CN119351209A - A nucleic acid analysis cartridge and a droplet generation system - Google Patents
A nucleic acid analysis cartridge and a droplet generation system Download PDFInfo
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- CN119351209A CN119351209A CN202411777811.2A CN202411777811A CN119351209A CN 119351209 A CN119351209 A CN 119351209A CN 202411777811 A CN202411777811 A CN 202411777811A CN 119351209 A CN119351209 A CN 119351209A
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6806—Preparing nucleic acids for analysis, e.g. for polymerase chain reaction [PCR] assay
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- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6844—Nucleic acid amplification reactions
- C12Q1/6851—Quantitative amplification
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Abstract
本发明公开了一种核酸分析卡盒及液滴生成系统，本方案包括核酸提取卡盒、液滴生成振动针和气泵连接器，其中，液滴生成振动针和气泵连接器均与核酸提取卡盒连通；核酸提取卡盒用于对样本进行核酸提取；气泵连接器用于与气泵连接以为核酸提取卡盒提供压力；液滴生成振动针通过振动、摆动、进动生成液滴。本申请的核酸分析卡盒包括对样本进行核酸提取的核酸提取卡盒以及用于生成液滴的液滴生成振动针，因此该结构能够在定量分析DNA或RNA过程中，可兼顾核酸提取以及液滴生成两种结构，无需转移核酸提取从而能够达到减少手工操作步骤，降低核酸污染风险，提高临床检测的周转效率的目的。
The present invention discloses a nucleic acid analysis cartridge and a droplet generation system, which includes a nucleic acid extraction cartridge, a droplet generation vibration needle and an air pump connector, wherein the droplet generation vibration needle and the air pump connector are both connected to the nucleic acid extraction cartridge; the nucleic acid extraction cartridge is used to extract nucleic acid from a sample; the air pump connector is used to connect to an air pump to provide pressure for the nucleic acid extraction cartridge; the droplet generation vibration needle generates droplets through vibration, swinging, and precession. The nucleic acid analysis cartridge of the present application includes a nucleic acid extraction cartridge for extracting nucleic acid from a sample and a droplet generation vibration needle for generating droplets, so that the structure can take into account both nucleic acid extraction and droplet generation in the process of quantitative analysis of DNA or RNA, without the need to transfer nucleic acid extraction, thereby achieving the purpose of reducing manual operation steps, reducing the risk of nucleic acid contamination, and improving the turnover efficiency of clinical testing.
Description
Technical Field
The invention relates to the technical field of in-vitro diagnosis, in particular to a nucleic acid analysis cartridge and a liquid drop generation system.
Background
Digital nucleic acid analysis, such as digital PCR, digital LAMP, digital RPA, etc., is a highly sensitive and highly accurate molecular biology technique that is used mainly for quantitative analysis of DNA or RNA. Compared with the traditional nucleic acid amplification analysis mode, the digital nucleic acid analysis is characterized in that a sample is divided into thousands of tiny reaction units (such as micro-droplets or micro-chambers), so that amplification and detection can be independently carried out in each reaction unit, and finally absolute quantification of the number of nucleic acid targets of the sample to be detected is realized through poisson distribution. Existing cell splitting approaches are typically implemented by micro-droplets or micro-chambers, however, these approaches rely heavily on microfluidic chips and lack the step of sample pretreatment.
Although there are currently some chip-independent micro-reaction unit building methods (CN 104324769B, CN216224451U, CN 110066721B), these methods focus on micro-droplet generation, but ignore the extremely important nucleic acid extraction step. The biological sample to be detected needs to be manually extracted and separated, and then the purified nucleic acid sample is introduced into a liquid drop generating device to generate an independent reaction unit, so that the steps of manual operation are increased, the risk of nucleic acid pollution is increased, and the turnover efficiency of clinical detection is reduced.
Therefore, how to reduce the manual operation steps, reduce the risk of nucleic acid pollution and improve the turnover efficiency of clinical detection in the process of quantitatively analyzing DNA or RNA becomes a technical problem to be solved urgently by those skilled in the art.
Disclosure of Invention
The invention provides a nucleic acid analysis cartridge and a liquid drop generation system, which are used for achieving the purposes of reducing manual operation steps, reducing the risk of nucleic acid pollution and improving the turnover efficiency of clinical detection in the process of quantitatively analyzing DNA or RNA.
In order to achieve the above object, the present invention provides the following technical solutions:
In a first aspect, the application provides a nucleic acid analysis cartridge comprising a nucleic acid extraction cartridge, a droplet generation vibrating needle and an air pump connector, wherein the droplet generation vibrating needle and the air pump connector are both communicated with the nucleic acid extraction cartridge, the nucleic acid extraction cartridge is used for extracting nucleic acid from a sample, the air pump connector is used for being connected with an air pump to provide pressure for the nucleic acid extraction cartridge, and the droplet generation vibrating needle generates droplets through vibration, swing and precession.
In some examples, the nucleic acid extraction cartridge includes a cartridge body, a first sealed aluminum foil, a single-sided tape, a second sealed aluminum foil, and a third sealed aluminum foil, wherein,
The cartridge body forms a plurality of chambers which are sequentially communicated so as to extract nucleic acid from a sample, each chamber is provided with a reagent filling hole, the chamber at the upstream end is further provided with a sample filling hole, the chamber at the downstream end is further provided with a first connecting port and a second connecting port, the first connecting port is used for connecting an air pump connector, the second connecting port is used for connecting a liquid drop generating vibrating needle, the first sealing aluminum foil is used for sealing the sample filling hole, the single-sided adhesive tape is used for sealing the reagent filling hole, the second sealing aluminum foil is used for sealing the first connecting port, and the third sealing aluminum foil is used for sealing the second connecting port.
In some examples, the sample addition aperture is disposed proximate to an end of the cartridge body that is left and the first and second connection ports are disposed proximate to an end of the cartridge body that is right.
