KR101347854B1 - Methed for Manufacturing Bio Chip by using Surface Energy Difference - Google Patents

Methed for Manufacturing Bio Chip by using Surface Energy Difference Download PDF

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KR101347854B1
KR101347854B1 KR1020100015005A KR20100015005A KR101347854B1 KR 101347854 B1 KR101347854 B1 KR 101347854B1 KR 1020100015005 A KR1020100015005 A KR 1020100015005A KR 20100015005 A KR20100015005 A KR 20100015005A KR 101347854 B1 KR101347854 B1 KR 101347854B1
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coating layer
hydrophilic
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surface energy
hydrophobic
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KR1020100015005A
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KR20110095503A (en
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김종수
양민양
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한국과학기술원
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Abstract

The present invention relates to a microarray biochip formation method using surface energy differences and a method for dispensing hydrophilic protein samples. More specifically, in the biochip manufacturing method, forming a hydrophobic SAM coating layer uniformly on one surface of the slide glass; Partially removing the hydrophobic SAM coating layer to form a micro array having a surface energy difference; Forming a hydrophilic coating layer on the portion from which the hydrophobic SAM coating layer has been removed; It relates to a biochip manufacturing method using the surface energy difference characterized in that it comprises the step of dispensing a hydrophilic protein sample on the hydrophilic coating layer.

Description

Biochip manufacturing method using surface energy difference {Methed for Manufacturing Bio Chip by using Surface Energy Difference}

The present invention relates to a biochip production method using the surface energy difference and to a biochip produced by the production method. More particularly, the present invention relates to a method for dispensing a hydrophilic protein sample more quickly and easily using contact pins in a micro array having a surface energy difference.

In the case of the conventional micro array biochip, in the process of forming a micro array pattern, a hydrophilic coating was applied to the entire surface of the slide glass, and protein samples were picked up one by one using a micro arrayer to manufacture a micro array pattern. That is, in manufacturing a biochip having a micro array pattern, first, a hydrophilic coating layer is uniformly coated on an entire surface of a slide glass by amine, aldehyde, epoxy coating, or the like.

Then, using a micro arrayer such as a contact pin, an ink-jet, an electrospray (electrospray) and the like by picking up a protein sample or a cell sample one by one on the coating layer to form a micro array pattern to produce a biochip. In this way, a microarray biochip is fabricated, and the next polymerization reaction is performed one by one at each spot of the array, or the next reaction reagent is raised as a whole using a slide glass to examine a desired reaction.

However, such a process requires a process of picking up desired samples one by one, so that it is not easy to form a micro array, and it takes a long time to form. In addition, in causing the next reaction, a hydrophilic coating layer is provided on the entire surface of the slide glass, thereby causing a problem in which unwanted reaction may occur at the side of the array spot.

Accordingly, the present invention has been made to solve the above problems, to provide a method of forming a micro array pattern having a surface energy difference, and to provide a biochip having such a pattern. That is, the hydrophobic SAM coating is uniformly formed on the entire slide glass, and the hydrophobic SAM coating layer is partially removed through an oxygen plasma apparatus using a laser plasma generation method or a mask to form a micro array pattern having a surface energy difference.

In addition, a hydrophilic coating layer is formed on the partially removed portion to provide a method for easily and quickly dispensing a hydrophilic protein sample in a desired portion. That is, the hydrophobic SAM coating layer is partially removed, and then the amine coating is applied to the removed portion so that the portion where the sample is to be placed is hydrophilic and the portion that is not hydrophobic is used to make the sample stick to the desired portion. do.

In addition, the present invention provides a method for dispensing a sample more quickly in a micro array pattern having a surface energy difference. Specifically, after the desired reagent is buried at the end of the contact pin, the slide glass is moved in a semi-contact state in parallel to provide a method for dispensing quickly. By using this method, it is possible to form precise biochips without nonspecific reactions in which reactions occur in portions other than the desired portions.

Other objects, specific advantages and novel features of the present invention will become more apparent from the following detailed description and preferred embodiments with reference to the accompanying drawings.

A first object of the present invention is a method for manufacturing a biochip, comprising: forming a hydrophobic coating layer on one side of a slide glass; Partially removing the hydrophobic coating layer to form a micro array having a surface energy difference; And dispensing a hydrophilic protein sample in a portion where the hydrophobic coating layer has been removed.

The hydrophobic coating layer forming step may be characterized by forming a hydrophobic SAM coating layer by uniformly treating the entire slide glass surface.

