WO2021139404A1 - 一种采样头、采样系统、质谱成像装置和采样方法 - Google Patents

一种采样头、采样系统、质谱成像装置和采样方法 Download PDF

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Publication number
WO2021139404A1
WO2021139404A1 PCT/CN2020/129153 CN2020129153W WO2021139404A1 WO 2021139404 A1 WO2021139404 A1 WO 2021139404A1 CN 2020129153 W CN2020129153 W CN 2020129153W WO 2021139404 A1 WO2021139404 A1 WO 2021139404A1
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sampling
flow channel
interface
cavity
head according
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PCT/CN2020/129153
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English (en)
French (fr)
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罗茜
邓卡
潘挺睿
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中国科学院深圳先进技术研究院
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Publication of WO2021139404A1 publication Critical patent/WO2021139404A1/zh

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/62—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating the ionisation of gases, e.g. aerosols; by investigating electric discharges, e.g. emission of cathode
    • H—ELECTRICITY
    • H01—ELECTRIC ELEMENTS
    • H01J—ELECTRIC DISCHARGE TUBES OR DISCHARGE LAMPS
    • H01J49/00—Particle spectrometers or separator tubes
    • H01J49/26—Mass spectrometers or separator tubes

Definitions

  • the invention relates to the technical field of lipidomics, and more specifically, to a sampling head, a sampling system, a mass spectrometry imaging device and a sampling method.
  • mass spectrometry analysis is performed on the surface material samples of the isolated tissue to obtain the metabolic molecular characteristics of the tumor tissue.
  • the freezing and cutting of the isolated tissue will cause the cells to fold and break, causing the loss of some key compound information and the interference of intracellular spillage. Compound increase.
  • the technical problem to be solved by the present invention is how to improve the sampling quality.
  • the present invention provides a sampling head, a sampling system, a mass spectrometry imaging device and a sampling method.
  • a sampling head including:
  • sampling cavity is arranged on the first end surface of the sampling body, and the sampling cavity and the sampled surface form a sampling area;
  • the first flow channel for injecting the extractant is arranged on the sampling body, and the first interface of the first flow channel is located on the second end surface of the sampling body, and the second flow channel of the first flow channel is The interface communicates with the sampling cavity;
  • a second flow channel for injecting air is arranged on the sampling body, and the first interface of the second flow channel is located on the second end surface of the sampling body, the second flow channel The second interface is connected to the sampling cavity;
  • a third flow channel for deriving sample droplets is arranged on the sampling body, and the first interface of the third flow channel is located on the second end surface of the sampling body, and the third flow channel is located on the second end surface of the sampling body.
  • the second interface of the flow channel communicates with the sampling cavity.
  • the second interface of the first flow channel and the second interface of the second flow channel are located at the top of the sampling cavity.
  • the second interface of the first flow channel gradually increases in diameter along the extraction agent injection direction.
  • the second interface of the first flow channel is concentric with the sampling cavity; the cross section of the second interface of the second flow channel is a fan-shaped structure.
  • the second interface of the second flow channel communicates with the second interface of the first flow channel, and communicates with the sampling cavity through the second interface of the first flow channel.
  • the second interface of the second flow channel is flush with the second interface of the first flow channel along the air injection direction.
  • the second interface of the third flow channel is close to the bottom of the sampling cavity.
  • the sampling body includes a first sampling body, a second sampling body, and a third sampling body, wherein the second sampling body is located between the first sampling body and the third sampling body.
  • the middle of the main body is located between the first sampling body and the third sampling body.
  • the first flow channel is located at the part of the first sampling body
  • the second flow channel is located at the part of the first sampling body
  • the third flow channel is located at the first sampling body.
  • a portion of the sampling body extends along the axial direction of the first sampling body.
  • the first flow channel is located in a part of the second sampling body
  • the second flow channel is located in a part of the second sampling body
  • the third flow channel is located in the first sampling body.
  • the part of the second sampling body is inclined to the sampling cavity.
  • the bend of the first flow channel, the bend of the second flow channel, and the bend of the third flow channel are smoothly connected.
  • the sampling cavity is located in the third sampling body, and the outer surface of the sampling body is an arc-shaped structure.
  • the sampling cavity includes a first sampling cavity and a second sampling cavity that are arranged concentrically, the first sampling cavity and the second interface of the first flow channel, the The second interface of the second flow channel communicates with the second interface of the third flow channel, and the second sampling cavity corresponds to the surface of the sampled tissue.
  • the caliber of the second sampling cavity is larger than the caliber of the first sampling cavity.
  • the part of the third flow channel located in the third sampling body is smoothly connected to the part of the third flow channel located in the second sampling body.
  • the sampling head is processed by injection molding or 3D printing process.
  • the present invention also discloses a sampling system, including the sampling head as described in any one of the above.
  • the invention also discloses a mass spectrometry imaging device, which includes the above-mentioned sampling system.
  • the present invention also discloses a sampling method, which applies the sampling head described in any one of the above, and the sampling method includes:
  • the sampling head is lifted off the surface to be sampled.
