect transistor, a silicon photonic structure, a two-dimensional micromaterial, a two-dimensional nanomaterial, a two-dimensional microstructure, and a two-dimensional nanostructure.

16. The microfluidic chip of claim 14, further comprising a filter at an outlet of the reservoir.

17. An apparatus for detecting a biomolecule, the apparatus comprising: a first reservoir configured to contain a sample, the sample including a target material; a plurality of second reservoirs, each of the plurality of second reservoirs including a reactant for the target material; a plurality of array of traps in which an enzyme reaction of a solution of the sample in which the reactant for the target material is dissolved occurs; an absorbent pad connected to the plurality of array of traps, wherein a position, a size, and a type of the absorbent pad are changed to control a flow rate and a flow volume of the solution of the sample through the traps included in each of the plurality of array of traps, an optical unit including a light source and a detector, the optical unit being configured to emit first light onto the solution of the sample in the plurality of array of traps during the occurrence of the enzyme reaction and to measure an optical signal reflected from the solution of the sample; and a processor configured to detect the biomolecule based on the optical signal.

18. The apparatus of claim 17, wherein, The target material includes a duplex of one or more of a ribonucleic acid, a deoxyribonucleic acid, a peptide nucleic acid, a locked nucleic acid, an oligopeptide, a protein, and a toxin.

19. The apparatus of claim 17, wherein, The reactant for the target material includes one or more of a reverse transcriptase, a polymerase, a ligase, a peroxidase, a primer, and a probe.

20. The apparatus of claim 19, wherein, The primer includes an oligonucleotide.

21. The apparatus of claim 19, wherein, The probe includes at least one of an oligonucleotide, a fluorescent material, and a quencher.

22. The apparatus of claim 17, wherein, The reactant for the target material is freeze-dried.

23. The apparatus of any one of claims 17-22, further comprising: A pretreatment unit configured to perform a pretreatment on the sample contained in the first reservoir, the pretreatment including at least one of heating, chemical treatment, magnetic bead treatment, solid phase extraction, and ultrasonic treatment.

24. The apparatus of any one of claims 17-22, further comprising: A temperature controller configured to control a temperature of the sample contained in the first reservoir.

25. The apparatus of claim 24, wherein, The temperature controller includes at least one of an optical heater including a light source configured to emit second light onto the first reservoir and a heating material configured to react to the second light, and an electrical heater including one of a heating element and a Peltier element.

26. The apparatus of any one of claims 17-22, wherein, The enzyme reaction includes at least one of a nucleic acid amplification reaction including at least one of a polymerase chain reaction amplification and an isothermal amplification, an oxidation-reduction reaction, and a hydrolysis reaction.

27. The apparatus of any one of claims 17-22, wherein, The optical signal includes at least one of fluorescence, phosphorescence, absorbance, and surface plasmon resonance.

28. A method of detecting a biomolecule, the method comprising: loading a sample into a first reservoir of a microfluidic chip; providing a sample loaded in a first reservoir to a plurality of second reservoirs each including a reactant for a target material; injecting a solution of the sample in which the reactant is dissolved from the plurality of second reservoirs into a trap array; measuring an optical signal during an enzyme reaction occurring in the solution of the sample injected into the trap array; and detecting a biomolecule based on the measured optical signal, wherein the microfluidic chip includes an absorption pad connected to the trap array, wherein a position, a size, and a type of the absorption pad are varied to control a flow rate and a flow volume of the solution of the sample passing through the traps included in the trap array. 29.The method of claim 28, further comprising performing a pretreatment on the sample loaded in the first reservoir, the pretreatment including at least one of heating, chemical treatment, magnetic bead treatment, solid phase extraction, and ultrasonic treatment.

30. The method of claim 28, wherein, The target material includes ribonucleic acid, and the reactant for the target material includes reverse transcriptase.

31. The method of claim 28, wherein, The enzyme reaction includes at least one of a nucleic acid amplification reaction including at least one of polymerase chain reaction amplification and isothermal amplification, an oxidation-reduction reaction, and a hydrolysis reaction.

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