WO2020244376A1

WO2020244376A1 - Method for manufacturing chromatographic separation micro-column, chromatographic separation micro-column, and gas analysis micro-system

Info

Publication number: WO2020244376A1
Application number: PCT/CN2020/090911
Authority: WO
Inventors: 段学欣; 胡继洲; 庞慰; 屈贺幂
Original assignee: 天津大学
Priority date: 2019-06-06
Filing date: 2020-05-18
Publication date: 2020-12-10
Also published as: CN110170183A

Abstract

Provided are a method for manufacturing a chromatographic separation micro-column, a chromatographic separation micro-column, and a gas analysis micro-system. The manufacturing method comprises: A, manufacturing a substrate of the chromatographic separation micro-column by using a silicon material; B, manufacturing a micro-channel with a spiral structure on an upper surface of the substrate; and C, bonding the bottom of a glass plate to the upper surface of the substrate to form the chromatographic separation micro-column. The above manufacturing method according to the present application is a pioneering manufacturing method for a chromatographic separation column, and is conducive to the manufacturing of chromatographic separation micro-columns, thereby facilitating the miniaturization of gas detection and analysis devices so as to realize the convenient and rapid analysis and detection of gas.

Description

Manufacturing method of micro chromatographic separation column, micro chromatographic separation column and micro gas analysis system

Technical field

The invention relates to the field of gas detection and analysis, and particularly relates to a method for manufacturing a micro chromatographic separation column, a micro chromatographic separation column and a micro gas analysis system.

Background technique

The detection of organic volatile gases, such as the detection of disease markers and environmental pollutants, plays a vital role in the early detection of some major diseases, including diabetes, renal failure, and the supervision and prevention of environmental pollution. Traditional gas detection methods are mostly large-scale laboratory-based analytical instruments, such as gas chromatography-mass spectrometers. Although these instruments can accurately detect the composition and content of mixed gases, these methods are complicated in process, time-consuming, and volumetric. Pangda cannot achieve on-site monitoring. Due to the large volume of the detector part of the traditional gas chromatograph, the miniaturization of the entire gas analysis system is restricted. In recent years, the miniaturization of the detector part of the gas chromatograph has been carried out. However, no substantial progress has been made so far. Therefore, there is an urgent need to solve or partially solve the above technical problems. In order to facilitate the analysis and detection of gas.

Summary of the invention

In view of this, the present application provides a method for manufacturing a micro chromatographic separation column, a micro chromatographic separation column, and a micro gas analysis system, which facilitates the realization of miniaturization and convenient gas detection.

This application provides a method for manufacturing a micro-chromatographic separation column, which is characterized in that it comprises:

A. Use silicon material to make micro-chromatographic separation column base;

B. Fabricating micro-channels with a square spiral structure on the upper surface of the substrate;

C. Bond the bottom of a glass plate to the upper surface of the substrate to form a miniature chromatography column.

From the above, the micro-channel chromatographic separation column of the present application is manufactured into a square spiral structure. This structure can maximize the separation efficiency of the chromatographic separation column. The glass plate (which can be a Pyrex glass plate ) Seal with the bottom plate. The above-mentioned manufacturing method of the present application is the first method for manufacturing a chromatographic separation column, which facilitates the manufacture of tiny chromatographic separation columns, facilitates the miniaturization of gas detection and analysis devices, and facilitates the realization of convenient gas analysis and detection.

Preferably, the step B includes:

B1. Through photolithography and deep silicon etching processes, a micro-channel with a square spiral structure is manufactured;

B2. The inner surface of the micro-channel is modified with a stationary phase.

Preferably, the step B2 includes:

B21. Activate the inner surface of the microfluidic channel by octamethylcyclotetrasiloxane;

B22. Modify 100% polydimethylsiloxane on the inner surface of the micro flow channel by dynamic coating;

B23. Cross-link the stationary phase to ensure the stability of the stationary phase;

B24. Heat aging for 4 hours.

From the above, it is beneficial to better realize the separation of mixed gas.