  • the second end surface of the sampling head is brought into parallel contact with the surface to be sampled, and then it remains motionless after full contact.
  • there is only air in the sampling cavity .
  • the extractant is injected into the sampling cavity from the first flow channel, and the injection is stopped after the sampling cavity is full.
  • the extractant contacts the sampled surface; then, the extractant is kept in contact with the sampled surface for a certain period of time to make the extraction fully occur. ; Thereafter, the air is injected from the second flow channel and the air is drawn out from the third flow channel simultaneously.
  • the liquid in the sampling cavity is transported out in the form of droplets through the third flow channel to enter the lower
  • the first-level analysis equipment because the air flows in and out of the two flow channels synchronously, no negative pressure will be formed in the sampling chamber, which will affect the liquid level position of the extractant entering the first flow channel; finally, the sampling is completed, and the sampling head is lifted and separated from the sampled surface. Since the sampling head in the present invention directly contacts the sampled surface, sampling can be achieved without being separated from the body. The method of droplet extraction will not cause trauma to the sampled surface.
  • the sampling cavity is close to the sampled surface, which improves the collection of samples. The concentration of the droplets reduces the possibility of missing key compound information, thereby improving the quality of sampling.
  • FIG. 1 is a schematic top view of a three-dimensional structure of a sampling head provided by an embodiment of the present invention
  • FIG. 2 is a schematic diagram of a bottom three-dimensional structure of a sampling head provided by an embodiment of the present invention
  • Figure 3 is a bottom perspective structural schematic diagram of a sampling head provided by an embodiment of the present invention.
  • Fig. 4 is a schematic diagram of an enlarged structure of part A in Fig. 3;
  • FIG. 5 is a schematic flowchart of a sampling method provided by an embodiment of the present invention.
  • FIG. 6 is a schematic flowchart of a sampling method provided by an embodiment of the present invention.
  • Mass spectrometry A method in which electric and magnetic fields are used to separate the moving ions according to their mass-to-charge ratios and then detect them.
  • the mass-to-charge ratio can identify substances.
  • Mass spectrometry imaging is an imaging method based on mass spectrometry technology. This method directly scans biological samples through mass spectrometry and can simultaneously analyze the spatial distribution characteristics of hundreds of molecules on the same tissue slice or tissue chip. To put it simply, mass spectrometry imaging technology is a method of imaging using a mass spectrometer that measures the mass-to-charge ratio to analyze the standard molecular weight of biomolecules under the control of a dedicated mass spectrometry imaging software.
  • Extraction Use an extractant to extract the substance.
  • Flow path The passage of fluid (gas/liquid) in the component.
  • the core of the present invention is to provide a sampling head, a sampling system, a mass spectrometry imaging device and a sampling method to improve sampling quality.
  • the sampling head in the embodiment of the present invention includes:
  • sampling cavity 200 is arranged on the first end surface of the sampling body, and the sampling cavity 200 and the sampled surface form a sampling area;
  • the first flow channel 300 for injecting the extractant is provided in the sampling body, and the first interface 301 of the first flow channel is located on the second end surface of the sampling body, and the second interface 302 of the first flow channel communicates with the sampling cavity 200 ;
  • the second flow channel 400 is used for injecting air.
  • the second flow channel 400 is arranged in the sampling body, and the first interface 401 of the second flow channel is located on the second end surface of the sampling body, and the second interface 402 of the second flow channel is connected to the sampling body.
  • a third flow channel 500 for deriving sample droplets is arranged on the sampling body, and the first interface 501 of the third flow channel is located on the second end surface of the sampling body, and the second interface 502 of the third flow channel
  • the sampling cavity 200 is connected.
  • the second end surface of the sampling head is brought into parallel contact with the surface to be sampled, and then remains motionless after complete contact.
  • the extractant is passed from the first flow channel. 300 is injected into the sampling cavity 200.
  • the injection is stopped.
  • the extractant contacts the sampled surface; then, the extractant is kept in contact with the sampled surface for a certain period of time to allow the extraction to fully occur; then, synchronization Air is injected from the second flow channel 400 and the air is extracted from the third flow channel 500.
  • the liquid in the sampling cavity 200 is transported out in the form of droplets through the third flow channel 500 to enter the next As the air flows in and out of the two flow channels synchronously, it will not form negative pressure in the sampling chamber, which affects the liquid level position of the extractant entering the first flow channel 300; finally, the sampling is completed, and the sampling head is lifted and separated from the sample chamber. Sampling surface. Since the sampling head in the present invention directly contacts the sampled surface, sampling can be achieved without being separated from the body. The method of droplet extraction will not cause trauma to the sampled surface.
  • the sampling cavity is close to the sampled surface, which improves the collection of samples. The concentration of the droplets reduces the possibility of missing key compound information, thereby improving the quality of sampling.
  • the sampling body 100 in the present invention is a solid structure to form the supporting body of the first flow channel 300, the second flow channel 400, the third flow channel 500 and the sampling cavity 200, which can be made of resin, plastic or glass. , It is processed through injection molding process and 3D printing technology. When 3D printing technology is used, UV curing 3D printing technology is especially used for processing.
