The present invention relates to a medical diagnostic chip and a method for manufacturing a medical diagnostic chip, and more particularly, to a method for manufacturing a medical diagnostic chip using mixed lithography.
Exosomes are endoplasmic reticulum substances (extracellular vesicles, hereinafter, “EVs”) secreted from cells and may be used as cancer-specific biomarkers. The exosomes are known to have sphere shapes with sizes of 50 nm to several hundred nanometers. It has been known that the exosomes have different secretory mechanisms of the exosomes and exosomal proteins and miRNAs contained in the exosomes depending on normal cells or cancer cells, and that components thereof vary according to a size thereof.
A method using a deterministic lateral displacement (DLD) structure is a method that may sort particles dissolved in a fluid by size using a micropillar or nanopillar structure. By using this, in U.S. Princeton University and IBM Research Institute, there is a case in which an exosome isolation device is manufactured using the nanopillar structure.
In the method of manufacturing the exosome isolation device chip in the above case, a silicon ship was covered with Borosilicate glass and then a wafer bonding was performed. When the chip is manufactured using such method, the state of the chip is non-uniform, and particularly, it is known that the leakage of the fluid is serious, and it was difficult to commercialize the device manufactured by such method.
The present invention has been made in an effort to easily manufacture a medical diagnostic chip capable of isolating exosome biomarkers from the human blood and sorting the isolated exosome biomarkers by size.
The problem to be solved by the present invention is not limited to the above-mentioned problems. The problems not mentioned will be clearly understood by those skilled in the art from the present specification and the accompanying drawings.
An exemplary embodiment of the present invention provides a method for manufacturing a medical diagnostic chip using a mixed lithography method.
The method may include forming first patterns in a first region using first lithography, and forming second patterns in a second region using second lithography, wherein a part of the second patterns is formed in a part of the first region among the region where the first region and the second region are adjacent to each other.
The first lithography may be electron beam lithography, and the second lithography may be photolithography.
The forming first patterns in the first region using the electron beam lithography may comprise forming nanopillar pattern.
The forming of the first patterns in the first region using the electron beam lithography may be forming the patterns using a positive electron beam resist.
The forming of the second patterns in the partial region of the first region in the region where the first region and the second region are adjacent to each other may be forming the patterns so that the second patterns using the second lithography are overlapped with an edge portion of the first region in the region where the first region and the second region are adjacent to each other.
The forming of the second patterns in the second region using the second lithography may be forming the patterns using a positive or negative photoresist.
Another exemplary embodiment of the present invention provides a method for manufacturing a medical diagnostic chip.
The forming a part of second patterns in the portion of the first region among the region where the first region and the second region are adjacent to each other comprises forming the second patterns using the second lithography as to overlap with an edge portion of the first region among the region where the first region and the second region are adjacent to each other.
The forming of the first patterns in the first region using the electron beam lithography may be forming the patterns in the form of having nanoholes.
The forming of the first patterns in the first region using the electron beam lithography may be forming the first patterns using a positive electron beam resist.
The forming of the second patterns so that the formed first region is protected may be forming the patterns so that the second patterns formed by using the second lithography do not affect the first patterns formed in the first region.
The forming of the second patterns in the second region using the second lithography may be forming the patterns using a positive or negative photoresist.
The method for manufacturing the medical diagnostic chip may further include pouring a polymer material into the formed chip; waiting for a predetermined time until the polymer material is hardened; and inverting the hardened polymeric material.
According to the present invention, it is possible to easily manufacture a medical diagnostic chip capable of isolating exosome biomarkers from the human blood and sorting the isolated exosome biomarkers by size.
According to the present invention, it is possible to manufacture a nanofluidic device chip in which nanopillar structures are arranged using a sacrificial process capable of manufacturing a nanofluidic device in a semiconductor FAB without secondary operations such as wafer bonding.
The effect of the present invention is not limited to the foregoing effects. Non-mentioned effects will be clearly understood by those skilled in the art from the present specification and the accompanying drawings.
Hereinafter, exemplary embodiments of the present invention will be described more fully hereinafter with reference to the accompanying drawings, in which exemplary embodiments of the invention are shown. However, the present invention can be variously implemented and is not limited to the following exemplary embodiments. In the following description of the present invention, a detailed description of known functions and configurations incorporated herein is omitted to avoid making the subject matter of the present invention unclear. In addition, the same reference numerals are used throughout the drawings for parts having similar functions and actions.