This application also provides a miniature chromatographic separation column manufactured based on the above manufacturing method, which is characterized in that it comprises:

Substrate, glass plate,

The upper surface of the substrate has micro-channels with a square spiral structure;

Wherein, the bottom of the glass plate is bonded to the upper surface of the substrate.

From the above, the micro-channel chromatographic separation column of the present application is manufactured into a square spiral structure. This structure can maximize the separation efficiency of the chromatographic separation column. The glass plate (which can be a Pyrex glass plate ) Seal with the bottom plate to make a tiny chromatographic separation column. The above-mentioned manufacturing method of the present application is the first method for manufacturing a chromatographic separation column, which is beneficial to the manufacture of tiny chromatographic separation columns and the miniaturization of gas detection and analysis devices.

Based on the above-mentioned micro chromatographic separation column, this application also provides a micro gas analysis system, including:

The injection system includes: a sample injection port and a sample injection pump; wherein the injection pump and the sample injection port are connected through a gas path tube to provide power support for sample injection;

The carrier gas subsystem, including a pressure control valve, a pressure gauge, and a flow meter, is used to accurately control the gas flow, and is connected to the outlet of the inlet system, and is used to load the sample into the micro chromatographic separation column;

Wherein, the micro chromatographic separation column is connected with the inlet system and the carrier gas subsystem for separating samples;

The array of bulk acoustic wave resonators is connected with the outlet of the miniature chromatographic separation column and is used for identifying and detecting gas.

From the above, the micro gas analysis system of the present application performs gas separation through a micro chromatographic separation column and gas identification and detection through a bulk acoustic wave resonator, so as to achieve convenient gas detection.

Preferably, the bulk acoustic wave resonator array includes:

A support plate on which a bulk acoustic wave resonator array area is arranged;

The glass microfluidic channel is arranged on the bulk acoustic wave resonator array area; wherein, two ends of the glass microfluidic channel are respectively provided with an air inlet and an air outlet; wherein, the air inlet and the air outlet Quartz capillaries are respectively connected to the upper part for gas circuit connection; the micro flow channel is designed as a rectangular embedded structure and processed by laser cutting technology. The design refers to the size of the resonator, so that the measured gas flows through the surface of the resonator sensing area accurately. At the same time, the dead volume that is unfavorable for detection is avoided. On this basis, the transmission electrode of the resonator is placed on the outside of the glass microchannel for wire connection and signal transmission.

Wherein, the air inlet is connected to the outlet of the micro chromatographic separation column through the quartz capillary tube; the air outlet is connected to an exhaust gas recovery device through the quartz capillary tube.

From the above, the provision of the above-mentioned glass microfluidic channel is beneficial to increase the contact between the gas and the bulk acoustic wave resonator, and is beneficial to better gas detection. The supporting plate is arranged to facilitate the arrangement of the resonators on it in the form of an array, and the supporting plate is provided with vent holes to facilitate the passage of gas.

Preferably, in the array of bulk acoustic wave resonators, different bulk acoustic wave resonators are modified with polymers that adsorb different types of measured gases.

From the above, by modifying different bulk acoustic wave resonators with different polymers, it is beneficial to the identification and detection of different gases in the unseparated mixed gas in the chromatographic separation column.

Preferably, the carrier gas subsystem includes:

Nitrogen cylinder, pressure control valve, pressure gauge and flow meter connected in sequence.

From the above, the pressure of the carrier gas output by the nitrogen cylinder can be controlled by setting the pressure control valve and the pressure gauge, and the flow rate of the carrier gas can be controlled by setting the flow meter.

Preferably, the system further includes:

A network analyzer connected to the array of bulk acoustic wave resonators for scanning and measuring in a wide frequency band to determine network parameters and display signals.

Preferably, the system further includes:

Temperature control and digital display for temperature control of the environment where the micro chromatographic separation column is located.

From the above, by setting the temperature control and digital display, the detection temperature can be controlled to better realize gas detection.