  • the first port 301 of the first flow channel is used for the external pipeline for injecting extractant
  • the first port 401 of the second flow channel is used for the external pipeline to inject the positive pressure gas source
  • the first port 501 of the third flow channel is used
  • a negative pressure outlet is formed in the external pipeline to export the sampling droplets.
  • the second interface 302 of the first flow channel is in communication with the sampling cavity
  • the second interface 402 of the second flow channel is in communication with the sampling cavity
  • the second interface 502 of the third flow channel is in communication with the sampling cavity.
  • the cross sections of the first flow channel 300, the second flow channel 400, and the third flow channel 500 are circular, elliptical, fan-shaped, and so on.
  • the second interface 302 of the first flow channel and the second interface 402 of the second flow channel are located at Sample the top of cavity 200. Therefore, when the extraction agent needs to be injected, the extraction agent is gradually injected downward from the top of the sampling cavity 200 through the second interface 302 of the first flow channel. When the extraction agent is full and the extraction agent fully contacts the metabolites on the collected surface, The second port 402 of the second flow channel gradually rushes into the positive pressure air source from the top of the sampling cavity 200, thereby squeezing the sampling liquid droplets in the sampling cavity 200 into the second port 502 of the third flow channel.
  • the concentration of the sample droplets can be increased, so that the detection rate of subsequent detection can be improved.
  • the third flow channel The second interface 502 is close to the bottom of the sampling cavity 200.
  • the second interface 302 of the first flow channel gradually increases in diameter along the extraction agent injection direction. Therefore, when the extraction agent enters the sampling cavity 200 through the first flow channel 300, it first passes through the expansion of the second interface 302 of the first flow channel. Entering into the sampling cavity 200 can gradually reduce the speed of the extractant entering the sampling cavity 200, reduce the generation of turbulence, and avoid the occurrence of surge phenomenon that blocks the first flow channel 300 and affects the injection of the extractant.
  • the second interface 302 of the first flow channel is concentric with the sampling cavity 200, or has a non-concentric design.
  • the cross section of the second interface 402 of the second flow channel is a fan-shaped structure. Due to the small air flow resistance and no residual viscosity, the shape of the second interface where the second flow channel 400 is connected to the sampling cavity 200 is designed as two concentric arcs (inferior arcs) with different radii and their end connections.
  • the enclosed fan-shaped structure makes the sampling head structure more compact.
  • the second interface 402 of the second flow channel directly communicates with the sampling cavity 200, or the second interface 402 of the second flow channel communicates with the second interface 302 of the first flow channel, and is connected to the sampling cavity through the second interface 302 of the first flow channel.
  • the cavity 200 is in communication.
  • the second interface 402 of the second flow channel when the second interface 402 of the second flow channel is in communication with the second interface 302 of the first flow channel, the second interface 402 of the second flow channel is flush with the second interface 302 of the first flow channel along the air injection direction. That is, the inner arc of the second interface 402 of the second flow channel of the fan-shaped structure is concentric with the smallest diameter of the second interface 302 of the first flow channel; the outer arc of the second interface 402 of the second flow channel is the same as that of the first flow channel. The largest diameter of the second interface 302 is concentric.
  • the sampling body 100 includes a first sampling body 101, a second sampling body 102, and a third sampling body 103, wherein the second sampling body 102 is located between the first sampling body 101 and the second sampling body 101.
  • the first sampling main body 101, the second sampling main body 102 and the third sampling main body 103 are an integral structure or a split structure, and when they are a split structure, they are connected by a bonding process.
  • the part of the first flow channel 300 located in the first sampling body 101 extends along the axial direction of the first sampling body 101; for the smoothness of the air injection, the second flow channel 400 is located in the first sampling body.
  • the part of the main body 101 extends along the axial direction of the first sampling main body 101; in order to derive the smoothness of the sampling liquid droplets, the part of the third flow channel 500 located in the first sampling main body 101 extends along the axial direction of the first sampling main body 101.
  • first flow channel 300 is located at the portion of the second sampling body 102
  • second flow channel 400 is located at the portion of the second sampling body 102
  • third flow channel 500 is located at the portion of the second sampling body 102 that is inclined to the sampling cavity 200.
  • the oblique arrangement can make the first flow channel 300, the second flow channel 400 and the third flow channel 500 located in the part of the second sampling body 102 occupy a smaller space, so that the diameter of the second sampling body 102 is smaller than that of the first sampling body 101. diameter.
  • the first flow channel 300, the second flow channel 400, and the third flow channel 500 located in the second sampling body 102 are arranged obliquely, the first flow channel 300, the second flow channel 400 and the third flow channel 500 all have bends In order to reduce the occurrence of stickiness or damage to the sample droplets due to the existence of the bend, the bend of the first flow channel 300, the bend of the second flow channel 400 and the bend of the third flow channel 500 Smooth transition connection.
