Microfluidic chip capable of flexible switching of multiple samples and multiple indicators in quantity, and intelligent detection system

Abstract

A microfluidic chip capable of flexible switching of multiple samples and multiple indicators in quantity, and an intelligent detection system. The microfluidic chip comprises: a chip body; a sample injection channel (1), wherein the sample injection channel (1) is arranged on the chip body, and a plurality of sample loading holes (11-16) are formed in the sample injection channel (1); an exhaust channel (2), wherein at least one exhaust channel (2) is arranged on the chip body, each exhaust channel (21, 22) is connected to the corresponding sample injection channel (1) by means of connecting channels (5) and microcavities (401-440), and each exhaust channel (21, 22) is provided with at least one exhaust hole (23, 24); and isolation cavities (31-35), wherein more than one isolation cavity (31-35) are arranged on flow channels between adjacent sample loading holes (11-16) and form simple valves with an expansion material to achieve flow path blocking and isolation.

Description

Flexible switching of microfluidic chips and intelligent detection systems for multiple samples and multiple indicators Technical Field

[0001] This application is about a multi-sample, multi-indicator, and flexible switching microfluidic chip and intelligent detection system, involving the fields of biomedicine, clinical medicine, food safety, and sanitation and epidemic prevention. Background Art

[0002] Nucleic acid protein detection and analysis are already widely used in biomedicine, clinical medicine, food safety, and epidemic prevention. Existing methods require the serial connection of multiple instruments, resulting in lengthy testing times, with results taking approximately 2-3 days to produce. Manual operation is complex, requiring a high level of technical proficiency and a heavy workload. These methods rely on specialized molecular biology laboratories, making them difficult to implement in primary healthcare settings, communities, supermarkets, and even homes.

[0003] Microfluidic chips are a relatively advanced method for nucleic acid and protein detection and analysis in recent years. However, the existing microfluidic chip structure is often relatively specialized and fixed. The corresponding number of samples added and the number of detection indicators are fixed as the microfluidic chip structure, which cannot be expanded and cannot adapt to new detection needs. In addition, microfluidic chips are relatively sophisticated and require precision machining and injection molding to ensure accuracy, which is relatively expensive. Once the microfluidic chip is not universal, it will bring limitations to the use of microfluidic chip test kits, and the corresponding production costs will be higher. This is not suitable for the promotion and application of microfluidic chip technology. This is also the fundamental reason why the cost of nucleic acid and protein detection based on microfluidic chips is high at this stage and cannot significantly reduce the detection cost. SUMMARY OF THE INVENTION

[0004] The present application provides a microfluidic chip and intelligent detection system with flexible switching of multiple samples and multiple indicators. The microfluidic chip includes a chip body; an injection pipe, an injection pipe is provided on the chip body, and a plurality of sample addition holes are provided on the injection pipe; an exhaust pipe, at least one exhaust pipe is provided on the chip body, each exhaust pipe is connected to the corresponding injection pipe through a connecting pipe and a microcavity, and each exhaust pipe is provided with at least one exhaust hole; an isolation cavity, one or more isolation cavities and expansion materials are provided on the flow channel between adjacent sample addition holes to form a simple valve to achieve flow path blocking and isolation. The present application sets a simple valve on the flow channel, and groups the microfluidic chip pipes and cavities by opening and closing the simple valve, so as to achieve flexible switching of the number of samples and the number of detection indicators, thereby improving the versatility of the microfluidic chip. Moreover, the intelligent detection system of the present application can realize fully integrated raw sample input and nucleic acid and protein analysis results output. Technical issues

[0005] This application aims to solve at least one of the technical problems existing in the prior art. To this end, in response to the above-mentioned problems, the purpose of this application is to provide a multi-sample and multi-indicator flexible switching microfluidic chip and intelligent detection system, which can realize flexible switching between the number of samples and the number of detection indicators on the microfluidic chip, significantly reduce manual operations, and effectively avoid cross contamination and infection. Technical Solutions

[0006] In order to achieve the above-mentioned invention objectives, the technical solutions adopted in this application are:

[0007] In a first aspect, the present application provides a microfluidic chip with flexible switching of multiple samples and multiple indicators, the microfluidic chip comprising:

[0008] Chip body;

[0009] A sampling pipe is provided on the chip body and is provided with a plurality of sampling holes;

[0010] An exhaust pipe, wherein at least one exhaust pipe is provided on the chip body, and each exhaust pipe is connected to the corresponding sampling pipe through a connecting pipe and a microcavity, wherein the two ends of a microcavity are connected to the sampling pipe and the exhaust pipe through a connecting pipe to form a detection channel, and the number of detection channels is set to be multiple; each exhaust pipe is provided with at least one exhaust hole;

[0011] Isolation cavity: more than one isolation cavity is provided on the flow channel between adjacent sample addition holes, and each isolation cavity is provided with a simple valve to achieve flow path blocking and isolation.

[0012] The microfluidic chip further comprises a simple valve made of an expandable material or a microstructure, wherein the expandable material expands to form the simple valve to achieve flow blocking and isolation, or the microstructure deforms the isolation cavity pipe through pressurization, heat pressing or ultrasound to form the simple valve to achieve flow blocking and isolation.

[0013] The microfluidic chip further has the sampling channel in a straight or curved shape, with sampling holes provided at both ends of the sampling channel, and a plurality of sampling holes provided at intervals in the middle of the sampling channel as required.

[0014] The microfluidic chip further comprises: an isolation cavity made of a water-swellable material, wherein the water-swellable material comprises a starch-grafted acrylate copolymer cross-linked product, an acrylamide-acrylate copolymer cross-linked product and / or a hydrogel resin; and when a sample is added to the sampling pipe, the swelling material swells with water to form a simple valve.

