CN117599870A - Microfluidic chip capable of flexibly switching multiple samples and multiple indexes and intelligent detection system - Google Patents
Microfluidic chip capable of flexibly switching multiple samples and multiple indexes and intelligent detection system Download PDFInfo
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- B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
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Abstract
The invention relates to a microfluidic chip with multiple samples and multiple indexes flexibly switched in quantity and an intelligent detection system, wherein the microfluidic chip comprises a chip body; the sample injection pipeline is arranged on the chip body and provided with a plurality of sample injection holes; the chip body is provided with at least one exhaust pipeline, each exhaust pipeline is connected with the corresponding sample injection pipeline through a connecting pipeline and the microcavity, and each exhaust pipeline is provided with at least one exhaust hole; the flow channel between the adjacent sample adding holes is provided with more than one isolating cavity and an expansion material to form a simple valve to realize flow channel blocking isolation. According to the invention, the simple valve is arranged on the flow channel, and the micro-fluidic chip pipeline and the cavity are grouped by the on-off of the simple valve, so that the flexible change switching of the sample number and the detection index number is realized, and the universality of the micro-fluidic chip is improved. Moreover, the intelligent detection system can realize the full-integrated original sample inlet and nucleic acid protein analysis result.
Description
Technical Field
The invention relates to a microfluidic chip with multiple samples and multiple indexes and flexible quantity switching and an intelligent detection system, and relates to the fields of biomedicine, clinical medicine, food safety and epidemic prevention.
Background
Nucleic acid protein detection assays have been widely used in the biomedical, clinical, food safety, and hygiene and epidemic prevention fields. The existing nucleic acid protein detection and analysis method can be completed by serially combining a plurality of instruments, the detection time is long, the result report can be obtained only about 2-3 days, the manual operation is very complicated, the requirements on the use technical level and the proficiency are high, the workload is large, a special molecular biology laboratory is required, and the method cannot be popularized and applied in basic medical units, communities, supermarkets, families and the like.
The microfluidic chip is a relatively advanced nucleic acid protein detection analysis method in recent years, the existing microfluidic chip structure is usually relatively special fixed, and the number of samples to be added and the number of indexes to be detected are fixed along with the microfluidic chip structure, so that expansion cannot be performed, and the new detection change needs cannot be met. And the micro-fluidic chip is relatively precise, precision machining and injection molding are needed to ensure the precision, and the cost is relatively high. Once the microfluidic chip has no universality, limitations are brought to the use of the microfluidic chip kit, the corresponding production cost is higher, the method is not suitable for popularization and application of the microfluidic chip technology, and the method is also the root cause that the detection cost cannot be greatly reduced due to higher nucleic acid protein detection cost based on the microfluidic chip at the present stage.
Disclosure of Invention
The present invention aims to solve at least one of the technical problems existing in the prior art. Therefore, the invention aims to provide the micro-fluidic chip and the intelligent detection system with the flexible switching of the number of the multiple samples and the number of the detection indexes, and the flexible switching between the number of the samples and the number of the detection indexes is realized on the micro-fluidic chip, so that the manual operation is greatly reduced, and the cross contamination and the infection are effectively avoided.
In order to achieve the aim of the invention, the invention adopts the following technical scheme:
in a first aspect, the present invention provides a microfluidic chip for flexibly switching a plurality of samples and a plurality of indexes, the microfluidic chip comprising:
a chip body;
the sample injection pipeline is arranged on the chip body, and a plurality of sample adding holes are formed in the sample injection pipeline;
the chip body is provided with at least one exhaust pipeline, each exhaust pipeline is connected with the corresponding sample injection pipeline through a connecting pipeline and a microcavity, two ends of one microcavity are respectively communicated with the sample injection pipeline and the exhaust pipeline through a connecting pipeline to form detection channels, and the number of the detection channels is set to be a plurality of; each exhaust pipeline is provided with at least one exhaust hole;
And more than one isolation cavity is arranged on the flow channel between the adjacent sample adding holes, and each isolation cavity is internally provided with a simple valve for realizing flow path blocking isolation.
The microfluidic chip further comprises a simple valve made of an expansion material or a microstructure, wherein the expansion material is expanded to form the simple valve to realize flow path blocking isolation, or the microstructure is used for enabling the isolation cavity pipeline to deform to form the simple valve through pressurization, hot pressing or ultrasonic to realize flow path blocking isolation.
The microfluidic chip is characterized in that the sample injection pipeline is in a straight line shape or a bent shape, sample injection holes are respectively formed in two ends of the sample injection pipeline, and a plurality of sample injection holes are formed in the middle of the sample injection pipeline at intervals according to requirements.
The microfluidic chip further comprises a water-swelling material, wherein the water-swelling material comprises starch grafted acrylate polymer cross-linked polymer, acrylamide-acrylate copolymer cross-linked polymer and/or hydrogel resin, and when a sample is added into the sample injection pipeline, the swelling material swells in water to form a simple valve.
The microfluidic chip further comprises a heating expansion material, wherein the heating expansion material comprises liquid metal, memory alloy, thermal expansion polymer material and/or thermal expansion polymer gel, and when the pipeline is heated to reach a set temperature, the expansion material is heated and expanded to form a simple valve.