In some examples, the loading well is located on the top surface of the cartridge body.
In some examples, the first connection port and the second connection port are disposed opposite each other.
In some examples, the first connection port is located on a top surface of the cartridge body and the second connection port is located on a bottom surface of the cartridge body.
In some examples, adjacent chambers are communicated by a slit having a cross-section that tapers from an upstream end to a downstream end.
In some examples, each chamber is further provided with a vent.
In some examples, the vent hole and the reagent filling hole are both located on the back of the cartridge body, wherein the reagent filling hole is lower in height than the vent hole in the height direction, and the single adhesive seals both the reagent filling hole and the vent hole.
In some examples, the reagent in at least one of the chambers is an aqueous phase incompatible organic reagent in a plurality of chambers in sequential communication to form an oil-water interface between two chambers adjacent thereto.
In some examples, seven chambers which are sequentially communicated are arranged in the cartridge main body, and a cracking chamber, a first oil phase separation chamber, a first cleaning chamber, a second oil phase separation chamber, a second cleaning chamber, a third oil phase separation chamber and an elution chamber are respectively arranged from the upstream end to the downstream end;
the number of the reagent filling holes is seven, and the reagent filling holes are respectively a first reagent filling hole, a second reagent filling hole, a third reagent filling hole, a fourth reagent filling hole, a fifth reagent filling hole, a sixth reagent filling hole and a seventh reagent filling hole;
seven vent holes are respectively a first vent hole, a second vent hole, a third vent hole, a fourth vent hole, a fifth vent hole, a sixth vent hole and a seventh vent hole;
the first reagent filling hole and the first vent hole are communicated with the cracking cavity, the second reagent filling hole and the second vent hole are communicated with the first oil phase separation cavity, the third reagent filling hole and the third vent hole are communicated with the first washing cavity, the fourth reagent filling hole and the fourth vent hole are communicated with the second oil phase separation cavity, the fifth reagent filling hole and the fifth vent hole are communicated with the second washing cavity, the sixth reagent filling hole and the sixth vent hole are communicated with the third oil phase separation cavity, and the seventh reagent filling hole and the sixth vent hole are communicated with the elution cavity.
In some examples, the cartridge body further comprises an eighth vent hole disposed proximate the loading hole, the first sealed aluminum foil sealing both the loading hole and the eighth vent hole.
In some examples, the droplet generation vibratory needle includes a hub adapter for connecting with the second connection port, a hose connecting the hub adapter and the vibratory microneedle.
In some examples, the interface adapter includes a plastic connector and a steel pin, the plastic connector being connected to the second interface, the steel pin being located within the plastic connector.
In a second aspect, the application also provides another nucleic acid analysis cartridge, which comprises a nucleic acid extraction cartridge, a liquid drop generation vibrating needle and an air inflation assembly, wherein the liquid drop generation vibrating needle and an air pump connector are both communicated with the nucleic acid extraction cartridge, the nucleic acid extraction cartridge is used for extracting nucleic acid from a sample, the air inflation assembly is used for providing pressure for the nucleic acid extraction cartridge, and the liquid drop generation vibrating needle generates liquid drops through vibration, swing and precession.
In some examples, the nucleic acid extraction cartridge includes a cartridge body, a first sealed aluminum foil, a single-sided tape, and a third sealed aluminum foil, wherein,
The cartridge body forms a plurality of chambers which are sequentially communicated so as to extract nucleic acid from a sample, each chamber is provided with a reagent filling hole, the chamber at the upstream end is further provided with a sample filling hole, the chamber at the downstream end is further provided with a second connecting port, the second connecting port is used for connecting a liquid drop generating vibrating needle, the first sealing aluminum foil is used for sealing the sample filling hole, the single-sided adhesive tape is used for sealing the reagent filling hole, and the third sealing aluminum foil is used for sealing the second connecting port.
In some examples, the inflation assembly includes a sleeve disposed on the cartridge body and in communication with the cavity at the downstream end, a pushrod slidably disposed within the sleeve and movable to apply pressure to the cavity at the downstream end, and a catch to retain the pushrod during storage.
In a third aspect, the present application provides a droplet generation system comprising a nucleic acid analysis cartridge, a culture dish, and an imaging mechanism, wherein the culture dish contains droplet generation oil, and the nucleic acid analysis cartridge is any one of the nucleic acid analysis cartridges described above.
In a fourth aspect, the present application provides a second droplet generation system comprising a nucleic acid analysis cartridge, a strip-shaped liquid reservoir and an imaging mechanism, wherein the strip-shaped liquid reservoir is an elongate liquid reservoir containing droplet generation oil therein, and the nucleic acid analysis cartridge is a nucleic acid analysis cartridge as defined in any one of the above.
In a fourth aspect, the present application provides a droplet generation system comprising a nucleic acid analysis cartridge, a droplet generation chip and an imaging mechanism, wherein the droplet generation chip is a typical droplet generation chip in the field of microfluidics, and the nucleic acid analysis cartridge is a nucleic acid analysis cartridge as described above.
According to the technical scheme, the nucleic acid analysis cartridge comprises the nucleic acid extraction cartridge for extracting nucleic acid from a sample and the liquid drop generating vibration needle for generating liquid drops, so that the structure can take both the nucleic acid extraction and the liquid drop generating structure into consideration in the process of quantitatively analyzing DNA or RNA, and the purposes of reducing manual operation steps, reducing the risk of nucleic acid pollution and improving the turnover efficiency of clinical detection can be achieved without transferring the nucleic acid extraction.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below. It is apparent that the drawings in the following description are only some examples or embodiments of the present invention, and it is possible for those of ordinary skill in the art to obtain other drawings from the provided drawings without inventive effort, and to apply the present invention to other similar situations from the provided drawings. Unless otherwise apparent from the context of the language or otherwise specified, like reference numerals in the figures refer to like structures or operations.