[0015] The microfluidic chip further comprises a heat-expandable material as the expansion material, which includes liquid metal, memory alloy, heat-expandable polymer material and / or heat-expandable polymer gel. When the pipeline is heated to a set temperature, the expansion material expands due to the heat to form a simple valve.

[0016] The microfluidic chip further comprises one or more isolation cavities provided on the flow channel, including the isolation cavities provided on the injection pipe and / or the connecting pipe, wherein the isolation cavities are provided in any one of the following forms:

[0017] The isolation cavity is arranged on the sampling pipe;

[0018] The isolation cavity is arranged on the connecting pipe, including: the isolation cavity is arranged at a tangent position of any connecting pipe, the isolation cavity is arranged at a position intersecting with a part of the connecting pipe, or the isolation cavity is connected to the connecting pipe through a section of pipe.

[0019] The microfluidic chip further has the vents covered with a waterproof breathable membrane, and the gas is discharged from the vents through the vent pipe; and / or the sample injection holes are covered with a sealing silicone rubber pad to prevent sample contamination.

[0020] In a second aspect, the present application further provides an intelligent detection system, comprising the microfluidic chip, the syringe-type sample preparation unit, the reagent storage unit, the optical detection system, the temperature control system, the heating unit, the heating and oscillation unit, the motion control system and / or the intelligent analysis system;

[0021] The injection tube sample preparation unit is configured to lyse the sample and extract, purify and concentrate nucleic acid and protein;

[0022] The reagent storage unit is configured to provide reagent storage for sample preparation of the injection tube sample preparation unit and reaction of the microfluidic chip;

[0023] The optical detection system is configured to detect the result of the reaction on the microfluidic chip;

[0024] The temperature control system is configured to perform constant temperature or variable temperature heating and temperature control on the sample preparation process in the injection tube sample preparation unit, and / or perform constant temperature or cyclic variable temperature heating and temperature control on the reaction process of the microfluidic chip;

[0025] The heating and shaking unit is configured to shake and / or heat the syringe-type sample preparation unit;

[0026] The heating unit is configured to heat and / or cool the microfluidic chip;

[0027] The motion control system is configured to control the sample preparation process in the syringe-type sample preparation unit and / or to perform motion control on the sample addition and / or reaction process of the microfluidic chip;

[0028] The intelligent analysis system is configured to perform human-computer interactive control of the sample preparation process and / or the reaction process of the microfluidic chip in the injection tube sample preparation unit, and / or store, analyze, display and / or directly issue early warning reports on the sample reaction detection results obtained by the optical detection system.

[0029] The intelligent detection system further comprises the syringe-type sample preparation unit comprising a syringe barrel, a piston, a filter membrane or filter paper, a sealing ring, a needle and a protective cover, wherein the piston is movably arranged in the syringe barrel, the filter membrane or filter paper and the sealing ring are arranged at the bottom of the syringe barrel, the needle is arranged at the bottom outlet of the syringe barrel, and the protective cover is arranged on the needle.

[0030] The intelligent detection system further comprises the syringe barrel pre-stored with swab preservation elution lysis solution and / or surface-modified magnetic beads, glass beads, nanomaterials or polymer materials, wherein the surface modification treatment includes broad-spectrum anion exchange modification that is negatively charged in an acidic environment, specific group modification based on nucleic acid hybridization or protein immune binding principles for capturing targets of interest, adsorption of negatively charged nucleic acid proteins in an acidic environment, release of negatively charged nucleic acid proteins in an alkaline environment, adsorption of nucleic acid proteins at low temperatures and / or release of nucleic acid proteins at high temperatures.

[0031] The intelligent detection system further comprises the microfluidic chip, syringe sample preparation unit, reagent storage unit, optical detection system, temperature control system, heating unit, heating and oscillation unit, motion control system and intelligent analysis system all used in combination to achieve fully integrated original sample input and nucleic acid and protein analysis result output; or, the syringe sample preparation unit, reagent storage unit, temperature control system, heating and oscillation unit, motion control system and intelligent analysis system are used in combination to form an independent sample processing system for sample lysis and nucleic acid and protein extraction, purification and concentration; or, the microfluidic chip, optical detection system, temperature control system, heating unit, motion control system and intelligent analysis system are used in combination to form an independent nucleic acid and protein detection intelligent analysis system. Beneficial effects

[0032] Due to the adoption of the above technical solution, this application has the following characteristics:

[0033] 1. Compared with the conventional microfluidic chip method, this application sets a simple valve on the flow channel, and groups the microfluidic chip pipelines and cavities by opening and closing the simple valve, so as to realize flexible switching of the number of samples and the number of detection indicators, improve the versatility of the microfluidic chip, lower the technical use threshold and the requirements for site environmental conditions, and meet the needs of popularization and application of microfluidic chip precision medicine molecular diagnosis.

[0034] 2. Compared with conventional biochemical analysis methods using centrifuge tubes or well plates, this application not only significantly reduces the consumption of sample reagents (<1µL / indicator), but also allows for the parallel detection of dozens or even hundreds of specific gene protein analysis indicators with a single injection, significantly reducing manual operation steps and labor intensity, making swab sampling and testing safer, more robust, and more efficient. In addition, users can automatically perform nucleic acid amplification or protein immunoassay analysis without the need for help or assistance from professional technicians, and without any site environment requirements. This allows for standardized operations on-site, at home, in the community, in medical institutions at all levels, in health and epidemic prevention departments, in food safety departments, and so on, to avoid the influence of human factors.

[0035] 3. Compared with the conventional swab elution method, this application is compatible with two methods of sealed elution separation of sampling contaminated samples, namely, adding eluent to the sampling swab or directly adding the sampling swab. The eluent is efficiently transferred in situ, and after sampling, the syringe is placed in the injection tube and the lid is no longer opened, which effectively avoids serious problems such as infection of subsequent operators and cross-contamination throughout the process, which cannot guarantee safety and reliability. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Various other advantages and benefits will become apparent to those skilled in the art upon reading the detailed description of the preferred embodiment below. The accompanying drawings are for illustration purposes only and are not to be considered as limiting the present application. Throughout the drawings, the same reference numerals are used to represent the same components. In the drawings:

[0037] FIG1 is a schematic structural diagram of a multi-sample, multi-indicator, and quantity-flexible switching microfluidic chip according to an embodiment of the present application.