The microfluidic chip further comprises more than one isolation cavity arranged on the flow channel, wherein the isolation cavity is arranged on the sample injection pipeline and/or the connecting pipeline, and the isolation cavity is arranged in any of the following modes:
the isolation cavity is arranged on the sample injection pipeline;
the isolation cavity is arranged on the connecting pipeline, and comprises: the isolation cavity is arranged at the tangential position of any connecting pipeline, is arranged at the position intersecting with the connecting pipeline or is connected with the connecting pipeline through a section of pipeline.
The microfluidic chip further comprises a waterproof and breathable film covered on the exhaust hole, and the gas is exhausted from the exhaust hole through the exhaust pipeline; and/or the sample adding hole is covered with a sealing silicone rubber pad to prevent sample introduction pollution.
In a second aspect, the invention also provides an intelligent detection system, which comprises the microfluidic chip, an injection tube type sample preparation unit, a reagent storage unit, an optical detection system, a temperature control system, a heating unit, a heating oscillation unit, a motion control system and/or an intelligent analysis system;
The injection tube type sample preparation unit is configured to crack a sample and extract and purify concentrated nucleic acid protein;
the reagent storage unit is configured to provide reagent storage for sample preparation of the injection tube type sample preparation unit and reaction of the microfluidic chip;
the optical detection system is configured to detect the result of the reaction on the microfluidic chip;
the temperature control system is configured to perform constant-temperature or variable-temperature heating temperature control on a sample preparation treatment process in the injection tube type sample preparation unit and/or perform constant-temperature or circulation variable-temperature heating temperature control on a microfluidic chip reaction process;
the heating oscillation unit is configured to oscillate and/or heat the injection tube type sample preparation unit;
the heating unit is configured to heat and/or refrigerate the microfluidic chip;
the motion control system is configured to control a sample preparation processing process in the injection tube type sample preparation unit and/or to perform motion control on the sample loading and/or reaction process of the microfluidic chip;
the intelligent analysis system is configured to perform man-machine interaction control on a sample preparation process and/or a reaction process of the microfluidic chip in the injection tube type sample preparation unit, and/or store, analyze, display and/or pre-warn direct report a sample reaction detection result obtained by the optical detection system.
The intelligent detection system is characterized in that the injection tube type sample preparation unit comprises an injection tube, a piston, a filter membrane or filter paper, a sealing ring, a needle and a protective sleeve, wherein the piston is movably arranged in the injection tube, the filter membrane or filter paper and the sealing ring are arranged at the bottom of the injection tube, the needle is arranged at the outlet of the bottom of the injection tube, and the protective sleeve is arranged on the needle.
The intelligent detection system further comprises a swab, a magnetic bead, a glass bead, a nano material or a high polymer material which is subjected to surface modification treatment and/or a preservation elution lysate in the injection tube, wherein the surface modification treatment comprises anion exchange broad-spectrum modification, negative charge in an acidic environment, specific group modification aiming at target capture based on a nucleic acid hybridization or protein immune combination principle, negative charge nucleic acid protein adsorption in the acidic environment, negative charge nucleic acid protein release in an alkaline environment, nucleic acid protein adsorption at a low temperature and/or nucleic acid protein release at a high temperature.
The intelligent detection system further comprises a microfluidic chip, an injection tube type sample preparation unit, a reagent storage unit, an optical detection system, a temperature control system, a heating unit, a heating oscillation unit, a motion control system and an intelligent analysis system which are all combined for use, so that a fully integrated original sample is fed in and a nucleic acid protein analysis result is obtained; or the injection tube type sample preparation unit, the reagent storage unit, the temperature control system, the heating oscillation unit, the motion control system and the intelligent analysis system are combined to form an independent sample processing system for sample pyrolysis, nucleic acid 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 combined to form an independent nucleic acid protein detection intelligent analysis system.
The invention adopts the technical proposal and has the following characteristics:
1. compared with the conventional microfluidic chip method, the method has the advantages that the simple valves are arranged on the flow channels, the microfluidic chip pipelines and the cavities are grouped through the on-off of the simple valves, the flexible change switching of the sample number and the detection index number is realized, the universality of the microfluidic chip is improved, the technical use threshold and the requirements on field conditions are reduced, and the requirements of the microfluidic chip on the popularization and application of the precise medical molecular diagnosis are met.
2. Compared with the biochemical analysis method of a conventional centrifuge tube or orifice plate, the method not only greatly reduces the consumption of sample reagents (can be less than 1 mu L/index), but also can be used for parallel detection of tens or even hundreds of specific gene protein analysis indexes by one-time sample injection, greatly reduces manual operation steps, reduces labor intensity, and ensures that swab sampling detection is safer, more robust and more efficient; in addition, the user can automatically perform nucleic acid amplification or protein immunodetection analysis without the help or assistance of professional technicians and site requirements, and can realize standardized operation and use of sites, families, communities, medical institutions at all levels, health epidemic prevention departments, food safety departments and the like, and the influence of human factors is avoided.
3. Compared with the conventional swab elution method, the method is compatible with the mode of adding the sampling swab eluent or directly adding the sampling swab in a sealing elution separation sampling attached sample 2, the eluent is transferred in situ efficiently, the whole process of uncapping is not closed after the sampling is carried out in the injection tube, and the serious problems that the safety and reliability of the subsequent operators are not guaranteed due to infection, whole process cross contamination and the like are effectively avoided.