The array forming step may be characterized by partially removing the hydrophobic coating layer by generating a plasma by scanning a laser on a portion of the hydrophobic coating layer to be removed.

The array forming step may be characterized in that the hydrophobic SAM coating layer is partially removed through the oxygen plasma apparatus using a mask having a pattern corresponding to the form of the array to be formed.

The mask may be characterized in that the plasma treatment is applied in a state of being bonded to the hydrophobic coating layer.

The mask may be characterized by adhering to the hydrophobic coating layer using glycerol or water.

According to a second aspect of the present invention, there is provided a biochip manufacturing method comprising: uniformly forming a hydrophobic SAM coating layer on one surface of a slide glass; Partially removing the hydrophobic SAM coating layer to form a micro array having a surface energy difference; Forming a hydrophilic coating layer on the portion from which the hydrophobic SAM coating layer has been removed; And it can be achieved by a biochip manufacturing method using the surface energy difference characterized in that it comprises the step of dispensing a hydrophilic protein sample on the hydrophilic coating layer.

The hydrophilic coating layer may be characterized in that the amine coating layer.

The amine coating layer may be formed by APTMS, amino propyl ethoxysilane or APTES treatment.

In the dispensing step, the hydrophilic protein sample may be characterized as being dispensed into the portion where the hydrophilic coating layer is present by the surface energy difference of the array.

After the dispensing step, the method may further comprise attaching a fluorescent protein for detection on the hydrophilic protein sample.

In addition, the fourth object of the present invention can be achieved as a biochip produced by the above manufacturing method.

According to a fifth aspect of the present invention, there is provided a method of forming a micro array, comprising: uniformly SAM-processing a surface of a slide glass to form a hydrophobic SAM coating layer; Partially removing the hydrophobic SAM coating layer; And forming a hydrophilic coating layer on the portion where the hydrophobic SAM coating layer has been removed.

The partial removal step may include: scanning a laser to the hydrophobic SAM coating layer to be removed; Generating a plasma phenomenon on the scanned portion; And partially removing the hydrophobic SAM coating layer.

The partial removing step includes fabricating a mask having a pattern corresponding to the shape of the micro array to be formed; Adhering the mask to the hydrophobic SAM coating layer; And generating a plasma phenomenon through the oxygen plasma apparatus to partially remove the hydrophobic SAM coating layer.

The hydrophilic coating layer forming step may be characterized in that the step of forming the amine coating layer by APTMS or APTES treatment.

A sixth object of the present invention is a method for dispensing a hydrophilic protein sample,

Forming a micro array having a surface energy difference by the forming method; And dispensing the hydrophilic protein sample to the portion where the hydrophilic coating layer is present due to the difference in surface energy of the hydrophilic protein sample.

Inserting a hydrophilic protein sample into the insert using a contact pin having an insert at the end; Semi-contacting the contact pin, into which the protein sample is inserted, to the hydrophilic coating layer; And dispensing the hydrophilic protein sample to the portion where the hydrophilic coating layer is present by moving the contact pins in parallel.

Thus, according to the biochip manufacturing method according to an embodiment of the present invention as described above, by using the difference in surface energy has the effect of reducing the reagents used, the process time.

A hydrophobic SAM coating layer is formed on the entire surface of the slide glass, and the SAM coating layer is partially removed by using a plasma phenomenon to produce a micro array pattern having a surface energy difference. Therefore, by forming a hydrophilic coating layer such as amine / aldehyde only in the removed portion, there is an advantage that can maximize the specific reaction and minimize the material loss.

In addition, the present invention enables the dispensing of samples faster and with minimal non-specific reactions by using microarray patterns with surface energy differences. In addition, in the method for dispensing a sample according to an embodiment of the present invention, after the desired reagent is buried at the end of the contact pin, the biochip is moved more quickly by moving the slide glass in a semi-contact state in parallel. Has the effect of making it. By using this method, there is an advantage in that a precise biochip can be formed without a nonspecific reaction in which a reaction occurs in a portion other than a desired portion.

Although the present invention has been described in connection with the above-mentioned preferred embodiments, it will be appreciated by those skilled in the art that various other modifications and variations can be made without departing from the spirit and scope of the invention, All fall within the scope of the appended claims.