[0038] FIG2 is a schematic diagram of the isolation cavity position structure of a simple valve according to an embodiment of the present application.

[0039] FIG3 is a schematic diagram of the microstructure of a simple valve according to an embodiment of the present application.

[0040] FIG4 is a schematic structural diagram of an intelligent detection system according to an embodiment of the present application.

[0041] FIG5 is a schematic structural diagram of an injection tube type sample preparation unit according to an embodiment of the present application.

[0042] FIG6 is a schematic structural diagram of independent nucleic acid / protein extraction, purification and concentration sample preparation according to one embodiment of the present application. Modes for Carrying Out the Invention

[0043] It should be understood that the terms used herein are for the purpose of describing specific example embodiments only and are not intended to be limiting. Unless the context clearly indicates otherwise, the singular forms "one", "an", and "" as used herein may also be meant to include plural forms. The terms "comprise", "include", "contain", and "have" are inclusive and therefore specify the presence of the stated features, steps, operations, elements, and / or parts, but do not exclude the presence or addition of one or more other features, steps, operations, elements, parts, and / or combinations thereof. The method steps, processes, and operations described herein are not to be construed as necessarily requiring them to be performed in the specific order described or illustrated, unless the order of execution is clearly indicated. It should also be understood that additional or alternative steps may be used.

[0044] Although the terms first, second, third, etc. can be used in the text to describe multiple elements, components, regions, layers and / or sections, these elements, components, regions, layers and / or sections should not be limited by these terms. These terms can only be used to distinguish an element, component, region, layer or section from another region, layer or section. Unless the context clearly indicates otherwise, terms such as "first", "second" and other numerical terms do not imply order or sequence when used in the text. Therefore, the first element, component, region, layer or section discussed below can be referred to as the second element, component, region, layer or section without departing from the teaching of the example embodiments.

[0045] For ease of description, spatially relative terms may be used herein to describe the relationship of one element or feature relative to another element or feature as shown in the figures, such as "inside," "outside," "inner side," "outer side," "lower," "upper," etc. Such spatially relative terms are intended to encompass different orientations of the device in use or operation in addition to the orientation depicted in the figures.

[0046] Since the existing microfluidic chips are not universal, the production cost is relatively high and the cost of nucleic acid protein detection based on microfluidic chips is relatively high. The present application provides a multi-sample multi-index flexible switching microfluidic chip, including a chip body; a sampling pipeline, a sampling pipeline is provided on the chip body, and a plurality of sample addition holes are provided on the sampling pipeline; an exhaust pipeline, at least one exhaust pipeline is provided on the chip body, and each exhaust pipeline is connected to the corresponding sampling pipeline through a connecting pipeline and a microcavity, wherein the two ends of a microcavity are connected to the sampling pipeline and the exhaust pipeline through a connecting pipeline to form a detection channel, and the number of detection channels is set to be several; each exhaust pipeline is provided with at least one exhaust hole; an isolation cavity, more than one isolation cavity is provided on the flow channel between adjacent sample addition holes, and each isolation cavity is provided with an expansion material or microstructure, wherein the expansion material forms a simple valve after expansion to achieve flow path blocking isolation, and the microstructure deforms the isolation cavity microstructure and the pipeline to form a simple valve to achieve flow path blocking isolation by pressurization, hot pressing or ultrasound. Moreover, the intelligent detection system of the present application can realize the fully integrated original sample input and nucleic acid protein analysis result output; it can also be simplified into an independent sample processing system for sample lysis and nucleic acid protein extraction, purification and concentration; it can also be compatible with nucleic acid proteins extracted by other sample preparation methods to form an independent nucleic acid protein detection intelligent analysis system. Compared with the microfluidic chip method of conventional nucleic acid amplification / protein immunoassay, the present application uses a simple valve flow isolation technology to achieve flexible switching between the number of samples and the number of detection indicators, and uses a fully integrated nucleic acid / protein extraction and purification method of an injection tube to realize the use of a hardware platform for both nucleic acid amplification / protein immunoassay systems. When in use, the user only needs to add the original sample, and the intelligent detection system can complete the "sample in, result out" fully integrated nucleic acid amplification / protein immunoreaction detection and analysis, without the need for complex professional technical operations and the need for a dedicated laboratory site environment. It can meet the needs of standardized operation and use of nucleic acid / protein analysis in the field, at home, in the community, in physical examination centers, medical institutions at all levels, health and epidemic prevention departments and food safety management departments, as well as biomedical research, biological and chemical warfare agent detection, environmental testing or other fields.

[0047] The following describes exemplary embodiments of the present application in more detail with reference to the accompanying drawings. Although exemplary embodiments of the present application are shown in the accompanying drawings, it should be understood that the present application can be implemented in various forms and should not be limited by the embodiments described herein. Instead, these embodiments are provided to enable a more thorough understanding of the present application and to fully convey the scope of the present application to those skilled in the art.

[0048] It should be noted that each structure of this embodiment can be supported and fixed by a corresponding structure, and the specific fixing method is not limited, as long as it can meet the corresponding functions of this application. In order to facilitate understanding, convenient use, and reduce weight, the drawings of this embodiment mainly use hollow cylinders, rectangles, squares, circles or ellipses to schematically implement the modules. This is only an example and is not limited to this. Only one or more repeating units are drawn. This is only an example and is not limited to this. In fact, the corresponding structure can be used for repeated implementation multiple times.