In summary, the method for manufacturing the micro chromatographic separation column provided by the present application manufactures the chromatographic separation column into a square spiral structure. This structure can maximize the separation performance of the chromatographic separation column. The glass plate is bonded by bonding. (It can be a Pyrex glass plate) and the bottom plate is sealed. The above-mentioned manufacturing method of the present application is the first method for manufacturing a chromatographic separation column, which is beneficial to the manufacture of tiny chromatographic separation columns and the miniaturization of gas detection and analysis devices. The analysis system provided by this application can conveniently realize the separation and detection of mixed gas. The whole system has the characteristics of miniaturization, simplicity, high recognition efficiency and compatibility with semiconductor technology. And the bulk acoustic wave resonator device of the present application can also be set as an array-type bulk acoustic wave resonator, and different bulk acoustic wave resonators are modified with polymers that have the function of adsorbing different types of gas to be measured, so as to achieve the traditional Qualitative and quantitative identification and detection of binary gas mixtures with overlapping peak positions that cannot be identified by a single gas chromatography separation column.

Description of the drawings

FIG. 1 is a schematic flowchart of a method for manufacturing a micro chromatographic separation column provided by an embodiment of the present application;

2 is a schematic diagram of the structure of a micro chromatographic separation column provided by an embodiment of the present application;

FIG. 3 is a flowchart of the modification of the stationary phase of a chromatographic separation column provided by an embodiment of the present application;

FIG. 4 is a schematic diagram of the principle of gas detection performed by the bulk acoustic wave resonator provided by the embodiment of the present application;

FIG. 5 is a schematic diagram of the structure of a bulk acoustic wave resonator and a glass microchannel above it according to an embodiment of the present application;

Fig. 6 is a schematic structural diagram of a micro gas analysis system provided by an embodiment of the present application.

Detailed ways

The technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art fall within the protection scope of the present invention.

Example one

As shown in Fig. 1, a method for manufacturing a miniature chromatographic separation column provided by this application includes:

S101. Use silicon material to make a micro-chromatographic separation column base;

S102. Fabricating micro flow channels with a square spiral structure on the upper surface of the substrate; it may also be a micro flow channel with an arc spiral structure.

Wherein, the micro flow channel with the square spiral structure can be fabricated on the substrate through photolithography or/and deep silicon etching process.

S103: Perform a stationary phase modification on the inner surface of the micro flow channel.

Among them, in order to better realize the separation of the mixed gas, proper stationary phase modification is required when manufacturing the micro chromatographic separation column. See FIG. 3, which specifically includes steps S301 to S304.

S301, activating the inner surface of the micro flow channel through octamethylcyclotetrasiloxane;

S302: Modify 100% polydimethylsiloxane on the inner surface of the micro flow channel by means of dynamic coating;

S303: Perform stationary phase crosslinking to ensure the stability of the stationary phase;

S304, high temperature aging for 4 hours to complete the entire coating process. High temperature aging is beneficial to achieve better separation of mixed gas.

S104. Bonding the bottom of the glass plate to the upper surface of the substrate on which the micro flow channel with a square spiral structure is made to form a micro flow channel chromatographic separation column.

The micro-channel chromatographic separation column of the present application is manufactured into a square spiral structure, which is equivalent to extending the length of the micro-channel chromatographic separation column, and therefore can maximize the separation performance of the chromatographic separation column. The glass plate (which can be a Pyrex glass plate) is sealed with the bottom plate. The above-mentioned manufacturing method of the present application is the first method for manufacturing a chromatographic separation column, which is beneficial to the manufacture of tiny chromatographic separation columns and the miniaturization of gas detection and analysis devices.

Example two

As shown in Fig. 2, the present application also provides a miniature chromatographic separation column manufactured based on the above manufacturing method, including:

The substrate 201 has micro-channels with a square spiral structure etched on its upper surface;

Glass plate 203,

Specifically, the micro chromatographic separation column substrate 201 is made of silicon material through photolithography and deep silicon etching processes to form a square spiral structure. This structure can maximize the separation efficiency of the chromatographic separation column by means of anodic bonding. The Pyrex glass plate 203 is sealed with the substrate 201, and the capillary glass tube 202 is inserted into the gas inlet and outlet to connect with the front and rear gas paths.