1 is a flowchart of a method of forming a micro array according to an embodiment of the present invention;
Figure 2a is a perspective view of a slide glass according to an embodiment of the present invention,
Figure 2b is a perspective view of a slide glass with a hydrophobic SAM coating layer formed on the upper surface according to an embodiment of the present invention,
Figure 2c is a perspective view of the slide glass in contact with the mask on the top surface of the hydrophobic SAM coating layer according to an embodiment of the present invention,
Figure 2d is also between the slide glass partially removed hydrophobic SAM coating layer according to an embodiment of the present invention,
FIG. 2E is a cross-section AA ′ of FIG. 2D;
3A is a cross-sectional view of a slide glass formed with a hydrophilic coating layer on a portion where a hydrophobic SAM coating layer has been removed according to one embodiment of the present invention;
3B is a perspective view of a biochip in which a protein sample is formed on an upper surface of a hydrophilic coating layer according to one embodiment of the present invention;
4 is a flow chart of a protein sample dispensing method according to an embodiment of the present invention,
5A is a perspective view of a state in which a contact pin in which a hydrophilic protein sample is stored is semi-contacted with a hydrophilic coating layer, according to an embodiment of the present invention;
Figure 5b is a perspective view of the slide glass after moving the contact pin in the direction of the arrow of Figure 5a,
5C is a cross-sectional view of the slide glass 10 when the contact pins 70 are moved in parallel according to one embodiment of the present invention.

With reference to the accompanying drawings will be described in detail a preferred embodiment that can be easily implemented by those skilled in the art to which the present invention pertains. However, the detailed description of known functions and configurations incorporated herein will be omitted when it may unnecessarily obscure the subject matter of the present invention.

The same reference numerals are used for portions having similar functions and functions throughout the drawings. Throughout the specification, when a part is 'connected' to another part, this includes not only 'directly connected' but also 'indirectly connected' with another element in between. do. In addition, "including" any component does not exclude other components unless specifically stated otherwise, it means that may further include other components.

<Method of forming micro array biochip using surface energy difference>

Hereinafter will be described a method for forming a micro array for manufacturing a biochip according to an embodiment of the present invention. First, FIG. 1 shows a flowchart of a method of forming a micro array according to an embodiment of the present invention.

First, to prepare a slide glass 10 to form a micro array having a surface energy difference (S10). 2A illustrates a perspective view of a slide glass 10 to form a micro array. Then, the entire surface of the slide glass 10 is uniformly treated with a self-assembled monolayer (SAM) to form a hydrophobic SAM coating layer 20 (S20).

2B illustrates a perspective view of a slide glass 10 in which a hydrophobic SAM coating layer 20 is formed by a SAM treatment according to an embodiment of the present invention. As shown in FIG. 2B, it can be seen that the hydrophobic SAM coating layer 20 is uniformly formed on the entire upper surface of the slide glass 10. Then, the hydrophobic SAM coating layer 20 is partially removed to form a pattern (S30).

The method of partially removing the hydrophobic SAM coating layer 20 will be described by way of example using a laser plasma generation method and an oxygen plasma apparatus using the mask 60. In the laser plasma generating method, the hydrophobic SAM coating layer 20 to be removed is scanned. The scanned portion is generated by removing plasma. That is, the hydrophobic SAM coating layer 20 is partially removed by scanning a laser on a portion to be filled with the hydrophilic protein sample 50 later.

In another embodiment, the mask 60 may be used to form the pattern by partially removing the hydrophobic SAM coating layer 20 more quickly. First, a mask 60 in which a plurality of holes 61 are formed is manufactured, and the mask 60 is bonded to the upper surface of the hydrophobic SAM coating layer 20. The mask 60 and the hydrophobic SAM coating layer 20 may be easily bonded using glycerol, water, or the like.

In addition, the mask 60 is subjected to plasma treatment in a state in which the mask 60 is attached to the hydrophobic SAM coating layer 20. The hydrophobic SAM coating layer 20 subjected to plasma treatment through the holes 61 formed in the mask 60 is removed. Figure 2c shows a perspective view of a state in which the mask 60 is bonded to the hydrophobic SAM coating layer 20, and subjected to a plasma treatment in accordance with an embodiment of the present invention.

As shown in FIG. 2C, a plurality of holes 61 are formed in the mask 60, and the plasma processing is performed while the mask 60 is adhered to the hydrophobic SAM coating layer 20. The hydrophobic SAM coating layer 20 subjected to plasma treatment is removed according to the pattern of the mask 60. Accordingly, the hydrophobic SAM coating layer 20 is partially removed to correspond to the hole 61 provided in the mask 60 to form a plurality of grooves 30.