In summary, the invention can effectively improve the universality of the microfluidic chip, solve the problems of advanced diagnosis technology and equipment requirements of intelligent medical treatment of a convenience system, realize forward movement of sanitary epidemic prevention and accurate medical treatment, sink to villages and towns, communities and families from large hospitals and third party inspection centers, effectively relieve the medical pressure of the current large hospitals, realize the coverage of the intelligent network of medical and sanitary epidemic prevention to the villages and towns, communities, families, large hospitals, third party inspection centers, sanitary epidemic prevention departments and the like, effectively improve the advanced scientific technology level of the accurate medical treatment and sanitary epidemic prevention of the whole people, and can be widely applied to sites, households, communities, village and town clinics, physical examination centers and clinical medical units at all levels, sanitary epidemic prevention departments, food safety management departments, biomedical scientific research, biochemical warfare agent detection, environmental detection or other fields.
Drawings
Various other advantages and benefits will become apparent to those of ordinary skill in the art upon reading the following detailed description of the preferred embodiments. The drawings are only for purposes of illustrating the preferred embodiments and are not to be construed as limiting the invention. Like parts are designated with like reference numerals throughout the drawings. In the drawings:
fig. 1 is a schematic structural diagram of a multi-sample multi-index number flexible switching microfluidic chip according to an embodiment of the present invention.
FIG. 2 is a schematic diagram of the isolation chamber position structure of a simple valve according to an embodiment of the invention.
FIG. 3 is a schematic diagram of the microstructure of a simple valve according to an embodiment of the invention.
Fig. 4 is a schematic structural diagram of an intelligent detection system according to an embodiment of the invention.
Fig. 5 is a schematic structural view of a syringe type sample preparation unit according to an embodiment of the present invention.
FIG. 6 is a schematic diagram of the structure of an isolated nucleic acid/protein extraction purification concentrate sample preparation according to an embodiment of the present invention.
Detailed Description
It is to be understood that the terminology used herein is for the purpose of describing particular example embodiments only, and is not intended to be limiting. As used herein, the singular forms "a", "an", and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. The terms "comprises," "comprising," "includes," "including," and "having" are inclusive and therefore specify the presence of stated features, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, steps, operations, elements, components, and/or groups thereof. The method steps, processes, and operations described herein are not to be construed as necessarily requiring their performance in the particular order described or illustrated, unless an order of performance is explicitly stated. It should also be appreciated that additional or alternative steps may be used.
Although the terms first, second, third, etc. may be used herein to describe various elements, components, regions, layers and/or sections, these elements, components, regions, layers and/or sections should not be limited by these terms. These terms may be only used to distinguish one element, component, region, layer or section from another region, layer or section. Terms such as "first," "second," and other numerical terms when used herein do not imply a sequence or order unless clearly indicated by the context. Thus, a first element, component, region, layer or section discussed below could be termed a second element, component, region, layer or section without departing from the teachings of the example embodiments.
For ease of description, spatially relative terms, such as "inner," "outer," "lower," "upper," and the like, may be used herein to describe one element or feature's relationship to another element or feature as illustrated in the figures. 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.
Because the existing microfluidic chip has no universality, the production cost is relatively high, and the nucleic acid protein detection cost based on the microfluidic chip is relatively high. The invention provides a micro-fluidic chip with multiple samples and multiple indexes, which comprises a chip body, wherein the micro-fluidic chip is flexibly switched in quantity; the sample injection pipeline is arranged on the chip body and provided with a plurality of sample injection holes; the chip body is provided with at least one exhaust pipeline, each exhaust pipeline is connected with a corresponding sample injection pipeline through a connecting pipeline and a microcavity, wherein two ends of the microcavity are respectively communicated with the sample injection pipeline and the exhaust pipeline through a connecting pipeline to form detection channels, and the number of the detection channels is set to be a plurality; each exhaust pipeline is provided with at least one exhaust hole; the isolation cavity is provided with more than one isolation cavity on the flow channel between the adjacent sample adding holes, and each isolation cavity is internally provided with an expansion material or a microstructure, wherein the expansion material is expanded to form a simple valve to realize flow path blocking isolation, and the microstructure enables the isolation cavity microstructure and the pipeline to deform to form the simple valve to realize flow path blocking isolation through pressurization, hot pressing or ultrasonic and the like. Moreover, the intelligent detection system can realize the full-integrated original sample inlet and nucleic acid protein analysis result; the method can also be simplified into a sample splitting and nucleic acid protein extracting, purifying and concentrating independent sample processing system; the method 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 conventional microfluidic chip method for nucleic acid amplification/protein immunoassay, the method can realize flexible switching of the mutual change between the number of samples and the number of detection indexes by a simple valve type flow path isolation technology, and realize sharing of one hardware platform by two systems of nucleic acid amplification/protein immunoassay by a syringe type full-integrated nucleic acid/protein extraction and purification method. When the kit is used, a user only needs to add an original sample, the intelligent detection system can complete detection analysis of full-integrated nucleic acid amplification/protein immune reaction of 'sample in and out', complicated professional technical operation is not needed, and the kit does not have special laboratory field requirements, and can meet the use requirements of nucleic acid/protein analysis standardized operation in the fields of site, house, communities, physical examination centers, medical units at all levels, health and epidemic prevention departments, food safety management departments, biomedical scientific research, biochemical warfare agent detection, environmental detection or other fields.