[0049] Example 1: As shown in FIG1 , the multi-sample, multi-index, and flexible switching microfluidic chip provided in this embodiment includes:

[0050] Chip body;

[0051] The chip body is provided with a linear or curved sampling channel, with a number of sample addition holes spaced apart. This embodiment is described using an S-shaped sampling channel 1 as an example, but this is not intended to be limiting. Each end of the S-shaped sampling channel 1 is provided with a sample addition hole 11 and 16, and each bend of the S-shaped sampling channel 1 is provided with a sample addition hole 12-15. In this embodiment, six sample addition holes 11-16 are provided, but this is not intended to be limiting. The location and number of the sample addition holes can be adjusted according to actual needs.

[0052] The chip body is also provided with at least one exhaust pipe 2. In this embodiment, two exhaust pipes 21 and 22 are provided. This is taken as an example, but is not limited to this. The number of exhaust pipes can be set according to actual detection needs. Each exhaust pipe is connected to the corresponding S-shaped sampling pipe 1 through a connecting pipe 5 and a microcavity. The two ends of a microcavity are respectively connected to the sampling pipe and the exhaust pipe through a connecting pipe 5 to form a detection channel. The number of detection channels can be set according to actual needs. In this embodiment, 40 detection channels are provided. This is taken as an example, but is not limited to this. Each exhaust pipe 21 (22) is provided with at least one exhaust hole 23 (24). Among them, the flow channel between adjacent sampling holes, such as the sampling pipe or the connecting pipe, can be provided with more than one isolation cavity. Each isolation cavity is provided with an expansion material or a microstructure. After the expansion material expands, a simple valve is formed to achieve flow path blocking isolation. The microstructure is deformed by pressurization, heat pressing or ultrasound to form a simple valve to achieve flow path blocking isolation. Therefore, this embodiment adopts a simple valve-type flow path isolation technology, sets a simple valve on the flow channel, and groups the microfluidic chip pipelines and microcavities by opening and closing the simple valve, thereby realizing flexible switching of the number of samples and the number of detection indicators.

[0053] In a preferred embodiment of the present application, the expansion material can be a water-swellable material, such as starch grafted acrylate polymer cross-linked material, acrylamide-acrylate copolymer cross-linked material, hydrogel resin, etc. When the sample is added to the inlet pipe, the expansion material expands in water to form a simple valve, thereby achieving flow path blocking and isolation.

[0054] Furthermore, the isolation cavity may be provided at any of the following locations on the flow channel:

[0055] As shown in FIG2 (a), the isolation cavity can be provided on the sampling pipeline. For example, the sampling pipelines between adjacent sampling holes are provided with isolation cavities 31-35. In each isolation cavity, for example, a simple valve formed by an expansion material is provided, which can realize rapid flow path blocking and isolation, ensuring that different samples can only enter the corresponding microcavity area after entering from different sampling holes, and will not spread and contaminate other microcavity areas.

[0056] The isolation chamber can be placed on the connecting pipe. As shown in Figure 2(b), the isolation chamber can be placed at any tangent point to the connecting pipe; as shown in Figure 2(c), the isolation chamber can be placed at a location that intersects a portion of the connecting pipe. As shown in Figure 2(d), the isolation chamber can be connected to the connecting pipe via a section of pipe. Therefore, an expandable material can be placed within the isolation chamber next to the connecting pipe. By varying the distance between the connecting pipe and the isolation chamber or the thickness of the pipe, the expandable material expands upon contact with water or heat, forming a simple valve. This can achieve flow path blocking and isolation with a lag of several seconds to several minutes, ensuring that the added sample completely fills the microcavity and expel all gas.

[0057] In a preferred embodiment of the present application, the microstructure can be deformed by applying pressure, heat, or ultrasound to the pipe to form a simple valve, thereby blocking and isolating the flow path. As shown in Figure 3, the microstructure is not limited to any shape and can be configured as needed, such as spherical, triangular, or sawtooth shapes.

[0058] In a preferred embodiment of the present application, the expansion material can also be placed in the isolation cavity using a heated expansion material, such as liquid metal, memory alloy, thermal expansion polymer material, thermal expansion polymer gel, etc. When the pipeline is heated to a certain temperature, the expansion material expands due to the heat to form a simple valve, thereby achieving flow blocking isolation.

[0059] Furthermore, the exhaust hole 23 (24) can be covered with a waterproof breathable membrane, and the gas is discharged from the exhaust hole 23 (24) through the exhaust pipe 21 (22).

[0060] Furthermore, the sample injection holes 11-16 are covered with sealing silicone rubber pads to prevent sample contamination.

[0061] In summary, when the multi-sample, multi-indicator, and flexible switching microfluidic chip of this embodiment is used, the simple valves in this embodiment are set in the isolation chambers 31-35 and 36-37, and the nucleic acid / protein analysis indicators are set in the microcavities 401-440 by low-melting-point agarose embedding or freeze-dried microsphere storage; the sample enters the injection pipe 1 from the injection hole 11-16, quickly fills the microcavity 401-440 through the connecting pipe 5, and is then blocked and isolated by the simple valve of the isolation chamber 36-37 set next to the connecting pipe or 31-35 on the injection pipe to prevent cross contamination. For example, when all the simple valves 31-35 of the isolation chamber are filled with water-expandable materials, the micro-chamber area is divided into 6 groups, corresponding to 6 sampling wells 11-16, and 6 samples can be input. The sample input into sampling well 11 corresponds to micro-chambers 401-405 for a total of 5 indicators to be detected, the sample input into sampling well 12 corresponds to micro-chambers 406-410 for a total of 5 indicators to be detected, the sample input into sampling well 14 corresponds to micro-chambers 411-415 and 421-425 for a total of 10 indicators to be detected, the sample input into sampling well 13 corresponds to micro-chambers 416-420 and 426-430 for a total of 10 indicators to be detected, the sample input into sampling well 15 corresponds to micro-chambers 431-435 for a total of 5 indicators to be detected, and the sample input into sampling well 16 corresponds to micro-chambers 436-440 for a total of 5 indicators to be detected. For example, when only portions 32 and 34 of the isolation chamber simple valves 31-35 are filled with water- or heat-expandable material, the microcavity area is divided into three groups. Only three corresponding sample loading holes, 11 or 12, 13 or 14, and 15 or 16, are needed to input three samples. The sample inputted into loading hole 11 or 12 corresponds to microcavities 401-410 for testing a total of 10 indicators, the sample inputted into loading hole 13 or 14 corresponds to microcavities 411-430 for testing a total of 20 indicators, and the sample inputted into loading hole 15 or 16 corresponds to microcavities 431-440 for testing a total of 10 indicators. Therefore, precisely based on this configuration of the isolation chamber simple valves 31-35, flexible switching combinations of adding 1-6 different sample quantities and testing 5-40 different test indicators can be achieved. Furthermore, as the sample feed line is extended and the number of microcavities increases, the corresponding number of samples and test indicators will be more diverse, meeting the needs of varying sample quantities and test indicators in different practical applications.