  • the sampling cavity 200 is located in the third sampling body 103, and the outer surface of the sampling body 100 is an arc-shaped structure. In this way, the diameter of the third sampling body 103 cannot be reduced, so that the effective sampling area is smaller, and the volume of the word sampling droplet is smaller, so that the sampling accuracy can be improved.
  • the sampling cavity 200 has a cylindrical structure or a hemispherical structure, the sampling cavity 200 has a semi-open structure and directly contacts the sampled surface, and the second interface 502 of the third flow channel is closer to the sampled surface, which improves the sampling
  • the concentration of the droplets can reduce the possibility of missing key compound information.
  • the area of the sampling cavity 200 in direct contact with the surface to be sampled can reach the order of millimeters or even hundreds of microns, and the smaller the sampling area of the sampling head, the higher the spatial resolution.
  • the sampling cavity 200 includes a first sampling cavity 201 and a second sampling cavity 202 concentrically arranged.
  • the first sampling cavity 201 and the second interface 302 of the first flow channel, the second interface 402 of the second flow channel, and the third The second interface 502 of the flow channel is in communication, and the second sampling cavity 202 corresponds to the surface of the tissue to be sampled.
  • the caliber of the second sampling cavity 202 is larger than the caliber of the first sampling cavity 201.
  • the second interface 502 of the third flow channel is close to the bottom of the sampling cavity 200.
  • the third flow channel 500 is partially located in the third sampling body 103, and the third flow channel 500
  • the part located in the third sampling body 103 and the part of the third flow channel 500 located in the second sampling body 102 are smoothly connected to avoid dead angles and reduce sample loss and pollution.
  • the present invention also discloses a sampling system, which includes a sampling head as described above. Since the above-mentioned sampling head has the above beneficial effects, the sampling system including the sampling head also has corresponding effects, which will not be repeated here.
  • the invention also discloses a mass spectrometry imaging device, which includes the above-mentioned sampling system. Since the above-mentioned sampling system has the above beneficial effects, the mass spectrometry imaging device including the sampling system also has corresponding effects, which will not be repeated here.