FIGS. 1-3 are schematic diagrams of a nucleic acid analysis cartridge according to an embodiment of the present invention;
FIGS. 4 a-5 are schematic diagrams of a nucleic acid extraction cartridge according to embodiments of the present invention;
FIGS. 6-7 b are schematic diagrams of a droplet-generating vibratory needle according to embodiments of the invention;
FIG. 8 is a schematic diagram of a nucleic acid extraction cartridge according to an embodiment of the present invention;
FIGS. 9 a-9 g are schematic diagrams showing the operation of the cartridge at various stages in the nucleic acid extraction using the nucleic acid analysis cartridge;
FIG. 10 is a schematic diagram of a first droplet generation system according to an embodiment of the present invention;
FIGS. 11a-11b are schematic illustrations of a second droplet generation system provided in accordance with embodiments of the present invention;
FIG. 12 is a schematic diagram of a third droplet generation system according to an embodiment of the invention;
FIG. 13 is a physical diagram of a nucleic acid analysis cartridge according to an embodiment of the present invention;
fig. 14-15 are schematic diagrams of another nucleic acid analysis cartridge according to an embodiment of the present invention.
In the figure, 10-nucleic acid analysis cartridge, 20-petri dish, 30-imaging mechanism, 40-strip-shaped liquid storage tank, 50-liquid drop generation chip;
100-nucleic acid extraction cartridge, 200-droplet generation vibrating needle, 300-air pump connector, 300' -inflation assembly;
110-a cartridge main body, 120-a first sealing aluminum foil, 130-single-sided adhesive tape, 140-a second sealing aluminum foil, and 150-a third sealing aluminum foil;
110 a-front, 110 b-back, 110 c-top, 110 d-bottom, 110 e-left, 110 f-right;
1101-cleavage chamber, 1102-first oil phase separation chamber, 1103-first wash chamber, 1104-second oil phase separation chamber, 1105-second wash chamber, 1106-third oil phase separation chamber, 1107-elution chamber, 1108-first slit, 1109-second slit, 1110-third slit, 1111-fourth slit, 1112-fifth slit, 1113-sixth slit, 1114-first connection port, 1115-second connection port;
1101 a-first reagent filling hole, 1102 a-second reagent filling hole, 1103 a-third reagent filling hole, 1104 a-fourth reagent filling hole, 1105 a-fifth reagent filling hole, 1106 a-sixth reagent filling hole, 1107 a-seventh reagent filling hole;
1101 b-first vent, 1102 b-second vent, 1103 b-third vent, 1104 b-fourth vent, 1105 b-fifth vent, 1106 b-sixth vent, 1107 b-seventh vent;
1101 c-sample-adding hole, 1101 d-eighth vent hole;
210-interface adapter, 220-hose, 230-vibrating microneedle, 211-plastic connector, 212-steel needle, 2301-plastic interface, 2302-microneedle;
310' -sleeve, 320' -push rod, 330' -buckle.
Detailed Description
As described in the background art, the invention aims to reduce manual operation steps, reduce the risk of nucleic acid pollution and improve the turnover efficiency of clinical detection in the process of quantitatively analyzing DNA or RNA. The embodiment of the invention discloses a nucleic acid analysis cartridge, which enables a nucleic acid extraction reagent to be stably separated by separating oil through structural design, and the prepared nucleic acid analysis cartridge can be stored or transported at low temperature for a long time.
Referring to fig. 1 to 13, the nucleic acid analysis cartridge 10 of the present application may include a nucleic acid extraction cartridge 110 for extracting nucleic acid from a sample, a droplet generation vibratory needle 200 for generating droplets by vibration, oscillation, precession, etc., and an air pump connector 300 for connecting with an air pump as a power source for subsequent droplet generation to provide pressure to the nucleic acid extraction cartridge.
The nucleic acid analysis cartridge 10 of the present application includes a nucleic acid extraction cartridge for extracting nucleic acid from a sample and a droplet generation vibrating needle 300 for generating droplets, so that the structure can achieve the purposes of reducing the number of manual steps, reducing the risk of nucleic acid contamination, and improving the turnover efficiency of clinical detection by taking into consideration both the nucleic acid extraction and droplet generation during quantitative analysis of DNA or RNA.
Referring to fig. 1 to 3, fig. 1 shows a perspective view of the nucleic acid extraction cartridge 100, the droplet generation vibratory needle 200, and the air pump connector 300 when not assembled together, fig. 2 shows a perspective view of the nucleic acid extraction cartridge 100, the droplet generation vibratory needle 200, and the air pump connector 300 when assembled together, and fig. 3 shows an exploded view of the nucleic acid extraction cartridge 100, the droplet generation vibratory needle 200, and the air pump connector 300 when not assembled together.
The nucleic acid extraction cartridge 100 may include a cartridge body 110, a first sealing aluminum foil 120, a single-sided tape 130, a second sealing aluminum foil 140, and a third sealing aluminum foil 150, wherein,
The cartridge body 110 is used for forming a plurality of chambers which are sequentially communicated to extract nucleic acid from a sample, each chamber is provided with a reagent filling hole, the chamber at the upstream end is further provided with a sample filling hole 1101c, the chamber at the downstream end is further provided with a first connection port 1114 and a second connection port 1115, the first connection port 1114 is used for connecting the air pump connector 300, the second connection port 1115 is used for connecting the droplet generation vibrating needle 200, the first sealing aluminum foil 120 is used for sealing the sample filling hole 1101c, the single-sided tape 130 is used for sealing the reagent filling hole, the second sealing aluminum foil 140 is used for sealing the first connection port 1114, and the third sealing aluminum foil 150 is used for sealing the second connection port 1115.
The sample addition well 1101c is used for adding a sample, and the reagent filling well is used for adding a reagent to the corresponding chamber. The sample processing device is divided into an upstream end and a downstream end according to the sample processing direction, wherein the chamber for sample adding is the upstream end and the downstream end for sample discharging is the downstream end for a plurality of chambers, and one end of each chamber, which is communicated with the previous chamber, is the upstream end and one end of each chamber, which is communicated with the next chamber, is the downstream end.
