KR20170127637A - Apparatus of Detecting Circulating Tumor Cell Clusters And Method there-of - Google Patents

Abstract

Disclosed are an apparatus for detecting circulating tumor cell (CTC) clusters and a method therefor. The apparatus for detecting circulatory tumor cell clusters of the present invention comprises: a body having an inlet for introducing blood, and a blood passage through which blood introduced from the inlet flows; and a CTC cluster filter connected to the blood passage in the body. The CTC cluster filter further includes: a filter substrate; and a plurality of microchannels vertically or diagonally formed on the filter substrate, and allowing, among a plurality of components making up blood, components to pass through, while blocking passage of first components which are larger than a specific size.

Description

[0001] Apparatus for Detecting Circulating Tumor Cell Clusters [0002]

The present invention relates to an apparatus and a method for detecting a circulating tumor cell cluster.

A circulating tumor cell cluster refers to a group of cancer cells circulating in the blood derived from a primary tumor.

 Circulating tumor cell clusters exhibit an increased metastatic propensity over monocytic tumor cells. A large number of circulating tumor cell clusters in patients shows negative results.

Circulating Tumor Cells die in circulation through the blood and are less likely to develop into tumors. On the other hand, in the case of two or more combined circulating tumor cells, the degree of metastasis increases as the number increases.

Therefore, the detection of circulating tumor cell clusters is more effective in detecting the metastatic potential of tumors than the detection of circulating tumor cells.

Accordingly, efforts are being made to detect circulating tumor cell clusters. One of them is the CTC cluster detection system developed by Harvard Medical School shown in FIG.

Referring to FIG. 1, the CTC cluster detection system developed by Harvard Medical School is a structure in which a micropillar (triangular column) is constructed on a two-dimensional plane, and a fluid flows in a plane, It takes a lot of time to analyze. Further, reverse flow is generated, and an expensive thermoelectric element cooling system or the like is required.

A microfluidic device for label-free, physical capture of circulating tumor cell clusters, Nature Methods 12, 685-691 (2015)

SUMMARY OF THE INVENTION The present invention has been made in view of the above problems, and it is an object of the present invention to provide an apparatus and a method for more effectively detecting a circulating tumor cell cluster in a short time.

An apparatus for detecting a circulating tumor cell cluster according to an embodiment of the present invention is an apparatus for detecting a CTC (Circulating Tumor Cell) cluster contained in blood, comprising an inlet through which the blood is introduced and an inlet through which the blood is introduced A body formed with a blood pathway through which blood flows; And a CTC cluster filter coupled to the blood path of the body.

The CTC cluster filter comprising: a filter substrate; And a plurality of microchannels formed perpendicularly or obliquely to the filter substrate, the plurality of microchannels passing through the rest without passing a first component of a certain size or more out of a plurality of components constituting the blood.

The cross-sectional area of the upper portion of each of the plurality of microchannels is larger than the cross-sectional area of the lower portion.

According to an embodiment, the filter substrate is made of glass, and the thickness FD1 of the filter substrate 210 may be 200 [mu] m to 300 [mu] m.

According to an embodiment, the filter substrate may be embodied as a metal, and the thickness FD1 of the filter substrate 210 may be between 20 micrometers and 50 micrometers.

According to another aspect of the present invention, there is provided an apparatus for detecting a circulatory tumor cell cluster, including: a body having an inlet through which blood flows and a blood path through which blood flows through the inlet; A CTC cluster filter attached to the body to allow the first component of the blood to pass through the CTC cluster filter; And a CTC filter for passing the rest of the blood through the CTC cluster filter without passing through the second component of the second size or more.

Each of the CTC cluster filter and the CTC filter includes: a filter substrate; And a plurality of microchannels formed perpendicularly or obliquely to the filter substrate, the microchannels serving as passages for the blood.

According to an embodiment, the body may be realized by joining an upper body 101, an intermediate body 102, and a lower body.

According to an embodiment, the upper body 101, the middle body 102, and the lower body are realized as glass, and the joining between the middle body 102 and the lower body is realized to be detachable using a silicone resin .

According to an embodiment, the vertical distance between the upper surface of the upper body 101 and the upper surface of the CTC cluster filter may be 0.3 mm to 0.5 mm.