It will be understood that the terms “comprises,” “comprising,” “includes,” “including,” “have,” “having,” etc., when used in this specification, specify the presence of stated features, integers, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof.
. As used herein, the singular forms “a”, “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. Further, shapes, sizes, and the like of the elements in the drawing may be exaggerated for clearer description.
It will be understood that, although the terms first, second, third etc. may be used herein to describe various elements, components, regions, layers and/or sections, these elements, components, regions, layers and/or sections should not be limited by these terms. These terms are only used to distinguish one element, component, region, layer or section from another region, layer or section. Thus, a first element, component, region, layer or section discussed below could be termed a second element, component, region, layer or section without departing from the teachings.
Referring to
If the array of the pillars is not inclined, biomolecules flow uniformly according to the flow of the fluid regardless of sizes thereof, which is called a laminar flow. When the array of the pillars is inclined with respect to the direction (vertical direction) in which the fluid flows as shown in
When the nanopillars are inclined as illustrated in
In order to manufacture the DLD structure as illustrated in
In the present invention, a medical diagnostic chip may be manufactured by a combination of a first lithography method and a second lithography method. In the present invention, patterns are formed on a substrate by mixing the first lithography method and the second lithography method, so that patterns having nanometer size and patterns having micrometer size may be formed on a single substrate. As a result, there is an effect that may be used as the medical diagnostic chip.
When the DLD structure is formed on the substrate by a conventional method, there is a problem in that the amount of a sample to be treated is too low and the efficiency is lowered. In the present invention, since a plurality of patterns may be formed on one substrate using mixed lithography, there is an effect that the treating efficiency may be increased.
More specifically, in the case of electron beam lithography, patterns having nanometer-level small sizes may be implemented, but the throughput is too low, so that it is very difficult to implement the patterns on a large area. In contrast, in the case of photolithography, it is easy to manufacture the patterns on the large area due to its high throughput, but it may be difficult to implement patterns having nanometer-level small sizes. In the present invention, since the patterns are formed on the substrate by mixing electron beam lithography and photolithography, there is an effect of simultaneously implementing patterns having nanometer-level small sizes and patterns having relatively large sizes on a large area.
There is a difference in protein components between EVs from cancer patients’ blood and EVs from normal humans, and when this difference is detected, it is possible to diagnose early whether or not to have cancer through a simple method.
In the description, it has been described that the medical diagnostic chip according to the present invention may be used for the method for early diagnosis of cancer cells. However, the use of the medical diagnostic chip manufactured according to the present invention is not limited to the exemplary embodiment, and may be variously used to sort various sizes of particles.
Hereinafter, a method of manufacturing the DLD structure on the substrate will be described in detail with reference to the drawings.
Referring to
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According to the characteristics of the electron beam lithography, a very small nanometer-sized pillar structure having sizes of several nanometers to several hundreds of nanometers may be manufactured in a limited region.
In the case of forming the nanopillar patterns using the electron beam lithography according to
According to
The etching includes a dry etching process or a wet etching process. In the present invention, the etching is mainly a dry etching process, and among them, reactive ion etching (RIE) may be used.
The etching in
Although not illustrated in
When the processes of
Referring to
The second region and the first region may be different regions. According to an example, the second region may be disposed to connect the plurality of first regions. A plurality of second regions may be provided. According to an example, the second regions may be disposed to be connected to both ends of the first region.
Referring to
A technical feature to be noted at this time is related to pattern formation in the second lithography in a region where the first region and the second region are adjacent to each other.
The photo patterns in the region where the first region and the second region are adjacent to each other need to be formed to be overlapped with the electron beam patterns formed in the previous step.
According to an example, at a point where the first region in which the electron beam patterns are formed and the second region in which the photo patterns are formed are adjacent to each other, the photo patterns may be partially overlapped with the edge portion of the first region. The photo patterns overlapped with the first region may be formed without overlapping with the nanopillar patterns formed on the first region.
The first region is a region where the nanopillar patterns illustrated in
That is, according to
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According to
Hereinafter, the effect of the medical diagnostic chip manufactured according to the exemplary embodiment of
Like an exemplary embodiment of
According to
According to
The overlapped regions of the two patterns may be about 3 to 5 µm.