The terms "first" and "second" are used above for descriptive purposes only and are not to be construed as indicating or implying relative importance or implicitly indicating the number of technical features indicated. Thus, a feature defining "a first" or "a second" may explicitly or implicitly include one or more such feature.
Among the chambers which are communicated in turn, the reagent in at least one chamber is an organic reagent which is incompatible with the water phase so as to form an oil-water interface between two adjacent chambers. The chambers filled with the organic reagents become oil phase separation chambers, the number of which is adjusted according to the ongoing operation of the analysis cartridge.
The liquid droplet generation vibration needle 200 and the air pump connector 300 pierce the third seal aluminum foil 150 and communicate with the second connection port 1115 to achieve air connection of the liquid droplet generation vibration needle 200 to the nucleic acid extraction cartridge 100, and the air pump connector 300 pierces the second seal aluminum foil 140 and communicates with the first connection port 1114 to achieve air connection of the air pump connector 300 to the nucleic acid extraction cartridge 100, when assembled to the cartridge body 110.
The shape of the cartridge body 110 in the present application is not particularly limited, and for convenience of sealing, the shape of the cartridge body 110 in the present application is a rectangular parallelepiped structure, and for convenience of understanding, a front surface 110a is a surface facing the reader, a rear surface 110b is a surface opposite to the front surface 110a, a top surface 110c and a bottom surface 110d are opposite in a height direction, and a left surface 110e and a right surface 110f are opposite in a length direction, and of course, the above definition of the surfaces is defined only by the orientation indicated by the drawing. Here, the height direction, the length direction, and the width direction are perpendicular to each other, and the height direction corresponds to the height of the cartridge body 110, the length direction corresponds to the length of the cartridge body 110, and the width direction corresponds to the width of the cartridge body 110.
In order to optimize the operation, the sample addition end is spaced apart from the droplet generation end by a preset distance, wherein the sample addition end is used for sample addition and the droplet generation end is used for droplet generation. In some examples of the present application, the well 1101c is disposed near an end of the left side 110e, and the first connection port 1114 and the second connection port 1115 are disposed near an end of the right side 110 f.
In order to optimize the above operation, the sample adding hole 1101c is located at one end of the top surface 110c and close to the left surface 110e, and is added in a top-down manner when the sample is added, which accords with the principle of gravity and is convenient to operate.
The first connection port 1114 and the second connection port 1115 are disposed opposite to each other, so that gas resistance from the first connection port 1114 to the second connection port 1115 can be reduced, and further, in order to ensure stability of forming droplets, the first connection port 1114 is located at the top surface 110c of the cartridge body 110, and the second connection port 1115 is located at the bottom surface 110d of the cartridge body 110, so that gas enters from the top of the cartridge body 110 and is formed from the bottom.
To further optimize the above scheme, reagent fills Kong Bikai are provided in the loading well 1101 c. Reagent filling holes are located on the front 110a, back 110b, and bottom 110d. The front 110a and back 110b sides are preferably selected.
Referring to fig. 4a, 4B, 4c and 5, fig. 4a shows a perspective view of the cartridge body 110, fig. 4B shows a cross-sectional view of section A-A of fig. 4a, fig. 4c shows a cross-sectional view of section B-B of fig. 4a, and fig. 5 shows a cross-sectional view of the cartridge body 110.
In the drawing, seven chambers are sequentially communicated in the cartridge main body 110, and from an upstream end to a downstream end (from left to right) are a cracking chamber 1101, a first oil phase separation chamber 1102, a first cleaning chamber 1103, a second oil phase separation chamber 1104, a second cleaning chamber 1105, a third oil phase separation chamber 1106 and an elution chamber 1107 respectively, wherein:
The lysis chamber 1101 is used for adding reagents such as lysis solution, magnetic beads, etc.
The first oil phase partition 1102, the second oil phase partition 1104, and the third oil phase partition 1106 are used for adding organic agents incompatible with the aqueous phase, such as mineral oil, paraffin oil, low-melting paraffin wax, and the like.
The first washing chamber 1103 and the second washing chamber 1105 are used to add washing liquid required for nucleic acid extraction.
Elution chamber 1107 is used to add the eluent needed for nucleic acid extraction.
Each chamber is correspondingly provided with seven reagent filling holes, namely a first reagent filling hole 1101a, a second reagent filling hole 1102a, a third reagent filling hole 1103a, a fourth reagent filling hole 1104a, a fifth reagent filling hole 1105a, a sixth reagent filling hole 1106a and a seventh reagent filling hole 1107a, wherein the first reagent filling hole is communicated with the cracking chamber 1101, the second reagent filling hole 1102a is communicated with the first oil phase separation chamber 1102, the third reagent filling hole 1103a is communicated with the first washing chamber 1103, the fourth reagent filling hole 1104a is communicated with the second oil phase separation chamber 1104, the fifth reagent filling hole 1105a is communicated with the second washing chamber 1105, the sixth reagent filling hole 1106a is communicated with the third oil phase separation chamber 1106, and the seventh reagent filling hole 1107a is communicated with the elution chamber 1107.
The first oil phase separation chamber 1102, the second oil phase separation chamber 1104, and the third oil phase separation chamber 1106 can form an oil-water interface between the first oil phase separation chamber 1102 and the pyrolysis chamber 1101 and between the first oil phase separation chamber 1102 and the first washing chamber 1103, the second oil phase separation chamber 1104 can form an oil-water interface between the second oil phase separation chamber 1104 and the first washing chamber 1103 and between the second oil phase separation chamber 1104 and the second washing chamber 1105, and the third oil phase separation chamber 1106 can form an oil-water interface between the third oil phase separation chamber 1106 and the second washing chamber 1105 and between the third oil phase separation chamber 1106 and the elution chamber 1107. So that the reagents in the corresponding chambers can be stably stored.