According to an embodiment, the blood path comprises a first blood path formed between the inlet and the CTC cluster filter; And a second blood path formed between the CTC cluster filter and the CTC filter, and an outlet port through which the blood that has passed through the CTC filter flows may be formed in the lower body.

According to the embodiment of the present invention, many microchannels are formed in the Z-axis to smooth the flow of the fluid (blood), and since the fluid flows in the Z-axis, no backflow occurs. Therefore, since the thermoelectric element, the cooling system, and the like are unnecessary, the unit price of the detection device can be reduced.

Further, according to the detection device of the present invention, the flow of the fluid (blood) is smooth and the detection speed is improved. Therefore, detection time and cost can be reduced.

In addition, according to the detection apparatus of the present invention, the filter can be configured in multiple stages to detect cells of various sizes, for example, CTC clusters as well as CTCs, leukocytes, etc. with one detection device.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a diagram depicting a prior art CTC cluster detection system.
2 is a schematic diagram of a detection device for detecting a circulating tumor cell cluster according to an embodiment of the present invention.
FIG. 3 conceptually illustrates the CTC cluster filter shown in FIG. 2. FIG.
4A is a diagram showing an example of a top view of the CTC cluster filter shown in FIG.
4B is a view showing another example of the top view of the CTC cluster filter shown in FIG.
4C is an enlarged plan view of part of FIG. 4B.
FIG. 4D is a bottom view corresponding to the plan view of FIG. 4C. FIG.
5 is another embodiment of a section cut perpendicularly to the CTC cluster filter shown in Fig.
6 is a schematic diagram of a detection device for detecting a circulating tumor cell cluster according to another embodiment of the present invention.
7 is a schematic diagram of a detection device for detecting a circulating tumor cell cluster according to another embodiment of the present invention.

It is to be understood that the specific structural or functional descriptions of embodiments of the present invention disclosed herein are only for the purpose of illustrating embodiments of the inventive concept, But may be embodied in many different forms and is not limited to the embodiments set forth herein.

Embodiments in accordance with the concepts of the present invention are capable of various modifications and may take various forms, so that the embodiments are illustrated in the drawings and described in detail herein. It should be understood, however, that it is not intended to limit the embodiments according to the concepts of the present invention to the particular forms disclosed, but includes all modifications, equivalents, or alternatives falling within the spirit and scope of the invention.

The terms first, second, etc. may be used to describe various elements, but the elements should not be limited by the terms. The terms are intended to distinguish one element from another, for example, without departing from the scope of the invention in accordance with the concepts of the present invention, the first element may be termed the second element, The second component may also be referred to as a first component.

It is to be understood that when an element is referred to as being "connected" or "connected" to another element, it may be directly connected or connected to the other element, . On the other hand, when an element is referred to as being "directly connected" or "directly connected" to another element, it should be understood that there are no other elements in between. Other expressions that describe the relationship between components, such as "between" and "between" or "neighboring to" and "directly adjacent to" should be interpreted as well.

The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. The singular expressions include plural expressions unless the context clearly dictates otherwise. In this specification, the terms "comprises ", or" having ", or the like, specify that there is a stated feature, number, step, operation, , Steps, operations, components, parts, or combinations thereof, as a matter of principle.

Unless defined otherwise, all terms used herein, including technical or scientific terms, have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Terms such as those defined in commonly used dictionaries are to be interpreted as having a meaning consistent with the meaning of the context in the relevant art and, unless explicitly defined herein, are to be interpreted as ideal or overly formal Do not.

In the drawings, the thicknesses of layers and regions are exaggerated for clarity. When a layer is referred to as being "on" another layer or substrate, or when it is mentioned that a layer is bonded or bonded to another layer or substrate, it may be formed directly on another layer or substrate, May be intervening. Like numbers refer to like elements throughout the specification.

Terms such as top, bottom, top, bottom, front, rear, or top, bottom, etc. are used to distinguish relative positions in the components. For example, in the case of naming the upper part of the drawing as upper part and the lower part as lower part in the drawings for convenience, the upper part may be named lower part and the lower part may be named upper part without departing from the scope of right of the present invention .

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail with reference to the preferred embodiments of the present invention with reference to the accompanying drawings.