  • the present invention also discloses a sampling method using any one of the above sampling heads, and the sampling method includes:
  • Step S1 Bring the second end surface of the sampling head into parallel contact with the surface to be sampled, and keep it still after being completely contacted;
  • Step S2 Inject the extractant into the sampling cavity 200 from the first flow channel 300, stop the injection after the sampling cavity 200 is full, and keep the extractant in contact with the sampled surface for a certain period of time;
  • Step S3 Simultaneously inject air from the second flow channel 400 and extract air from the third flow channel 500, and drive the liquid in the sampling cavity 200 in the form of droplets through the third flow channel 500 under the driving of air pressure;
  • Step S4 After the sampling is completed, the sampling head is lifted off the surface to be sampled.
  • connection should be understood in a broad sense.
  • it can be a fixed connection, a detachable connection, or an integral connection; it can be a mechanical connection, It can also be an electrical connection; it can be directly connected, or indirectly connected through an intermediate medium, and it can be the internal communication between two components.
  • connection should be understood in a broad sense.
  • it can be a fixed connection, a detachable connection, or an integral connection; it can be a mechanical connection, It can also be an electrical connection; it can be directly connected, or indirectly connected through an intermediate medium, and it can be the internal communication between two components.

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Abstract

一种采样头、采样系统、质谱成像装置和采样方法，采样头包括：采样本体；采样空腔(200)，采样空腔(200)设置在采样本体的第一端面，采样空腔(200)与被采样表面形成采样区域；用于注入萃取剂的第一流道(300)；用于注入空气的第二流道(400)以及用于导出采样液滴的第三流道(500)。采样头直接与被采样表面接触，无需离体就能够实现采样，采用液滴萃取的方式，不会对被采样表面造成创伤，采样空腔(200)贴近被采样表面，提高了采集样本液滴的浓度，减少了关键化合物信息丢失的可能性，从而提高了采样质量。

Description

一种采样头、采样系统、质谱成像装置和采样方法 技术领域
本发明涉及脂质组学技术领域，更具体地说，涉及一种采样头、采样系统、质谱成像装置和采样方法。
 背景技术
随着质谱技术的发展，脂质组学在肿瘤生物标志物的识别、疾病诊断、药物靶点及先导化合物的发现和药物作用机制研究等方面已展现出广泛的应用前景。目前，通过对离体的组织表面物质样本进行质谱分析以得到肿瘤组织的代谢分子特性，而离体的组织冰冻和切割会造成细胞折叠和破碎，使得部分关键化合物信息丢失和细胞内溢出的干扰化合物增多。
因此，如何提高采样质量，是目前本领域技术人员亟待解决的问题。
 技术问题
有鉴于此，本发明所要解决的技术问题是如何提高采样质量，为此，本发明提供了一种采样头、采样系统、质谱成像装置和采样方法。
 技术解决方案
为实现上述目的，本发明提供如下技术方案：
一种采样头，包括：
采样本体；
采样空腔，所述采样空腔设置在所述采样本体的第一端面，所述采样空腔与被采样表面形成采样区域；
用于注入萃取剂的第一流道，所述第一流道设置在所述采样本体，且所述第一流道的第一接口位于所述采样本体的第二端面，所述第一流道的第二接口连通所述采样空腔；
用于注入空气的第二流道，所述第二流道设置在所述采样本体，且所述第二流道的第一接口位于所述采样本体的第二端面，所述第二流道的第二接口连通所述采样空腔；以及
用于导出采样液滴的第三流道，所述第三流道设置在所述采样本体，且所述第三流道的第一接口位于所述采样本体的第二端面，所述第三流道的第二接口连通所述采样空腔。