In order to improve the smoothness of filling the reagent, each chamber is also provided with a vent hole. On the premise that the cartridge main body 110 includes seven chambers, the number of ventilation holes is seven, namely, a first ventilation hole 1101b, a second ventilation hole 1102b, a third ventilation hole 1103b, a fourth ventilation hole 1104b, a fifth ventilation hole 1105b, a sixth ventilation hole 1106b, and a seventh ventilation hole 1107b. The first reagent filling hole and the first vent hole 1101b are communicated with the lysis chamber 1101, the second reagent filling hole 1102a and the second vent hole 1102b are communicated with the first oil phase separation chamber 1102, the third reagent filling hole 1103a and the third vent hole 1103b are communicated with the first washing chamber 1103, the fourth reagent filling hole 1104a and the fourth vent hole 1104b are communicated with the second oil phase separation chamber 1104, the fifth reagent filling hole 1105a and the fifth vent hole 1105b are communicated with the second washing chamber 1105, the sixth reagent filling hole 1106a and the sixth vent hole 1106b are communicated with the third oil phase separation chamber 1106, and the seventh reagent filling hole 1107a and the sixth vent hole 1106b are communicated with the elution chamber 1107.
In order to reduce the number of sealing steps, the reagent filling hole and the vent hole are both located on the back surface 110b, wherein the height of the reagent filling hole is lower than the height of the vent hole in the height direction. The single glue 130 can seal both the reagent filling holes 1101a-1107a and the vent holes 1101b-1107b.
Similarly, to improve smoothness of sample application, the cartridge main body 110 may further include an eighth vent 1101d, where the eighth vent 1101d communicates with the outside during sample application. To reduce the sealing step, the eighth vent hole 1101d is disposed near the loading hole 1101c, and the loading hole 1101c and the eighth vent hole 1101d may be sealed at the same time using the first sealing aluminum foil 120.
Adjacent chambers are communicated through narrow openings, and the cross sections of the narrow openings gradually become smaller from the upstream end to the downstream end, namely, the narrow openings are furled. The various liquids in the cartridge form an oil-water interface at the narrow opening of the adjacent chamber, and are stable under the surface tension of oil-water two phases, and can bear a certain degree of disturbance. In the case that the cartridge body 110 includes seven chambers, the number of slits is six, and from left to right, the first slit 1108, the second slit 1109, the third slit 1110, the fourth slit 1111, the fifth slit 1112, and the sixth slit 1113 are respectively, the first slit 1108 communicates with the cleavage chamber 1101 and the first oil phase separation chamber 1102, the second slit 1109 communicates with the first oil phase separation chamber 1102 and the first washing chamber 1103, the third slit 1110 communicates with the first washing chamber 1103 and the second oil phase separation chamber 1104, the fourth slit 1111 communicates with the second oil phase separation chamber 1104 and the second washing chamber 1105, the fifth slit 1112 communicates with the second washing chamber 1105 and the third oil phase separation chamber 1106, and the sixth slit 1113 communicates with the third oil phase separation chamber 1106 and the elution chamber 1107.
When filling reagents, the first sealed aluminum foil 120, the second sealed aluminum foil 140 and the third sealed aluminum foil 150 are used for respectively sealing the sample adding hole 1101c and the vent hole 1101d, the first connecting port 1114 and the second connecting port 1115 of the cartridge main body 110, reagents such as a lysis solution required by nucleic acid extraction, magnetic beads and the like are added into the lysis cavity 1101 through the reagent filling port 1101a, organic reagents incompatible with water phase such as mineral oil, paraffin oil and low melting point paraffin are added into the first oil phase separation cavity 1102 through the reagent filling port 1102a, cleaning liquid required by nucleic acid extraction is added into the first cleaning cavity 1103 through the reagent filling port 1103a, organic reagents incompatible with water phase such as mineral oil, paraffin oil and low melting point paraffin oil are added into the second cleaning cavity 1104 through the reagent filling port 1104a, organic reagents incompatible with water phase such as mineral oil, paraffin oil and low melting point paraffin oil are added into the third oil phase separation cavity 1106 through the reagent filling port 1106a, eluent required by nucleic acid extraction is added into the elution cavity 1107 through the reagent filling port 1107a, the eluent required by nucleic acid extraction can be the LAMP reaction system, and the amplification reaction system such as the amplification system of the amplification reaction cartridge 110 can be finally carried out by sealing the back side of the cartridge main body 110. At this time, the nucleic acid extraction cartridge 100 containing the nucleic acid extraction reagent can be stored or transported for a long time at a low temperature, and each liquid state in the cartridge body 110 is shown in fig. 8, wherein black is an oil phase organic reagent and gray is an aqueous phase reagent.
Referring to fig. 6, 7a and 7b, fig. 6 shows an exploded view of the droplet generation vibratory needle 200, fig. 7a shows a front view of the droplet generation vibratory needle 200, and fig. 7b shows a cross-sectional view of section C-C of fig. 7 a.
The illustrated drop generating vibrating needle 200 can include an interface adapter 210, a hose 220, and a vibrating microneedle 230. The interface adapter 210 is used to connect with the second connection port 1115, and the hose 220 connects the interface adapter 210 and the vibrating microneedle 230.
The interface adapter 210 may include a plastic connector 2101 and a steel needle 2102, wherein the plastic connector 2101 is configured to connect with the second connection port 1115, and the steel needle 2102 is disposed at an end of the plastic connector 2101 near the second connection port 1115, for puncturing the third sealed aluminum foil 150. The flexible tube 220 has better flexibility and can be bent, and the vibrating microneedle 230 can comprise a plastic connector 2301 and a microneedle 2302, wherein the outer diameter of the microneedle is about 20 microns, and the inner diameter of the microneedle is about 10 microns. In use, the steel needle 2102 pierces the third sealed aluminum foil 150, and the droplet generation vibrating needle 200 is connected to the liquid path of the nucleic acid extraction cartridge 100.