An apparatus according to an embodiment of the present invention can detect CTC clusters from a sample (e.g., blood) to be diagnosed (or detected). Further, an apparatus according to an embodiment of the present invention may detect CTC.

The term " CTC " or " CTC cluster " refers to any tumor cell or cluster of tumor cells found in a sample of a subject.

Typically, CTC is peeled off from solid tumors. Thus, CTC may be an epithelial cell that is detached from solid tumors found at very low concentrations in the circulating blood of patients with cancer (or tumors). CTC can also be melanocytes from mesothelioma or melanoma from sarcoma. CTC may also be a cell derived from a primary, secondary or tertiary tumor.

Tumors herein are not limited to any particular tumor, and may include various known tumor types.

A "sample" of a subject refers to any sample suitable for detecting CTC clusters, according to an apparatus and method according to embodiments of the present invention. For example, the sample may be blood collected from a subject, but is not limited thereto.

2 is a schematic diagram of a detection device for detecting a circulating tumor cell cluster according to an embodiment of the present invention. FIG. 3 conceptually illustrates the CTC cluster filter shown in FIG. 2. FIG.

2 and 3, a detection apparatus 10A according to an embodiment of the present invention includes a body 100A and a CTC cluster filter 200. [

Body 100A includes an inlet 110, a blood path 120, and an outlet 130.

For example, a sample inlet 110 is formed in the upper part of the body. The inlet 110 is connected to the blood path 120 formed in the body 100A.

The blood path 120 is connected to the CTC cluster filter 200.

The CTC cluster filter 200 may be mounted to the outlet 130 of the body 100A.

The blood sample is then injected into the blood path 120 within the body 100A through the inlet 110 and into the CTC cluster filter 200 through the blood path 120.

The body 100A may be formed of glass, but is not limited thereto. For example, the body 100A may be made of plastic or other material.

The CTC cluster filter 200 is a filter that does not pass the CTC cluster 230 of a certain size or more among the blood samples but passes the rest. Accordingly, the components of the blood sample larger than a certain size are left in the CTC cluster filter 200, and the remainder flows out through the outlet 130.

The CTC cluster filter 200A according to the embodiment of FIG. 3 includes a filter substrate 210 and a plurality of microchannels 220A formed on the filter substrate 210 in a vertical direction. For example, the CTC cluster filter 200 may be implemented by forming a plurality of microchannels 220 in a vertical (i.e., Z-axis) or diagonal (oblique) manner to the filter substrate 210. In the embodiment of FIG. 3, the microchannel 220A is implemented as a Z-axis, but in other embodiments it may be implemented as an angled channel having an arbitrary angle in the Z-axis.

The filter substrate 210 may be made of glass. When the filter substrate 210 is formed of glass, the thickness FD1 of the filter substrate 210 preferably falls within a range of 200 mu m to 300 mu m.

According to an embodiment, the filter substrate 210 may be embodied as a metal. For example, the filter substrate 210 may be formed of a metal or an alloy containing at least one of nickel, lead, silver, copper, tin, zinc, and aluminum, and may be formed by nickel plating or gold plating.

When the filter substrate 210 is made of metal, the thickness FD1 of the filter substrate 210 preferably falls within a range of 20 to 50 mu m.

When the CTC cluster filter 200A is a metal filter, it is preferable to finally perform gold plating so as to be cell-friendly.

The plurality of microchannels 220A is the passage through which the blood passes. Each of the plurality of micro-channels 220A is formed so that the cross-sectional area of the lower opening portion 223 is smaller than the cross-sectional area of the upper opening portion 221. [

One embodiment of a method of forming a plurality of microchannels 220A when the filter substrate 210 is a glass substrate is described. However, according to the embodiment, the method of forming the plurality of microchannels 220A may be different, and the material of the filter substrate 210 may also be varied as described above.

(Hereinafter referred to as a " channel region ") in which the microchannels 220A are to be formed on the glass substrate 210). That is, a grid pattern may be drawn on the glass substrate 210, or a pattern sheet may be attached to the channel region. Then, only the channel region in the glass substrate 210 can be subjected to laser exposure processing.

For example, a predetermined grid pattern is displayed on the glass substrate 210 to display a channel region, and then the channel region is exposed with a laser according to the drawn grid pattern to form a grid pattern.