[0062] Example 2: This example provides a fully integrated nucleic acid amplification or protein immune response intelligent detection system for injection tube sample preparation, which enables the entry of multiple samples of biological samples containing but not limited to one or more mixtures of pathogens, microorganisms, tissue cells, exosomes, extracellular vesicles, etc., and the output of detection result reports of multiple nucleic acid / protein analysis indicators.

[0063] As shown in Figure 4, the fully integrated nucleic acid amplification or protein immune reaction intelligent detection system for syringe-type sample preparation provided in this embodiment includes the multi-sample and multi-indicator quantity flexible switching microfluidic chip 10 described in Example 1, one or more syringe-type sample preparation units 20 for nucleic acid / protein extraction and purification, one or more reagent storage units 30, an optical detection system 40, a temperature control system 50, a heating unit 60, a heating and oscillation unit 70, a motion control system 80 and / or an intelligent analysis system 90.

[0064] The syringe sample preparation unit 20 is configured to perform automated nucleic acid / protein extraction, purification, and concentration processing on the original sample in a syringe by combining one or more of the following methods: high temperature and / or vibration disruption and / or chemical reagent lysis;

[0065] The reagent storage unit 30 is configured to set up multiple reagent and waste liquid storage chambers according to the needs of nucleic acid / protein sample preparation and amplification / immune reaction. The corresponding reagents are stored inside and are sealed with rubber stoppers, suitable for syringe needles to be inserted for sampling or discharge of waste liquid;

[0066] The optical detection system 40 is configured to detect the results of nucleic acid amplification or protein immune reaction on the microfluidic chip 10 with flexible switching of multiple samples and multiple indicators;

[0067] The temperature control system 50 is configured to perform constant or variable temperature heating and temperature control on the sample preparation process in the injection tube-type nucleic acid / protein extraction and purification sample preparation unit, and / or perform constant or cyclic variable temperature heating and temperature control on the nucleic acid amplification or protein immunoreaction process of the multi-sample, multi-index, and flexible switching microfluidic chip 10;

[0068] The heating unit 60 is configured to heat and / or cool the multi-sample and multi-indicator quantity flexibly switched microfluidic chip 10;

[0069] The heating and shaking unit 70 is configured to shake and / or heat the syringe-type sample preparation unit 20;

[0070] The motion control system 80 is configured to perform oscillation and crushing control, liquid aspiration / discharge control, etc. during the sample preparation process in the syringe-type nucleic acid / protein extraction and purification sample preparation unit, and / or perform motion control on the microfluidic chip 10 for flexible switching of multiple samples and multiple indicators for sample addition and nucleic acid amplification or protein immune reaction;

[0071] The intelligent analysis system 90 is configured to perform human-computer interactive control of the sample preparation process of nucleic acid / protein extraction, purification, and concentration of biological samples and the detection process of nucleic acid amplification or protein immune reaction, and / or store, analyze, display and / or directly report the results of nucleic acid amplification or protein immune reaction detection of biological samples.

[0072] In a preferred embodiment of the present application, as shown in FIG5 , the syringe-type sample preparation unit of this embodiment is configured as two parallel sample preparation units, and one of the syringe-type sample preparation units 20 is used as a specific embodiment for description, and includes a syringe barrel 201, a piston 202, a filter membrane or filter paper 203, a sealing ring 204, a needle 205, and a protective cover 206. The piston 202 is movably disposed within the syringe barrel 201, the filter membrane or filter paper 203 and the sealing ring 204 are disposed at the bottom of the syringe barrel 201, the needle 205 is disposed at the bottom outlet of the syringe barrel 201, and the needle 205 is provided with a protective cover 206.

[0073] Furthermore, the syringe barrel 201 is pre-loaded with a lysis preservation solution for sample inactivation and prevention of nucleic acid and protein degradation. The piston 202 is first removed, and swab sampling or minimally invasive sampling methods are used to add one or more mixed original samples including but not limited to pathogens, microorganisms, tissue cells, exosomes, exosomes, etc., such as swab wash fluid, biopsy puncture fluid, saliva, sputum, sweat, blood, urine, feces, etc., to the preservation solution of the syringe barrel 201, and the piston 202 is installed and adjusted to the appropriate position, and then installed in the syringe tube sample preparation fully integrated nucleic acid amplification or protein immune response intelligent detection system. The automatic control of the syringe tube sample preparation fully integrated nucleic acid amplification or protein immune response intelligent detection system can realize the "sample in, result out" fully automated nucleic acid amplification or protein immune response precision medicine molecular diagnosis.