Referring to fig. 8, fig. 8 shows a state in which the nucleic acid extraction cartridge 100 stores each reagent. Wherein black is the oil phase organic reagent separating each aqueous phase, and grey is the aqueous phase nucleic acid extraction reagent. The two phases of oil and water exist stably due to the design of the slots 1108-1113.
Referring to FIGS. 9 a-9 g, FIGS. 9 a-9 g illustrate the process of nucleic acid extraction of the nucleic acid extraction cartridge 100 using the magnetic bead method.
First, the first sealed aluminum foil 120 is pierced by the pipette tip, the sample is introduced into the lysis chamber 1101 through the sample introduction hole 1101c, the excess air is discharged through the vent hole 1101d, then the sample introduction hole 1101c and the vent hole 1101d are sealed with a single-sided tape, and then the nucleic acid extraction cartridge main body 110 is connected to the air pump connector 300 and the droplet generation vibratory needle 200, respectively, the air pump connector 300 being an adapting member of the air pump, and being connected to the air pump, the air pump does not provide pressure, here is dead end, so that the liquid in the elution chamber 1107 can stably exist without flowing out from the droplet generation vibratory needle 200, as shown in fig. 9 a.
Next, the magnet is tightly attached to the front surface 110a of the cartridge opposite to the cleavage cavity 1101 in the cartridge main body 110, and the magnetic beads enriched with nucleic acids are gathered on the inner wall of the cleavage cavity 1101 as shown in fig. 9 b.
And then slowly enters the first oil phase separation chamber 1102 through the first slit 1108 under the influence of the magnet, as shown in fig. 9 c.
Continuing to move the magnet, the nucleic acid enriched beads are then passed through the second slit 1109 into the first washing chamber 1103 for bead washing, as shown in FIG. 9 d.
Continuing to move the magnet, the nucleic acid-enriched magnetic beads are passed through the third slit 1110, the second oil phase separation chamber 1104, and the fourth slit 1111 into the second washing chamber 1105 for the second washing of the magnetic beads, as shown in FIG. 9 e.
Then, the magnet is moved continuously, the magnetic beads enriched with nucleic acid are put into the elution cavity 1107 through the fifth slit 1112, the third oil phase separation cavity 1106 and the sixth slit 1113 to elute the nucleic acid, and the eluted nucleic acid is fully mixed with the amplification system, as shown in FIG. 9 f.
Finally, the beads are enriched with a magnet and once through the sixth slit 1113, the third oil phase separation chamber 1106, the fifth slit 1112 into the second wash chamber 1105 as shown in fig. 9 g.
Referring to fig. 10, fig. 10 shows a schematic diagram of a first droplet generation system.
The droplet generation system comprises a nucleic acid analysis cartridge 10, a culture dish and an imaging mechanism, wherein the culture dish 20 contains droplet generation oil, and the vibrating microneedle 230 penetrates into the oil phase liquid level by 0-1mm. At this time, the external air pump supplies pressure, the amplification system in the elution chamber 1107 flows out from the vibrating microneedle 230 through the droplet generation vibrating needle 200 under the action of air pressure, the droplet generation vibrating needle 200 swings left and right, vibrates left and right or precesses around the rotation center under the action of external driving force, and at this time, the amplification system flowing out from the vibrating microneedle 230 is subjected to shearing force generated by the droplet generation oil which is still in the culture dish 20, is dispersed into droplets and is settled at the bottom of the culture dish 20 for tiling. The droplet-forming oil here may be a mineral oil containing a surfactant, isopropyl palmitate or a settable oil phase subjected to hydrosilylation reaction by heat over a Pt catalyst. After the completion of the droplet generation, the dish 20 containing the droplet is heated on a heating device to perform a nucleic acid amplification reaction, which may be RPA, LAMP, PCR, or the like. Finally, fluorescence imaging is carried out on the culture dish 20 after reaction, the culture dish is moved to an imaging mechanism 30 for detection, and the original target content is calculated through poisson distribution.
Referring to fig. 11a and 11b, fig. 11a and 11b show schematic diagrams of a second droplet generation system.
The droplet generation system comprises a nucleic acid analysis cartridge 10, a strip-shaped liquid storage tank 40 and an imaging mechanism, wherein the strip-shaped liquid storage tank 40 is a strip-shaped liquid storage tank, liquid droplet generation oil is contained in the strip-shaped liquid storage tank, a vibrating microneedle 230 penetrates into the liquid level of an oil phase for 0-1mm, the strip-shaped liquid storage tank 40 is arranged on the surface of a heating device capable of controlling the temperature, and the heating device is provided with two temperature areas, namely a low temperature area (lower than room temperature) and a high temperature area (39 ℃ or 65 ℃). At this time, the external air pump supplies pressure, the amplification system in the elution chamber 1107 flows out from the vibrating microneedle 230 through the droplet generation vibrating needle 200 under the action of air pressure, the droplet generation vibrating needle 200 swings left and right or precesses around the rotation center under the action of external driving force, the amplification system flowing out from the vibrating microneedle 230 is subjected to shearing force generated by the droplet generation oil which stands still in the strip-shaped liquid storage tank 40, is dispersed into droplets and is settled at the bottom of the strip-shaped liquid storage tank 40 to be spread, meanwhile, the strip-shaped liquid storage tank 40 is slowly pushed from left to right, the strip-shaped liquid storage tank 40 gradually enters into a high temperature region from a low temperature region, the droplets are heated to a reaction temperature when reaching the high temperature region, and the internal amplification system starts the nucleic acid amplification reaction. As the strip reservoir 40 moves gradually, it enters the detection zone of the imaging mechanism 40, as shown in fig. 11 b. By setting the proper moving time and the proper droplet generation speed, the pipeline working mode of detecting the nucleic acid of the micro droplets while generating can be realized, the detection process is similar to the detection of a punching paper tape, the droplets are regarded as through holes in the punching paper tape, the negative and positive droplets in the strip-shaped liquid storage tank 40 are continuously counted, and the method is suitable for detecting a large number of droplets while generating and amplifying. The droplet-forming oil here may be a mineral oil containing a surfactant, isopropyl palmitate or a settable oil phase subjected to hydrosilylation reaction by heat over a Pt catalyst.