Exemplary embodiments of the present invention will be described in more detail below with reference to the accompanying drawings. While exemplary embodiments of the present invention are shown in the drawings, it should be understood that the present invention may be embodied in various forms and should not be limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art.
It should be noted that, each structure of the present embodiment may be supported and fixed by a corresponding structure, and a specific fixing manner is not limited, so long as the corresponding function of the present invention can be satisfied, and in order to facilitate understanding, facilitate use, reduce weight, etc., the drawing of the present embodiment is mainly implemented by using a hollow cylinder, a rectangle, a square, a circle, or an ellipse, etc. for schematic module, which is only used as an example, and not limited thereto, and only one or more repeating units are drawn, which is only used as an example, and not limited thereto, and may be implemented repeatedly by using a corresponding structure.
Embodiment one: as shown in fig. 1, the multi-sample multi-index flexible switching microfluidic chip provided in this embodiment includes:
A chip body;
a linear or curved sample injection pipeline is arranged on the chip body, and a plurality of sample adding holes are arranged on the sample injection pipeline at intervals. The present embodiment is described with reference to the S-shaped sample introduction pipe 1, which is not limited thereto. The two ends of the S-shaped sample feeding pipe 1 are respectively provided with a sample feeding hole 11, 16, and the bending parts of the S-shaped sample feeding pipe 1 are respectively provided with a sample feeding hole 12-15, and this embodiment is provided with 6 sample feeding holes 11-16, which are taken as an example, and the invention is not limited thereto, and the positions and the number of the sample feeding holes can be set according to actual needs.
The chip body is further provided with at least one exhaust pipe 2, and this embodiment is provided with two exhaust pipes 21, 22, which is not limited thereto, and the number of exhaust pipes may be set according to actual detection requirements. Each exhaust pipeline is connected with the corresponding S-shaped sample injection pipeline 1 through a connecting pipeline 5 and a microcavity, wherein two ends of a microcavity are respectively connected with the sample injection pipeline and the exhaust pipeline through a connecting pipeline 5 to form detection channels, the number of the detection channels can be set according to actual needs, and 40 detection channels are arranged in the embodiment, so that the method is not limited to the embodiment. At least one exhaust hole 23 (24) is provided in each exhaust pipe 21 (22). More than one isolation cavity can be arranged on a runner, such as a sample feeding pipeline or a connecting pipeline, between adjacent sample feeding holes, an expansion material or a microstructure is arranged in each isolation cavity, a simple valve is formed after the expansion material expands and is used for realizing flow path blocking isolation, and the microstructure enables the micro structure of the isolation cavity and the pipeline to deform to form the simple valve through pressurization, hot pressing or ultrasonic and the like to realize flow path blocking isolation. Therefore, the simple valve type flow path isolation technology is adopted in the embodiment, the simple valve is arranged on the flow path, the micro-fluidic chip pipeline and the micro-cavity are grouped through the on-off of the simple valve, and flexible change switching of the sample quantity and the detection index quantity is realized.
In a preferred embodiment of the present invention, the swelling material may be a water-swellable material, such as a starch grafted acrylate polymer cross-linked, an acrylamide-acrylate copolymer cross-linked, a hydrogel resin, etc., which swells to form a simple valve when a sample is introduced into the sample introduction pipe, thereby realizing flow path blocking isolation.
Further, the position of the isolation cavity on the flow channel can be any one of the following:
as shown in fig. 2 (a), the isolation cavities may be disposed on the sample injection pipeline, for example, the sample injection pipelines between adjacent sample injection holes are all provided with isolation cavities 31-35, and each isolation cavity is provided with an expansion material to form a simple valve, so that rapid flow path blocking isolation can be realized, and it is ensured that after different samples enter from different sample injection holes, only the corresponding microcavity region can be accessed, and diffusion pollution cannot occur to other microcavity regions.
The isolation cavity may be disposed on the connecting pipes, as shown in fig. 2 (b), and the isolation cavity may be disposed at any connecting pipe tangent position; as shown in fig. 2 (c), the isolation chamber may be provided at a position intersecting the connecting pipe portion. As shown in fig. 2 (d), the isolation chamber may be connected to the connection pipe through a length of pipe. Therefore, the expansion material can be arranged in the isolation cavity beside the connecting pipeline, the simple valve can be formed by changing the distance between the connecting pipeline and the isolation cavity or the thickness of the pipeline and expanding the expansion material when the expansion material is contacted with water or heated, the flow path blocking isolation with delay of a few seconds to a few minutes can be realized, the added sample is ensured to be fully filled in the micro-cavity, and all gases are discharged.
In a preferred embodiment of the invention, the microstructure can be pressurized, hot pressed or ultrasonic, so that the microstructure and the pipeline are deformed to form a simple valve, and the flow path blocking isolation is realized. As shown in fig. 3, the microstructure is not limited to any shape, and may be provided as desired, for example, spherical, triangular, zigzag, or the like.
In a preferred embodiment of the present invention, the expansion material may be a heated expansion material, such as a liquid metal, a memory alloy, a thermally-expanded polymer material, a thermally-expanded polymer gel, or the like, placed in the isolation chamber, and when the pipe is heated to a certain temperature, the expansion material is heated to expand to form a simple valve, thereby realizing the flow path blocking isolation.