 The pattern shape can be crystallized by heat-treating the glass substrate having the grid pattern formed thereon. For example, the glass substrate subjected to the laser exposure treatment may be put into a heat treatment apparatus and subjected to heat treatment at a predetermined temperature for a predetermined period of time to crystallize the channel region.

The temperature during the heat treatment may be 500 ° C or more, for example, 550 ° C to 800 ° C (550 ° C to 800 ° C). According to the heat treatment, the channel region can be in a crystalline state.

The glass substrate 210 excluding the crystallized channel region may remain in the amorphous state.

Next, the crystallized channel region in the glass substrate 100 may be removed to form the actual microchannels 220A. According to an embodiment, the channel region crystallized through the etching process can be etched. By etching the crystallized channel region through the etching process, microchannels 220A passing through the glass substrate 210 can be formed.

The microchannel 220A according to the embodiment of FIG. 3 may be oblique. The diameter of the upper surface 221 of the serpentine microchannel 220A is different from the diameter R2 of the lower surface 223 and the vertical cross section is formed in a trapezoidal shape. A blood sample is introduced through the upper opening 221 of the microchannel 220A (i.e., the opening having a large sectional area) 221 and the blood sample is introduced through the lower end opening of the microchannel 220A (i.e., . The CTC cluster filter 230 may include a plurality of components constituting a blood sample flowing into each of the microchannels 220A of the CTC cluster filter 200. For example, , And does not flow out through the lower end opening portion 223. In contrast, components of a blood sample that are less than a certain size (e.g., CTC) flow out through the bottom opening 223.

The microchannel 220A may not pass through the CTC cluster 230 and the single CTC 240 may be implemented to pass through the microchannel 220A. The width R1 of the upper end opening 221 of each of the microchannels 220A may be 50 占 퐉 to 100 占 퐉 and the width R2 of the lower end opening 223 may be 10 占 퐉 to 30 占 퐉.

FIG. 4A is a view showing an example of a top view of the CTC cluster filter 200A shown in FIG. 3, FIG. 4B is a view showing another example of a top view of the CTC cluster filter 200A shown in FIG. 3, 4B is an enlarged plan view of part 250 of FIG. 4B, and FIG. 4D is a bottom view corresponding to the plan view of FIG. 4C.

Referring to FIGS. 4A and 4B, the plane pattern of the CTC cluster filter 200A may vary. 4A and 4B, the gray portion represents the substrate 210 of the CTC cluster filter 200A and the white portion represents the top opening 221 of the microchannel 220A of the CTC cluster filter 200A.

4A to 4D, the upper opening 221 and the lower opening 223 of the microchannel 220A may each be a rectangle or an ellipse. However, the shape of the upper end opening 221 and the lower end opening 223 of the microchannel 220A may be different. The width R1 of the upper end opening 221 of the microchannel 220A is larger than the width R2 of the lower end opening 223. That is, the cross-sectional area of the upper opening 221 of the microchannel 220A is formed to be larger than the cross-sectional area of the lower opening 223.

5 is another embodiment of a cross section cut perpendicularly to the CTC cluster filter 200 shown in FIG. For example, FIG. 5 may be a view showing a section cut perpendicularly along A-A 'in FIG. 4C or 4D. As shown in FIG. 5, the microchannel 220B of the CTC cluster filter 200 may be in a streamlined form.

In the streamlined microchannel 220B, the cross-sectional area of the upper opening 221 is larger than the opening of the lower opening 223.

As described above, the detection apparatus 10A for detecting the circulating tumor cell cluster according to the embodiment of the present invention includes the CTC cluster filter 200A having the plurality of microchannels 220A and 220B formed in the vertical (Z-axis) , 200B are used to detect CTC clusters.

Many microchannels formed in the Z-axis in the CTC cluster filters 200A, 200B smooth the flow of fluid (blood). Therefore, the time required for CTC cluster detection is short.

Further, since the fluid flows in the Z-axis, no backflow occurs. Therefore, a separate device such as a backflow prevention element or a cooling element is not required.

6 is a schematic diagram of a detection device 10B for detecting a circulating tumor cell cluster according to another embodiment of the present invention. Referring to FIG. 6, the detection apparatus 10B includes a body 100B and a CTC cluster filter 200 and a CTC filter 300. In FIG.