Referring to fig. 12, fig. 12 shows a schematic diagram of a third droplet generation system.
The droplet generation system comprises a nucleic acid analysis cartridge 10, a droplet generation chip 50 and an imaging mechanism, wherein the droplet generation chip 50 is a typical droplet generation chip in the field of microfluidics, and micro droplets are generated in the droplet generation chip by means of T-shaped tubes, flow focusing, coaxial flow and the like. At this time, the 230 microneedle of the nucleic acid analysis cartridge 10 is inserted into the droplet generation chip as an aqueous phase input, the external air pump of the nucleic acid analysis cartridge 10 is used as a driving source, the other inlet of the droplet generation chip is used as an oil phase input, and there are additional droplet generation oil and a corresponding driving source. The generated droplets can be subjected to in-situ amplification detection in a chip, or can be collected and transferred to an EP tube for amplification detection. The droplet-forming oil here may be a mineral oil containing a surfactant, isopropyl palmitate or a settable oil phase subjected to hydrosilylation reaction by heat over a Pt catalyst.
Referring to FIG. 13, FIG. 13 is a physical view of a nucleic acid extraction cartridge 100 according to the present invention. Wherein the dark portions are colored with nucleic acid extraction-related aqueous reagents and the partially transparent liquid between the dark portions is mineral oil used as a separate aqueous phase.
Referring to fig. 14 and 15, fig. 14 shows a perspective view of another nucleic acid analysis cartridge 10, and fig. 14 shows an exploded view of another nucleic acid analysis cartridge 10.
The illustrated nucleic acid analysis cartridge 10 is different from the nucleic acid analysis cartridge 10 shown in fig. 1 to 3 in that the structure for providing pressure is changed. In this example, the pressure providing structure may be an air charging assembly 300 'including a sleeve 310', a push rod 320', and a buckle 330', wherein the sleeve 310 'is disposed on the cartridge body 110 and communicates with a cavity at a downstream end, the push rod 320' is slidably disposed inside the sleeve 310 'and applies pressure to the eluting cavity 1107 by moving, and the buckle 330' is used to limit the push rod 320 'during storage, preventing the position of the push rod 320' from being changed due to jolt and shake, etc., and affecting the internal pressure balance.
By slowly pushing the push rod 320', pressure can be applied to the elution chamber 1107, so that liquid in the elution chamber is slowly discharged, and the same effect as an external air pump is achieved. The buckle 330' is used for limiting the push rod 320' during storage, so as to prevent the position of the push rod 320' from changing due to jolt and shake, etc., and influence the internal pressure balance. The above design makes the nucleic acid analysis cartridge 10 more integrated, reduces gas path connections, reduces the risk of nucleic acid contamination, and reduces the requirements for associated instrumentation, with specific embodiments not substantially different from the cartridges described above.
The above description is only illustrative of the preferred embodiments of the present invention and the technical principles applied, and is not intended to limit the present invention. Various modifications and variations of the present invention will be apparent to those skilled in the art. The scope of the invention is not limited to the specific combination of the above technical features, but also covers other technical features formed by any combination of the above technical features or their equivalents without departing from the inventive concept. Such as the above-mentioned features and the technical features disclosed in the present invention (but not limited to) having similar functions are replaced with each other.
Claims (21)
1. The nucleic acid analysis cartridge is characterized by comprising a nucleic acid extraction cartridge, a liquid drop generation vibrating needle and an air pump connector, wherein the liquid drop generation vibrating needle and the air pump connector are communicated with the nucleic acid extraction cartridge, the nucleic acid extraction cartridge is used for extracting nucleic acid from a sample, the air pump connector is used for being connected with an air pump to provide pressure for the nucleic acid extraction cartridge, and the liquid drop generation vibrating needle generates liquid drops through vibration, swing and precession.
2. The nucleic acid analysis cartridge of claim 1, wherein the nucleic acid extraction cartridge comprises a cartridge body, a first sealed aluminum foil, a single-sided tape, a second sealed aluminum foil, and a third sealed aluminum foil, wherein,
The cartridge body is provided with a plurality of chambers which are sequentially communicated, so as to extract nucleic acid from a sample, each chamber is provided with a reagent filling hole, the chamber at the upstream end is further provided with a sample adding hole, the chamber at the downstream end is further provided with a first connecting port and a second connecting port, the first connecting port is used for connecting an air pump connector, the second connecting port is used for connecting a liquid drop generating vibration needle, the first sealing aluminum foil is used for sealing the sample adding hole, the single-sided adhesive tape is used for sealing the reagent filling holes, the second sealing aluminum foil is used for sealing the first connecting port, and the third sealing aluminum foil is used for sealing the second connecting port.
3. The nucleic acid analysis cartridge according to claim 2, wherein the sample addition hole is provided near an end of the left side of the cartridge body, and the first connection port and the second connection port are provided near an end of the right side of the cartridge body.
4. The nucleic acid analysis cartridge of claim 3, wherein the loading well is located on a top surface of the cartridge body.
5. The nucleic acid analysis cartridge of claim 3, wherein the first connection port and the second connection port are disposed opposite each other.
6. The nucleic acid analysis cartridge of claim 5, wherein the first connection port is located on a top surface of the cartridge body and the second connection port is located on a bottom surface of the cartridge body.
7. The nucleic acid analysis cartridge of claim 5, wherein adjacent chambers are in communication via a slit having a cross-section that tapers from an upstream end to a downstream end.