Further, the vent hole 23 (24) may be covered with a waterproof and breathable film, and the gas is discharged from the vent hole 23 (24) through the vent pipe 21 (22).
Further, the sample addition holes 11-16 are covered with a sealing silicone rubber pad to prevent sample introduction pollution.
In summary, when the multi-sample multi-index flexible switching microfluidic chip of this embodiment is used, the simple valves in this embodiment are disposed in the isolation cavities 31-35 and 36-37, and the nucleic acid/protein analysis index is disposed in the microcavity 401-440 by means of low-melting agarose embedding or freeze-drying microsphere storage; samples enter the sample injection pipeline 1 from the sample injection holes 11-16, pass through the connecting pipeline 5 to rapidly fill the microcavities 401-440, and then are blocked and isolated by simple valves of isolation cavities arranged beside 36-37 or 31-35 on the sample injection pipeline, so as to prevent cross contamination. For example, when all of the isolation chambers Jian Yifa-35 are filled with water or a heating expansion material, the microcavity area is divided into 6 groups, corresponding to 6 sample-filling holes 11-16, 6 samples can be filled, the sample filled in the sample-filling hole 11 corresponds to microcavities 401-405 and totally detects 5 indexes, the sample filled in the sample-filling hole 12 corresponds to microcavities 406-410 and totally detects 5 indexes, the sample filled in the sample-filling hole 14 corresponds to microcavities 411-415 and 421-425 and totally detects 10 indexes, the sample filled in the sample-filling hole 13 corresponds to microcavities 416-420 and 426-430 and totally detects 5 indexes, the sample filled in the sample-filling hole 15 corresponds to microcavities 431-435 and the sample filled in the sample-filling hole 16 corresponds to microcavities 436-440 and totally detects 5 indexes. For example, when only part 32 or 34 of the isolation cavities Jian Yifa-35 is filled with water or heating expansion material, the microcavity area is divided into 3 groups, only 3 sample holes 11 or 12, 13 or 14, 15 or 16 are needed, 3 samples can be input, the samples input by the sample holes 11 or 12 correspond to microcavities 401-410 to detect 10 indexes in total, the samples input by the sample holes 13 or 14 correspond to microcavities 411-430 to detect 20 indexes in total, and the samples input by the sample holes 15 or 16 correspond to microcavities 431-440 to detect 10 indexes in total. Therefore, based on the arrangement of the isolating cavities Jian Yifa 31-35, flexible switching combination of adding 1-6 different sample numbers and detecting 5-40 different detection index numbers can be realized. And along with the extension of the sample feeding pipeline and the increase of the number of the microcavities, the corresponding change of the number of the samples and the number of the detection indexes is richer, and the requirement of the change of the number of the samples and the number of the detection indexes in different practical applications can be met.
Embodiment two: the embodiment provides an intelligent detection system for fully integrating nucleic acid amplification or protein immune reaction in the preparation of a syringe type sample, which realizes the report output of the detection results of multiple sample entry and multiple nucleic acid/protein analysis indexes of one or more mixed samples including but not limited to pathogenic bacteria, microorganisms, tissue cells, exosomes, exovesicles and the like in biological samples.
As shown in fig. 4, the injection tube type sample preparation fully integrated nucleic acid amplification or protein immune reaction intelligent detection system provided in this embodiment includes the multi-sample multi-index number flexible switching microfluidic chip 10, one or more injection tube 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 oscillation unit 70, a motion control system 80 and/or an intelligent analysis system 90 described in the first embodiment.
A syringe-type sample preparation unit 20 configured to perform one or more methods of high temperature and/or shake disruption and/or chemical reagent lysis combined automated nucleic acid/protein extraction purification concentration processing on the original sample within one syringe;
a reagent storage unit 30 configured to set a plurality of reagent and waste liquid storage cavities according to nucleic acid/protein sample preparation and amplification/immunoreaction requirements, wherein corresponding reagents are stored in the waste liquid storage cavities, and the reagent storage cavities are sealed by rubber plugs, so that the reagent storage cavities are suitable for inserting and sampling a syringe needle or discharging waste liquid;
An optical detection system 40 configured to detect the result of nucleic acid amplification or protein immune reaction on the multi-sample multi-index quantity flexible switching microfluidic chip 10;
a temperature control system 50 configured to perform constant temperature or variable temperature heating and temperature control on a sample preparation process in the injection tube type nucleic acid/protein extraction and purification sample preparation unit, and/or perform constant temperature or circulation variable temperature heating and temperature control on a nucleic acid amplification or protein immune reaction process of the multi-sample multi-index number flexible switching microfluidic chip 10;
a heating unit 60 configured to heat and/or cool the multi-sample multi-index number flexible switching microfluidic chip 10;
a heating oscillation unit 70 configured to oscillate and/or heat the syringe-type sample preparation unit 20;
a motion control system 80 configured to perform vibration crushing control, liquid suction/liquid discharge control, etc. on a sample preparation process in the injection tube type nucleic acid/protein extraction and purification sample preparation unit, and/or to flexibly switch the number of multiple samples and multiple indexes of the microfluidic chip 10 to perform sample addition and nucleic acid amplification or protein immune reaction processes, etc.;
the intelligent analysis system 90 is configured to perform man-machine interaction control on a nucleic acid/protein extraction, purification, concentration sample preparation process and a nucleic acid amplification or protein immune reaction detection process of the biological sample, and/or store, analyze, display and/or pre-warn direct report on a nucleic acid amplification or protein immune reaction detection result of the biological sample.