The detecting device 10B of Fig. 6 further includes a CTC filter 300 as compared to the detecting device 10A of Fig. Accordingly, the structure of the body 100B is also different from the structure of the body 100A of the detection device 10A of FIG.

The body 100B of the detection device 10B of FIG. 6 includes an inlet 110, first and second blood passages 120-1 and 120-2, and an outlet 130.

For example, an inlet 110 is formed at an upper portion of the body 100B. The inlet 110 is connected to the first blood path 120-1 formed inside the body 100B.

The first blood path 120-1 is connected to the top of the CTC cluster filter 200. [

The lower portion of the CTC cluster filter 200 is connected to the second blood path 120-2.

Thus, the blood sample is injected through the inlet 110 into the first blood path 120-1 inside the body 100B. The blood sample flows into the CTC cluster filter 200 through the first blood path 120-1.

The CTC cluster filter 200 is a filter that does not pass components of a blood sample larger than a first size (for example, larger than a first diameter) but passes the rest. Accordingly, CTC clusters of a specific size or larger are detected without passing through the CTC cluster filter 200. The CTC cluster 230 that does not pass through the CTC cluster filter 200 and remains in the filter 200 may be observed using a microscope.

The blood that has passed through the CTC cluster filter 200 flows into the CTC filter 300 through the second blood path 120-2.

The CTC filter 300 may be implemented similarly to the CTC cluster filter 200 described above with reference to FIGS. Each of the microchannels 210 of the CTC filter 300 may be narrower than each of the microchannels 220A and 220B of the CTC cluster filter 200. [

For example, the cross-sectional area of the top opening of the CTC filter 300 is smaller than the cross-sectional area of the top opening 221 of the CTC cluster filter 200 and the cross-sectional area of the bottom opening of the CTC filter 300 is smaller than the cross- (223).

The CTC filter 300 is a filter that passes the components of the blood that have passed through the CTC cluster filter 200 over a second size (for example, a second diameter or more) but do not pass therethrough. At this time, the second size (e.g., the second diameter) is smaller than the first size (e.g., the first diameter).

Accordingly, the CTC included in the blood that has passed through the CTC cluster filter 200 can be detected by the CTC filter 300.

The CTC detected by the CTC filter 300 can be analyzed using a spectrometer (spectrometer or spectrometer). For example, the CTC remaining in the filter 300 without passing through the CTC filter 300 may be analyzed using a spectroscopic device, or the CTC may be separated from the CTC filter 300, .

The CTC filter 300 may be mounted to the outlet 130. Thus, the components of the blood sample above the second size remain in the CTC filter 300, and the remainder flows out through the outlet 130.

The body 100B of the detection device 10B may be formed of glass, but is not limited thereto. For example, the body 100B may be made of plastic or other material.

The body 100B may be realized by joining two or more partial bodies 101, 102, and 103 together. For example, the body 100B may be embodied as an upper body 101, an intermediate body 102, and a lower body 103.

The joining between the partial bodies 101, 102, and 103 can be realized as necessary by using a silicone resin (ultraviolet curing type or the like).

The body 100B can be implemented using tempered glass so that it does not break well upon separation. The thinner the upper body 101, the intermediate body 102, and the lower body 103, the easier it is to separate them. However, the thicknesses DL1, DL2, and DL3 of the upper body 101, the intermediate body 102, and the lower body 103 respectively correspond to the thickness (FD1 in FIG. 3) of the CTC cluster filter 200 and the thickness In consideration of the thickness of the substrate. The focal length of the microscope for observing the CTC cluster 230 may also be considered.

The microscope for observing the CTC cluster 230 may be located above the upper body 101, as shown in FIG. Accordingly, in consideration of the focal length of the microscope, the vertical distance (DFC) between the upper surface of the upper body 101 and the upper surface of the CTC cluster filter 200 preferably falls between 0.3 mm and 0.5 mm.

7 is a schematic diagram of a detection device 10C for detecting a circulating tumor cell cluster according to another embodiment of the present invention.

The detection device 10C according to the embodiment of FIG. 7 is similar in configuration and operation to the detection device 10B according to the embodiment of FIG. 6, and therefore, the description is focused on differences in order to avoid duplication of description.