FIG. 2D illustrates a perspective view of a slide glass 10 having a hydrophobic SAM coating layer 20 having a plurality of grooves 30 formed therein. As shown in FIG. 2D, it can be seen that the hydrophobic SAM coating layer 20 has been partially removed and correspondingly removed to correspond to the pattern of the mask 60. In an embodiment, it can be seen that the pattern consists of nine grooves 30, as shown in FIG. 2D. The grooves 30 may have a diameter of several hundreds to hundreds of micrometers.

 Thus, it can be seen that the pattern of the partially removed hydrophobic SAM coating layer 20 is determined by the pattern of the mask 60. By adjusting the pattern of the mask 60, the shape and size of the pattern provided in the hydrophobic SAM coating layer 20 can be adjusted.

FIG. 2E is a sectional view taken along the line A-A 'of FIG. 2D. As illustrated in FIG. 2E, the upper surface of the slide glass 10 has a portion where the hydrophobic SAM coating layer 20 and the hydrophobic SAM coating layer 20 are removed. Then, the hydrophilic coating layer 40 is formed on the portion of the hydrophobic SAM coating layer 20 is removed (S40). Hydrophilic coatings mainly use amine coatings. At this time, the amine coating may be performed through APTMS, APTES treatment and the like.

3A illustrates a cross-sectional view of a slide glass 10 in which a hydrophilic coating layer 40 is formed in a portion where a hydrophobic SAM coating layer 20 is removed according to an embodiment of the present invention. As shown in FIG. 3A, it can be seen that the upper surface of the slide glass 10 has a hydrophilic coating layer 40 and a hydrophobic SAM coating layer 20 formed thereon. Therefore, a portion of the slide glass 10 is hydrophilic and the other portion is provided with a hydrophobic SAM coating layer 20 to produce a micro array having a surface energy difference.

When the protein sample 50 (eg, NHS-BIOTIN) that reacts with the hydrophilic coating layer 40 is dispensed, the protein sample 50 does not react with the hydrophobic SAM coating layer 20, and the hydrophilic coating layer ( 40) will only be placed in the presence. Therefore, by fabricating a micro array having a hydrophilic coating layer 40 and a hydrophobic SAM coating layer 20 having a surface energy difference, it is possible to manufacture a biochip more quickly and easily.

< Dispensing  Method>

Hereinafter, a method of dispensing a sample 50 in a micro array having a surface energy difference according to an embodiment of the present invention will be described. 4 illustrates a flowchart of a sample dispensing method according to an embodiment of the present invention. First, a slide glass 10 in which a micro array pattern is formed is prepared (S100).

As described above, the micro array is formed by uniformly SAM-processing the entire surface of the slide glass 10 to form a hydrophobic SAM coating layer 20, and partially using a laser plasma generation method or a mask 60 to form a hydrophobic SAM coating layer ( 20) will be removed. And, it is produced by forming a hydrophilic coating layer 40 on the portion of the hydrophobic SAM coating layer 20 is removed.

Then, the hydrophilic protein sample 50 is dispensed onto the hydrophilic coating layer 40 by using a contact pin 70 having an insert 71 at the end. Specifically, the contact pin 70 may store the hydrophilic protein sample 50 in the insertion unit 71 by using a capillary phenomenon (S200). The hydrophilic protein sample 50 causes the contact pins 70 stored in the insertion part 71 to be semi-contacted to the upper surface of the slide glass 10 on which the micro-array is formed (S300).

In the semi-contact state defined in the specification of the present invention, the tip of the contact pin 70 in which a small amount of the sample 50 is stored does not contact the hydrophilic coating layer 40, and the insertion portion 71 of the contact pin 70 is used. It means that only the sample 50 in contact with the contact state.

FIG. 5A illustrates a perspective view of the contact pin 70 in which the hydrophilic protein sample 50 is stored in semi-contact with the hydrophilic coating layer 40, according to an embodiment of the present invention. As shown in FIG. 5A, the hydrophilic protein sample 50 does not react with the hydrophobic SAM coating layer 20 but is buried in response to the portion where the hydrophilic coating layer 40 is present.

Then, when the contact pins 70 are moved in parallel while maintaining the semi-contact state (S400), the hydrophobic SAM coating layer 20 does not react, but only in the grooves 30 in which the hydrophilic coating layer 40 exists. In response, the hydrophilic protein sample 50 is placed into the groove 30 (S500). 5B shows a perspective view of the slide glass 10 after moving the contact pin 70 in the direction of the arrow of FIG. 5A.