In a preferred embodiment of the present invention, as shown in fig. 5, the syringe-type sample preparation unit of the present embodiment is configured as two parallel sample preparation units, and one syringe-type sample preparation unit 20 is illustrated as a specific embodiment, 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 sheath 206. Wherein, the piston 202 is movably arranged in the syringe barrel 201, the filter membrane or filter paper 203 and the sealing ring 204 are arranged at the bottom of the syringe barrel 201, the needle 205 is arranged at the bottom outlet of the syringe barrel 201, and the protective sleeve 206 is arranged on the needle 205.
Further, the syringe barrel 201 is preloaded with sample inactivation and anti-nucleic acid protein degradation lysis preservation solution, the piston 202 is firstly taken down, one or more mixed original samples including but not limited to pathogenic bacteria, microorganisms, tissue cells, exosomes, exovesicles and the like are adopted by means of swab sampling or minimally invasive sampling, such as swab washing liquid, biopsy puncture liquid, saliva sputum, sweat, blood, urine, stool and the like, are added into the preservation solution of the syringe barrel 201, the piston 202 is loaded and adjusted to a proper position, and then the sample is mounted into an intelligent detection system for preparing full-integration nucleic acid amplification or protein immune reaction by the syringe barrel sample, so that the full-automation nucleic acid amplification or protein immune reaction accurate medical molecular diagnosis of 'sample input and output' can be realized through the automatic control of the intelligent detection system for full-integration nucleic acid amplification or protein immune reaction by the syringe barrel sample preparation.
Further, the syringe barrel 201 is pre-stored with a swab preservation elution lysate and/or magnetic or glass beads or other nanomaterials or polymeric materials after surface modification treatment, including but not limited to anion exchange type broad spectrum modification negatively charged in an acidic environment, specific group modification for target capture of interest based on nucleic acid hybridization or protein immunobinding principles, etc., adsorption of negatively charged nucleic acid proteins or other biological samples in an acidic environment, release of negatively charged nucleic acid proteins or other biological samples in an alkaline environment, or adsorption of nucleic acid proteins or other biological samples at low temperature, release of nucleic acid proteins or other biological samples at high temperature. Therefore, the invention adopts the strategies of concentration and purification of the nucleic acid protein by adopting a filter membrane or filter paper and/or magnetic beads or anion exchange adsorption, and the like, is not only suitable for detecting and analyzing the nucleic acid protein of different biological samples such as pathogenic bacteria, microorganisms, tissue cells, exosomes, exovesicles and the like, but also can effectively reduce the using amount of eluent and improve the initial concentration of the recovered attached samples or the cracked nucleic acid protein and the like which are used later by nearly hundred times.
In a preferred embodiment of the present invention, as shown in fig. 6, under the combined action of the temperature control system 50, the heating oscillation unit 70 and the motion control system 80, the injection tube type sample preparation unit 20 generates the independent or combined biological sample lysis effects of oscillation mechanical disruption, high temperature lysis, etc., or can generate one or more combined biological sample lysis effects of high temperature, mechanical disruption, chemical reagent lysis in combination with the chemical lysis reagent pre-installed in the injection tube, so as to release nucleic acid protein from the original biological sample of the injection tube, and sequentially suck various reagents from the reagent storage unit 30 under the action of the motion control system 80, and discharge the waste liquid generated in the intermediate treatment process into the waste liquid storage cavity of the reagent storage unit 30, thereby realizing the automatic nucleic acid/protein extraction, purification and concentration treatment of the original sample in one injection tube, and finally injecting the purified and concentrated nucleic acid/protein into the multi-sample multi-index quantity flexible switching microfluidic chip 10 or other nucleic acid protein detection systems, thereby meeting the sample preparation application requirements of the automatic nucleic acid/protein extraction, purification and concentration treatment of the original sample.
In a preferred embodiment of the present invention, the reagent storage unit 30 is provided with a plurality of reagent storage cavities and at least 1 large-volume waste liquid storage cavity, and is provided with a rubber plug seal, so that the reagent storage unit is suitable for inserting a syringe needle into a sample or discharging waste liquid, and the requirement of nucleic acid/protein extraction, purification and concentration treatment of biological samples is met.
In a preferred embodiment of the present invention, the heating and vibrating unit 70 is used for performing high temperature and/or vibration disruption and/or chemical reagent lysis on the original biological sample in the syringe barrel 201 to perform a sample lysis treatment in combination with one or more methods, so as to efficiently separate and generate nucleic acid proteins.
In a preferred embodiment of the present invention, the optical detection system 40 performs detection such as wide-field imaging, confocal scanning, etc. on the result of nucleic acid amplification or protein immune reaction by using the prior art, including an objective lens, an illumination source, an excitation color filter, an imaging lens, an emission color filter and a detector, and can perform fluorescent signal detection by switching the color filters, or can perform white light interference hyperspectral signal thickness decoding super-resolution measurement by placing the color filters in the gaps, and can also perform turbidity, phase contrast, chromaticity, spectrum or other spectrophotometry measurement by using a mobile phone or human eyes, which is not described herein.