6 and 7, the detection device 10C further includes an inlet tube 111 and an outlet tube 131 in addition to the body 100B and the CTC cluster filter 200 and the CTC filter 300 do.

The inlet tube 111 may be coupled to the inlet 110 to facilitate entry of the blood sample. The outlet tube 131 may be coupled to the outlet 130 to facilitate the outflow of blood through the CTC filter 300.

According to the embodiment of Figs. 6 and 7, the detection devices 10B and 10C are configured to include two stages of filters 200 and 300, but the number of filters may be different. Accordingly, it is possible to detect cells of various sizes, for example, CTC clusters as well as CTCs, leukocytes, etc., with one detection device 10B or 10C.

According to the embodiment of the present invention, the detection devices 10A, 10B, and 10C can be implemented with a disposable diagnostic kit. The detection devices 10A, 10B, and 10C according to the embodiment of the present invention form many microchannels along the Z-axis to smooth the flow of fluid (blood). Thus, the detection speed is improved. Therefore, according to the embodiment of the present invention, detection time and cost can be reduced.

While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that the invention is not limited to the disclosed exemplary embodiments, but, on the contrary, It should be understood that various modifications may be made by those skilled in the art without departing from the spirit and scope of the present invention.

10A, 10B, 10C: Detecting device
110: inlet
120, 120-1, 120-2: blood path
130: Outlet
200A, 200B: CTC cluster filter
210: filter substrate
221: upper opening
220A, 220B: Microchannel
223: Lower opening
300: CTC filter

Claims (12)

1. A circulating tumor cell cluster detection apparatus for detecting a circulating tumor cell (CTC) cluster contained in blood,
A body having an inlet through which the blood flows and a blood passage through which the blood flows through the inlet; And
And a CTC cluster filter coupled to the blood path of the body,
The CTC cluster filter
A filter substrate; And
And a plurality of microchannels formed perpendicularly or obliquely to the filter substrate so as to pass the first component of a predetermined size or more out of a plurality of components constituting the blood,
Wherein a cross-sectional area of an upper portion of each of the plurality of microchannels is larger than a cross-sectional area of a lower portion thereof. 2. The filter of claim 1, wherein the filter substrate is embodied as glass,
Wherein the thickness of the filter substrate is 200 탆 to 300 탆. 3. The filter according to claim 2, wherein the filter substrate is embodied as a metal,
Wherein the thickness of the filter substrate is 20 占 퐉 to 50 占 퐉. 2. The method of claim 1, wherein the vertical cross-
A vertical, a streamline, or an oblique line. 2. The apparatus of claim 1,
And an outlet through which the blood that has passed through the CTC cluster filter flows out. 1. A circulating tumor cell cluster detection apparatus for detecting a circulating tumor cell (CTC) cluster contained in blood,
A body having an inlet through which the blood flows and a blood passage through which the blood flows through the inlet;
A CTC cluster filter attached to the body to allow the first component of the blood to pass through the CTC cluster filter; And
And a CTC filter for passing the second component of the blood having passed through the CTC cluster filter,
Each of the CTC cluster filter and the CTC filter
A filter substrate; And
And a plurality of microchannels formed perpendicularly or obliquely to the filter substrate and serving as a path of the blood. 7. The apparatus of claim 6, wherein the body
An intermediate body, and a lower body. [8] The apparatus of claim 7, wherein the upper body, the middle body, and the lower body are made of glass, and the junction between the middle body and the lower body is separable using silicone resin. 8. The apparatus of claim 7, wherein the vertical distance between the upper surface of the upper body and the upper surface of the CTC cluster filter is 0.3 mm to 0.5 mm. 8. The method of claim 7, wherein the blood path
A first blood path formed between the inlet and the CTC cluster filter; And
And a second blood path formed between the CTC cluster filter and the CTC filter,
And an outlet through which the blood that has passed through the CTC filter flows out is formed in the lower body. 8. The method of claim 7, wherein the circulating tumor cell cluster detection device
An inlet tube coupled to the inlet; And
And an outlet tube coupled to the outlet. 8. The method of claim 7, wherein the material of the CTC cluster filter or the CTC filter is a metal comprising at least one of copper, nickel, silver, tin, and zinc,
Wherein when the CTC cluster filter or the CTC filter is a metal filter, it is finally plated with gold.

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