在本发明其中一个实施例中，所述第一流道的第二接口和所述第二流道的第二接口位于所述采样空腔的顶部。
在本发明其中一个实施例中，所述第一流道的第二接口沿萃取剂注入方向口径逐渐变大。
在本发明其中一个实施例中，所述第一流道的第二接口与所述采样空腔同心；所述第二流道的第二接口的截面为扇形结构。
在本发明其中一个实施例中，所述第二流道的第二接口与所述第一流道的第二接口连通，并通过所述第一流道的第二接口与所述采样空腔连通。
在本发明其中一个实施例中，沿空气注入方向所述第二流道的第二接口与所述第一流道的第二接口持平。
在本发明其中一个实施例中，所述第三流道的第二接口靠近所述采样空腔的底部。
在本发明其中一个实施例中，所述采样主体包括第一采样主体、第二采样主体和第三采样主体，其中，所述第二采样主体位于所述第一采样主体和所述第三采样主体的中间。
在本发明其中一个实施例中，所述第一流道位于所述第一采样主体的部分、所述第二流道位于所述第一采样主体的部分和所述第三流道位于所述第一采样主体的部分沿所述第一采样主体的轴向延伸。
在本发明其中一个实施例中，所述第一流道位于所述第二采样主体的部分、所述第二流道位于所述第二采样主体的部分和所述第三流道位于所述第二采样主体的部分向所述采样空腔倾斜设置。
在本发明其中一个实施例中，所述第一流道的弯折处、所述第二流道的弯折处和所述第三流道的弯折处圆滑过渡连接。
在本发明其中一个实施例中，所述采样空腔位于所述第三采样主体中，且所述采样主体的外表面为圆弧状结构。
在本发明其中一个实施例中，所述采样空腔包括同心设置的第一采样空腔和第二采样空腔，所述第一采样空腔与所述第一流道的第二接口、所述第二流道的第二接口和所述第三流道的第二接口连通，所述第二采样空腔与被采样组织的表面对应。
在本发明其中一个实施例中，所述第二采样空腔的口径大于所述第一采样空腔的口径。
在本发明其中一个实施例中，所述第三流道位于所述第三采样主体的部分与所述第三流道位于所述第二采样主体的部分圆滑过渡连接。
在本发明其中一个实施例中，所述采样头由注塑或3D打印工艺加工而成。
本发明还公开了一种采样系统，包括如上述中任一项所述的采样头。
本发明还公开了一种质谱成像装置，包括上述所述的采样系统。
本发明还公开了一种采样方法，应用上述中任一项所述的采样头，该采样方法包括：
将采样头的第二端面平行接触被采样表面，完全接触后保持不动；
将萃取剂由第一流道注入采样空腔，采样空腔充满后停止注入，保持萃取剂与被采样表面接触一定时间；
同步由第二流道注入空气并由第三流道抽出空气，在气压驱动下，将采样空腔中的液体以液滴的形式，通过第三流道输送出去；
采样完成，采样头被抬升脱离被采样表面。
 有益效果
从上述的技术方案可以看出，使用本发明中的采样头时，首先将采样头的第二端面平行接触被采样表面，完全接触后保持不动，此时采样空腔中仅有空气；其次，将萃取剂由第一流道注入采样空腔，采样空腔充满后停止注入，此过程中萃取剂与被采样表面接触；继而，保持萃取剂与被采样表面接触一定时间，使萃取作用充分发生；其后，同步由第二流道注入空气并由第三流道抽出空气，在气压驱动下，将采样空腔中的液体以液滴的形式，通过第三流道输送出去，以进入下一级分析设备，由于空气同步地由两流道流入流出，不会在采样腔内形成负压，影响萃取剂进入第一流道中的液面位置；最后，采样完成，采样头被抬升脱离被采样表面。由于本发明中的采样头直接与被采样表面接触，无需离体就能够实现采样，采用液滴萃取的方式，不会对被采样表面造成创伤，采样空腔贴近被采样表面，提高了采集样本液滴的浓度，减少了关键化合物信息丢失的可能性，从而提高了采样质量。
 附图说明
图1为本发明实施例所提供的一种采样头的俯视立体结构示意图；
图2为本发明实施例所提供的一种采样头的仰视立体结构示意图；
图3为本发明实施例所提供的一种采样头的仰视透视结构示意图；
图4为图3中A部分的放大结构示意图；
图5为本发明实施例所提供的一种采样方法的流程示意图；
图6为本发明实施例所提供的一种采样方法的流程示意图；
 本发明的最佳实施方式
术语解释：
质谱分析：用电场和磁场将运动的离子按它们的质荷比分离后进行检测的方法，可以通过质荷比辨识物质。
质谱成像技术：质谱成像是以质谱技术为基础的成像方法，该方法通过质谱直接扫描生物样品成像，可以在同一张组织切片或组织芯片上同时分析数百种分子的空间分布特征。简单而言，质谱成像技术就是借助于质谱的方法，再配套上专门的质谱成像软件控制下，使用一台通过测定质荷比来分析生物分子的标准分子量的质谱仪来成像的方法。
萃取：使用萃取剂提取物质。
表面采样：从被采样表面提取物质样本。
在体：不采用离体切片方式，直接在被采样表面操作。
流道：流体（气/液）在元件内的通路。
本发明的核心在于提供一种采样头、采样系统、质谱成像装置和采样方法，以提高采样质量。
此外，下面所示的实施例不对权利要求所记载的发明内容起任何限定作用。另外，下面实施例所表示的构成的全部内容不限于作为权利要求所记载的发明的解决方案所必需的。
为此，请参阅图1至图4，本发明实施例中的采样头，包括：
采样本体；
采样空腔200，采样空腔200设置在采样本体的第一端面，采样空腔200与被采样表面形成采样区域；
用于注入萃取剂的第一流道300，第一流道300设置在采样本体，且第一流道的第一接口301位于采样本体的第二端面，第一流道的第二接口302连通采样空腔200；
用于注入空气的第二流道400，第二流道400设置在采样本体，且第二流道的第一接口401位于采样本体的第二端面，第二流道的第二接口402连通采样空腔200；以及
用于导出采样液滴的第三流道500，第三流道500设置在采样本体，且第三流道的第一接口501位于采样本体的第二端面，第三流道的第二接口502连通采样空腔200。