8. The nucleic acid analysis cartridge of claim 5, wherein each of the chambers is further provided with a vent.
9. The nucleic acid analysis cartridge as claimed in claim 5, wherein the vent hole and the reagent filling hole are both located on a back surface of the cartridge body, wherein in a height direction, a height of the reagent filling hole is lower than a height of the vent hole, and the single-sided tape seals both the reagent filling hole and the vent hole.
10. The nucleic acid analysis cartridge of claim 2, wherein among the plurality of chambers in sequential communication, at least one of the chambers is an aqueous phase incompatible organic reagent to form an oil-water interface between two chambers adjacent thereto.
11. The nucleic acid analysis cartridge according to claim 10, wherein seven chambers are provided in the cartridge body, which are sequentially communicated, from an upstream end to a downstream end, respectively including a lysis chamber, a first oil phase separation chamber, a first washing chamber, a second oil phase separation chamber, a second washing chamber, a third oil phase separation chamber, and an elution chamber;
the number of the reagent filling holes is seven, and the reagent filling holes are respectively a first reagent filling hole, a second reagent filling hole, a third reagent filling hole, a fourth reagent filling hole, a fifth reagent filling hole, a sixth reagent filling hole and a seventh reagent filling hole;
Seven vent holes are respectively a first vent hole, a second vent hole, a third vent hole, a fourth vent hole, a fifth vent hole, a sixth vent hole and a seventh vent hole;
The first reagent filling hole and the first vent hole are communicated with the cracking cavity, the second reagent filling hole and the second vent hole are communicated with the first oil phase separation cavity, the third reagent filling hole and the third vent hole are communicated with the first washing cavity, the fourth reagent filling hole and the fourth vent hole are communicated with the second oil phase separation cavity, the fifth reagent filling hole and the fifth vent hole are communicated with the second washing cavity, the sixth reagent filling hole and the sixth vent hole are communicated with the third oil phase separation cavity, and the seventh reagent filling hole and the sixth vent hole are communicated with the elution cavity.
12. The nucleic acid analysis cartridge of claim 11, wherein the cartridge body further comprises an eighth vent hole disposed adjacent to the loading hole, the first sealed aluminum foil sealing both the loading hole and the eighth vent hole.
13. The nucleic acid analysis cartridge of claim 2, wherein the droplet generation vibrating needle comprises an interface adapter for connecting with the second connection port, a hose connecting the interface adapter and the vibrating microneedle, and a vibrating microneedle.
14. The nucleic acid analysis cartridge of claim 13, wherein the interface adapter comprises a plastic connector and a steel needle, the plastic connector being coupled to the second interface, the steel needle being located within the plastic connector.
15. The nucleic acid analysis cartridge is characterized by comprising a nucleic acid extraction cartridge, a liquid drop generation vibrating needle and an inflation assembly, wherein the liquid drop generation vibrating needle and the air pump connector are communicated with the nucleic acid extraction cartridge, the nucleic acid extraction cartridge is used for extracting nucleic acid from a sample, the inflation assembly is used for providing pressure for the nucleic acid extraction cartridge, and the liquid drop generation vibrating needle generates liquid drops through vibration, swing and precession.
16. The nucleic acid analysis cartridge of claim 15, wherein the nucleic acid extraction cartridge comprises a cartridge body, a first sealed aluminum foil, a single-sided tape, and a third sealed aluminum foil, wherein,
The cartridge body is provided with a plurality of chambers which are sequentially communicated, so that nucleic acid extraction is performed on a sample, each chamber is provided with a reagent filling hole, the chamber at the upstream end is further provided with a sample filling hole, the chamber at the downstream end is further provided with a second connecting port, the second connecting port is used for connecting a liquid drop generating vibration needle, the first sealing aluminum foil is used for sealing the sample filling hole, the single-sided adhesive tape is used for sealing the reagent filling holes, and the third sealing aluminum foil is used for sealing the second connecting port.
17. The nucleic acid analysis cartridge of claim 16, wherein the inflation assembly includes a sleeve disposed on the cartridge body and in communication with the cavity at the downstream end, a pushrod slidably disposed within the sleeve and movable to apply pressure to the cavity at the downstream end, and a catch for limiting the pushrod during storage.
18. The nucleic acid analysis cartridge of claim 16, wherein the reagents in at least one of the chambers are aqueous phase incompatible organic reagents in a plurality of chambers in sequential communication to form an oil-water interface between two chambers adjacent thereto.
19. A droplet generation system comprising a nucleic acid analysis cartridge, a culture dish, and an imaging mechanism, wherein the culture dish contains droplet generation oil, and wherein the nucleic acid analysis cartridge is the nucleic acid analysis cartridge of any one of claims 1 to 18.
20. A droplet generation system comprising a nucleic acid analysis cartridge, a strip reservoir and an imaging mechanism, wherein the strip reservoir is an elongate reservoir containing droplet generation oil therein, and wherein the nucleic acid analysis cartridge is a nucleic acid analysis cartridge as claimed in any one of claims 1 to 18.
21. A droplet generation system comprising a nucleic acid analysis cartridge, a droplet generation chip, and an imaging mechanism, wherein the droplet generation chip is typical of a microfluidic field, the nucleic acid analysis cartridge being a nucleic acid analysis cartridge according to any one of claims 1 to 18.
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| Application Number | Priority Date | Filing Date | Title |
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| CN202411777811.2A CN119351209A (en) | 2024-12-05 | 2024-12-05 | A nucleic acid analysis cartridge and a droplet generation system |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202411777811.2A CN119351209A (en) | 2024-12-05 | 2024-12-05 | A nucleic acid analysis cartridge and a droplet generation system |
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| CN119351209A true CN119351209A (en) | 2025-01-24 |
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| CN202411777811.2A Pending CN119351209A (en) | 2024-12-05 | 2024-12-05 | A nucleic acid analysis cartridge and a droplet generation system |
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| CN (1) | CN119351209A (en) |
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- 2024-12-05 CN CN202411777811.2A patent/CN119351209A/en active Pending
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