That is, when the photolithography patterns are formed after the electron beam lithography patterns are formed, the photo patterns are formed to overlapped with the region where the first region and the second region are adjacent to each other, so that the electron beam patterns and the photo patterns may be naturally connected to each other.
According to the observation result of
More specifically,
According to the manufacturing method of the medical diagnostic chip manufactured according to the exemplary embodiment of
When the nanopillars formed in the manufactured medical diagnostic chip are large, soluble proteins and EVs may be isolated, and when the nanopillars are small, EVs may be sorted by size.
Referring to
In this case, the electron beam resist may be a positive resist. According to
The criteria for sorting the electron beam patterns into nanopillars and nanoholes are as follows.
In the case of forming the electron beam patterns as nanopillar patterns, pillars having nano diameters are formed in the first region by etching the oxide film using the nanopillar type electron beam pattern as an etching mask.
In the case of forming the electron beam patterns as nanohole patterns, nanoholes having nano diameters are formed in the second region by etching the oxide film using the nanohole type electron beam pattern as an etching mask.
The photolithography patterns in
In the exemplary embodiment of
In the exemplary embodiment of
On the other hand, in the exemplary embodiment of the process according to
Referring to
According to
According to
As described above, the sorting of the device is possible only by using the shape of nanopillars. The medical diagnostic chip formed according to the process embodiment of
More specifically, a polymer material may be poured into the nanohole structure completed according to the process of
As another method, more specifically, the nanohole structure completed according to the process of the exemplary embodiment of
According to an example, it is assumed that a nanohole structure is a silicon (Si) material, a covering material is silicon oxide, and XeF2 is used as an etching gas. At this time, since XeF2 as the etching gas has a property of selectively etching only the silicon material, XeF2 as the etching gas may be used in the sacrificial process. In this case, the silicon material etched by the XeF2 etching gas corresponds to the sacrificial material.
The example is merely an exemplary embodiment, and various etching gases or etching liquids, substrates, and the like that may be used in the sacrificial process may be provided.
According to
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That is, according to
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According to
Referring to
It is possible to mix and form patterns having nanopillars and micropillars by using the methods for manufacturing the medical diagnostic chip as described above. According to the size of an endoplasmic reticulum to be isolated, an interval and the shape of the electron beam lithography patterns may be adjusted, and the intervals of the photolithography patterns may also be adjusted.
In addition, in the example, an example of forming only a nanopillar structure on one substrate or forming only a nanohole structure on one substrate was illustrated, but it is also possible to simultaneously form the nanopillar structure or the nanohole structure on one substrate.
According to an exemplary embodiment of the present invention, the nanopillar structure may be directly manufactured on a silicon wafer and used as a medical diagnostic chip by itself. According to the method manufactured according to another exemplary embodiment of the present invention, it is possible to form a chip having a polymer nanopillar structure by using a silicon wafer formed to have a nanohole structure as a template or a mold. In addition, a chip may be formed through a process of converting a nanohole structure into a nanopillar structure by a sacrificial process. According to the present invention, it is possible to implement nanometer-level small structures on a large area of millimeters or more.
According to the present invention, pillars having micrometer-level sizes may be used as a means for flowing samples, and the samples may be isolated or sorted through the nanopillar structure. The isolating or sorting of the samples may vary depending on the size of the nanopillar structure.
According to an example, the samples may be isolated through the nanopillars having a size of 400 nm, and the samples may be sorted by size through the nanopillars having a size of 200 nm. This may be processed by patterns formed by the first lithography method.
It is to be understood that the exemplary embodiments are presented to assist in understanding of the present invention, and the scope of the present invention is not limited, and various modified exemplary embodiments thereof are included in the scope of the present invention. The technical protection scope of the present invention should be determined by the technical idea of the appended claims, and it should be understood that the technical protective scope of the present invention is not limited to the literary disclosure itself in the appended claims, but the technical value is substantially affected on the equivalent scope of the invention.
Number | Date | Country | Kind |
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10-2019-0127217 | Oct 2019 | KR | national |
Filing Document | Filing Date | Country | Kind |
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PCT/KR2020/013998 | 10/14/2020 | WO |