In a preferred embodiment of the present invention, the temperature control system 50 is combined with the heating unit 60 to implement constant temperature or circulation temperature-changing heating temperature control for the nucleic acid amplification or protein immune reaction process of the multi-sample multi-index quantity flexible switching micro-fluidic chip 10, so as to meet the requirement of nucleic acid constant temperature or circulation temperature-changing amplification or protein immune reaction.
Further, the temperature control system 50 is combined with the heating oscillation unit 70 to realize constant temperature or variable temperature heating and temperature control for the sample preparation treatment process in the injection tube type nucleic acid/protein extraction and purification sample preparation unit, so as to meet the sample preparation requirement of nucleic acid/protein extraction and purification.
In a preferred embodiment of the present invention, the motion control system 80 is combined with the heating oscillation unit 70 to perform oscillation crushing control, pipetting/draining control, etc. on the sample preparation process in the injection tube type nucleic acid/protein extraction purification sample preparation unit.
Further, the motion control system 80 cooperates with the optical detection system 40 to realize motion control of the nucleic acid amplification or protein immune reaction process of the multi-sample multi-index number flexible switching micro-fluidic chip 10, thereby meeting the requirement of imaging or confocal scanning detection of real-time signals of nucleic acid amplification or protein immune reaction of micro-cavities in the multi-sample multi-index number flexible switching micro-fluidic chip 10.
In a preferred embodiment of the present invention, the intelligent analysis system 90 includes a microprocessor signal storage processing and analysis unit, a wired or wireless communication interface, a display terminal, a cloud big data server, etc., and combines the temperature control system 50, the motion control system 80 and the optical detection system 40 to implement man-machine interaction control on biological sample preparation processing and nucleic acid amplification or protein immune response detection processes, and store, analyze, display and/or pre-warn direct report on detection results, wherein,
the signal storage processing and analyzing unit is provided with a big data priori knowledge base of specific gene protein detection indexes of various viruses, pathogenic bacteria, tumors, cancers and the like in the accurate medical molecular diagnosis, and performs artificial intelligence or/and big data analysis on the nucleic acid protein molecular diagnosis detection results sampled by the swab based on the big data priori knowledge base of the specific gene protein detection indexes to obtain specific gene protein detection identification results of various biomedical indexes.
The wired or wireless communication interface is used for transmitting the detection and identification results of the specific gene proteins to mobile phones of related personnel or directly reporting the detection and identification results to a cloud big data server or a national epidemic disease, serious chronic disease, malignant tumor and cancer health epidemic prevention and health risk monitoring network platform, so as to realize intelligent medical networking among individuals, families, communities, village and town clinics, various levels of medical units and health epidemic prevention departments, and predict and early warn high-incidence infectious diseases, serious chronic diseases, malignant tumors, cancers and the like.
And the display terminal is used for displaying the detection and identification results of the specific gene proteins of various biomedical indexes.
Further, the intelligent analysis system 90 also has intelligent analysis functions such as artificial intelligence and machine learning of multi-index combined detection results, and further improves the accuracy and reliability of the nucleic acid or protein molecular diagnosis results.
In a preferred embodiment of the present invention, the microfluidic chip 10, the optical detection system 40, the temperature control system 50, the heating unit 60, the motion control system 80 and the intelligent analysis system 90 in the injection tube type sample preparation fully integrated nucleic acid amplification or protein immune reaction intelligent detection system can be combined to form an independent nucleic acid protein detection intelligent analysis system, which can be compatible with nucleic acid/protein samples obtained by using a conventional sample preparation method, the sample is added into the multi-sample multi-index number by a manual mode to flexibly switch the microfluidic chip 10, and then the corresponding optical detection system 40, the temperature control system 50, the heating unit 60, the motion control system 80 and/or the intelligent analysis system 90 are combined to perform intelligent detection analysis of nucleic acid amplification or protein immune reaction.
In a preferred embodiment of the present invention, as shown in fig. 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 oscillation unit 70, the motion control system 80, and the microprocessor signal storage processing and analysis unit of the intelligent analysis system 90 may be separately combined to form an independent nucleic acid/protein extraction and purification concentrated sample preparation system, so as to meet the application requirements of other detection methods requiring nucleic acid proteins.
In summary, according to the intelligent detection system provided by the invention, a user can operate by himself and simultaneously perform detection of a plurality of samples, two or more (up to hundreds of) pathogenic bacteria (bacteria, fungi, viruses, microorganisms, model organisms and the like) infection indexes or specific gene proteins of tumor and cancer analysis indexes, and the sample reagent consumption of each detection index can be reduced from tens of microliters to less than 1 microliter according to requirements. In addition, the simple valve type flow path isolation technology and the multi-sample multi-index quantity flexible switching micro-fluidic chip effectively improve the universality of the micro-fluidic chip and realize flexible change switching of the sample quantity and the detection index quantity.
In this specification, each embodiment is described in a progressive manner, and identical and similar parts of each embodiment are all referred to each other, and each embodiment mainly describes differences from other embodiments. In the description of the present specification, reference to the terms "one preferred embodiment," "further," "specifically," "in the present embodiment," etc., means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the embodiments of the present specification. In this specification, schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, the different embodiments or examples described in this specification and the features of the different embodiments or examples may be combined and combined by those skilled in the art without contradiction.