使用本发明中的采样头时，首先将采样头的第二端面平行接触被采样表面，完全接触后保持不动，此时采样空腔200中仅有空气；其次，将萃取剂由第一流道300注入采样空腔200，采样空腔200充满后停止注入，此过程中萃取剂与被采样表面接触；继而，保持萃取剂与被采样表面接触一定时间，使萃取作用充分发生；其后，同步由第二流道400注入空气并由第三流道500抽出空气，在气压驱动下，将采样空腔200中的液体以液滴的形式，通过第三流道500输送出去，以进入下一级分析设备，由于空气同步地由两流道流入流出，不会在采样腔内形成负压，影响萃取剂进入第一流道300中的液面位置；最后，采样完成，采样头被抬升脱离被采样表面。由于本发明中的采样头直接与被采样表面接触，无需离体就能够实现采样，采用液滴萃取的方式，不会对被采样表面造成创伤，采样空腔贴近被采样表面，提高了采集样本液滴的浓度，减少了关键化合物信息丢失的可能性，从而提高了采样质量。
需要说明的是，本发明中采样主体100为实体结构以形成第一流道300、第二流道400、第三流道500和采样空腔200的支撑主体，其可以为树脂、塑料或者玻璃材质，通过注塑工艺、3D打印技术加工而成，当采用3D打印技术时，特别采用紫外光固化3D打印技术进行加工。
第一流道的第一接口301用于外接管路用于进行注入萃取剂，第二流道的第一接口401用于外接管路注入正压气源，第三流道的第一接口501用于外接管路形成负压出口导出采样液滴。第一流道的第二接口302与采样腔体连通，第二流道的第二接口402与采样腔体连通，第三流道的第二接口502与采样腔体连通。第一流道300、第二流道400、第三流道500的横截面为圆形、椭圆形、扇形等等结构。
其中，由于第一流道300和第二流道400分别注入萃取剂和空气，为了方便施压以及充满采样空腔200，第一流道的第二接口302和第二流道的第二接口402位于采样空腔200的顶部。因此，当需要注入萃取剂时，通过第一流道的第二接口302自采样空腔200的顶部逐渐向下注入萃取剂，当萃取剂充满且萃取剂与被采集表面的代谢物充分接触后，由第二流道的第二接口402自采样空腔200的顶部逐渐冲入正压气源，从而挤压采样空腔200中的采样液滴进入第三流道的第二接口502。为了使得高浓度的采样液滴首先进入第三流道的第二接口502中，提高采样液滴的浓度，从而能够提高后续检测的检测检出率，本发明实施例中，第三流道的第二接口502靠近采样空腔200的底部。
第一流道的第二接口302沿萃取剂注入方向口径逐渐变大，因此，萃取剂通过第一流道300进入采样空腔200中时，首先经过第一流道的第二接口302扩张的作用下再进入至采样空腔200中，能够逐步降低进入采样空腔200中的萃取剂的速度，减少湍流现象产生，避免出现喘振现象而堵塞第一流道300，影响萃取剂的注入。第一流道的第二接口302与采样空腔200同心，或者非同心设计。
第二流道的第二接口402的截面为扇形结构。由于空气流阻小且无残余粘滞等问题，第二流道400接入采样空腔200的第二接口形状被设计为两条半径不同的同心圆弧（劣弧）及其端点连线所围成的扇形结构，如此采样头结构更加紧凑。
第二流道的第二接口402直接与采样空腔200连通，或者第二流道的第二接口402与第一流道的第二接口302连通，并通过第一流道的第二接口302与采样空腔200连通。
其中，第二流道的第二接口402与第一流道的第二接口302连通时，沿空气注入方向第二流道的第二接口402与第一流道的第二接口302持平。即，作为扇形结构的第二流道的第二接口402的内圆弧与第一流道的第二接口302的最小径同心；第二流道的第二接口402的外圆弧与第一流道的第二接口302的最大径同心。
为了方便描述，在本发明其中一个实施例中，采样主体100包括第一采样主体101、第二采样主体102和第三采样主体103，其中，第二采样主体102位于第一采样主体101和第三采样主体103的中间。其中第一采样主体101、第二采样主体102和第三采样主体103为一体式结构或者分体式结构，当为分体式结构时，通过粘结工艺进行连接。
为了萃取剂的注入时的顺畅性，第一流道300位于第一采样主体101的部分沿第一采样主体101的轴向延伸；为了空气注入时的顺畅性，第二流道400位于第一采样主体101的部分沿第一采样主体101的轴向延伸；为了导出采样液滴的顺畅性，第三流道500位于第一采样主体101的部分沿第一采样主体101的轴向延伸。
进一步的，第一流道300位于第二采样主体102的部分、第二流道400位于第二采样主体102的部分和第三流道500位于第二采样主体102的部分向采样空腔200倾斜设置。倾斜设置能够使得第一流道300、第二流道400和第三流道500位于第二采样主体102的部分占用的空间更小，从而使得第二采样主体102的直径小于第一采样主体101的直径。
由于位于第二采样主体102的第一流道300、第二流道400和第三流道500倾斜设置，因此，第一流道300、第二流道400和第三流道500均存在弯折处，为了减少由于弯折处的存在出现粘滞、或者损坏采样液滴的情况发生，第一流道300的弯折处、第二流道400的弯折处和第三流道500的弯折处圆滑过渡连接。
为了进一步减少采样的面积，本发明实施例中，采样空腔200位于第三采样主体103中，且采样主体100的外表面为圆弧状结构。如此不能够减少第三采样主体103的直径，从而使得有效的采样面积更小，而单词采样液滴体积会更小，从而能够提高采样精度。
进一步的，采样空腔200为圆柱结构或半球形结构，采样空腔200为半开口结构直接与被采样表面直接接触，且第三流道的第二接口502更加靠近被采集表面，提高了采样液滴的浓度，从而能够减少关键化合物信息丢失可能性。且采样空腔200与被采样表面直接接触的面积能够达到毫米级甚至百微米级，而采样头采样的面积越小空间分辨率越高。采样空腔200包括同心设置的第一采样空腔201和第二采样空腔202，第一采样空腔201与第一流道的第二接口302、第二流道的第二接口402和第三流道的第二接口502连通，第二采样空腔202与被采样组织的表面对应。在本发明其中一个实施例中，第二采样空腔202的口径大于第一采样空腔201的口径。
为了提高采样液滴的浓度，第三流道的第二接口502靠近采样空腔200的底部，为此，第三流道500有部分结构位于第三采样主体103中，而第三流道500位于第三采样主体103的部分与第三流道500位于第二采样主体102的部分圆滑过渡连接，避免死角产生，减少样本损失以及污染产生。