Similar to the first embodiment, in order to better realize the separation of the mixed gas, the manufactured micro chromatographic separation column needs to be modified with an appropriate stationary phase. In this embodiment, as shown in Figure 3,

S301, use octamethylcyclotetrasiloxane to activate the inner surface of the micro flow channel,

S302: Select a dynamic coating method to modify 100% polydimethylsiloxane on the chromatographic separation column, that is, the side wall of the inner surface of the micro flow channel,

S303, cross-link the stationary phase to ensure the stability of the stationary phase,

S304, high temperature aging for 4 hours to complete the entire coating process.

The microchannel chromatographic separation column of the present application is manufactured into a square spiral structure, which can maximize the separation performance of the chromatographic separation column. The glass plate (which can be a Pyrex glass plate) and the substrate are bonded by bonding. Seal to make a tiny chromatographic separation column. The above-mentioned manufacturing method of the present application is the first method for manufacturing a chromatographic separation column, which is beneficial to the manufacture of tiny chromatographic separation columns and the miniaturization of gas detection and analysis devices.

Example three

Based on the above-mentioned micro chromatographic separation column, as shown in Figure 6 is a micro gas analysis system provided by this application for detecting organic volatile gases, for example, alkanes in liquid form at room temperature; aromatics related to environmental pollution Compounds; alcohols and aldehydes contained in human exhaled breath; aromas emitted by fruits and crops at different growth stages; gas markers of some major diseases; simulants of chemical warfare agents, etc. The micro gas analysis system specifically includes:

The sample injection port 104 and the sample injection pump 105 are connected in series with gas through the pipeline.

The nitrogen cylinder 101, the pressure control valve and the pressure gauge 102, and the flow rate gauge 103 are connected in series in sequence through the pipeline.

A miniature chromatographic separation column 107 for separating the gas to be measured, a bulk acoustic wave resonator array 109, and a network analyzer 110 for signal driving and displaying the bulk acoustic wave resonator array 109. The timing switch 108 is used to control the gas detection according to a set time.

The temperature control and digital display 106 for temperature control of the environment where the micro chromatographic separation column 107 is located can better realize the separation of gas by controlling the temperature of the micro chromatographic separation column 107. The best setting temperature is 100°C.

In order to explain this application more clearly, some of the above components are introduced in detail below:

The nitrogen cylinder 101, the pressure control valve, the pressure gauge 102 and the flow meter 103 constitute a carrier gas subsystem. The nitrogen cylinder 101 contains high-pressure nitrogen (which can be stored in the nitrogen cylinder 101 in liquid form), and the released nitrogen is used as the carrier gas; the pressure of the output carrier gas can be controlled by setting the pressure control valve and the pressure gauge 102, and the preferred setting is 15psi pressure; the flow rate of the output carrier gas can be controlled by setting the flow meter 103, and the flow rate is preferably set to 20ml/min.

The bulk acoustic wave resonator array 109 is used to further detect the gas separated by the micro chromatographic separation column 107 to obtain detection data signals. Among them, in order to help reduce dead volume, enhance detection performance, and better perform gas detection, as shown in FIG. 5, the structure of the bulk acoustic wave resonator array 109 is as follows, which includes:

The support plate 53, the front of the support plate 53 has a glass micro-channel 55, the air inlet and the air outlet are respectively arranged at the left and right ends of the glass micro-channel 55; the air inlet and the air outlet are respectively connected with a quartz capillary 52, Connected to the gas circuit; among them, the glass micro-runner adopts laser processing to ensure the accuracy of its size. In fact, the micro-manufacturing method can also be used to directly fabricate the micro-chromatographic separation column and the detector on the same substrate, but this method is expensive and difficult to process. In this example, laser processing is selected to make glass Micro flow channel and bonding.

A bulk acoustic wave resonator array 54 is provided on the support plate 53, and the mixed gas sample 51 enters the above-mentioned air inlet through the quartz capillary 52.

That is, the bulk acoustic wave resonator array 54 is arranged on the support plate 53 under the glass microchannel, and the glass microchannel 55 forms a gas detection cavity. Among them, different bulk acoustic wave resonators are modified with polymers that have the function of adsorbing different types of gas to be measured, thereby facilitating the detection of mixed gases that cannot be separated by the micro chromatographic separation column 107. Moreover, the detection effect is best when the frequency of the bulk acoustic wave resonator is set to 2.44 GHz.