[0074] Furthermore, the syringe barrel 201 is pre-stored with swab-preserved elution and lysis solution and / or surface-modified magnetic beads or glass beads or other nanomaterials or polymer materials. The surface modification treatment includes but is not limited to broad-spectrum anion exchange modification that is negatively charged in an acidic environment, specific group modification based on nucleic acid hybridization or protein immunobinding principles for capturing targets of interest, etc., which adsorb negatively charged nucleic acid proteins or other biological samples in an acidic environment and release negatively charged nucleic acid proteins or other biological samples in an alkaline environment, or adsorb nucleic acid proteins or other biological samples at low temperatures and release nucleic acid proteins or other biological samples at high temperatures. Therefore, the present application adopts strategies such as filter membranes or filter paper and / or magnetic beads or anion exchange adsorption nucleic acid protein concentration and purification, which is not only suitable for nucleic acid protein detection and analysis of different biological samples such as pathogens, microorganisms, tissue cells, exosomes, and exosomes, but can also effectively reduce the amount of eluent used and increase the initial concentration of subsequent use such as recovered adhered samples or lysed nucleic acid proteins by nearly a hundred times.

[0075] In a preferred embodiment of the present application, as shown in Figure 6, the syringe-type sample preparation unit 20, under the joint action of the temperature control system 50, the heating and oscillation unit 70 and the motion control system 80, produces independent or combined biological sample lysis effects such as oscillation mechanical crushing and high-temperature lysis. It can also and / or be combined with the chemical lysis reagent pre-installed in the syringe to produce one or more combined biological sample lysis effects of high temperature, mechanical crushing, and chemical reagent lysis, so that the original biological sample in the syringe releases nucleic acid proteins, and under the action of the motion control system 80, various reagents are sequentially sucked from the reagent storage unit 30, and the waste liquid generated in the intermediate processing process is discharged into the waste liquid storage chamber of the reagent storage unit 30, so as to realize the automated nucleic acid / protein extraction, purification and concentration treatment of the original sample in one syringe, and finally the purified and concentrated nucleic acid / protein is injected into the multi-sample, multi-indicator and quantity-flexible switching microfluidic chip 10 or other nucleic acid protein detection system, so as to meet the sample preparation application needs of automated nucleic acid / protein extraction, purification and concentration treatment of the original sample.

[0076] In a preferred embodiment of the present application, the reagent storage unit 30 is provided with multiple reagent storage chambers and at least one large-volume waste liquid storage chamber, which is sealed with a rubber stopper and suitable for the insertion of a syringe needle to absorb samples or discharge waste liquid, thereby meeting the needs of nucleic acid / protein extraction, purification and concentration processing of biological samples.

[0077] In a preferred embodiment of the present application, the heating and shaking unit 70 is used to perform a sample lysis treatment on the original biological sample in the syringe barrel 201 by a combination of high temperature and / or shaking crushing and / or chemical reagent lysis, so as to efficiently separate and produce nucleic acid proteins.

[0078] In a preferred embodiment of the present application, the optical detection system 40 uses existing technologies to perform wide-field imaging, confocal scanning and other detections on the results of nucleic acid amplification or protein immune reaction, including an objective lens, an illumination light source, an excitation filter, an imaging lens, an emission filter and a detector. Fluorescence signal detection can be performed by switching the filter, and the filter can be placed in an empty position to perform white light interference hyperspectral signal thickness decoding super-resolution measurement. Turbidity, phase contrast, colorimetry, spectrum or other spectrophotometric measurements can also be performed using a mobile phone or the human eye, etc., which will not be elaborated here.

[0079] In a preferred embodiment of the present application, the temperature control system 50 is combined with the heating unit 60 to realize constant temperature or cyclic temperature heating and temperature control of the nucleic acid amplification or protein immune reaction process of the microfluidic chip 10 with flexible switching of multiple samples and multiple indicators, thereby meeting the needs of constant temperature or cyclic temperature amplification of nucleic acids or protein immune reaction.

[0080] Furthermore, the temperature control system 50 is combined with the heating and shaking unit 70 to achieve constant temperature or variable temperature heating and temperature control of the sample preparation process in the injection tube type nucleic acid / protein extraction and purification sample preparation unit, meeting the sample preparation needs of nucleic acid / protein extraction and purification.

[0081] In a preferred embodiment of the present application, the motion control system 80 is combined with the heating and shaking unit 70 to implement shaking and crushing control, liquid aspiration / discharge control, etc. for the sample preparation process in the injection tube type nucleic acid / protein extraction and purification sample preparation unit.

[0082] Furthermore, the motion control system 80 works in conjunction with the optical detection system 40 to realize motion control of the nucleic acid amplification or protein immune response process of the microfluidic chip 10 with flexible switching of multiple samples and multiple indicators, meeting the needs of imaging or confocal scanning detection of real-time signals of nucleic acid amplification or protein immune response of the microcavity in the microfluidic chip 10 with flexible switching of multiple samples and multiple indicators.

[0083] In a preferred embodiment of the present application, the intelligent analysis system 90 includes a microprocessor signal storage, processing and analysis unit, a wired or wireless communication interface, a display terminal and a cloud big data server, etc., in conjunction with the temperature control system 50, the motion control system 80 and the optical detection system 40, to achieve human-computer interactive control of the biological sample preparation and nucleic acid amplification or protein immune reaction detection process, and to store, analyze, display and / or directly report the detection results, wherein,

[0084] The signal storage, processing and analysis unit is equipped with a big data priori knowledge base of specific gene protein detection indicators for precision medical molecular diagnosis of various viruses, pathogens, tumors and cancers. Based on the big data priori knowledge base of specific gene protein detection indicators, artificial intelligence and / or big data analysis is performed on the nucleic acid protein molecular diagnostic test results of swab samples to obtain specific gene protein detection and identification results of various biomedical indicators.

[0085] Wired or wireless communication interface, used to transmit the detection and identification results of specific gene proteins to the mobile phones of relevant personnel, or directly report to the cloud big data server or the national health and epidemic prevention and health risk monitoring network platform for epidemic infectious diseases, major chronic diseases, malignant tumors and cancers, to realize smart medical networking between individuals, families, communities, township clinics and medical units and health and epidemic prevention departments at all levels, and to predict and warn of highly prevalent infectious diseases, major chronic diseases, malignant tumors and cancers.