本发明还公开了一种采样系统，包括如上述中任一项的采样头。由于上述采样头具有以上有益效果，包括该采样头的采样系统也具有相应的效果，此处不再赘述。
本发明还公开了一种质谱成像装置，包括上述的采样系统。由于上述采样系统具有以上有益效果，包括该采样系统的质谱成像装置也具有相应的效果，此处不再赘述。
请参阅图5和图6，本发明还公开了一种采样方法，应用上述中任一项的采样头，该采样方法包括：
步骤S1：将采样头的第二端面平行接触被采样表面，完全接触后保持不动；
步骤S2：将萃取剂由第一流道300注入采样空腔200，采样空腔200充满后停止注入，保持萃取剂与被采样表面接触一定时间；
步骤S3：同步由第二流道400注入空气并由第三流道500抽出空气，在气压驱动下，将采样空腔200中的液体以液滴的形式，通过第三流道500输送出去；
步骤S4：采样完成，采样头被抬升脱离被采样表面。
在本申请的描述中，需要说明的是，术语“中心”、“上”、“下”、“左”、“右”、“竖直”、“水平”、“内”、“外”等指示的方位或位置关系为基于附图所示的方位或位置关系，仅是为了便于描述本申请和简化描述，而不是指示或暗示所指的装置或元件必须具有特定的方位、以特定的方位构造和操作，因此不能理解为对本申请的限制。此外，术语“第一”、“第二”、“第三”仅用于描述目的，而不能理解为指示或暗示相对重要性。
除非另有明确的规定和限定，术语“安装”、“相连”、“连接”应做广义理解，例如，可以是固定连接，也可以是可拆卸连接，或一体地连接；可以是机械连接，也可以是电连接；可以是直接相连，也可以通过中间媒介间接相连，可以是两个元件内部的连通。对于本领域的普通技术人员而言，可以具体情况理解上述术语在本申请中的具体含义。
对所公开的实施例的上述说明，使本领域专业技术人员能够实现或使用本发明。对这些实施例的多种修改对本领域的专业技术人员来说将是显而易见的，本文中所定义的一般原理可以在不脱离本发明的精神或范围的情况下，在其它实施例中实现。因此，本发明将不会被限制于本文所示的这些实施例，而是要符合与本文所公开的原理和新颖特点相一致的最宽的范围。

Claims (19)

  1. 一种采样头，其特征在于，包括：
    采样本体；
    采样空腔，所述采样空腔设置在所述采样本体的第一端面，所述采样空腔与被采样表面形成采样区域；
    用于注入萃取剂的第一流道，所述第一流道设置在所述采样本体，且所述第一流道的第一接口位于所述采样本体的第二端面，所述第一流道的第二接口连通所述采样空腔；
    用于注入空气的第二流道，所述第二流道设置在所述采样本体，且所述第二流道的第一接口位于所述采样本体的第二端面，所述第二流道的第二接口连通所述采样空腔；以及
    用于导出采样液滴的第三流道，所述第三流道设置在所述采样本体，且所述第三流道的第一接口位于所述采样本体的第二端面，所述第三流道的第二接口连通所述采样空腔。
  2. 如权利要求1所述的采样头，其特征在于，所述第一流道的第二接口和所述第二流道的第二接口位于所述采样空腔的顶部。
  3. 如权利要求2所述的采样头，其特征在于，所述第一流道的第二接口沿萃取剂注入方向口径逐渐变大。
  4. 如权利要求3所述的采样头，其特征在于，所述第一流道的第二接口与所述采样空腔同心；所述第二流道的第二接口的截面为扇形结构。
  5. 如权利要求4所述的采样头，其特征在于，所述第二流道的第二接口与所述第一流道的第二接口连通，并通过所述第一流道的第二接口与所述采样空腔连通。
  6. 如权利要求5所述的采样头，其特征在于，沿空气注入方向所述第二流道的第二接口与所述第一流道的第二接口持平。
  7. 如权利要求1所述的采样头，其特征在于，所述第三流道的第二接口靠近所述采样空腔的底部。
  8. 如权利要求1至6中任一项所述的采样头，其特征在于，所述采样主体包括第一采样主体、第二采样主体和第三采样主体，其中，所述第二采样主体位于所述第一采样主体和所述第三采样主体的中间。
  9. 如权利要求8所述的采样头，其特征在于，所述第一流道位于所述第一采样主体的部分、所述第二流道位于所述第一采样主体的部分和所述第三流道位于所述第一采样主体的部分沿所述第一采样主体的轴向延伸。
  10. 如权利要求9所述的采样头，其特征在于，所述第一流道位于所述第二采样主体的部分、所述第二流道位于所述第二采样主体的部分和所述第三流道位于所述第二采样主体的部分向所述采样空腔倾斜设置。
  11. 如权利要求8所述的采样头，其特征在于，所述第一流道的弯折处、所述第二流道的弯折处和所述第三流道的弯折处圆滑过渡连接。
  12. 如权利要求8所述的采样头，其特征在于，所述采样空腔位于所述第三采样主体中，且所述采样主体的外表面为圆弧状结构。
  13. 如权利要求12所述的采样头，其特征在于，所述采样空腔包括同心设置的第一采样空腔和第二采样空腔，所述第一采样空腔与所述第一流道的第二接口、所述第二流道的第二接口和所述第三流道的第二接口连通，所述第二采样空腔与被采样组织的表面对应。
  14. 如权利要求13所述的采样头，其特征在于，所述第二采样空腔的口径大于所述第一采样空腔的口径。
  15. 如权利要求13所述的采样头，其特征在于，所述第三流道位于所述第三采样主体的部分与所述第三流道位于所述第二采样主体的部分圆滑过渡连接。
  16. 如权利要求1所述的采样头，其特征在于，所述采样头由注塑或3D打印工艺加工而成。
  17. 一种采样系统，其特征在于，包括如权利要求1至16中任一项所述的采样头。
  18. 一种质谱成像装置，其特征在于，包括权利要求17所述的采样系统。
  19. 一种采样方法，其特征在于，应用权利要求1至16中任一项所述的采样头，该采样方法包括：
    将采样头的第二端面平行接触被采样表面，完全接触后保持不动；
    将萃取剂由第一流道注入采样空腔，采样空腔充满后停止注入，保持萃取剂与被采样表面接触一定时间；
    同步由第二流道注入空气并由第三流道抽出空气，在气压驱动下，将采样空腔中的液体以液滴的形式，通过第三流道输送出去；
    采样完成，采样头被抬升脱离被采样表面。
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