As shown in FIG. 5B, when the contact pins 70 pass in parallel, the hydrophilic protein sample 50 is provided in the groove 30 in which the hydrophilic coating layer 40 exists. Therefore, simply moving the contact pins 70 in parallel can easily store the sample 50 into the groove (30). This is made possible by micro arrays with surface energy differences. In addition, when the contact pin 70 is moved in the direction of the arrow shown in FIG. 5B, the hydrophilic protein sample 50 is stored into the groove 30 (where the hydrophilic coating layer 40 exists) and the hydrophobic SAM coating layer is stored. There is no sample 50 at 20.

5C illustrates a cross-sectional view of the slide glass 10 when the contact pins 70 are moved in parallel in accordance with one embodiment of the present invention. As shown in FIG. 5C, when the contact pin 70 storing the sample 50 in the insert 71 is moved in parallel in a semi-contact state, the sample 50 reacts only with the hydrophilic coating layer 40. It can be seen that the fixed inside the groove (30).

The biochip thus formed is detected using Surface Plasmon Resonanace (SPR). In addition, the analysis may be performed after attaching a fluorescent protein for detection (eg, streptomycin: Cy3, Cy2, Cy5) to the protein sample 50 dispensed on the hydrophilic coating layer 40.

10: slide glass
20: hydrophobic SAM coating layer
30: home
40: hydrophilic coating layer
50: Sample
60: mask
61: hole
70: contact pin
71: inserting

Claims (20)

In the biochip manufacturing method,
Forming a hydrophobic SAM coating layer uniformly on one surface of the slide glass;
Partially removing the hydrophobic SAM coating layer to form a micro array having a surface energy difference;
Forming a hydrophilic coating layer on the portion where the hydrophobic SAM coating layer is removed;
Dispensing a hydrophilic protein sample on the hydrophilic coating layer; And
Attaching a fluorescent protein for detection on the hydrophilic protein sample,
Forming the micro array,
Scanning a laser on the hydrophobic SAM coating layer to be removed, generating a plasma phenomenon on the scanned portion, and partially removing the hydrophobic SAM coating layer,
Forming the hydrophilic coating layer is
Forming an amine coating layer by APTMS or APTES treatment,
Dispensing is,
The hydrophilic protein sample is dispensed into the portion where the hydrophilic coating layer is present by the surface energy difference of the micro array, inserting the hydrophilic protein sample into the insert using a contact pin having an insert at the end, Semi-contacting the contact pin, into which the hydrophilic protein sample is inserted, to the hydrophilic coating layer and displacing the contact pin in parallel to dispense the hydrophilic protein sample into the portion where the hydrophilic coating layer is present. Biochip manufacturing method using the surface energy difference. delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete
KR1020100015005A 2010-02-19 2010-02-19 Methed for Manufacturing Bio Chip by using Surface Energy Difference KR101347854B1 (en)

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Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101324199B1 (en) * 2010-09-16 2013-11-06 한국과학기술원 Protein binding method using mixed self assembled monolayers and protein chip using thereof
KR101337504B1 (en) * 2011-12-19 2013-12-05 한국기계연구원 Bio chip and Method for manufacturing thereof
KR101494415B1 (en) * 2013-05-14 2015-02-23 (주) 엠에이케이 The method for making the hydrophilic pattern on the glass
WO2016159068A1 (en) * 2015-03-30 2016-10-06 凸版印刷株式会社 Microwell array, manufacturing method thereof, microfluidic device, method for sealing aqueous liquid in well of microwell array, and method for analyzing aqueous liquid
KR102138005B1 (en) * 2018-10-26 2020-07-28 계명대학교 산학협력단 Thin film pattern formation method using 3D printing and Manufacturing method of bio-diagnosis apparatus by the same

Citations (3)

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Publication number Priority date Publication date Assignee Title
KR20030088782A (en) * 2002-05-15 2003-11-20 삼성전자주식회사 A process for producing array plate for a biomolecule comprising a hydrophilic region and a hydrophobic region
US20050002985A1 (en) 2001-10-30 2005-01-06 Heal Richard David Albert Device with recessed tracks for forming a cellular network
JP2005300262A (en) 2004-04-08 2005-10-27 Sony Corp Detecting surface, its manufacturing method, sensor chip, and dna chip

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050002985A1 (en) 2001-10-30 2005-01-06 Heal Richard David Albert Device with recessed tracks for forming a cellular network
KR20030088782A (en) * 2002-05-15 2003-11-20 삼성전자주식회사 A process for producing array plate for a biomolecule comprising a hydrophilic region and a hydrophobic region
JP2005300262A (en) 2004-04-08 2005-10-27 Sony Corp Detecting surface, its manufacturing method, sensor chip, and dna chip

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