[0086] The display terminal is used to display the specific gene protein detection and identification results of various biomedical indicators.

[0087] Furthermore, the intelligent analysis system 90 also has intelligent analysis functions such as artificial intelligence and machine learning for the results of multi-indicator combined detection, further improving the accuracy and reliability of nucleic acid or protein molecule diagnosis results.

[0088] In a preferred embodiment of the present application, the microfluidic chip 10, optical detection system 40, temperature control system 50, heating unit 60, motion control system 80 and intelligent analysis system 90 in the fully integrated nucleic acid amplification or protein immune response intelligent detection system for injection tube sample preparation can be used in combination to form an independent nucleic acid protein detection intelligent analysis system, which is compatible with nucleic acid / protein samples obtained using conventional sample preparation methods. The samples can be manually added to the microfluidic chip 10 in multiple samples and multiple indicators, and the microfluidic chip 10 can be flexibly switched. Then, the corresponding optical detection system 40, temperature control system 50, heating unit 60, motion control system 80 and / or intelligent analysis system 90 are used in combination to perform intelligent detection and analysis of nucleic acid amplification or protein immune response.

[0089] In a preferred embodiment of the present application, as shown in Figure 6, the injection tube-type nucleic acid / protein extraction and purification sample preparation unit 20, the reagent storage unit 30, the temperature control system 50, the heating and shaking unit 70, the motion control system 80, and the microprocessor signal storage, processing, and analysis unit of the intelligent analysis system 90 can also be used in combination to form an independent nucleic acid / protein extraction, purification, and concentration sample preparation system to meet the application needs of other detection methods requiring nucleic acids and proteins.

[0090] In summary, the intelligent detection system provided by this application allows users to independently operate and simultaneously perform multiple samples, two or more (up to hundreds) of pathogenic bacteria (bacteria, fungi, viruses, microorganisms, model organisms, etc.) infection indicators, or specific gene protein detection indicators for tumor and cancer analysis. The sample reagent consumption for each detection indicator can be reduced from tens of microliters to less than 1 microliter as needed. In addition, the simple valve flow isolation technology and the flexible switching microfluidic chip for multiple samples and multiple indicators provided by this application effectively improve the versatility of microfluidic chips and realize flexible switching of the number of samples and the number of detection indicators.

[0091] Each embodiment in this specification is described in a progressive manner, and the same or similar parts between the embodiments can be referred to each other, and each embodiment focuses on the differences from other embodiments. In the description of this specification, the reference terms "a preferred embodiment", "further", "specifically", "in the present embodiment", etc. mean that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the embodiment of this specification. In this specification, the schematic representation of the above terms does not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in a suitable manner in any one or more embodiments or examples. In addition, those skilled in the art can combine and combine the different embodiments or examples described in this specification and the features of different embodiments or examples, unless they are contradictory.

[0092] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present application, rather than to limit them. Although the present application has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or make equivalent replacements for some of the technical features therein. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present application.

[0093] CROSS-REFERENCE TO RELATED APPLICATIONS

[0094] This application claims priority to the Chinese patent application (application number 202311511660.1) filed on November 14, 2023, the entire contents of which are incorporated herein by reference. Industrial Applicability

[0095] This application can effectively improve the versatility of microfluidic chips, solve the problem of advanced diagnostic technology and equipment needs for convenient smart medical care, and realize the advancement of health and epidemic prevention and precision medicine, from large hospitals and third-party testing centers to townships, communities, and families, effectively alleviating the current pressure on large hospitals to seek medical treatment, and realizing the intelligent network of medical, health and epidemic prevention covering townships, communities, families, large hospitals, third-party testing centers, health and epidemic prevention departments, etc., effectively improving the advanced scientific and technological level of national precision medicine and health and epidemic prevention, and can be widely used in on-site, home, community, township clinics, physical examination centers and clinical medical units at all levels, health and epidemic prevention departments, food safety management departments, as well as biomedical research, biological and chemical warfare agent detection, environmental testing or other fields.

Claims

1. A microfluidic chip with flexible switching of multiple samples and multiple indicators, characterized in that: The microfluidic chip includes: Chip body; A sampling pipeline, which is arranged on the chip body and has a plurality of sampling holes; An exhaust pipeline, at least one exhaust pipeline is provided on the chip body, each of the exhaust pipelines is connected to the corresponding sample introduction pipeline through a connecting pipeline and a microcavity, wherein two ends of a microcavity are respectively connected to the sample introduction pipeline and the exhaust pipeline through a connecting pipeline to form a detection channel, and the number of the detection channels is set to be several; each of the exhaust pipelines is provided with at least one exhaust hole; Isolation cavity: more than one isolation cavity is arranged on the flow channel between adjacent sample addition holes, and each isolation cavity is provided with a simple valve to achieve flow path blocking and isolation.

2. The microfluidic chip according to claim 1, characterized in that: The simple valve adopts an expansion material or a microstructure, wherein the expansion material expands to form the simple valve to achieve flow path blocking and isolation, or the microstructure deforms the isolation cavity pipeline through pressurization, heat pressing or ultrasound to form the simple valve to achieve flow path blocking and isolation.

3. The microfluidic chip according to claim 2, characterized in that: The isolation cavity is made of water-swellable material, which includes starch-grafted acrylate polymer cross-linked material, acrylamide-acrylate copolymer cross-linked material and / or hydrogel resin. When a sample is added to the sampling pipeline, the swelling material swells with water to form a simple valve.

4. The microfluidic chip according to claim 2, characterized in that: The expansion material is a heat expansion material, which includes liquid metal, memory alloy, heat expansion polymer material and / or heat expansion polymer gel. When the pipeline is heated to a set temperature, the expansion material expands due to the heat to form a simple valve.