Among them, in order to detect the modification of the bulk acoustic wave resonator, a characterization device can also be set up, including: a Fourier transform infrared spectrometer, used to characterize whether the polymer is successfully modified on the surface of the bulk acoustic wave resonator; and atomic force Microscope, used to characterize the morphology and thickness of the polymer film modified on the surface of the bulk acoustic wave resonator.

Among them, the detection principle of the bulk acoustic wave resonator is: as shown in Figure 4, when the gas to be measured after chromatographic separation by the chromatographic separation column reaches the surface of the resonator sensing area of the bulk acoustic wave resonator through the gas path, it will cause the device to resonate The frequency has a certain degree of decline, and the degree of decline is positively correlated with the gas concentration (quantitative identification). The gas is qualitatively identified according to the time the gas passes through, so as to achieve further detection of organic volatile gases.

In order to better explain the technical solution of this application, the working principle of the gas detection system of this application is now explained as follows:

First, the sample to be tested (in order to achieve more efficient gas separation and detection, 5 microliters of the test agent that is liquid at room temperature are mixed in sequence as the sample to be tested). Specifically, use the headspace micro-injection The sample needle drives the sample to be tested into the sample injection port 104 at a constant speed, and the sample to be tested is connected to the gas path between the carrier gas subsystem and the micro chromatographic separation column 107 under the drive of the sample pump 105. Driven by the carrier gas output from the carrier gas subsystem, the sample is sent to the micro chromatographic separation column 107 for gas separation. This period of time can last for 2 minutes.

The gas to be measured output by the micro chromatographic separation column 107 is continuously loaded into the BAW array 109 by the carrier gas, and the change in the resonance frequency of the BAW resonator array 109 is detected, and the data is analyzed and analyzed by the network analyzer 110. display.

Among them, when it is difficult to chromatographically separate some mixed gases through a chromatographic separation column (the obtained peak positions overlap), the present invention can also achieve further detection. The following is a specific description:

In the present invention, different polymers are modified on different bulk acoustic wave resonators in the bulk acoustic wave resonator array to realize the identification of different gases in the unseparated mixed gas after passing through the micro chromatographic separation column. Specifically, for example, in order to qualitatively and quantitatively identify the first gas and the second gas with different mixing ratios that are difficult to separate by the chromatographic separation column, the bulk acoustic wave resonators in the array are modified with polymer A and polymer B, respectively. Among them, the bulk acoustic wave resonator modified by polymer A has a greater response to the first gas, and the bulk acoustic wave resonator modified by polymer B has a greater response to the second gas. Based on this orthogonality, it can be Realize the distinction of mixed gas.

It is worth noting that although the bulk acoustic wave resonator, as a highly sensitive mass sensor, can serve as a detector for a miniature gas chromatographic analysis system (that is, the gas detection system of the present application), its stability in response to changes in chromatographic conditions is still Need to prove. Therefore, this application also sets up the following experiments for this. This application changes the sample injection volume, gas flow rate, and temperature of the chromatographic separation column of the gas analysis system, and monitors the change of the resonance frequency of the bulk acoustic wave resonator to obtain the information of film modification and gas adsorption. According to the structure of example three, Under the sample to be tested and the orderly changing chromatographic conditions, the response changes of the resonator when the chromatographic conditions are changed are monitored to evaluate the adaptability of the resonator as a detector of a miniature gas chromatography system. The specific analysis is as follows: When the sample injection volume is linearly increased in the experiment, it is found that the response signal measured by the resonator also linearly increases; when the gas flow rate is increased sequentially, the retention time of the measured gas will decrease sequentially. It is because after the flow rate increases, the gas to be tested will reach the surface of the device faster and be detected; when the temperature of the oven is gradually increased, the signal spectrum can also be observed to shrink in the negative direction of the x-axis, that is, the retention time of the gas to be tested Decrease, this is because the increase of the oven temperature will cause the distribution coefficient of the gas to be measured between the gas phase and the stationary phase to decrease, so the gas to be measured flows faster in the gas path and the retention time is reduced. The above rules are the same as those of traditional gas chromatographs in response to changes in chromatographic conditions. Therefore, the bulk acoustic wave resonator has good adaptability as a detector of a micro gas chromatograph analysis system and can be used as a detector of a micro gas chromatograph system.