Finally, it should be noted that: the above embodiments are only for illustrating the technical solution of the present invention, and are not limiting; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit and scope of the technical solutions of the embodiments of the present invention.
Claims (10)
1. The utility model provides a micro-fluidic chip that many index quantity of multiple samples are nimble switches which characterized in that, this micro-fluidic chip includes:
a chip body;
the sample injection pipeline is arranged on the chip body, and a plurality of sample adding holes are formed in the sample injection pipeline;
the chip body is provided with at least one exhaust pipeline, each exhaust pipeline is connected with the corresponding sample injection pipeline through a connecting pipeline and a microcavity, two ends of one microcavity are respectively communicated with the sample injection pipeline and the exhaust pipeline through a connecting pipeline to form detection channels, and the number of the detection channels is set to be a plurality of; each exhaust pipeline is provided with at least one exhaust hole;
And more than one isolation cavity is arranged on the flow channel between the adjacent sample adding holes, and each isolation cavity is internally provided with a simple valve for realizing flow path blocking isolation.
2. The microfluidic chip according to claim 1, wherein the simple valve is made of an expansion material or a microstructure, wherein the expansion material expands to form the simple valve to realize flow path blocking isolation, or the microstructure deforms the isolation cavity pipe to form the simple valve by pressurization, hot pressing or ultrasound to realize flow path blocking isolation.
3. The microfluidic chip according to claim 2, wherein the isolation cavity is made of a water-swellable material, the water-swellable material comprises a starch grafted acrylate polymeric cross-linked polymer, an acrylamide-acrylate co-cross-linked polymer and/or a hydrogel resin, and the swellable material swells in water to form a simple valve when the sample is added into the sample introduction pipe.
4. The microfluidic chip according to claim 2, wherein the expansion material is a heated expansion material, the heated expansion material comprising a liquid metal, a memory alloy, a thermally-expanded polymeric material and/or a thermally-expanded polymeric gel, and the expansion material is thermally expanded to form a simple valve when the conduit is heated to a set temperature.
5. The microfluidic chip according to claim 1, wherein more than one isolation cavity is arranged on the flow channel, and the isolation cavity is arranged on the sample introduction pipeline and/or the connecting pipeline, wherein the isolation cavity is arranged in any of the following forms:
the isolation cavity is arranged on the sample injection pipeline;
the isolation cavity is arranged on the connecting pipeline, and comprises: the isolation cavity is arranged at the tangential position of any connecting pipeline, is arranged at the position intersecting with the connecting pipeline or is connected with the connecting pipeline through a section of pipeline.
6. The microfluidic chip according to claim 1, wherein the vent holes are covered with a waterproof and breathable film, and gas is exhausted from the vent holes through the exhaust pipe; and/or the sample adding hole is covered with a sealed silicone rubber pad to prevent sample introduction pollution; and/or the sample injection pipeline adopts a straight line shape or a curved shape, sample injection holes are respectively formed at two ends of the sample injection pipeline, and a plurality of sample injection holes are formed in the middle of the sample injection pipeline at intervals according to requirements.
7. An intelligent detection system, characterized by 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 oscillation unit, the motion control system and/or the intelligent analysis system according to any one of claims 1 to 6;
The injection tube type sample preparation unit is configured to crack a sample and extract and purify concentrated nucleic acid protein;
the reagent storage unit is configured to provide reagent storage for sample preparation of the injection tube type 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 temperature control on a sample preparation treatment process in the injection tube type sample preparation unit and/or perform constant-temperature or circulation variable-temperature heating temperature control on a microfluidic chip reaction process;
the heating oscillation unit is configured to oscillate and/or heat the injection tube type sample preparation unit;
the heating unit is configured to heat and/or refrigerate the microfluidic chip;
the motion control system is configured to control a sample preparation processing process in the injection tube type sample preparation unit and/or to perform motion control on the sample loading and/or reaction process of the microfluidic chip;
the intelligent analysis system is configured to perform man-machine interaction control on a sample preparation process and/or a reaction process of the microfluidic chip in the injection tube type sample preparation unit, and/or store, analyze, display and/or pre-warn direct report a sample reaction detection result obtained by the optical detection system.
8. The intelligent detection system according to claim 7, wherein the syringe type sample preparation unit comprises a syringe barrel, a piston, a filter membrane or filter paper, a sealing ring, a needle and a protective sleeve, 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 sleeve is arranged on the needle.
9. The intelligent detection system according to claim 8, wherein the syringe barrel is pre-stored with a swab preservation elution lysate and/or surface-modified magnetic beads, glass beads, nanomaterials or polymeric materials, wherein the surface modification treatment comprises anion exchange broad-spectrum modification of specific group modification for target capture of interest based on nucleic acid hybridization or protein immunobinding principles negatively charged in an acidic environment, 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 temperature and/or release of nucleic acid proteins at high temperature.
10. The intelligent detection system according to any one of claims 7 to 9, wherein 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 oscillation unit, the motion control system and the intelligent analysis system are all combined for use, so as to realize full-integrated raw sample feeding and nucleic acid protein analysis result outputting; or the injection tube type sample preparation unit, the reagent storage unit, the temperature control system, the heating oscillation unit, the motion control system and the intelligent analysis system are combined to form an independent sample processing system for sample pyrolysis, nucleic acid 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 combined to form an independent nucleic acid protein detection intelligent analysis system.
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