5. The microfluidic chip according to claim 1, characterized in that: The flow channel is provided with one or more isolation cavities, including providing the isolation cavity on the injection pipe and / or the connecting pipe, wherein the isolation cavity is provided in any of the following forms: The isolation cavity is arranged on the sampling pipeline; The isolation cavity is arranged on the connecting pipe, including: the isolation cavity is arranged at any tangent position of the connecting pipe, the isolation cavity is arranged at a position intersecting with a part of the connecting pipe, or the isolation cavity is connected to the connecting pipe through a section of pipe.

6. The microfluidic chip according to claim 1, characterized in that: The exhaust hole is covered with a waterproof breathable membrane, and the gas is discharged from the exhaust hole through the exhaust pipe; and / or the sample injection hole is covered with a sealing silicone rubber pad to prevent sample contamination; and / or the sample injection pipe is straight or curved, and sample injection holes are respectively arranged at both ends of the sample injection pipe, and a plurality of sample injection holes are arranged in the middle of the sample injection pipe at intervals as needed.

7. An intelligent detection system, characterized in that: The microfluidic chip, the injection tube sample preparation unit, the reagent storage unit, the optical detection system, the temperature control system, the heating unit, the heating oscillation unit, the motion control system and / or the intelligent analysis system according to any one of claims 1 to 6 are included; The injection tube sample preparation unit is configured to lyse the sample and extract, purify and concentrate nucleic acid proteins; The reagent storage unit is configured to provide reagent storage for sample preparation of the injection tube sample preparation unit and reaction of the microfluidic chip; The optical detection system is configured to detect the result of the reaction of the microfluidic chip; The temperature control system is configured to perform constant temperature or variable temperature heating and temperature control on the sample preparation process in the injection tube sample preparation unit, and / or perform constant temperature or cyclic variable temperature heating and temperature control on the microfluidic chip reaction process; The heating and shaking unit is configured to shake and / or heat the syringe tube sample preparation unit; The heating unit is configured to heat and / or cool the microfluidic chip; The motion control system is configured to control the sample preparation process in the injection tube sample preparation unit and / or to perform motion control on the sample addition and / or reaction process of the microfluidic chip; The intelligent analysis system is configured to perform human-computer interactive control on the sample preparation process and / or the reaction process of the microfluidic chip in the injection tube sample preparation unit, and / or store, analyze, display and / or directly warn the sample reaction detection results obtained by the optical detection system.

8. The intelligent detection system according to claim 7, characterized in that: The microfluidic chip, the injection tube sample preparation unit, the reagent storage unit, the optical detection system, the temperature control system, the heating unit, the heating and oscillating unit, the motion control system and the intelligent analysis system are all used in combination to realize fully integrated input of original samples and output of nucleic acid and protein analysis results; or, the injection tube sample preparation unit, the reagent storage unit, the temperature control system, the heating and oscillating unit, the motion control system and the intelligent analysis system are used in combination to form an independent sample processing system for sample lysis and nucleic acid and protein extraction, purification and concentration; or, the microfluidic chip, the optical detection system, the temperature control system, the heating unit, the motion control system and the intelligent analysis system are used in combination to form an independent nucleic acid and protein detection intelligent analysis system.

9. The intelligent detection system according to claim 7, characterized in that: The syringe sample preparation unit comprises a syringe barrel, a piston, a filter membrane or filter paper, a sealing ring, a needle and a protective cover, wherein the piston is movably arranged in the syringe barrel, the filter membrane or filter paper and the sealing ring are arranged at the bottom of the syringe barrel, the needle is arranged at the bottom outlet of the syringe barrel, and the protective cover is arranged on the needle.

10. The intelligent detection system according to claim 9, characterized in that: The microfluidic chip, the injection tube sample preparation unit, the reagent storage unit, the optical detection system, the temperature control system, the heating unit, the heating and oscillating unit, the motion control system and the intelligent analysis system are all used in combination to realize fully integrated input of original samples and output of nucleic acid and protein analysis results; or, the injection tube sample preparation unit, the reagent storage unit, the temperature control system, the heating and oscillating unit, the motion control system and the intelligent analysis system are used in combination to form an independent sample processing system for sample lysis and nucleic acid and protein extraction, purification and concentration; or, the microfluidic chip, the optical detection system, the temperature control system, the heating unit, the motion control system and the intelligent analysis system are used in combination to form an independent nucleic acid and protein detection intelligent analysis system.

11. The intelligent detection system according to claim 9, characterized in that: The syringe barrel is pre-stored with swab preservation elution lysis solution and / or magnetic beads, glass beads, nanomaterials or polymer materials that have been surface-modified, wherein the surface modification treatment includes broad-spectrum modification of anion exchange that is negatively charged in an acidic environment, specific group modification based on nucleic acid hybridization or protein immune binding principles for capturing targets of interest, adsorption of negatively charged nucleic acid proteins in an acidic environment, release of negatively charged nucleic acid proteins in an alkaline environment, adsorption of nucleic acid proteins at low temperatures and / or release of nucleic acid proteins at high temperatures.

12. The intelligent detection system according to claim 11, characterized in that: The microfluidic chip, the injection tube sample preparation unit, the reagent storage unit, the optical detection system, the temperature control system, the heating unit, the heating and oscillating unit, the motion control system and the intelligent analysis system are all used in combination to realize fully integrated input of original samples and output of nucleic acid and protein analysis results; or, the injection tube sample preparation unit, the reagent storage unit, the temperature control system, the heating and oscillating unit, the motion control system and the intelligent analysis system are used in combination to form an independent sample processing system for sample lysis and nucleic acid and protein extraction, purification and concentration; or, the microfluidic chip, the optical detection system, the temperature control system, the heating unit, the motion control system and the intelligent analysis system are used in combination to form an independent nucleic acid and protein detection intelligent analysis system.

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