In summary, the method for manufacturing the micro chromatographic separation column provided by the present application manufactures the chromatographic separation column into a square spiral structure. This structure can maximize the separation performance of the chromatographic separation column. The glass plate is bonded by bonding. (It can be a Pyrex glass plate) and the bottom plate is sealed. The above-mentioned manufacturing method of the present application is the first method for manufacturing a chromatographic separation column, which is beneficial to the manufacture of tiny chromatographic separation columns and the miniaturization of gas detection and analysis devices. The analysis system provided by this application can conveniently realize the separation and detection of mixed gas. The whole system has the characteristics of miniaturization, simplicity, high recognition efficiency and compatibility with semiconductor technology. And the bulk acoustic wave resonator of the present application can also be set as an array-type bulk acoustic wave resonator, and different bulk acoustic wave resonators are modified with polymers that have the function of adsorbing different types of gas to be measured, so as to achieve the traditional Qualitative and quantitative identification and detection of binary gas mixtures with overlapping peak positions that cannot be identified by a single gas chromatography separation column.

The above descriptions are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the present invention. Within the scope of protection.

Claims

A manufacturing method of a miniature chromatographic separation column is characterized in that it comprises the steps:

A. Use silicon material to make micro-chromatographic separation column base;

B. Making a spiral structure of micro flow channels on the upper surface of the substrate;

C. Bonding the bottom of a glass plate with the upper surface of the substrate to form a miniature chromatographic separation column.
The method according to claim 1, wherein the step B comprises:

B1, through a photolithography or/and deep silicon etching process, fabricating micro-channels with a spiral structure on the substrate;

B2. The inner surface of the micro-channel is modified with a stationary phase.
The method according to claim 2, wherein the step B2 comprises:

Activating the inner surface of the microfluidic channel by octamethylcyclotetrasiloxane;

Modifying polydimethylsiloxane on the inner surface of the micro flow channel by means of dynamic coating;

Perform fixed-phase cross-linking;

Heating aging.
A miniature chromatographic separation column manufactured based on any manufacturing method of claims 1 to 3, characterized in that it comprises:

Substrate, glass plate,

The upper surface of the substrate has micro-channels with a spiral structure;

Wherein, the bottom of the glass plate is bonded to the upper surface of the substrate.
A micro gas analysis system based on the micro chromatographic separation column according to claim 4, characterized in that it comprises:

The injection system includes: a sample injection port and a sample injection pump; wherein the injection pump and the sample injection port are connected through a gas path tube to provide power support for sample injection;

The carrier gas subsystem includes a nitrogen cylinder, a pressure control valve, a pressure gauge, and a flow meter connected to the carrier gas in sequence, which is used to control the gas flow, and is connected to the outlet of the inlet system and then connected to the inlet of the micro chromatographic separation column , Used to load the sample to the micro chromatographic separation column;

The array of bulk acoustic wave resonators is connected with the outlet of the miniature chromatographic separation column and is used for identifying and detecting gas.
The system of claim 5, wherein the array of bulk acoustic wave resonators comprises:

A support plate on which a bulk acoustic wave resonator array area is arranged;

The glass microfluidic channel is arranged on the bulk acoustic wave resonator array area; wherein, two ends of the glass microfluidic channel are respectively provided with an air inlet and an air outlet; wherein, the air inlet and the air outlet For gas connection;

Wherein, the air inlet is connected to the outlet of the micro chromatographic separation column; the air outlet is connected to an exhaust gas recovery device.
The system according to claim 5, wherein in the array of bulk acoustic wave resonators, different bulk acoustic wave resonators are modified with different polymers for adsorbing different types of measured gases.
The system according to claim 5, further comprising:

A network analyzer connected to the bulk acoustic wave resonator array and used for scanning and measuring in a wide frequency band to determine network parameters and display signals.
The system according to claim 5, further comprising:

A temperature control device that adjusts the temperature of the environment where the micro chromatographic separation column is located.